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Editors: Afifi, Adel K.; Bergman, Ronald A.

Title: Functional Neuroanatomy: Text and Atlas, 2nd Edition

Copyright ©2005 McGraw-Hill

> Front of Book > Editors

Editors
Adel K. Afifi M.D., M.S.
Professor of Pediatrics
Neurology, and Anatomy and Cell Biology, University of Iowa, College
of Medicine, Iowa City, Iowa

Ronald A. Bergman Ph.D.

Professor Emeritus of Anatomy and Cell Biology
University of Iowa, College of Medicine, Iowa City, Iowa

Secondary Editors
This book was set in Adobe Garamond by MidAtlantic Books and
Journals.
Isabel Nogueira
Editor
Janet Foltin
Editor
Jason Malley
Editor
Lester A. Sheinis
Editor
Richard C. Ruzycka
Production Supervisor
Eve Siegel
Text Designer
Charissa Baker
Illustration Manager
Maria T. Magtoto
Illustration Coordinator
Janice Bielawa
Cover Designer
Alexandra Nickerson
Indexer
Quebecor Dubuque was printer and binder

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Ovid: Functional Neuroanatomy: Text and Atlas Página 1 de 1

Editors: Afifi, Adel K.; Bergman, Ronald A.

Title: Functional Neuroanatomy: Text and Atlas, 2nd Edition

Copyright ©2005 McGraw-Hill

> Front of Book > Dedication

Dedication

To our families and to the memories of our parents and Mohammed A.

Soweid, Samih Y. Alami, and Ramez and Nabih K. Afifi

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Ovid: Functional Neuroanatomy: Text and Atlas Página 1 de 1

Editors: Afifi, Adel K.; Bergman, Ronald A.

Title: Functional Neuroanatomy: Text and Atlas, 2nd Edition

Copyright ©2005 McGraw-Hill

> Front of Book > Notice

Notice

Medicine is an ever-changing science. As new research and clinical

experience broaden our knowledge, changes in treatment and drug
therapy are required. The authors and the publisher of this work have
checked with sources believed to be reliable in their efforts to provide
information that is complete and generally in accord with the standards
accepted at the time of publication. However, in view of the possibility
of human error or changes in medical sciences, neither the authors nor
the publisher nor any other party who has been involved in the
preparation or publication of this work warrants that the information
contained herein is in every respect accurate or complete, and they
disclaim all responsibility for any errors or omissions or for the results
obtained from use of the information contained in this work. Readers
are encouraged to confirm the information contained herein with other
sources. For example and in particular, readers are advised to check
the product information sheet included in the package of each drug
they plan to administer to be certain that the information contained in
this work is accurate and that changes have not been made in the
recommended dose or in the contraindications for administration. This
recommendation is of particular importance in connection with new or
infrequently used drugs.

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Ovid: Functional Neuroanatomy: Text and Atlas Página 1 de 2

Editors: Afifi, Adel K.; Bergman, Ronald A.

Title: Functional Neuroanatomy: Text and Atlas, 2nd Edition

Copyright ©2005 McGraw-Hill

> Front of Book > Preface

Preface

The attractive features of the second edition are the same as those of
the first edition, namely: limited authorship, consistent and easy-to-
read style, complete and balanced but nonexhaustive coverage of
neuroanatomy, emphasis on human neuroanatomy, simplified
schematics to illustrate neural pathways, clinical correlation chapters,
key concepts for easy pre-exam review, derivation of terms and
historical perspective of common eponyms, and an extensive atlas of
spinal cord and brain sections as well as magnetic resonance images
(MRI) in three planes.

In this edition, all chapters have been updated to reflect the current
state of knowledge. four new chapters are added: two are related to
the reticular Formation, Wakefulness and Sleep; one on the Control of
Posture and Movement, and one on The Approach to the Patient with
Neurologic Disorder. The illustrations have been improved and several
new illustrations have also been added. The Key Concepts have been
placed at the beginning of each chapter and can easily be identified by
this icon

. New references have been added to the Suggested Readings at the

end of each chapter. the text in the margins of the pages has been
expanded and relocated for more efficient use of space. Boldface
emphasis of some terms in the text has been removed to allow easier
flow of text. These terms are now listed in the Terminology section at
the end of each chapter and are highlighted in blue color in the text.
Leaders in the Atlas have been improved to make it easier for the
reader to identify the intended structures.

We are grateful to the many colleagues and students who wrote

reviews and/or made comments or suggestions about the first edition.
their comments and suggestions were helpful in developing the second
edition. We want in particular to acknowledge the following colleagues
and students: Steven Anderson, Nadia Bahuth, Antoine Becharea,
Daniel Bonthius, Deema Fattal, Aleyamma Fenn, Tiny jaentsch, Jean
Jew, Kokoro Ozaki, Paul Reimann, Ergun Uc, and Gary Van Hoesen.

We want to thank Karen Boatman who was instrumental in typing

additions to the chapters and the new chapters. Her inquisitive interest

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in the subject made it a pleasure to work with her. Karolyn Leary

assisted us in typing some of the text and relieved Karen from many
other office tasks to allow her to devote time to the book.

Special thanks to the staff of McGraw-Hill and in particular to isabel

Nogueira who initiated the proposal for the second edition and provided
valuable advice and guidance during the early phase of its preparation;
Janet Foltin, Jason Malley, and Lester A. Sheinis who most ably
oversaw the tedious editorial task of its production; Richard C.
Ruzycka, production supervisor; Eve Siegel, text designer; Charissa
Baker, illustration manager; Maria T. Magtoto, illustration coordinator;
Janice Bielawa, cover designer; Alexandra Nickerson, indexer; and
Keith Donnellan, of Dovetail Content Solutions, who directed the
copyediting of the manuscript.
Adel K. Afifi M.D., M.S.

Ronald A. Bergman Ph.D.

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Ovid: Functional Neuroanatomy: Text and Atlas Página 1 de 28

Editors: Afifi, Adel K.; Bergman, Ronald A.

Title: Functional Neuroanatomy: Text and Atlas, 2nd Edition

Copyright ©2005 McGraw-Hill

> Table of Contents > Part I - Text > 1 - Neurohist ology

1
Neurohistology

The Cells and Their Unique Characteristics

Overview of Neurons
Perikaryon
Axon (Axis cylinder, Remak's band)
Dendrites
Neuroglia
Ganglia
Craniospinal Ganglia
Autonomic Ganglia
Nerve Fibers
Myelinated Nerve Fibers
Unmyelinated Nerve Fibers
Conduction of Nerve Impulses
Axonal Transport
Synapse
Neuromuscular Junction
Receptor Organs of Sensory Neurons
Free (Nonencapsulated) Nerve Endings
Encapsulated Nerve Endings
Reaction of Neurons to Injury
Cell Body and Dendrites
Axon
Nerve Growth Factors
Clinical Correlation
Neuronal Plasticity

KEY CONCEPTS

A neuron consists of a perikaryon (cell body) and its processes (axon and dendrites). Neurons
vary in size and shape, and each neuron has one axon and many dendrites.

Perikaryal organelles that are found in axons include mitochondria, microtubules,

microfilaments, neurofilaments, neurotubules, smooth endoplasmic reticulum, lysosomes, and
vesicles.

Dendrites contain all the perikaryal organelles except the Golgi complex.

Neuroglia are the supporting elements of the central nervous system. They include macroglia
(astrocytes and oligodendroglia), microglia, and ependymal cells.

Astrocytes are metabolic intermediaries for nerve cells. Fibrous astrocytes also serve a repair
function after neural injury.

Oligodendroglia elaborate central nervous system myelin.

Microglia play a role in repair of the central nervous system.

Craniospinal ganglia include the dorsal root ganglia and the ganglia of cranial nerves V, VII,
VIII, IX, and X.

Peripheral nerves are surrounded by three connective tissue sheaths. Endoneurium invests
individual axons, perineurium invests groups of axons in fascicles, and epineurium invests the
whole nerve.

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Two types of axonal transport occur in axons: anterograde and retrograde.

On the basis of their function, synapses are classified into excitatory and inhibitory.

Sensory receptor organs are classified according to their location (skin or joints), structure
(encapsulated or free), function (nociceptor or mechanoreceptor), adaptive properties (slowly or
quickly adapting), or a combination of these categories.

Neurons react to injury by undergoing characteristic changes that occur proximal

(chromatolysis) and distal (wallerian degeneration) to the site of the injury.

Clinically, nerve injury is classified according to the degree of severity into conduction block
(neurapraxia), loss of axonal continuity (axonotmesis), and loss of nerve trunk continuity
(neurotmesis).

P.4
The cells of the nervous system can be divided into two groups: nerve cells (neurons) and supporting cells
(glia). Nerve cells are all associated with each other as a functional syncytium, a complex network somewhat
like that found in a telephone company switch board. Neurons communicate with each other through
specialized areas of neuronal contact called synapses. The complexity of the synaptic relationships among
billions of neurons forms the basis for the behavioral complexity of humans.

THE CELLS AND THEIR UNIQUE CHARACTERISTICS

Overview of Neurons
A neuron, or nerve cell (the terms may be used interchangeably), has a cell body, or perikaryon (the
part containing the nucleus), and all its processes (axon and dendrites). The names given to neurons
were suggested by their size, shape, appearance, functional role, or presumed discoverer [e.g., Purkinje cell
(neuron) of the cerebellum]. The size and shape of neuronal cell bodies are remarkably variable. The
diameter of the cell body may be as small as 4 µm (granule cell of the cerebellum) or as large as 125 µm
(motor neuron of the spinal cord). Nerve cells may have a pyramidal, flask, stellate, or granular shape
(Figure 1-1). An additional feature of these perikarya is the number and organization of their processes.
Some neurons have few dendrites, while others have numerous dendritic projections. With two known
exceptions (the axonless amacrine cell of the retina and the granule cells of the olfactory bulb), all neurons
have at least one axon and one or more dendrites.

In general, three basic types of neurons are recognized:

1. Unipolar or pseudounipolar neurons (e.g., sensory [or dorsal root] ganglion cells) have a spherical cell
body with single process that bifurcates (Figure 1-1H).

2. Bipolar neurons (e.g., cochlear and vestibular peripheral ganglia and olfactory and retinal receptor
cells) are spindle-shaped, with one process at each end of the cell (Figure 1-1I).

3. Multipolar neurons (e.g., autonomic ganglia and the enormous population of cells in the central nervous
system) have one axon and many dendritic processes (Figure 1-1 A–G).

The most interesting feature of the neurons is their processes. In humans, the axon of a neuron, the effector
part of the cell, may be a meter or more in length, extending from the spinal cord to the fingers or toes or
from the neurons of the cerebral cortex to the distal extent of the spinal cord. The dendrites, the primary
receptor area of the cell, are variable in number and in branching pattern, which in some cases enormously
increases a neuron's surface area.

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Figure 1-1. Schematic diagram illustrating variations in neuronal size, shape, and processes. A.
Pyramidal neuron. B. Flask-shaped Purkinje neuron. C. Stellate neuron. D. Granular neuron. E.
Multipolar anterior horn neuron. F. Multipolar sympathetic ganglion neuron. G. Multipolar
parasympathetic ganglion neuron. H. Pseudounipolar dorsal root ganglion neuron. I. Bipolar neuron. cb,
cell body; Ax, axon.

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Figure 1-2. Schematic diagram of motor neuron and its organelles. A. Neuronal cell body and its
processes. B. Golgi apparatus. C. Neurofilaments. D. Lipochrome pigment. E. Melanin pigment.

P.5

Perikaryon
The perikaryon, or cell body, contains the nucleus and a number of organelles (Figure 1-2).

The nucleus is usually round and centrally located. The nucleoplasm is typically homogeneous and stains
poorly with basic dyes (nuclear stains). This indicates that the deoxyribonucleic acid (DNA) is dispersed and
is in its functionally active form. The nucleoplasm is said to be in its euchromatic form. In stark contrast,
each nucleus contains one deeply stainable (with basic dyes) nucleolus, composed in part of ribonucleic acid
(RNA), which normally is present within the nucleus. The nuclear contents are enclosed in a distinct nuclear
membrane.

The cytoplasm surrounding the nucleus is filled with a variety of organelles and inclusions.

The most dramatic organelle is the so-called chromophil substance (because of its affinity for basic dyes), or
Nissl bodies (after its discoverer). Nissl bodies (Figure 1-2A) are particularly prominent in somatic motor
neurons, such as those found in the anterior horn of the spinal cord or in some motor cranial nerve nuclei (in
this case, the term nuclei refers to a cluster of cell bodies in the central nervous system rather than the
nuclei of neurons). Nissl bodies, which are distinctive in shape and abundant, are composed of membrane-
bound ribonucleoproteins (also known as granular endoplasmic reticulum). The role of the nucleus,
nucleolus, and cytoplasmic RNA in protein synthesis is well established. Thus, the cell body synthesizes
cytoplasmic proteins and other essential constituents, which are distributed throughout the neuron for
maintenance and the functional activities that will be discussed below.

Nissl bodies are found not only in the cell body but also in dendrites. Hence, they too are involved in
synthetic activity. The presence of Nissl bodies in dendrites confirms their identity as dendrites, something
that otherwise would be impossible in the study of the dense mix of dendrites and axons in the neuropil.

Nissl bodies are absent from the axon hillock (part of the perikaryon from which the axon arises). Nissl
bodies undergo characteristic changes (chromatolysis) in response to axonal injury (see below).

Numerous mitochondria dispersed throughout the cytoplasm play a vital role in the metabolic activity of the
neuron.

P.6
The Golgi apparatus (Figure 1-2B), which originally was discovered in neurons, is a highly developed system
of flattened vesicles and small oval and/or round agranular vesicles. The Golgi apparatus is thought to be
the region of the cell that receives the synthetic products of the Nissl substance to allow additional synthetic
activity. It is thought that the Golgi area is the site where carbohydrates are linked to protein in the
synthesis of glycoproteins. The small vesicles arising from this organelle may be the source of synaptic

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vesicles and their contents, which are found in axon terminals.

Neurofibrils (Figure 1-2C) are found in all neurons and are continuous throughout all their processes. They
are composed of subunits (neurofilaments) that are 7.5 to 10 nm in diameter and thus are below the limit of
resolution of the light microscope. Aggregates of abnormal neurofibrils (neurofibrillary tangles) accumulate
in neurons in Alzheimer's disease. In addition to neurofilaments, there are neurotubules with an external
diameter of about 25 nm; these structures are similar to those found in cells that are not neuronal.
Neurotubules are concerned with the rapid transport of protein molecules synthesized in the cell body, which
are carried through the dendrites and axon. Neuronal perikarya also contain 5- to 8-nm neurofilaments or
actin filaments, which form a network under the plasma membrane.

Most large nerve cells contain lipochrome pigment granules (Figure 1-2D). These granules apparently
accumulate with age and are more evident during the advancing age of the organism. In addition, certain
nerve cells found in specific locations of the brain contain black (melanin pigment) granules (Figure 1-2E).

All these organelles and inclusions are features of the perikaryon, marking it as the neuron's trophic center.
The separation of a process (axon or dendrite) from the perikaryon results in the disintegration of the
process.

Axon (Axis Cylinder, Remak's Band)

A single axon arises from the cell body. The point of departure of the axon is known as the axon hillock. The
axon may be very long (120 cm or more) and is uniformly cylindrical. The diameter of axons is also variable
and is related to their function.

The origin of the axon is the axon hillock, a small part of the cell body that is devoid of Nissl substance.
Beneath the neuronal membrane at the axon hillock is a dense layer of granular material about 200 Å thick.
In addition, there is a confluence of microtubules that exhibit clustering and cross-linkage. The area between
the perikaryon (and axon hillock) and the axon is called the initial segment. This segment is short, narrow,
and devoid of myelin. It is at this segment that the nerve impulse or action potential is initiated. Just beyond
the initial segment, many axons become myelinated; this increases their diameter in a uniform manner until
an axon terminates at its end organ.

The axoplasm contains many organelles, such as mitochondria, microtubules, microfilaments,

neurofilaments, neurotubules, smooth endoplasmic reticulum, lysosomes, and vesicles of various sizes
(Figure 1-3). The axon, unlike the cell body, does not have any structures associated with protein synthesis
or assembly (ribosomes, rough endoplasmic reticulum [Nissl substance], and the Golgi complex). The
smallest axoplasmic components are the microfilaments, which are paired helical chains of actin. The
microfilaments usually are located in the cortical zone near the axolemma; their protein, actin (associated
with the contractile process), may play a role in intraaxonal transport.

Neurofilaments (7.5 to 10 nm in diameter) are larger than microfilaments and more prevalent. They are
scattered throughout the axoplasm, but not in a recognizable pattern. Neurofilaments are composed of three
proteins with a molecular mass of 68 to 200 kDa, subunits of the protein tubulin. They are readily
disassembled by intrinsic proteases and disappear rapidly in damaged axons. Microtubules are axially
arranged hollow cylinders that measure 23 to 25 nm in diameter and are of indefinite length. The number of
microtubules within an axon varies in direct relation to axonal mass and the type of nerve; they are more
numerous in unmyelinated axons.

Figure 1-3. Schematic diagram showing part of neuronal perikaryon, its axon hillock, and axon.

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Mitochondria vary in number in an inverse ratio to axonal cross-sectional area. They are often
topographically related to one or more microtubules.

Smooth endoplasmic reticulum (SER) provides secretory vesicles along the axon. SER is functionally
concerned with axonal transport. Secretory vesicles range in size from 40 to 100 µm. Concentrations of
vesicles are found in association with nodes of Ranvier (see below) and within nerve terminals.

Lysosomes usually are found near nodes of Ranvier and accumulate rapidly during the degeneration of
nerves after an injury.

Axons retain a uniform diameter throughout their length. Axons may have collateral branches proximally and
usually branch extensively at their distal ends (telodendria) before terminating by synaptic contact with
dendrites and cell bodies of other neurons or on effector organs (muscles and glands).

Axons may be myelinated or unmyelinated (Figure 1-4). In both cases, however, the axons are ensheathed
by supporting cells: Schwann cells in the peripheral nervous system and oligodendroglia cells in the central
nervous system.

Myelinated axons are formed when they become wrapped (Figure 1-5) in multiple layers of Schwann or
oligodendroglia plasmalemma (cell membrane). The process of myelination is discussed later in this chapter.

The myelin sheath is discontinuous at the distal ends of each cell (Schwann or oligodendroglia) involved in
the ensheathing process. The area of discontinuity between cells is known as a node of Ranvier (Figure 1-6)
and is the site of voltage-gated sodium channels and other ionic displacements involved in impulse
conduction (action potentials). The electric impulse flows across a myelinated axon by jumping from node to
node. This
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type of impulse conduction is known as saltatory conduction; it tends to increase the conduction speed of the
action potential. The nodes of Ranvier are not lined up with those of adjacent axons, and the myelin sheaths
serve as electric insulation; hence, there is little if any spurious activation of axons.

Figure 1-4. Schematic diagram of cross sections of a peripheral nerve stained to show myelin sheaths
(A) and axons (B)

Myelin, which is composed of a variable number of tight wrappings of cell membrane around axons, is a lipid-
protein complex. When it is prepared for light microscopy, lipid is extracted or lost during tissue preparation,
leaving behind in the sectioned tissue a resistant proteolipid artifact known as neurokeratin.

In addition to myelin sheaths, peripheral nerve fibers are surrounded by connective tissue, the endoneurium.
Connective tissues are continuous with each other throughout the nerve, but they are named differently
according to their locations. The tissue covering individual axons is known as endoneurium, that surrounding
a grouping of axons is known as perineurium, and that covering the entire nerve (a recognizable multibundle
of axons) is known as the epineurium. The perineurium constitutes a barrier preventing certain substances
from entry to the axons.

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Figure 1-5. Schematic diagram of the process of formation of myelin sheaths. A and B show formation
of myelin sheath by concentric double layers of Schwann cell (SC) membranes wrapping themselves
around the axon (Ax). C shows how protoplasmic surfaces of the membrane become fused together to
form the major dense lines. D shows how several unmyelinated axons are contained within the
infoldings of a single Schwann cell.

Figure 1-6. Schematic diagram of the structure of a myelin-ated peripheral nerve.

Myelinated axons vary in diameter from 1 to 20 µm, whereas unmyelinated axons are not larger than 2 µm.
The size of the nerve fiber (the axon plus its myelin) has a direct relationship to the rate of impulse
conduction; large myelinated fibers conduct nerve impulses at a faster rate than do small unmyelinated
axons.

Dendrites
Neurons possess a single axon but usually have more than one dendrite, although there are exceptions (see
below). Dendrites may increase the receptive surface area of the cell body enormously. Another method of
increasing the receptive surface area of dendrites involves numerous projections from the dendrites known
as spines or gemmules, which represent sites of synaptic contact by axon terminals from other neurons.

Dendrites contain all the organelles found in the neuroplasm of the perikaryon except the Golgi
apparatus. Neurons that receive axon terminal or synaptic contacts from a variety of central nervous
system sources may have an extremely complex dendritic organization. An outstanding example of this
complexity is found in Purkinje cells in the cerebellum. Cells of the central nervous system and autonomic
ganglia have dendrites extending from their perikarya. Cells with multiple dendrites are called multipolar;
those which possess only axonlike processes extending from each end of the cell are named bipolar neurons.
Bipolar neurons are found only in the retina of the eye, olfactory receptors, and the peripheral ganglia of the
vestibulocochlear nerve (cranial nerve VIII). Sensory neurons in the dorsal root ganglia of spinal neurons are
referred to as pseudounipolar because only a single process leaves the cell body before bifurcating to form
proximal and distal segments.

The processes of bipolar and pseudounipolar neurons are axonlike in structure; they have a limited or
specific receptive capacity. These neurons of the peripheral nervous system usually retain the diversified
terminal axonal branching when they enter the central nervous system (brain and spinal cord).

A unique and unusual cell found in the retina, the amacrine cell, is regarded as an axonless neuron.

P.8

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Neuroglia
The supporting cells between the neurons of the central nervous system are referred to as neuroglia
(Figure 1-7). There are several varieties, which may be organized as follows:

1. Astrocytes

a. Fibrous

b. Protoplasmic

2. Oligodendroglia

3. Ependymal cells

4. Microglia

Astrocytes and oligodendroglia are also known as the macroglia.

A. ASTROCYTES (ASTROGLIA)
Astrocytes are the largest of the neuroglia. They are branched stellate cells. The nuclei of these cells are
ovoid, are centrally located, and stain poorly because they lack significant amounts of heterochromatin and
have no nucleoli. The nuclei do contain euchromatin, which does not stain with typical nuclear stains and is
characteristic of active nuclear activity in its cellular function.

The cytoplasm of astrocytes may contain small round granules and glial filaments composed of glial fibrillary
acidic protein (GFAP).

The processes of astroglia attach to and completely cover the outer surface of capillaries (perivascular end
feet or footplates) as well as the pia mater (glia limitans).

During development, astrocytes (radial glia) provide a framework which guides neuronal migration.

1. Fibrous astrocytes.
Fibrous astrocytes (Figure 1-7C) have thin, spindly processes that radiate from the cell body and terminate
with distal expansions or footplates, which are also in contact with the external walls of blood vessels within
the central nervous system. The foot processes form a continuous glial sheath, the so-called perivascular
limiting membrane, surrounding blood vessels.

The cytoplasm of fibrous astrocytes contains filaments that extend throughout the cell as well as the usual
(the generic group of) cytoplasmic organelles.

Fibrous astrocytes, which are found primarily within the white matter, are believed to be concerned with
metabolite transference and the repair of damaged tissue (scarring).

2. Protoplasmic astrocytes.
Protoplasmic astrocytes (Figure 1-7A, B) have thicker and more numerous branches. They are in close
association with neurons and may partially envelop them; thus, they are known as satellite cells. Since they
have a close relationship to neurons, they are located primarily in the gray matter, where the cell bodies are
found. Their function is not entirely clear, but they serve as a metabolic intermediary for nerve cells.

B. OLIGODENDROGLIA
Oligodendroglia (Figure 1-7D) have fewer and shorter branches than do astrocytes. Their nuclei are
round and have condensed, stainable (heterochromatin) nucleoplasm. The cytoplasm is densely filled
with mitochondria, microtubules, and ribosomes but is devoid of neurofilaments. Oligodendroglia cells are
found in both gray and white matter. They usually are seen lying in rows among axons in the white matter.
Electron microscopic studies have implicated the oligodendroglia in myelination within the central nervous
system in a
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manner similar to that of Schwann cells in the peripheral nervous system. Within the gray matter, these cells
are closely associated with neurons (perineuronal satellite cells), as are the protoplasmic astrocytes.

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Figure 1-7. Schematic diagram of types of neuroglia showing the thick and numerous processes of
protoplasmic astrocytes and the slender and few processes of microglia (A), protoplasmic astrocytes in
close proximity to neurons (B), fibrous astrocyte with processes in contact with a blood vessel (C),
oligodendroglia in close proximity to a neuron (D), and ependymal cells lining central canal of the spinal
cord (E).

C. EPENDYMAL CELLS
Ependymal cells (Figure 1-7E) line the central canal of the spinal cord and the ventricles of the brain. They
vary from cuboidal to columnar in shape and may possess cilia. Their cytoplasm contains mitochondria, a
Golgi complex, and small granules. These cells are involved in the formation of cerebrospinal fluid. A
specialized form of ependymal cell is seen in some areas of the nervous system, such as the subcommissural
organ.

D. MICROGLIA
The microglia (Figure 1-7A), unlike other nerve and glial cells, are of mesodermal origin and enter the
central nervous system early in its development. Their cell bodies are small, usually with little
cytoplasm, but are densely staining and have somewhat flattened and elongated nuclei. These cells have few

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processes, occasionally two, at either end. The processes are spindly and bear small thorny spines.
Normally, the function of the microglia is uncertain, but when destructive lesions occur in the central
nervous system, these cells enlarge and become mobile and phagocytic. Thus, they become the
macrophages, or scavenger cells, of the central nervous system.

Glial cells have been described as the electrically passive elements of the central nervous system. However,
it has been shown that glial cells in culture can express a variety of ligand- and voltage-gated ion channels
that previously were believed to be properties of neurons. Although numerous ion channels have been
described—sodium, calcium, chloride, and potassium—their full functional significance is uncertain.
Oligodendrocytes have been shown to quickly change the potassium gradient across their cell membranes,
giving rise to a potential change; thus, they serve as highly efficient potassium buffers.

Receptors for numerous neurotransmitters and neuromodulators, such as gamma-aminobutyric acid (GABA),
glutamate, noradrenaline, and substance P, have been demonstrated on glia cells, particularly astrocytes.
Patch clamp studies have revealed that these glial receptors are similar in many respects to those on
neurons.

GANGLIA
Ganglia are defined as collections of nerve cell bodies located outside the central nervous system. There are
two types of ganglia: craniospinal and autonomic.

Craniospinal Ganglia
The craniospinal ganglia (Figure 1-1H) are located in the dorsal roots of the 31 pairs of spinal nerves
and in the sensory roots of the trigeminal (cranial nerve V), facial (cranial nerve VII), vestibulocochlear
(cranial nerve VIII), glossopharyngeal (cranial nerve IX), and vagus (cranial nerve X) nerves. The dorsal
root ganglia and the cranial nerve ganglia are concerned with sensory reception and distribution. They
receive stimulation from the external and internal environments at their distal ends and transmit nerve
impulses to the central nervous system. The ganglion cells of the spinal group are classified as
pseudounipolar neurons, whereas the ganglion cells of the vestibular and cochlear nerves are bipolar neurons
(Figure 1-1I).

Craniospinal ganglion cells vary in size from 15 to 100 µm. In general, these cells fall into two size groups.
The smaller neurons have unmyelinated axons, whereas the larger cells have myelinated axons. Each
ganglion cell is surrounded by connective tissue and supporting cells (the perineuronal satellite cells or
capsule cells). From each cell, a single process arises to bifurcate and by doing so forms an inverted T or Y
shape (Figure 1-1H). This axonlike structure extends to appropriate proximal and distal locations. The
intracapsular process may be coiled (so-called glomerulus) or relatively straight. The bipolar ganglion cells
of the vestibular and cochlear cranial nerves are not, however, encapsulated by satellite cells.

Autonomic Ganglia
Autonomic ganglia are clusters of neurons found from the base of the skull to the pelvis, in close association
with and bilaterally arranged adjacent to vertebral bodies (sympathetic ganglia), or located within the organ
they innervate (parasympathetic ganglia).

In contrast to cranial-spinal ganglia, the ganglion cells of the autonomic nervous system (sympathetic and
parasympathetic) are multipolar (Figure 1-1F, G) and receive synaptic input from various areas of the
nervous system. Autonomic ganglion cells are surrounded by connective tissue and small perineuronal
satellite cells that are located between the dendrites and are in close association with the cell body.

Autonomic cells range in diameter from 20 to 60 µm and have clear (euchromatic) spherical or oval nuclei,
with some cells being binucleate. The cytoplasm contains neurofibrils and small aggregates of RNA, a Golgi
apparatus, small vesicles, and the ubiquitous mitochondria.

The dendritic processes of two or more adjacent cells often appear tangled and may form dendritic
glomeruli; such cells usually are enclosed in a single capsule. The terminal arborizations of the ganglionic
axons synapse on these dendritic glomeruli as well as on the dendrites of individual ganglion cells. In
general, the preganglionic arborization of a single axon brings that axon into synaptic contact with numerous
ganglion cells. The axons of these ganglion cells are small in diameter (0.3 to 1.3 µm). Autonomic ganglion
cells within the viscera (intramural, parasympathetic ganglia) may be few in number and widely distributed.
They are not encapsulated but are contained within connective tissue septa in the organ that is innervated.
The cells of the autonomic ganglia innervate visceral effectors such as smooth muscle, cardiac muscle, and
glandular epithelium.

NERVE FIBERS
A peripheral nerve is composed of nerve fibers (axons) that vary in size, are myelinated or unmyelinated,
and transmit nerve impulses either to or from the central nervous system. Peripheral nerves are often mixed
nerves because they usually are composed of both motor and sensory fibers. Nerves containing only sensory
fibers are called sensory nerves; those which contain only motor fibers are called motor nerves. The
structural organization changes along the length of the nerve because of the repeated division and union of

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different nerve fascicles, resulting in complex fascicular formations.

The nerve fibers that make up a peripheral nerve have been classified according to size and other functional
characteristics (Table 1-1). Axons designated as A alpha axons range in size from 12 to 22 µm; A beta, from
5 to 12 µm; A gamma, from 2 to 8 µm; and A delta, from 1 to 5 µm. Preganglionic sympathetic fibers that
are
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less than 3 µm in diameter are designated as B fibers. All these structures are myelinated nerve fibers. The
smallest axons (0.1 to 3 µm in diameter) are designated C fibers and are unmyelinated.

Table 1-1. Some Properties of Mammalian Peripheral Nerve Fibers.

Nerve Number Function and/or source Fiber Myelination Conduction

fiber designation size velocity
type (µm) (ms)

A alpha Ia Proprioception, stretch 12– ++ 70–120

(α) (muscle, spindle, 22
annulospiral receptor), and
motor to skeletal muscle
fibers (extrafusal)

Ib Contractile force (Golgi 12– ++ 70–120

tendon organ) 22

A beta II Pressure, stretch (muscle 5–12 ++ 30–70

(β) spindle, flower spray
receptor), touch, and
vibratory sense

A II Motor to muscle spindle 2–8 ++ 15–30

gamma (intrafusal muscle fibers)
(γ)

A delta III Some nerve endings serving 1–5 + 5–30

(δ) pain, temperature, and touch

B - Sympathetic preganglionic <3 + 3–15

axons

C IV Other pain, temperature, and 0.1– - 0.6–2.0

mechanical receptors; 1.3
sympathetic, postganglionic
axons (motor to smooth
muscle and glands)

NOTE: ++, thickly myelinated; +, thinly myelinated; -, nonmyelinated.

A peripheral nerve may be composed of thousands of axons, but the number of axons in each peripheral
nerve is variable. Some axons supply many end structures; others, a few.

Examination of nerve cross sections reveals that the amount of connective tissue varies from 25 to 85
percent. This value also varies from place to place and from nerve to nerve. For example, connective tissue
is increased at points where nerves cross joints or where there are relatively greater numbers of smaller
nerve fascicles or bundles within the peripheral nerve. The connective tissue elements provide the great
tensile strength of peripheral nerves; because connective tissue ensheaths the axons, it prevents injury or
damage caused by stretching.

Three parts of the connective tissue sheath are recognized (Figure 1-8). The outer sheath, the
epineurium, is relatively thick and is partially composed of loose (areolar) connective tissue. It contains
blood and lymphatic vessels. It is also contiguous with the dura mater where a peripheral nerve leaves the
central nervous system. The epineurium gives the nerve its cordlike appearance and consistency and
separates it from the surrounding tissues. The epineurium acts as a “shock absorber” that dissipates stresses

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set up in a nerve when that nerve is subjected to pressure or trauma. Nerves composed of closely packed
fasciculi with little supporting epineurial tissue are more vulnerable to mechanical injury than are nerves in
which fasciculi are more widely separated by a greater amount of epineurial tissue. Epineurial collagenous
fibers are continuous with the dense perineurium, which separates and encompasses groups of axons into
fascicles of different sizes. The perineurium also partitions the fascicles and follows nerve branches to the
periphery, where they terminate on each individual axon (so-called sheath of Henle). These partitions, or
septa, may be traversed by small blood vessels, and the perineurium is continuous with the pia-arachnoid
membrane. The perineurium also gives tensile strength and some elasticity to the nerve.

The perineurium is also considered a specialized structure that provides active transport of selected
materials across the perineural cells from and into the nerve fascicles. It also acts as a diffusion (blood-
nerve) barrier similar to the pia-arachnoid, with which it is continuous.

The innermost sheath of connective tissue, the endoneurium, invests each individual axon and is continuous
with the connective
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tissue that forms the perineurium and epineurium. This connective tissue provides a tough, protective
tubular sheath for the delicate axons. Within the endoneurium and surrounding each myelinated or
unmyelinated axon are Schwann cells. Schwann cells produce the myelin sheath (Figure 1-6). This nucleated
sheath of peripheral nerve fibers is also known as the neurolemma or the sheath of Schwann.

Figure 1-8. Schematic diagram of a cross section of a peripheral nerve showing the formation of three
connective tissue septae: endoneurium, epineurium, and perineurium.

In general, large axons are myelinated and small axons are unmyelinated. It is not known which factors
determine the selection of fibers for myelination, but axon caliber and trophic influences on Schwann cells by
the axon have been implicated. The conduction velocity of axons is directly related to axon diameter and the
thickness of the myelin sheath. Conduction velocity rises with increasing axon diameter and increasing
thickness of the myelin sheath.

Nerves are well supplied by a longitudinally arranged anastomosing system of blood vessels that originate
from larger arteries and veins, perforating muscular vessels, and periosteal vessels. These vessels ramify
within the epineurium and extend to reach the perineurium and endoneurium.

Anastomoses between arterioles, between venules, and between arterioles and venules are common. There
are numerous anastomoses between epineurial and perineurial arterioles and endoneurial capillaries.

Electron microscopy has revealed structural differences between epineurial and endoneurial vessels. The
endothelial cells that make up epineurial vessels have cell junctions of the “open” variety, which allow
extravasation of protein macromolecules. Small amounts of serum proteins can diffuse into the epineurium
but cannot pass through the perineurium. Endoneurial vessels, in contrast, have endothelial cells with tight

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junctions, which prevent the extravasation of proteins within the endoneurial space. These vessels, along
with the perineurium, constitute the blood-nerve barrier.

Myelinated Nerve Fibers

Electron microscopic studies have demonstrated that most axons greater than 1 µm in diameter are
myelinated. The myelin sheath, a proteophospholipid complex, is formed by many concentric double layers of
Schwann cell membrane. The double layer of cell membrane is tightly wound, expressing the neuroplasm
between the layers, and the inner or protoplasmic surfaces of the cell membrane become fused, forming the
dense, thicker lamellae of the myelin sheath (so-called major dense lines) seen on electron microscopy. The
inner, less dense lamellae (so-called intraperiod lines) are formed by the outer surfaces of the cell
membrane.

The myelin sheath is not continuous over the entire length of the axon but is interrupted at either end
because Schwann cells are much shorter than axons. Therefore, a gap always exists between adjacent
Schwann cells; this gap is referred to as a node of Ranvier. Many Schwann cells are needed to myelinate a
single axon. Sodium channels are known to be clustered at nodes of Ranvier, but they are also present in
lower numbers in the internodal axonal membrane. The electron microscope has revealed that interdigitating
processes of Schwann cells partially cover the node.

The internodal distance is inconstant because of variations in the size of Schwann cells, differences in fiber
diameter, and differences between animal species; it ranges between 400 and 1500 µm. The axon at the
node of Ranvier also shows variations unique to this region. For example, the number of mitochondria at the
node is fivefold that found in other areas. Lamellated autophagic vesicles, smooth endoplasmic profiles,
glycogen granules, and lysosomelike granules are also more numerous at this site. There is also a relative
swelling of the axon at the node.

The remarkable ultrastructural organization of the node of Ranvier suggests that the entire paranodal region,
the adjacent Schwann cell membranes, and the nodal region of the axon may constitute or be thought of as
a single functional unit.

Occasionally, myelin shows localized incomplete fusion of Schwann cell membrane, and small amounts of
Schwann cell protoplasm may be found trapped between the membranes. These areas of incomplete fusion
are called Schmidt-Lanterman clefts (Figure 1-6). Their significance is not understood, but they may be an
artifact or represent a shearing deficit in the formation of myelin or may merely represent a distension of
areas of the myelin sheath in which Schwann cell cytoplasm was inadvertently left behind as the cell wound
around the axon in the process of forming the myelin sheath. Once trapped, it is probably irremovable but
produces no demonstrable change in function.

Axonal myelin ends near the terminal arborization of the axon.

Research has established the fact that the axon provides the “signal” for myelination to take place. This
signal probably is carried by molecules on the axonal membrane.

Myelination within the central nervous system is accomplished by oligodendroglia cells in a manner similar to
that described above for the peripheral nervous system. The major difference in the central nervous system
myelin is that the internodal distance and the gap of the node of Ranvier are smaller. In addition, in the
peripheral nervous system one Schwann cell produces myelin for a part of a single axon, whereas in the
central nervous system one oligodendroglia cell produces the myelin sheath segment for an entire group of
axons in its vicinity, with the number ranging from 3 to 200 axons.

Unmyelinated Nerve Fibers

Unlike their larger counterparts, several (8 to 15) small axons may be contained within the infolding of a
single Schwann cell (Figure 1-5D), from which they are separated by a constant peri-axonal space. The
invested axon appears in cross section to be suspended in the cytoplasm by a short segment of the
invaginated outer membrane, which, after surrounding the axon, is directed back to the surface in close
approximation to the incoming membrane. The similarity in appearance of this arrangement to a cross-
sectional intestine with its supporting mesentery has prompted the use of the term mesaxon for
nonmyelinated axons suspended by the cell membrane and located below the cell's outer surface (and
surrounded by neuroplasm). Unmyelinated axons do not have nodes of Ranvier. Within the central nervous
system, glia cells have the same function as Schwann cells in that they ensheathe the nonmyelinated axons.

Conduction of Nerve Impulses

The cell membrane plays a key role in nerve transmission. In unmyelinated fibers the electric impulse is
conducted via ion movement across an ionic destabilized cell membrane. The change in permeability of the
membrane allows the influx of sodium ions and the efflux of potassium ions, resulting in a localized reversal
of charge of the cell membrane; this is followed by a destabilization of adjacent membrane segments,
resulting in a propagated action potential. This is followed by the restoration of the resting potential
difference between the inside and the outside of the axon of the previously freely permeable membrane.
Sodium and potassium levels inside and outside the axon are restored to their resting values.

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In myelinated fibers, permeability changes occur only at the nodes of Ranvier. The insulating effect of the
myelin between the nodes prevents propagation of the action potential along the axon; instead, the impulse
jumps from node to node. This type of conduction is known as saltatory conduction and is considerably faster
than the process of continuous conduction found in nonmyelinated nerve fibers. Loss of the myelin sheath,
known as demyelination, can disrupt conduction. Diseases in which this is known to occur (e.g., multiple
sclerosis) produce profound neurologic deficits.

Axonal Transport
Proteins synthesized in the perikaryon are transported throughout the cell and through the axon to its
terminal. Axonal transport flows in two directions: anterograde, or toward the axon terminal, and
retrograde, or from the axon terminal to the cell body (Figure 1-9). Anterograde transport flows primarily at
two rates: a fast rate (100 to 400 mm/day) and a slow rate (0.25 to 3 mm/day).

The retrograde transport system is very important for recycling intraaxonal proteins and neurotransmitters
and for the movement of extraneural substances from nerve endings to the neuron, providing a mechanism
that allows trophic influences from end organs to have an effect on neurons. Retrograde axoplasmic
transport is fast and occurs at about half the velocity (50–250 mm/day) of the fast anterograde component.
There is no slow retrograde transport component. There is also no rate difference of material transport
between sensory and motor axons.

Microtubules are involved in fast anterograde and retrograde transport; thus, microtubule-disrupting drugs
such as colchicine and vinblastine prevent fast axonal transport. In fast anterograde transport, a
characteristic protein called kinesin is known to provide the motive force to drive organelles along
microtubules. A different protein, dynein, is involved in fast retrograde transport.

Figure 1-9. Schematic diagram of anterograde and retrograde axonal transport.

Substances that are moved are carried in the mitochondria or small vesicles of SER. The substances that are
transported include enzymes of neurotransmitter metabolism and peptide neurotransmitters and
neuromodulators. Fast axonal transport requires energy in the form of high-energy phosphate compounds
(adenosine triphosphate [ATP]); therefore, it is necessary for the neuron to be oxygenated adequately. Any
interruption of mitochondrial oxidative phosphorylation causes the cessation of axoplasmic flow and
transport.

Substances transported by the slow component include structural proteins such as tubulin, actin, and
neurofilamentous proteins. The underlying mechanism of motility for slow transport is unclear.

Based on the concept of anterograde and retrograde axonal transport, neuroanatomic tracing methods have
been developed to study neural connectivity. A radioactively labeled amino acid injected into a region of
neuronal perikarya is incorporated into proteins and is transported anterogradely to the axon terminal.
Alternatively, a histochemically demonstrable enzyme such as horseradish peroxidase travels retrogradely
from the axonal terminals to the soma, or cell body. Different fluorescent dyes injected at different sites
travel retrogradely to the neuron or neurons that project on those sites. Cell bodies sending axons to the
two injected sites fluoresce in different colors. A neuron whose axon branches end in both injected areas will
be labeled in two colors.

The existence of a transport system in axons was surmised by Descartes and rediscovered in the 1940s by
Paul Weiss and his co-workers who coined the term axonal flow.

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SYNAPSE
The simplest unit of segmental nerve function requires two neurons: a sensory or receptor neuron and a
motor or effector neuron. This arrangement is found in the simplest reflexes, for example, the patellar
tendon reflex (knee jerk). The structural-functional coupling of these two neurons occurs through what is
termed a synapse. The terminal arborizations of the sensory neuron (axons) are dilated into small knobs or
boutons (so-called boutons terminaux, a term coined by a French investigator), which lie in contact with the
dendrites, cell bodies, and axons of effector neurons (Figure 1-10). These small bulbs contain synaptic
vesicles that range in size from 300 to 600 nm and may be round or flattened on two sides. The vesicles
appear empty but actually contain the neurotransmitter acetylcholine. In other kinds of synapses, the
vesicles may contain an electron-dense dark particle termed a core or a dark core vesicle that is presumed
to be catecholamine. Acetylcholine and catecholamine are only two of several chemical transmitter
substances that facilitate the transfer of nerve impulses from one neuron to another, at and across the
synapse, or to a nonneuronal effector organ such as a gland or muscle.

Electron microscopy has revealed the specialized structure of the synapse, which consists of thickened pre-
and/or postsynaptic membranes separated by a synaptic gap (or cleft) of about 20 nm. Although not all
synapses are structurally identical, they are recognizably related. The membrane thickenings of the pre- and
postsynaptic membranes represent accumulations of cytoplasmic proteins beneath the plasmalemma (cell
membrane). In addition to synaptic vesicles, the synaptic terminal contains a collection of mitochondria and
some neurofilaments.

When an action potential arrives at an axon terminal (end bulb or bouton terminaux), the membrane of the
terminal is depolarized and Ca 2 + ions enter the permeable terminal and promote the fusion of synaptic
vesicles with the presynaptic membrane
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(membrane of the terminal bulb). The neurotransmitter, for example, acetylcholine, contained within the
synaptic vesicles is released by exocytosis into the synaptic gap, or cleft (a space of 20 nm), where it
diffuses out and binds to receptors on the postsynaptic membrane and promotes increased permeability of
the postsynaptic membrane. The ionic permeability of the postsynaptic membrane is increased, leading to
the membrane's depolarization and the generation of an action potential in the target postsynaptic cell
(gland, muscle, or nerve) membrane.

Figure 1-10. Schematic diagram showing axosomatic, axodendritic, and axoaxonic synapses (A), and
ultrastructural components of the synapse (B).

Increasing evidence indicates the importance of protein phosphorylation in the regulation of the function of a
presynaptic nerve terminal. Major synaptic vesicle–associated proteins include the synapsins (Ia and Ib, IIa
and IIb), synaptophysin, and synaptobrevin. The precise physiologic functions of these phosphoproteins are
unknown, but that of synapsin I is becoming increasingly apparent. Phosphorylation of synapsin I occurs in
response to nerve impulses and to a variety of neurotransmitters acting at presynaptic receptors.
Dephosphosynapsin I binds to vesicles and inhibits their availability for release.

Phosphorylation of synapsin I decreases its affinity for synaptic vesicles, which then become available for
release. In addition to their role in neurotransmitter release, proteins of the synapsin family may regulate
the formation of presynaptic nerve terminals. Synapsin expression has been shown to correlate temporally
with synapse formation during development and to play a causal role in synaptogenesis.

Functionally, synapses may be excitatory or inhib-itory; transmission usually is unidirectional and not
obligatory, except at the neuromuscular junction. Electron microscopy, however, has shown a wide
variety of structural arrangements in synapses; this suggests that transmission may in some cases be
bidirectional.

Some synapses, termed electric, have no synaptic vesicles, and the adjacent cell membranes (pre- and

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postsynaptic) are fused. The fused membranes of electric synapses are called tight junctions or gap
junctions. The transmission at these junctions occurs by electrotonic depolarization; it may be bidirectional,
and this type of synapse is considered obligatory. These synapses are not common in the mammalian
nervous system.

Synapses have been classified by their structural associations as follows:

1. Axoaxonic: axon to axon

2. Axodendritic: axon to dendrite

3. Axosomatic: axon to cell body

4. Dendrodendritic: dendrite to dendrite

5. Neuromuscular: axon to muscle fiber

In chemical synapses, the following substances have been identified as transmitters:

1. Acetylcholine

2. Monoamines (noradrenaline, adrenaline, dopamine, serotonin)

3. Glycine

4. GABA

5. Glutamic acid

Two natural brain peptide neurotransmitters—endorphins and enkephalins—have been shown to be potent
inhibitors of pain receptors. They exhibit a morphinelike analgesic effect.

Other peptide hormones, such as substance P, cholecystokinin, vasopressin, oxytocin, vasoactive intestinal
peptides (VIP), and bombesin, have been described in different regions of the brain, where they act as
modulators of transmitter action.

The available data assign a role for peptides in chemical transmission that is auxiliary to that of classical
neurotransmitters, but in some neuronal systems peptides play the main role. This is especially apparent in
hypothalamic neurosecretory cells that produce and release the posterior pituitary hormones vasopressin and
oxytocin.

Besides their role in transmission, peptides seem to have a trophic function. Tachykinins have been shown to
stimulate the growth of fibroblasts and smooth muscle fibers; VIPs affect bone mineralization and stimulate
the growth of human keratinocytes.

Increasing evidence has suggested a messenger role for peptides in the nervous system. Peptides have their
own receptors in the nervous system, and receptors for tachykinins, substance P, neurokinin A (substance
K), and neurotensin have been cloned.

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Neuromuscular Junction
The neuromuscular junction (also called the myoneural junction or motor end plate) is a synapse between a
motor nerve terminal and the subjacent part of the muscle fiber. Motor neurons branch variably and
extensively near their termination at the muscle fiber. One neuron may innervate as few as 10 (eye muscles)
or as many as 500 (leg muscles) or more skeletal muscle fibers. A motor neuron and the muscle fibers that it
innervates constitute a motor unit. The motor unit, not the individual muscle fiber, is the basic unit of
function.

As a nerve fiber approaches a muscle fiber, it loses its myelin sheath and forms a bulbous expansion that
occupies a trough on the muscle fiber surface (Figure 1-11). The trough is variable in its complexity, and no
two subneural troughs appear exactly alike. There is no evidence that this variability has functional
significance. The terminal expansion of the nerve fiber is covered by a cytoplasmic layer of Schwann cells,
the neurilemmal sheath. The endoneurial sheath of connective tissue that surrounds the nerve fiber outside
the neurilemmal sheath is, however, continuous with the connective tissue sheath of the muscle fiber.

The motor end plate (or end plate) is 40 to 60 µm in diameter. They are typically located near the midpoint
of the muscle fiber or are somewhat more proximal.

The axonal terminal contains synaptic vesicles (filled with acetylcholine) and mitochondria. The synaptic gap
between the nerve and muscle is about 50 µm. The postsynaptic membrane of the muscle has numerous
infoldings called junctional folds. When a motor neuron is activated (fired), the nerve impulse reaches the
axon terminal and the contents of the synaptic vesicle (acetylcholine) in the terminal are discharged into the
gap or cleft between the pre- and postsynaptic membranes. Once the acetylcholine is released into the cleft,
it diffuses very quickly to combine with acetylcholine receptors in the muscle membrane. The binding of
acetylcholine to the receptor makes the muscle membrane more permeable to sodium. This in turn

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depolarizes the muscle cell membrane, leading to the appearance of a propagated muscle action potential
and muscular contraction. This synaptic activity is always excitatory and is normally obligatory, that is, all or
none.

The subneural sarcolemma or postsynaptic membrane contains the enzyme acetylcholinesterase, which
breaks down the depolarizing transmitter. This allows the muscle membrane to reestablish its resting
condition.

The most common disorder of the neuromuscular junction is a disease known as myasthenia gravis, which is
characterized by the onset of muscular weakness after muscle use and the improvement of muscular
strength with rest. In this disease, antibodies bind to acetylcholine receptors and render them less
accessible to released acetylcholine. Receptor blockade also occurs with curare (South American arrow
poison) and with a family of small protein toxins that are found in the venoms of various poisonous snakes.
Commercial pesticides and nerve gases interfere
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with neuromuscular transmission by inhibiting the hydrolysis (destruction) of acetylcholine, thus prolonging
its effect on the muscle and thereby inactivating the muscle. Botulinum toxin, some snake toxins, and a
toxin in the venom of black widow spider, however, interferes with neuromuscular transmission by blocking
the release of acetylcholine from the presynaptic membrane.

Figure 1-11. Schematic diagram of the motor end plate. A. Light microscopic appearance. B.
Ultrastructural appearance.

RECEPTOR ORGANS OF SENSORY NEURONS

Sensory receptors may be classified by function, for example, nociceptor (pain) or mechanoreceptor; by
structure, for example, encapsulated or nonencapsulated (so-called free); by a combination of both
structure and function; or by anatomic location, for example exteroceptors (skin receptors), proprioceptors
(muscle, tendon, joint receptors), and visceroceptors (receptors in internal body organs).

Sensory receptors provide information about the location, intensity, and duration of a peripheral stimulus.
They are designed to change (transduce) one kind of energy to another (i.e., touch to electrochemical nerve
impulse).

Each receptor possesses a different sensitivity and different adaptive properties based on its response to
continuous monotonic stimulation. Receptors may adapt quickly or slowly. Quickly (fast) adapting receptors
(phasic receptors) produce impulses that gradually decrease in strength in response to constant and
unvarying stimuli. Slowly adapting receptors (tonic receptors) continue their response level throughout their
activation and the duration of stimulation. Fast adapting receptors thus detect transient and rapidly changing

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stimuli, whereas slow adapting receptors detect a sustained stimulus.

Slowly adapting receptors are of two types. Type I receptors have no spontaneous discharge at rest and are
more sensitive to vertical displacement. Type II receptors maintain a slow regular discharge at rest and are
more sensitive to stretch. A more detailed discussion of specific receptor types appears in Chapter 23.

Free (Nonencapsulated) Nerve Endings

The receptors known as free nerve endings are the axonal endings designed for sensory reception. Their
name arose not in a functional sense but rather in a structural one.

This type of receptor has the widest distribution throughout the body and is most numerous in the skin.
Additional locations include the mucous membranes, deep fascia, muscles, and visceral organs; these
receptors are ubiquitous. The distal arborizations are located in the epithelium between the cells, the
epithelium of the skin (Figure 1-12A), the cornea, and the mucous membranes lining the digestive and
urinary tracts, as well as in
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all the visceral organs and blood vessels. In addition, they are associated with hair follicles and respond to
the movement of hair. Certain specialized epithelial cells (neuroepithelium), such as those found in taste
buds (Figure 1-12B), olfactory epithelium, and the cochlear and vestibular organs (hair cells), receive free
(receptor) endings. Tendons, joint capsules, periosteum, and deep fascia also may have this type of ending.
Endings of this kind probably respond directly to a wide variety of stimuli, including pain, touch, pressure,
and tension, and respond indirectly through so-called neuroepithelia to sound, smell, taste, and position
sense. The axons of these sensory receptors may be myelinated or unmyelinated.

Figure 1-12. Schematic diagram of receptor organs. A. Free nerve endings. B. Taste bud. C. Meissner's
corpuscle. D. Pacinian corpuscle. E. Krause's corpuscle. F. Ruffini's corpuscle.

Merkel's corpuscles are slowly adapting type I mechanoreceptors that are distributed in the germinal layer
(stratum basale) of the epidermis. Groups of 5 or 10 of these corpuscles are interspersed among the basal
layer cells. Unmyelinated free nerve endings form an axonal expansion (e.g., Merkel's disk) that is closely
applied to a modified epidermal cell (Merkel's cell). Merkel's cells are found in glabrous skin and in the outer
sheaths of hairs in hairy skin. These endings are also found in areas of transition between hairy skin and
mucous membrane. Synapselike junctions have been observed between Merkel's disks and Merkel's cells;
their functional significance is uncertain. This receptor subserves the sensory modality of constant touch or
pressure and is responsible for the tactile gnosis of static objects. They are thus important for Braille
reading. The discharge frequency of Merkel's corpuscles is temperature-dependent. Cooling the skin
increases the discharge frequency, and warming inhibits the discharge rate.

Encapsulated Nerve Endings

This group of receptors includes the corpuscles of Meissner, Vater-Pacini, Golgi-Mazzoni, and Ruffini; the so-
called end bulbs; the neuromuscular spindles; and the tendon organ of Golgi.

A. MEISSNER'S TACTILE CORPUSCLES

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Meissner's corpuscles are elongated, rounded bodies of spirals of receptor endings (Figure 1-12C) that are
fitted into dermal papillae beneath the epidermis; they are about 100 µm in diameter. A Meissner's corpuscle
possesses a connective tissue sheath that encloses the spiral stacks of horizontally arranged epithelioid
cells. The endoneurium is continuous with the capsule. When the myelin sheath terminates, the axon (A beta
fiber) arborizes among the epithelial cells. From one to four myelinated axons, as well as unmyelinated
axons, enter the capsule. Meissner's corpuscles are distributed widely in the skin but are found in the
greatest numbers in the hairless (glabrous) skin of the finger, palm of the hand, plantar surface of the foot,
toes, nipples, and lips. These corpuscles are rapidly adapting mechanoreceptors.

Sensory modality subserved by Meissner's corpuscles is low-frequency (30 to 40 Hz) flutter-vibration and
moving touch. Under sustained pressure, an impulse is produced at the onset, removal, or change of
magnitude of the stimulus. Meissner's corpuscles are thus best suited to signal direction and velocity of
moving objects on the skin.

B. VATER-PACINI CORPUSCLES
Vater-Pacini, more commonly known as pacinian, corpuscles (Figure 1-12D) are the largest and most widely
distributed encapsulated receptor organs. They range up to 4 mm in length but usually are smaller; they are
the only macroscopic receptor organ in the body. The capsule is elliptical in shape and is composed of
concentric lamellae of flattened cells (fibroblasts) supported by collagenous tissue that invests the
unmyelinated distal segment of a large myelinated (A beta) axon. The interlamellar spaces are filled with
fluid. Because of their size, these corpuscles are provided with their own blood supply, which also makes
them unique. Histologically, when cut or sectioned, they look like a divided onion, to which they have been
likened.

Vater-Pacini corpuscles are mechanoreceptors that are sensitive to vibration. They are maximally responsive
at 250 to 300 Hz. These corpuscles are rapidly adapting receptors that respond only transiently to on
vibration and off vibration or at the end of a step-wise change in stimulus position. The recovery cycle of
this receptor is very short (5 to 6 ms). The rapid adaptation of pacinian corpuscles is a function of the
connective tissue capsule that surrounds the central neural elements. The removal of the connective tissue
capsule transforms a pacinian corpuscle from a rapidly adapting receptor to a slowly adapting one.

These ubiquitous receptors are distributed profusely in the subcutaneous connective tissue of the hands and
feet. They are also found in the external genitalia, nipples, mammary glands, pancreas and other viscera,
mesenteries, linings of the pleural and abdominal cavities, walls of blood vessels, periosteum, ligaments,
joint capsules, and muscles. Of the estimated 2 × 10 9 pacinian corpuscles in the human skin, more than one-
third are in the digits of the hand and more than 1000 can be found in a single finger.

C. GOLGI-MAZZONI CORPUSCLES
Golgi-Mazzoni corpuscles are quickly adapting receptor organs that are lamellated (like the pacinian
corpuscles); however, instead of a single receptor terminal, the unmyelinated receptor is arborized with
varicosities and terminal expansions. These corpuscles are distributed in the subcutaneous tissue of the
hands, on the surface of tendons, in the periosteum adjacent to joints, and elsewhere. Their function is
uncertain but probably is related to the detection of vibration with a maximal response under 200 Hz.

D. RUFFINI'S CORPUSCLES
Elongated and complex, Ruffini's corpuscles (Figure 1-12F) are found in the dermis of the skin, especially the
fingertips, but are widely distributed, especially in joint capsules. The receptor endings within the capsule
ramify extensively among the supporting connective tissue bundles. These type II slowly adapting
mechanoreceptors have been associated with sensations of pressure and touch as a velocity and position
detector. The discharge of Ruffini's corpuscles is temperature-dependent, increasing with skin cooling and
decreasing with skin warming. Three types of Ruffini's corpuscles have been identified in joint capsules,
based on their position-related discharge. All three maintain constant baseline output, but each type
responds differently. One type responds maximally at extreme flexion, another type at extreme extension,
and a third midway between flexion and extension of the joint.

E. END BULBS
The end bulbs resemble the corpuscles of Golgi-Mazzoni. They have a connective tissue capsule enclosing a
gelatinous core in which the terminal, unmyelinated endings arborize extensively. The end bulbs of Krause
(Figure 1-12E) have been associated with sensations of temperature (cold) and are located strategically and
distributed widely. The structural complexity of these end bulbs varies remarkably, as does their size. It is
likely that they serve a wide variety of different functions; their size and distribution,
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however, preclude easy analysis. Much confusion has arisen regarding the end bulbs of Krause, since Krause
identified and named two morphologically different structures of end bulbs.

F. NEUROMUSCULAR SPINDLES
Neuromuscular spindles are found in skeletal muscle and are highly organized. Muscle spindles are
distributed in both flexor and extensor muscles but are more abundant in muscles that control fine

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movements (extraocular muscles, intrinsic hand muscles). Each muscle spindle is less than 1 cm long and
contains 2 to 12 specialized striated fibers (intrafusal fibers) in a capsule parallel with the surrounding
skeletal muscle fibers (extrafusal muscle fibers). Histologically, the muscle spindle is composed of two types
of intrafusal muscle fibers (Figure 1-13A). The nuclear chain fiber is smaller in diameter and shorter in
length and contains a single row of centrally located nuclei. The nuclear bag fiber, which is larger and
longer, contains a cluster of many nuclei in a baglike dilatation in the central part of the fiber. In contrast to
extrafusal skeletal muscle fibers, cross-striations in intrafusal fibers are limited to the ends of the muscle
fibers. Thus, intrafusal muscle fibers contract their end parts but not their middle.

Each intrafusal muscle fiber is supplied with both efferent and afferent nerve fibers. The efferent fibers
(gamma efferents), axons of gamma motor neurons in the anterior horn of the spinal cord, terminate on the
polar ends of both the nuclear chain fibers and the nuclear bag fibers. The afferent nerve fibers originate
from two types of receptor endings on the intrafusal fibers: the annulospiral (primary) endings and the
flower spray (secondary) endings. The annulospiral endings are reticulated branching endings that are
situated around the central portion of both nuclear chain fibers and nuclear bag fibers; they are better
developed, however, on the nuclear bag fibers. The so-called flower spray endings are scattered diffusely
along the length of the intrafusal fibers but are found especially on each side of the central portion adjacent
to the annulospiral endings. Both nuclear chain fibers and nuclear bag fibers contain this type of ending.

The receptor endings of intrafusal muscle fibers respond to the stretching of extrafusal muscle fibers or their
tendons. The activity of the spindle ceases with the relaxation of tension in the spindle, when the skeletal
muscle contracts. The receptor endings also may be stimulated by the stretching of intrafusal muscle fibers
secondary to gamma motor nerve activity, which contracts the polar ends of intrafusal muscle fibers, thus
stretching the receptor portions of the fibers.

A static stimulus such as that which occurs in sustained muscle stretching stimulates both the annulospiral
and the flower spray endings. By contrast, only the annulospiral (primary) endings respond to brief
(dynamic) stretching of the muscle or to vibration.

The afferent nerves emanating from the receptor endings (type Ia fibers from primary endings, and type II
fibers from secondary endings) project on alpha motor neurons in the spinal cord, which in turn supply the
extrafusal fibers. Thus, when a muscle is stretched by tapping its tendon, as is done clinically, the
stimulated receptor endings initiate an impulse in the afferent nerves which stimulates the alpha motor
neurons and results in a reflex muscle contraction. As soon as the skeletal muscle contracts, the tension in
the intrafusal muscle fibers decreases, the receptor response diminishes or ceases, and the muscle relaxes.
This is the basis of all monosynaptic stretch reflexes (e.g., knee jerk, biceps jerk). Gamma efferent activity
plays a role in sensitizing the receptor endings to a stretch stimulus and helping maintain muscle tone.

G. TENDON ORGANS OF GOLGI

Tendon organs of Golgi are slowly adapting receptors (Figure 1-13B) located in tendons close to their
junction with skeletal muscle fibers and are in series with extrafusal muscle fibers. The organ consists of
fascicles of tendon ensheathed by a connective tissue capsule. The capsule encloses the distal end of a large
(12 µm) myelinated fiber, which divides repeatedly before it splits into unmyelinated (receptor) segments.
These branchlets terminate in ovoid expansions that intermingle with and encircle
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the fascicles of collagenous tissue that constitute the tendon. Tendon organs respond to tension in skeletal
muscle fibers that is developed by stretching the muscle or actively contracting the muscle. The tension thus
developed deforms the receptor endings and “sets off” a nerve impulse that is transmitted to the spinal cord.
Afferent nerves (type Ib fibers) emanating from Golgi tendon organs project on inhibitory interneurons in the
spinal cord. Thus, when a muscle (along with its tendon) is stretched excessively, the muscle relaxes. In
contrast to muscle spindles, Golgi tendon organs do not receive efferent innervation from the spinal cord,
and thus are not influenced by the central nervous system.

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Figure 1-13. Schematic diagram of the neuromuscular spindle (A) and the Golgi tendon organ (B).

REACTION OF NEURONS TO INJURY

The reaction of neurons to injury has been studied extensively in experimental animals, with the
findings confirmed in humans; in fact, this has become one of the methods employed in the study of cell
group (nuclei) and fiber tracts. Responses can be divided into those which occur proximal to the site of the
injury and those which occur distal to it (Figure 1-14). If death of the nerve cell does not occur, regenerative
activity in the form of nerve sprouts emanating from the proximal stump may begin as early as 24 hours
after an injury.

Cell Body and Dendrites

If an axon is severed or crushed, the following reactions can be found in the cell body (Figure 1-14C) and
dendrites proximal to the site of injury.

1. The entire cell, including the nucleus and nucleolus, swells; the nucleus shifts from its usual central
position to a peripheral part of the cell.

2. The Nissl bodies (tigroid substance) undergo chromatolysis (i.e., they become dispersed, and the sharp
staining pattern disappears). This process is most marked in the central portion of the cell (former
perinuclear location) but may extend peripherally to involve Nissl bodies in the dendrites. The process
of chromatolysis reflects a change in the metabolic priority from that geared to the production of
neurotransmitters needed for synaptic activity to that involving the production of materials needed for
axonal repair and growth. The central cell body must synthesize new messenger RNA, lipids, and
cytoskeletal proteins. The components of the cytoskeleton most important for axonal regeneration are
actin, tubulin, and neurofilament protein. These proteins are carried by slow anterograde axonal
transport at a rate of 5 to 6 mm/day, which correlates with the maximal rate of axonal elongation
during regeneration. Another group of proteins whose synthesis is increased during regeneration of
nerve cells consists of growth-associated proteins (GAPs), which travel by fast axonal transport at a
rate of up to 420 mm/day. Although GAPs do not initiate, terminate, or regulate growth, they are
essential for regeneration. Neurono-tropic factors (NTFs) from the periphery signal to the cell body that
an injury has occurred and travel by retrograde axonal transport.

3. The other organelles, including the Golgi apparatus and mitochondria, proliferate and swell.

The speed at which these changes occur, as well as their degree, depends on several factors, including the
location of the injury, the type of injury, and the type of neuron involved. The closer the injury is to the cell
body and the more complete the interruption of the axon is, the more severe the reaction is and the poorer
are the chances of full recovery. In general, this reaction is seen more often in motor neurons than in
sensory neurons.

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Figure 1-14. Schematic diagram of a normal neuron (A), site of injury (B), and reaction to injury (C).

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The reactions of the cell body and dendrites to axonal injury are termed retrograde cell changes. After about
3 weeks, if the cell survives the injury, the cell body and its processes begin to regenerate. Full recovery
takes 3 to 6 months. The nucleus returns to its central location and is normal in size and configuration. The
staining characteristics and structure of the organelles also return to normal. If regeneration fails, the cell
atrophies and is replaced by glia.

Axon
After an injury, the axon undergoes both retrograde (proximal) and anterograde (distal) degeneration.
Retrograde degeneration usually involves only a short segment of the axon (a few internodes). If the injury
to the neuron is reversible, regenerative processes begin with the growth of an axon sprout as soon as new
cytoplasm is synthesized and transported from the cell body. The regenerative sprouting of the proximal
axon stump requires elongation of the axon. This process is mediated by a growth cone at the tip of the
regenerating fiber. Growth cones were first described by Ramon y Cajal, who compared their advance
through solid tissue to that of a battering ram. Growth cones release a protease that dissolves the matrix,
permitting their advance through the tissues. Growth cones have mobile filopodia (extruding from a flattened
sheet of lamellipodia), enabling them to move actively and explore the microenvironment of a regenerating
axon. Growth cones play an essential role in axon guidance and can respond to contact guidance clues
provided by laminin and fibronectin, two major glycoprotein components of the basal laminae of Schwann
cells.

Shortly after a nerve injury and before the onset of wallerian degeneration, severe degeneration of the tips
of the proximal and distal stumps occurs. This injury is secondary to an influx of sodium and calcium and a
massive loss of potassium and protein. The axonal debris and normal tissue scarring may prevent the growth
cone of the proximal stump from reaching a healthy distal stump.

Distal to the site of the injury (Figure 1-14C), the severed axon and its myelin sheath undergo what is
known as secondary, or wallerian, degeneration, named in recognition of its description by Augustus Waller
in 1852. The axon, deprived of its continuity with the supporting and nutritive materials from the cell body,
begins to degenerate within 12 hours. The axon degenerates before its Schwann cell sheath does and
appears beaded and irregularly swollen within 1 week. The axonal reaction extends distally to involve the
synapse. The fragmented portions of the axon are phagocytized by invading macrophages. This process may
take considerably longer within the central nervous system.

Along with degeneration of the axon, the myelin sheath begins to fragment and undergo dissolution within
the Schwann cell. Macrophages also play an important role in the removal of myelin breakdown products.
The degenerative process occurs within the endoneurium and is soon followed by mitotic activity in the
Schwann cells, which form a tubelike sleeve within the endoneurium along the entire length of the
degenerated axon. Endoneurial tubes persist after the myelin and the axonal debris have been cleared. The
proliferating Schwann cells align longitudinally within the endoneurial tube, creating a continuous column of
cells named Büngner's bands. The growth of axons from the proximal stump begins within 10 hours and may
traverse the gap between the proximal and distal ends of the axon and enter the Schwann cell tubes
(neurolemma). Although many small axonal sprouts may enter a single tube, only one will develop its normal
diameter and appropriate sheath; the others will degenerate. This may occur within 2 or 3 weeks, since
regenerative growth normally takes place at a rate of 1.5 to 4 mm/day. Failure to establish a pathway for
regrowth of the axonal sprouts may result in the formation of a neuroma, which is often a source of pain.

It must be pointed out that chance plays a major role in this regenerative activity. If a sensory axon enters
a sheath formerly occupied by a motor axon or vice versa, the growing axon will be nonfunctional and the
neuron will atrophy. Accurate growth and innervation of the appropriate distal target are thus of critical
importance to the success of nerve regeneration. In this context, the target of innervation can exert a
guiding “neurotropic” influence on a regenerating axon. Forrsman in 1898 and Ramon y Cajal subsequently
showed that the advancing tip of a regenerating axon is chemotropically attracted to its appropriate distal
nerve target. Recent experimental studies have confirmed this. In addition, although the process of
degeneration is similar in the central and peripheral nervous systems, there is a marked difference in the
success of the regenerative process in the two systems. What has been described above applies primarily to
regeneration in the peripheral nervous system. Degeneration of a neuron usually is limited to its perikaryon
and processes. In certain areas of the nervous system, however, degeneration of a neuron is transmitted to
the neuron, with which it makes a connection. This type of degeneration is known as transneuronal
degeneration.

Nerve Growth Factors

Successful nerve regeneration requires neuronal growth. Four classes of nerve growth factors are essential
for optimal nerve growth: (1) NTFs, or survival factors, (2) neurite-promoting factors (NPFs), which control
axonal advance and influence the rate, incidence, and direction of neurite growth, (3) matrix-forming

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precursors (MFPs), possibly fibrinogen and fibronectin, which contribute fibrin products to the nerve gap and
provide a scaffolding for the ingrowth of cells, and (4) metabolic and other factors.

NTFs are macromolecular proteins that promote the survival and growth of neuronal populations. They are
present in the target of innervation, where they are taken up by the nerve terminals and transported by
retrograde axonal transport back to the cell body. These factors exert a supportive or survival-promoting
effect. The best known NTF is nerve growth factor (NGF).

NPFs are substrate-bound glycoproteins that strongly promote the initiation and extension of neurites.
Laminin and fibronectin, two components of the basal lamina, have been shown to promote neurite growth.
Although NPFs were presumed to exert their neurite-promoting activity by increasing the adhesion of the
growth cones to the surface of the basal lamina, recent studies have shown that NPFs promote neurite
growth independent of growth cone adhesion.

After a nerve injury, a polymerized fibrin matrix is formed from the fibrinogen and fibronectin found in
exudates from the cut nerve ends. This matrix is important for the migration of Schwann cells and other cells
into the gap between the cut ends.

Metabolic and other factors that promote nerve regeneration include sex hormones, thyroid hormone,
adrenal hormones, insulin, and protease inhibitors.

Clinical Correlation
There are at present two classifications of nerve injury that are based on the nature of the lesion in the
nerve. The first classification, proposed by Seddon, recognizes three degrees of severity of nerve
injury: (1) conduction block
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(neurapraxia), (2) loss of axonal continuity (axonotmesis), and (3) loss of nerve trunk continuity
(neurotmesis). The second classification, proposed by Sunderland, includes five degrees of nerve injury
(Table 1-2, Figure 1-15).

Table 1-2. Nerve Injury.

Degree Wallerian Endoneurium Perineurium Epineurium Nerve Nerve

of degeneration continuity continuity continuity fiber trunk
severity continuity continuity

I - + + + + +

II + + + + + +

III + - + + - +

IV + - - + - +

V + - - - - -

NOTE: +, present; -, absent.

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Figure 1-15. Schematic diagram of the five types of nerve injury.

I. The first and least severe degree consists of a temporary physiologic conduction block in which axonal
continuity is not interrupted. The conduction across the injured segment of nerve is blocked.
Conduction proximal and distal to the block is normal. The three connective tissue sheaths are intact.

II. In the second degree wallerian degeneration is present distal to the nerve lesion. Continuity of the
endoneurial sheath is preserved and permits regeneration of the distal segment of the nerve. The peri-
and epineurial sheaths are also preserved.

III. The third degree is characterized by the loss of continuity of nerve fibers. The internal fascicular
structure is disorganized, the endoneurial sheath becomes discontinuous, and wallerian degeneration is
present. Peri- and epineurial sheaths are, however, preserved. Axon regeneration in this type of injury
is negligible because of the development of intrafascicular fibrosis and the loss of continuity of the
endoneurial sheath.

IV. In the fourth degree fascicular nerve structure is destroyed. Endo- and perineurial sheaths are
discontinuous. The epineurial sheath is intact. Regenerating axon growth is blocked by fibrous tissue
scarring. This type of injury requires excision of the injured nerve segment and nerve repair.

V. The fifth degree represents the complete loss of continuity of the nerve trunk. There is discontinuity of
the axon and the endo-, peri-, and epineurial sheaths.

Table 1-2 gives a summary of Sunderland's classification; Figure 1-15 shows a diagrammatic representation
of the different stages of nerve injury.

Neuronal Plasticity
It was thought at one time that the mature central nervous system is incapable of recovering its function
after an injury. However, recent studies have demonstrated that the central nervous system may not be so
static or rigid. It has been shown that after an injury the neuronal circuitry may reorganize itself by forming
new synapses to compensate for those lost to injury. This property of forming new channels of
communication after an injury is known as neuronal plasticity.

Neuronal plasticity is most dramatic after partial denervation. In such a situation, the remaining unaffected
axons projecting on the partially denervated region develop axonal sprouts that grow and form new synaptic
contacts to replace those lost by denervation.

The ability of the mature central nervous system to form these sprouts and functional synapses varies from
one region to another and from one species to another. The factor or factors that promote sprout formation
and synaptogenesis in some but not all regions or species are not fully known and are the subject of

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intensive research. The identification of factors that promote neuronal plasticity in the injured mature
central nervous system may have a great impact on the recovery of function in paraplegic patients and
stroke victims.

This discussion of plasticity has focused on the regenerative ability of the central nervous system after an
injury. It must be emphasized, however, that plasticity in its broader sense is an ongoing phenomenon.
Although brains are grossly similar anatomically, physiologically, and biochemically, the behavior of humans
differs from individual to individual. This difference in behavior reflects the plasticity of the brain in adapting
to its environment.

TERMINOLOGY
Astrocyte (Greek astron, “star”; kytos, “hollow vessel”).
A starlike cell. The processes of astrocytes give them a starlike shape.

Axon (Greek axon, “axis”).

The process of a neuron by which impulses are conducted. The axon, passing through its tubular sheaths,
forms the axis of the nerve. The axis cylinder, of unmyelinated nerve fibers, was described by Robert Remak
in 1838.

Axon hillock.
The part of a neuron perikaryon that gives rise to the axon.

Axonotmesis.
A lesion of a peripheral nerve that produces discontinuity of axons with preservation of the supporting
connective tissue sheaths.

Boutons terminaux.
A French term for what Cajal in 1903 called terminal buttons to describe axon terminations in a synapse.

Büngner's bands.
Chains of multiplying Schwann cells that facilitate the regeneration of axons after an axonal injury.
Described by Otto von Büngner (1858–1905), a German surgeon.

Chromatolysis (Greek chromatos, “color”; lysis, “dissolution”).

Dissolution of the Nissl bodies of a neuron as a result of injury to its axon. The term was introduced by
Georges Marinesco, a Romanian neurologist, in 1909.

Dendrite (Greek dendron, “tree”).

Processes of neurons may branch in a treelike fashion. This term was introduced by Camillo Golgi, an Italian
anatomist, in about 1870.

End bulbs of Krause.

Encapsulated end organs which are widely distributed and are associated with temperature sensation. Named
after Wilhelm Johann Friedrich Krause (1833–1910), who described them in 1860.

Ependyma (Greek, upper “garment”).

The lining cells of the brain ventricles and the central canal of the spinal cord. The term was introduced by
Rudolph Ludwig Karl Virchow, a German pathologist.

Golgi apparatus.
A perinuclear accumulation of smooth membrane vesicles and cisternae that are well developed in cells
engaged in protein synthesis and secretion. Described by Camillo Golgi, an Italian anatomist, in 1896.

Golgi, Camillo (1844–1926).

Italian anatomist who, in his kitchen, developed, in 1873, the Golgi stain (silver chromate or nitrate, and
osmic tetroxide) to demonstrate neurons and myelin sheath respectively. He shared the Nobel Prize, in
1906, with Ramon y Cajal. He is credited with description of the Golgi apparatus, the Golgi tendon organ,
and Golgi-type neurons.

Golgi-Mazzoni corpuscles.
Described by Camillo Golgi (1844–1926), an Italian anatomist, and Vittorio Mazzoni, an Italian physician.

Henle, Friedrich Gustav Jacob (1809–1885).

German anatomist and pathologist. Made many important contributions in microscopic anatomy and
especially in the study of epithelium and endothelium. He led a life filled with politics, romance, and
intrigue. His importance to the development of histology is comparable to that of Andreas Vesalius in gross
anatomy. Among his friends was the composer Felix Mendelsohn.
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Meissner's corpuscles.
Encapsulated nerve endings. They were described by George Meissner, a German anatomist, in 1853.

Merkel's corpuscles.
Free nerve endings distributed in the germinal layer of the epidermis. They convey touch sensation.

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Described by Friedrich Sigmund Merkel, a German anatomist, in 1880. Merkel (1845–1919) also introduced
into anatomic illustrations the colors red for arteries, blue for veins, and yellow for nerves.

Microglia (Greek mikros, “small”; glia, “glue”).

Small interstitial, nonneural supporting cells in the central nervous system. Also known as Hortega cells after
del Rio Hortega, who described them in 1921.

Neurapraxia (Latin neuralis, “nerve”; Greek apraxia, “absence of action”).

Failure of nerve conduction in the absence of structural damage.

Neurotmesis (Latin neuralis, “nerve”; Greek tmesis, “cutting”).

Partial or complete severance of a nerve with disruption of the axon and myelin sheath and connective tissue
elements.

Nissl, Franz (1860–1919).

German neurologist. Described the chromophil substance named after him (Nissl substance) in 1884. He was
known by his students as the “punctator maximus” because of his enthusiasm to perform lumbar punctures.

Nissl bodies.
Granular endoplasmic reticulum of neurons. Named after Franz Nissl, a German neurologist, who described it
in 1884.

Nodes of Ranvier.
Interruptions in a myelin sheath along the axon at which Schwann cell cytoplasm comes in contact with the
axon. Described by Louis Antoine Ranvier, a French histologist, in 1871. Prior to that time, interruptions of
the myelin sheaths at regular intervals were considered artifactual. Using silver impregnation staining
method, Ranvier described “small black, transverse lines of remarkable clarity like rungs of a ladder” which
he called “the constriction ring of the nerve tube”. Ranvier also concluded that each internodal segment was
a cellular unit joined to its neighbor at the constriction.

Oligodendroglia (Greek oligos, “little, few”; dendron, “dendrite”; glia, “glue”).

Neuroglial cells with few branches. Described by Rio del Hortega, Spanish neuroanatomist, in 1921.

Purkinje cells.
Flask-shaped large cells in the cerebellum. Described by Johannes Purkinje, a Bohemian physiologist, in
1837.

Remak, Robert (1815–1865).

German physiologist and neurologist who described the axon (named it axis cylinder) and the origin of axons
from nerve cells.

Ruffini's corpuscles.
Encapsulated nerve endings described by Angelo Ruffini (1874–1929), an Italian anatomist, in 1898.

Schmidt-Lanterman clefts.
Areas of incomplete fusion of Schwann cell membranes around the axon. Named after Henry D. Schmidt, an
American pathologist who described them in 1874, 3 years before A. J. Lanterman, a German anatomist,
described them.

Schwann cell.
A myelin-forming cell in the peripheral nervous system. Named after Theodor Schwann, a German anatomist,
who described them in 1838.

Synapse (Greek synapsis, “a conjunction, connection, clasp”).

A term introduced by Sherrington in 1897 to describe the junction between two neurons and between
neurons and muscles. Sherrington had considered the term syndesm but changed to synapse at the
suggestion of the Greek scholar Verrall.

Tendon organs of Golgi.

Stretch receptors in tendons close to their junction with the muscle fiber. Named after Camillo Golgi, an
Italian anatomist.

Vater-Pacini corpuscles.
Encapsulated nerve endings with a wide distribution. Rapidly adapting mechanoreceptors. Named after
Abraham Vater (1684–1751), a German anatomist, and Filippo Pacini (1812–1883), an Italian anatomist who
rediscovered them about a century after Vater. The corpuscles were first depicted by Lehman in 1741 from a
preparation made by Vater, who called them papillae nervae. Shekleton (1820–1824) dissected the same
nerves and receptors 10 years before they were seen by Pacini. He placed a beautiful specimen in the
Museum of the Royal College of Surgeons in Dublin. Pacini then “rediscovered” them in 1835. The name
pacinian corpuscles was used by Friedrich Henle, a German anatomist, and Rudolph Kolliker, a Swiss
anatomist, in 1844. Shekleton's contribution has almost been forgotten.

Wallerian degeneration.
Changes in an axon and its myelin sheath distal to the site of severance of the axon. Named after Augustus
Waller (1816–1870), an English physiologist who described the phenomenon between 1850 and 1852.

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SUGGESTED READINGS
Afifi AK, Bergman RA: Basic Neuroscience: A Structural and Functional Approach, 2nd ed. Baltimore,
Urban & Schwarzenberg, 1986.

Altman J: Microglia emerge from the fog. Trends Neurosci 1994; 17:47–49.

Barr ML, Kiernan JA: The Human Nervous System: An Anatomical Viewpoint, 6th ed. Philadelphia,
Lippincott, 1993.

Bergman RA et al: Atlas of Microscopic Anatomy. Philadelphia, Saunders, 1989.

Bergman RA et al: Histology. Philadelphia, Saunders, 1996.

Edelman G: Cell adhesion molecules in the regulation of animal form and tissue pattern. Annu Rev Cell
Biol 1986; 2:81–116.

Fawcett D et al: A Textbook of Histology, 12th ed. New York, Chapman & Hall, 1994.

Gluhbegovic N, Williams TH: The Human Brain: A Photographic Guide. Philadelphia, Harper & Row, 1980.

Hall ZW: An Introduction to Molecular Neurobiology. Sunderland, MA, Sinauer, 1992.

Hillman H, Darman J: Atlas of the Cellular Structure of the Human Nervous System. London, Academic
Press, 1991.

Hogan MJ et al: Histology of the Human Eye. Philadelphia, Saunders, 1971.

Hudspeth AJ: The hair cells of the inner ear. Sci Am 1983; 248:54–64.

Jones E: The nervous tissue. In Weiss L (ed): Cell and Tissue Biology: A Textbook of Histology, 6th ed.
Baltimore, Urban & Schwarzenberg, 1988:277–352.

Junge D: Nerve and Muscle Excitation, 3rd ed. Sunderland, MA, Sinauer Associates, 1992.

Kimelberg H, Norenberg M: Astrocytes. Sci Am 1989; 260:66–76.

Laws ER Jr; Udvarhelyi GB: The Peripheral Nerves. In Walker EA (ed): The Genesis of Neuroscience. Park
Ridge, Illinois, The American Association of Neurological Surgeons, 1998:145–155.

Levi-Montalcini R: The nerve growth factor 35 years later. Science 1987; 237:1154–1162.

Levitan I, Kaczmarek L: The Neuron: Cell and Molecular Biology. New York, Oxford University Press,
1991.

Lim DJ: Functional structure of the organ of corti: A review. Hear Res 1986; 22:117–146.

Matthews GG: Cellular Physiology of Nerve and Muscle, 2d ed. Boston, Blackwell, 1991.

Meredith GE, Arbuthnott GW: Morphological Investigations of Single Neurons in Vitro. New York, Wiley,
1993.

McDevitt D: Cell Biology of the Eye. New York, Academic Press, 1982.

Murphy S: Astrocytes: Pharmacology and Function. New York, Academic Press, 1993.

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Nicholls JG, Martin AR: From Neuron to Brain: A Cellular Approach to the Function of the Nervous
System, 3rd ed. Sunderland, MA, Sinauer Associates, 1992.

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Pappas G, Purpura D: Structure and Function of Synapses. New York, Raven Press, 1972.

Peters A et al: The Fine Structure of the Nervous System: The Neurons and Their Supporting Cells, 3rd
ed. New York, Oxford University Press, 1990.

Robinson P et al: Phosphorylation of dynamin I and synaptic vesicle recycling. Trends Neurosci 1994;
17:348–353.

Schwartz J: The transport of substances in nerve cells. Sci Am 1980; 242:152–171.

Shepherd G: The Synaptic Organization of the Brain, 3rd ed. New York, Oxford University Press, 1990.

Siegel G et al: Basic Neurochemistry. New York, Raven Press, 1989.

Smith CUM: Elements of Molecular Neurobiology. New York, Wiley, 1989.

Steward O: Principles of Cellular, Molecular and Developmental Neuroscience. New York, Springer, 1989.

Terzis JK, Smith KL: The Peripheral Nerve: Structure, Function, and Reconstruction. New York, Raven
Press, 1990.

Thoenen H, Kreutzberg G: The role of fast transport in the nervous system. Neurosci Res Prog Bull 1982;
20:1–138.

Vallee RB, Bloom GS: Mechanism of fast and slow transport. Annu Rev Neurosci 1991; 14:59–92.

Walz W: Role of glial cells in the regulation of the brain ion microenvironment. Prog Neurobiol 1989;
33:309–333.

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Editors: Afifi, Adel K.; Bergman, Ronald A.

Title: Functional Neuroanatomy: Text and Atlas, 2nd Edition

Copyright ©2005 McGraw-Hill

> Table of Contents > Part I - Text > 2 - Gross Topography

2
Gross Topography

Central Nervous System

Brain
Cerebral Dural Venous Sinuses
External Topography of the Brain
Lateral Surface
Medial Surface
Ventral Surface
Cerebellum and Brain Stem
Internal Topography of the Brain
Coronal Sections
Axial Sections

KEY CONCEPTS

The nervous system can be divided into three parts: central, peripheral,
and autonomic.

The brain is composed of the two cerebral hemispheres, the brain stem,
and the cerebellum.

There are three layers of meninges: dura mater, arachnoid mater, and pia
mater.

The epidural space, a potential space between the skull and the dura
mater, is the site of epidural arterial hemorrhage, a life-threatening condition
that usually is due to a traumatic rupture of the middle meningeal artery.

The subdural space, between the dura mater and the arachnoid mater, is
the site of subdural venous hemorrhage.

The subarachnoid space, between the arachnoid mater and the pia mater,
contains cerebrospinal fluid. It is also the site of subarachnoid hemorrhage
resulting from rupture of cerebral blood vessels on the pia mater.

On the lateral surface of the cerebral hemisphere three landmarks—the

central (rolandic) sulcus, the lateral (sylvian) fissure, and a line connecting
the tip of the parieto-occipital sulcus and the preoccipital notch—delineate
four lobes: frontal, parietal, temporal, and occipital.

The medial surface of the hemisphere shows the corpus callosum, septum
pellucidum, fornix, and diencephalon, along with the medial surfaces of the

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frontal, parietal, occipital, and temporal lobes.

Components of the limbic lobe, the subcallosal gyrus, the cingulate gyrus,
the parahippocampal gyrus, and the uncus are seen to advantage on the
medial surface of the cerebral hemisphere.

Cranial nerves and related structures commonly seen on the ventral

surface of the brain include the olfactory tract and bulb, the optic chiasm, and
the oculomotor, trigeminal, abducens, facial, and cochleovestibular nerves.

For didactic purposes, the nervous system is conventionally divided into three
major parts: the central nervous system (CNS), peripheral nervous system, and
autonomic nervous system. Although this division simplifies the study of a complex
system, the three component parts act in concert in the overall control and integration
of the motor, sensory, and behavioral activities of the organism. A great deal of effort
has been expended to elucidate the structure, connectivity, and function of the nervous
system. The methodologic creativity and observational acumen of anatomists,
physiologists, psychologists, and physicians have been impressive and rewarding, but
their work is far from finished.

The term central nervous system refers to the brain and the spinal cord. The term
peripheral nervous system refers to cranial
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nerves, the spinal nerves, the ganglia associated with the cranial and spinal nerves,
and the peripheral receptor organs. The term autonomic nervous system refers to the
part of the nervous system involved mainly in the regulation of visceral function; its
component parts are located partly within the CNS and partly within the peripheral
nervous system.

This chapter is concerned mainly with the gross features of the CNS. Its purposes are
to acquaint the student with the terminologic jargon used in the neurologic sciences
and provide an orientation to the major components of this system.

CENTRAL NERVOUS SYSTEM

The CNS usually is considered to have two major divisions: the brain and the spinal
cord. The brain is subdivided into the following structures:

1. The two cerebral hemispheres

2. The brain stem, consisting of the diencephalon, mesencephalon (midbrain),

pons, and medulla oblongata

3. The cerebellum

The cerebral hemispheres and diencephalon are discussed in this chapter. The gross
topography of the rest of the brain stem, the cerebellum, and the spinal cord are
presented in other chapters in this book.

BRAIN
The word brain derives from the Anglo-Saxon word Braegen, which may have common

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root with the Greek word Bregma (the upper part of the head). The first mention of the
brain specifically as an organ occurs in the papyri of ancient Egypt. The ancient
Egyptians (3,000–2,500 BC) did not consider the brain of importance. They promoted
the cardiocentric concept in which the heart was the seat of the soul. Among the
ancient Greeks, Plato promoted the cephalocentric theory and coined the term
“enkephalon”. According to Plato, the brain gyri and sulci were analogous to ridges and
furrows of a plowed field for planting of a divine seed to produce consciousness. In
contrast, Aristotle promoted the Egyptian cardiocentric theory. He considered the heart
to be the center of the body. The brain was analogous to clouds of steam where the
blood pumped by the heart is cooled. Gyri and sulci were believed to be ripples on the
clouds. For centuries, arguments persisted as to the function of the brain, whether it
was the seat of emotions or the abode of the soul. It is only within the last two
hundred years that any real conception of the function of the brain began to be
obtained.

The brain is semisolid in consistency and conforms to the shape of its container. It
weighs approximately 1400 g in an adult. The male brain is on average slightly heavier
than the female brain, although this has no relationship to intelligence. The largest
human brain on record weighed 2850 g and came from a mentally defective individual
with epilepsy. In contrast, Einstein's brain weighed 1230 g. The brain weights of other
notable persons are listed in Table 2-1.

The brain is protected from the external environment by three barriers:

1. Skull

2. Meninges

3. Cerebrospinal fluid

Table 2-1. Brain Weights of Some Notable Persons.

Person Weight

Anatole France (French writer and Nobel laureate) 1040 g

Franz Gall (father of cerebral localization) 1198 g

Baron George Eugene Housmann (French city planner) 1225 g

Friedrich Tiedemann (German physician) 1253 g

Louis Agassiz (Swiss American zoologist) 1495 g

Daniel Webster (American statesman and lawyer) 1518 g

Immanuel Kant (German metaphysician) 1600 g

William Makepeace Thackeray (English novelist) 1658 g

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George Leopold Chretien Cuvier (French zoologist) 1830 g

Ivan Turgenieff (Russian novelist) 2010 g

The bony skull is the major barrier against physical trauma to the brain.

The meninges are organized into three layers named in order of their proximity to
the skull:

1. Dura mater

2. Arachnoid mater

3. Pia mater

The dura mater (Latin, “hard mother”) is a tough, fibrous connective tissue (Figure 2-
1) arranged in two layers. An outer parietal (periosteal) layer adheres to the skull and
forms its peri-osteum, and an inner meningeal layer is in contact with the arachnoid
mater. These two layers of dura are adherent to each other except at the sites of
formation of dural venous sinuses such as the superior sagittal (Figure 2-2).

The meningeal dura mater has three major reflections which separate components of
the brain. The falx cerebri (Figure 2-2) is a vertical reflection between the two cerebral
hemispheres. The tentorium cerebelli (Figure 2-2) is a horizontal reflection between
the posterior (occipital) parts of the cerebral hemispheres and the cerebellum. The falx
cerebelli is a vertical reflection which incompletely separates the two cerebellar
hemispheres at the inferior surface. The meningeal layer of the dura mater of the brain
is continuous with the dura mater that covers the spinal cord.

The arachnoid mater (Greek arachne, “spider”) (Figure 2-3) is a nonvascular membrane
of an external mesothelium that is joined with weblike trabeculae to the underlying pia
mater.

The pia mater is a thin translucent membrane that is intimately adherent to brain
substance. Blood vessels of the brain are located on the pia mater (Figure 2-3). The
arachnoid mater and the pia mater are collectively referred to as the pia-arachnoid
membrane because of their close structural and functional relationships.

The meninges are subject to the infection known as meningitis. This is a serious, life-
threatening condition that requires immediate medical treatment. The three layers of
meninges are separated from each other and from the bony skull by the following
spaces.

1. The epidural space is located between the dura mater and the bony skull.
Trauma to the skull with rupture of the middle meningeal artery (Figure 2-1)
leads to epidural hemorrhage, or the accumulation of arterial blood in the epidural
space. Because of the pressure produced by a hemorrhage in a closed container

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such as the skull, an epidural hemorrhage is handled as an acute, life-threatening

emergency calling for surgical intervention to evacuate the accumulated arterial
blood in the epidural space and control the bleeding.

Figure 2-1. Lateral view of the brain showing the dura mater meningeal
layer and the middle meningeal artery. (From N. Gluhbegovic and T. H.
Williams: The Human Brain: A Photographic Guide. Harper & Row, 1980,
courtesy of the authors.)

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Figure 2-2. Midsagittal section of the cranium showing the falx cerebri and
tentorium cerebelli. (From N. Gluhbegovic and T. H. Williams: The Human
Brain: A Photographic Guide. Harper & Row, 1980, courtesy of the authors.)

Figure 2-3. Dorsal view of the brain showing the arachnoid meningeal layer
and arachnoid granulations. (From N. Gluhbegovic and T. H. Williams: The
Human Brain: A Photographic Guide. Harper & Row, 1980, courtesy of the
authors.)

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2. The subdural space lies between the dura mater and the arachnoid mater.
Trauma to the skull may rupture the bridging veins, leading to subdural
hemorrhage, or the accumulation of blood in the subdural space. This condition
also calls for surgical intervention to evacuate the accumulated venous blood and
control the bleeding.

3. The subarachnoid space is located between the arachnoid mater and the pia
mater. This space contains cerebrospinal fluid (CSF) and cerebral blood
vessels (Figure 2-3). Rupture of such vessels leads to subarachnoid hemorrhage,
or the accumulation of blood in the subarachnoid space. This condition may result
from trauma to the head, congenital abnormalities in vessel structure
(aneurysms), or high blood pressure. The subarachnoid space underlying the
superior sagittal sinus contains arachnoid granulations (Figures 2-2 and 2-3),
sites of CSF absorption into the superior sagittal sinus.

The third barrier that protects the brain, the CSF, is the subject of Chapter 29.

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CEREBRAL DURAL VENOUS SINUSES (Figure 2-4)

Cerebral dural venous sinuses are endothelial-lined venous channels, devoid of valves,
located between the periosteal and meningeal layers of dura mater. The superior and
inferior sagittal sinuses lie in the superior and inferior margins of the falx cerebri,
respectively. Caudally, the inferior sagittal sinus is joined by the great cerebral vein of
Galen to form the straight sinus (sinus rectus) located at the junction of the falx
cerebri and tentorium cerebelli. The straight sinus drains into the confluence of sinuses
(torcular Herophili). The two transverse sinuses arise from the confluence of sinuses
and pass laterally and forward in a groove in the occipital bone. At the occipitopetrosal
junction, the two transverse sinuses curve downward and backward to form the sigmoid
sinuses, which drain into the internal jugular veins. The occipital sinus connects the
confluence of sinuses to the marginal sinus at the foramen magnum. The superior
petrosal sinus lies in the dura at the anterior border of the tentorium cerebelli. The
inferior petrosal sinus extends between the clivus and the petrous bone. The cavernous
sinus lies on each side of the sphenoid sinus, the sella turcica, and the pituitary gland.
Dural venous sinuses serve as low-pressure channels for venous blood flow back to the
systemic circulation. Obstruction of one or more of these sinuses as a result of trauma,
infection, or hypercoagulable states results in major neurologic signs including stroke,
increased intracranial pressure, loss of consciousness, and intracranial bleed.

EXTERNAL TOPOGRAPHY OF THE BRAIN

For convenience, the topography of the brain will be discussed as it is viewed on the
lateral, the medial, and the ventral surfaces of the brain.

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Figure 2-4. Lateral (A) and medial (B) surfaces of brain showing sites of dural
venous sinuses.

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Lateral Surface
The lateral surface of the brain is marked by two principal landmarks that divide
the cerebral hemispheres into lobes (Figure 2-5). The lateral fissure (sylvian
fissure) and the central sulcus (rolandic sulcus) divide the cerebral hemisphere into the
frontal lobe (dorsal to the lateral fissure and rostral to the central sulcus), temporal
lobe (ventral to the lateral fissure), and parietal lobe (dorsal to the lateral fissure and

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caudal to the central sulcus). If a line were drawn from the parieto-occipital sulcus
(best seen on the medial aspect of the hemisphere) onto the lateral aspect of the
hemisphere down to the preoccipital notch, it would delineate the boundaries of the
parietal and temporal lobes rostrally from that of the occipital lobe caudally. The
frontal, temporal, parietal, and occipital lobes are named after the skull bones that
overlie them. Lying deep within the lateral fissure and seen only when the banks of the
fissure are separated is the insula, or island of Reil (Figure 2-6), which is involved
primarily with autonomic function.

A. FRONTAL LOBE
Rostral to the central sulcus, between it and the precentral sulcus, is the precentral
gyrus (primary motor area), which is one of the most important cortical areas involved
with movement (Figure 2-7). Although movement can be elicited by stimulation of a
number of cortical areas, movement developed by stimulation of the precentral gyrus is
achieved at a relatively low threshold of stimulation. Body parts are disproportionately
and somatotopically represented in the primary motor area. The representation of the
face is lower than the upper extremity representation, followed in ascending order by
the trunk and the lower extremity. The leg and foot are represented on the medial
surface of the precentral gyrus. In the face area of the precentral gyrus, the lip
representation is disproportionately large compared with its actual size on the face;
the same applies to the thumb representation in the hand area. This disproportionate
representation of body parts in the primary motor cortex is known as the motor
homunculus.

Stimulation of specific areas of the precentral gyrus results in the movement of a

single muscle or a group of muscles in the contralateral part of the body. Lesions of
the precentral gyrus result in contralateral paralysis (loss of movement). This is most
marked in muscles used for fine motor performance, such as buttoning a shirt or
writing.

Rostral to the precentral sulcus is the premotor area, another important area for
movement. Blood flow studies have shown that this area plays a role in initiating new
programs for movement and introducing changes in programs that are in progress.

Rostral to the premotor area, the frontal lobe is divided by two sulci—the superior and
inferior frontal sulci—into three gyri: the superior, middle, and inferior frontal gyri. The
middle frontal gyrus contains Brodmann's area, which is important for conjugate eye
movements. This area is known as the area of frontal eye fields. The inferior frontal
gyrus is subdivided by two sulci extending from the lateral (sylvian) fissure: the
anterior horizontal and anterior ascending rami. Rostral to the anterior horizontal
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ramus is the orbital gyrus; between the two rami is the triangular gyrus, and caudal to
the anterior ascending ramus is the opercular gyrus. The triangular gyrus and the
immediately adjacent part of the opercular gyrus constitute Broca's area, which in the
dominant (left) hemisphere represents the motor area for speech. Lesions in this area
result in an inability to express oneself in spoken language (aphasia).

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Figure 2-5. Lateral view of the brain showing the four lobes (frontal, parietal,
temporal, occipital) and the cerebellum. (From N. Gluhbegovic and T. H. Williams:
The Human Brain: A Photographic Guide. Harper & Row, 1980, courtesy of the
authors.)

Figure 2-6. Schematic diagram of the brain showing the insula in the depth of the
lateral fissure.

B. PARIETAL LOBE
Caudal to the central sulcus, between it and the postcentral sulcus, is the postcentral
gyrus, a primary sensory (somesthetic) area involved in general body sensation (Figure
2-8). Body representation in the primary sensory area is similar to that described
above for the primary motor area. The disproportionate and somatotopic representation
of body parts in this area is known as the sensory homunculus. Stimulation of this area

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in humans and other primates elicits sensations of tingling and numbness in the part of
the body that corresponds to (and is contralateral to) the area stimulated. A lesion in
this area results in the loss of sensation contralateral to the site of the lesion.

Caudal to the postcentral gyrus, the intraparietal sulcus extends horizontally across the
parietal lobe, dividing it into superior and inferior parietal lobules. The superior
parietal lobule is involved with the behavioral interaction of an individual with the
surrounding space. A lesion in this lobule, especially in the right (nondominant)
hemisphere, results in neglect of body parts contralateral to the lesion. Such
individuals may neglect to shave the face or dress body parts contralateral to the
lesion. The inferior parietal lobule contains two important gyri: the supramarginal and
angular gyri. The supramarginal gyrus caps the end of the
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sylvian fissure, whereas the angular gyrus caps the end of the superior temporal
sulcus. The two gyri are involved in the integration of diverse sensory information for
speech and perception. Lesions in these two gyri in the dominant hemisphere result in
disturbances in language comprehension and object recognition.

Figure 2-7. Lateral view of the brain showing the major sulci and gyri in the
frontal lobe. SFG, superior frontal gyrus; MFG, middle frontal gyrus; IFG, inferior
frontal gyrus; ORB, orbital gyrus; TR, triangular gyrus; OP, opercular gyrus, Pre
CG, precentral gyrus; Pre MA, premotor area. (From N. Gluhbegovic and T. H.
Williams: The Human Brain: A Photographic Guide. Harper & Row, 1980, courtesy
of the authors.)

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Figure 2-8. Lateral view of the brain showing the major sulci and gyri in the
parietal lobe. Post CG, postcentral gyrus; SPL, superior parietal lobule; SMG,
supramarginal gyrus; AG, angular gyrus. (From N. Gluhbegovic and T. H. Williams:
The Human Brain: A Photographic Guide. Harper & Row, 1980, courtesy of the
authors.)

C. TEMPORAL LOBE
Three gyri constitute the lateral surface of the temporal lobe. The superior, middle,
and inferior temporal gyri are separated by the superior and middle sulci (Figure 2-9).
The inferior temporal gyrus extends over the inferior border of the temporal lobe onto
the ventral surface of the brain. The superior temporal gyrus contains on its dorsal
border (the bank of the lateral fissure) the transverse temporal gyri of Heschl (primary
auditory area). Caudal to the transverse gyri of Heschl in the superior temporal gyrus
is Wernicke's area, which is involved in the comprehension of spoken language. The
inferior temporal gyrus is involved with the perception of visual form and color.

D. OCCIPITAL LOBE
On the lateral aspect of the brain the occipital lobe (Figure 2-5) merges with the
parietal and temporal lobes, separated from them by an imaginary line drawn between
the tip of the parieto-occipital fissure and the preoccipital notch. The occipital pole
contains a portion of the primary visual area, which is more extensive on the medial
aspect of the occipital lobe.

Fissures and sulci of the cerebral hemisphere become much more prominent in
degenerative brain disorders such as Alzheimer's disease because of atrophy of the gyri
(Figure 2-10).

Medial Surface
The corpus callosum, in a midsagittal section of the brain, stands out prominently
as a C-shaped massive bundle of fibers (Figure 2-11). The corpus callosum
generally is subdivided into a head (rostrum) at the rostral extremity, a large body
extending across the frontal and parietal lobes, a genu (knee) connecting the rostrum
and the body, and a splenium at the caudal extremity. It consists of fibers that connect

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the two cerebral hemispheres. Behavioral studies have shown that the corpus callosum
plays an important role in the transfer of information between the two hemispheres.
Lesions in the corpus callosum, which disconnect the right hemisphere from the left
hemisphere, result in the isolation of both hemispheres so that each will have its own
learning processes and memories that are inaccessible to the other.

Dorsal to the corpus callosum, separated from it by the pericallosal sulcus, is the
cingulate gyrus, which follows the contours of the corpus callosum and occupies parts
of the frontal and parietal lobes. The cingulate gyrus is part of the limbic system,
which affects visceral function, emotion, and behavior. The cingulate gyrus is
separated from the rest of the frontal and parietal lobes by the cingulate sulcus. Dorsal
to the cingulate gyrus, extensions of the pre- and postcentral gyri onto the medial
aspect of the brain form the paracentral lobule. The motor and sensory representations
of the contralateral lower extremity are thus located in the paracentral lobule. The
precuneus is the part of the parietal lobe that is caudal to the paracentral lobule,
between the marginal and parieto-occipital sulci. The parieto-occipital sulcus is
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well delineated on the medial surface of the brain and defines the boundaries between
the parietal and occipital lobes. Extending at approximately right angles from the
parieto-occipital sulcus in the occipital lobe is the calcarine sulcus, which divides the
occipital lobe into a dorsal cuneus gyrus and a ventral lingual gyrus. The primary visual
area is situated on each bank of the calcarine sulcus. Lesions of the primary visual
area produce a loss of vision in the contralateral half of the visual field, a condition
known as hemianopia.

Figure 2-9. Lateral view of the brain showing the major sulci and gyri in the
temporal lobe. STG, superior temporal gyrus; MTG, middle temporal gyrus; ITG,
inferior temporal gyrus. (From N. Gluhbegovic and T. H. Williams: The Human
Brain: A Photographic Guide. Harper & Row, 1980, courtesy of the authors.)

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Figure 2-10. Lateral view of the brain in Alzheimer's disease showing prominent
sulci and atrophy of gyri. (Courtesy of G. Van Hoesen.)

Figure 2-11. Midsagittal view of the brain showing major sulci and gyri. PCL,
paracentral lobule; Pre Cu G, precuneus gyrus; Cu G, cuneus gyrus; LG, lingual
gyrus; CG, cingulate gyrus; S, splenium of corpus callosum; B, body of corpus
callosum; G, genu of corpus callosum; R, rostrum of corpus callosum; FX, fornix;
TH, thalamus; HT, hypothalamus; A, anterior commissure; SP, septum pellucidum.

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(From N. Gluhbegovic and T. H. Williams: The Human Brain: A Photographic Guide.

Harper & Row, 1980, courtesy of the authors.)

Ventral to the corpus callosum is the septum pellucidum, a thin partition that separates
the two lateral ventricles. At the inferior border of the septum pellucidum is another C-
shaped fiber bundle, the fornix, which connects the temporal lobe (hippocampal
formation) and the diencephalon. Only a small part of the fornix is seen in midsagittal
sections of the brain.

Rostral to the anterior extent of the fornix is a small bundle of fibers, the anterior
commissure, which connects the two temporal lobes and olfactory or smell structures in
both hemispheres. Recent evidence points to a wider distribution of anterior
commissure fibers than was previously believed. The anterior commissure in humans
has been shown to be composed of an anterior limb involved with olfaction and a
posterior limb containing neocortical fibers that connect visual and auditory areas in
the temporal lobes. There is strong support for the idea that the anterior commissure
plays a role in the interhemispheric transfer of visual information.

Extending from the ventral border of the anterior commissure to the ventral border of
the diencephalon is a thin membrane, the lamina terminalis. This lamina marks the
most anterior boundary of the embryologic neural tube.

Behind the rostral extremity of the fornix and extending in an oblique manner caudally
is the hypothalamic sulcus. This sulcus divides the diencephalon into a dorsal thalamus
and a ventral hypothalamus. The midline area between the two thalami and
hypothalami is occupied by the slit-like third ventricle. In some brains the two thalami
are connected across the midline by the interthalamic adhesion (intermediate mass).
The thalamus is the gateway to the cerebral cortex. All sensory inputs except olfaction
pass through the thalamus before reaching the cortex. Similarly, motor inputs to the
cerebral cortex pass through the thalamus. The hypothalamus is a major central
autonomic and endocrine center. It plays a role in activities such as feeding, drinking,
sexual behavior, emotional behavior, and growth.

The dorsal border of the thalamus is the stria medullaris thalami, a thin band which
extends caudally to merge with the habenular nuclei. Above the dorsal and caudal part
of the diencephalon lies the pineal gland, which is assumed to have an endocrine
function. The stria medullaris thalami, habenular nuclei, and pineal gland constitute
the epithalamus.

The continuation of the cingulate gyrus in the temporal lobe (Figure 2-12) is the
parahippocampal gyrus, a component of the limbic lobe. The parahippocampal gyrus is
continuous with the
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uncus (another component of the limbic lobe) in the tip of the temporal lobe. The
collateral sulcus separates the parahippocampal gyrus from the fusiform
(occipitotemporal) gyrus.

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Figure 2-12. Midsagittal view of the brain showing components of the limbic lobe.
CG, cingulate gyrus; CC, corpus callosum; SP, septum pellucidum; SCG,
subcallosal gyrus; PHG, parahippocampal gyrus; U, uncus; FG, fusiform gyrus.
(From N. Gluhbegovic and T. H. Williams: The Human Brain: A Photographic Guide.
Harper & Row, 1980, courtesy of the authors.)

Extending from the diencephalon caudally are the mesencephalon (midbrain), pons,
and medulla oblongata (Figure 2-13). The cerebellum occupies a position between the
occipital lobe, pons, and medulla oblongata (Figure 2-13).

The medial surface of the brain shows the components of the limbic lobe (Figure
2-12), including the subcallosal gyrus, cingulate gyrus, parahippocampal gyrus,
and uncus. The limbic lobe forms the core of the limbic system, which is discussed in
Chapter 21.

Parasagittal sections of the brain (Figure 2-14) show deeper structures that are not
seen in midsagittal sections, such as the basal ganglia (caudate nucleus, putamen,
globus pallidus) and the internal capsule. Lateral extension of the thalamus is also
seen in such sections. The caudate nucleus, putamen, and globus pallidus are known
collectively as the corpus striatum. They are the basal ganglia of the brain and play a
role in the regulation of movement. The caudate nucleus and putamen are collectively
known as the striatum and are separated by the anterior limb of the internal capsule.
The putamen and globus pallidus are collectively known as the lenticular nucleus. Both
nuclei are separated from the thalamus by the posterior limb of the internal capsule.
The internal capsule carries motor and sensory fibers from the cerebral cortex to lower
centers and vice versa. Lesions of the internal capsule result in contralateral motor
deficits (paralysis) and sensory deficits.

Ventral Surface
Portions of the frontal and temporal lobes, the cerebellum, and the brain stem appear
on this surface of the brain (Figure 2-15).

A. FRONTAL LOBE
The ventral surface of the frontal lobe shows a longitudinal sulcus—the olfactory
sulcus—in which the olfactory tract and bulb are located. Medial to the olfactory sulcus
is the gyrus rectus; lateral to the olfactory sulcus is the orbital gyrus. At the caudal
extremity of the olfactory tract is the anterior perforated substance, the site of
perforating blood vessels that pass to deeper regions of the brain.

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B. TEMPORAL LOBE
The ventral surface of the temporal lobe shows the continuation of the inferior
temporal gyrus from the lateral surface. Medial to the inferior temporal gyrus is the
occipitotemporal (fusiform) gyrus. The collateral sulcus separates the occipitotemporal
gyrus from the more medial parahippocampal gyrus and uncus, which constitute parts
of the limbic lobe.

Cerebellum and Brain Stem

The ventral surface of the brain also shows the ventral surfaces of the cerebellum,
pons, medulla oblongata, and diencephalon as well as the cranial nerves and the circle
of Willis (Figures 2-16 and 2-17).

The ventral surface of the cerebellum (Figure 2-16) shows the cerebellar hemispheres,
including the tonsils and flocculus. Tonsillar herniation (herniation of cerebellar tonsils
through the foramen magnum) under a marked increase in intracranial pressure (from
a tumor or intracranial hemorrhage) is a life-threatening condition. The midline
cerebellum (vermis) is made visible when the medulla oblongata is lifted.

Cranial nerves and related structures that usually are visible on the ventral
surface of the brain include the olfactory tract and bulb, the optic chiasm, and the
oculomotor, trigeminal, abducens, facial, and cochleovestibular nerves (Figure 2-17).

Figure 2-13. Midsagittal view of the brain showing components of the brain stem.
(From N. Gluhbegovic and T. H. Williams: The Human Brain: A Photographic Guide.
Harper & Row, 1980, courtesy of the authors.)

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Figure 2-14. Parasagittal section of the brain showing the basal ganglia and
internal capsule.

Figure 2-15. Ventral view of the brain showing major sulci and gyri. (From N.
Gluhbegovic and T. H. Williams: The Human Brain: A Photographic Guide. Harper &
Row, 1980, courtesy of the authors.)

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Figure 2-16. Ventral view of the brain showing the cranial nerves. (From N.
Gluhbegovic and T. H. Williams: The Human Brain: A Photographic Guide. Harper &
Row, 1980, courtesy of the authors.)

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Figure 2-17. Ventral view of the brain showing cranial nerves and the circle of
Willis.

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The olfactory tract is located in the olfactory sulcus on the ventral surface of the
frontal lobe. Tumors in this area may encroach on the olfactory tract and present with
loss of the sense of smell. The optic chiasma is ventral to the diencephalon and rostral
to the infundibular stalk. Lesions in this site that encroach on the optic chiasm present
with loss of vision in the bitemporal visual fields (bitemporal hemi-anopia). The
oculomotor nerve exits on the ventral surface of the brain between the posterior
cerebral and superior cerebellar arteries. Aneurysms (saccular dilatations) of either of
these arteries encroaching on the oculomotor nerve present with oculomotor nerve
palsy (drooping of the eyelid, a dilated pupil that is nonresponsive to light stimulation,
and deviation of the eye down and out). The trigeminal nerve is a robust structure on
the ventrolateral surface of the pons. Two components of the nerve are usually visible:
a larger (portio major) sensory and a smaller (portio minor) motor component. The
abducens nerve is visible in a paramedian position in the groove separating the pons
from the medulla oblongata. The facial and cochleovestibular nerves are visible in the
angle between the cerebellum, pons, and medulla oblongata (cerebellopontine angle).
Tumors arising in this angle (acoustic neuromas) usually present with hearing loss
because of early involvement of the cochleovestibular nerve.

The trochlear nerve is slender and often is lost during the process of brain acquisition
from the skull. The glossopharyngeal, vagus, accessory, and hypoglossal nerves are
composed of a series of slender filaments aligned along the rostrocaudal surface of the
medulla oblongata.

Components of the circle of Willis that usually are visible on the ventral surface of the
brain include the following arteries (Figure 2-17): internal carotid, anterior cerebral,

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anterior communicating, posterior communicating, and posterior cerebral. These

arteries form a circle around the diencephalon. The basilar artery occupies a groove
(basilar groove) on the ventral surface of the pons. The superior cerebellar, anterior
inferior cerebellar, and paramedian arterial branches of the basilar artery usually are
visible. The two vertebral arteries are visible on the ventral surface of the medulla
oblongata. They give rise to the anterior spinal artery, which supplies the paramedian
medulla and spinal cord, and the posterior inferior cerebellar artery (PICA), which has
a characteristic S configuration and supplies the dorsolateral part of the medulla and
the inferior part of the cerebellum.

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INTERNAL TOPOGRAPHY OF THE BRAIN

Internal brain topography is presented here in a few selective coronal and axial
sections. A more complete set of coronal, axial, and sagittal sections is shown in the
Atlas.

Coronal Sections
Four representative rostrocaudal coronal sections are considered.

A. SECTION AT LEVEL OF ANTERIOR LIMB OF INTERNAL

CAPSULE (Figure 2-18)
At this level the anterior limb of the internal capsule separates the caudate nucleus
medially from the putamen laterally. The caudate nucleus shows its characteristic bulge
into the lateral ventricle. This bulge is lost in degenerative diseases of the caudate
nucleus such as Huntington's chorea. The corpus callosum is continuous with the deep
white matter of the cerebral hemispheres. The septum pellucidum is ventral to the
corpus callosum and forms a partition between the two lateral ventricles.

B. SECTION AT LEVEL OF ANTERIOR COMMISSURE (Atlas

Figure 4-5)
At this level the anterior commissure courses ventral to the globus pallidus. Dorsal to
the corpus callosum is the cingulate gyrus. The caudate nucleus is smaller and retains
its characteristic relationship to the lateral ventricle. The putamen is larger and is
lateral to the globus pallidus; the two basal ganglia nuclei are separated from the
thalamus by the posterior limb of the internal capsule. The fornix is seen in two sites:
ventral to the corpus callosum and ventral to the thalamus.

C. SECTION AT LEVEL OF OPTIC TRACT (Figure 2-19)

At this level the optic tracts course in the ventral part of the brain on their way to the
lateral geniculate nucleus of the thalamus. Each optic tract carries fibers from the
ipsilateral and contralateral retinas. The fornix is dorsal and medial to the optic tracts,
separating the hypothalamus into lateral and medial regions. The anterior commissure
is seen beneath the putamen. The thalamus is larger and is clearly divided into medial
and lateral nuclear groups by the internal medullary lamina. The mamillothalamic tract
courses within the thalamus on its way from the mamillary body to the anterior nuclear
group of the thalamus. The posterior limb of the internal capsule separates the
lenticular nucleus (putamen and globus pallidus) from the thalamus. Coursing from the
globus pallidus to the thalamus is a bundle of fibers, the ansa lenticularis. Lateral to
the putamen is the external capsule, one of the efferent (corticofugal) cortical bundles.
Between the external and extreme capsules lies the claustrum.

D. SECTION AT LEVEL OF MAMILLARY BODIES (Atlas Figure

4-9)

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At this caudal diencephalic level the mamillary bodies occupy the ventral surface of the
brain. Emanating from the mamillary bodies are the mamillothalamic tracts on their
way to the anterior nucleus of the thalamus. The thalamus at this level is rather large
and is separated from the putamen and the globus pallidus by the posterior limb of the
internal capsule. Medial to the internal capsule and dorsolateral to the mamillary body
is the subthalamic nucleus, a component of the diencephalon that is involved with
movement. Lesions of the subthalamic nucleus give rise to a characteristic involuntary
movement disorder contralateral to the lesion known as hemiballismus. The caudate
nucleus at this level is small. Between the two diencephalons is the cavity of the third
ventricle. The insula (island of Reil) is seen deep within the lateral (sylvian) fissure.

Axial Sections
A few representative axial sections are considered.

Figure 2-18. Coronal section of the brain at the level of the anterior limb of the
internal capsule.

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Figure 2-19. Coronal section of the brain at the level of the optic tract.

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A. SECTION AT LEVEL OF CORPUS CALLOSUM (Figure 2-20)

At this level the corpus callosum interconnects the two halves of the brain and is
continuous with the white matter core of both hemispheres. The caudate nucleus is
shown bulging into the lateral ventricle. The internal capsule is lateral to the caudate
and continuous with the white matter core of the hemispheres.

B. SECTION AT LEVEL OF THALAMUS AND BASAL GANGLIA

(Figure 2-21)
At this level the frontal, temporal, and occipital lobes are seen. The insula (island of
Reil) is buried deep within the sylvian fissure. The frontal (anterior) horn, body, and
atrium (trigone) of the lateral ventricle are seen. The atrium of the lateral ventricle
contains abundant choroid plexus (glomus). The septum pellucidum separates the two
frontal horns. Ventral to the septum is the fornix. The head of the caudate nucleus is
seen bulging into the frontal horn of the lateral ventricle. The tail of the caudate,
which is much smaller than the head, is seen more caudally overlying the atrium
(trigone). The anterior and posterior limbs of the internal capsule are both seen. The
anterior limb separates the caudate and putamen nuclei, whereas the posterior limb
separates the thalamus and putamen. The rostral part and the caudal part (splenium)
of the corpus callosum are also seen.

C. SECTION AT LEVEL OF ANTERIOR COMMISSURE (Atlas

Figure 3-12)
At this level the anterior commissure is seen rostral to the putamen, the globus
pallidus, and the columns of the fornix. The posterior limb of the internal capsule
separates the thalamus from the globus pallidus. Dorsomedial to the thalamus is the
stria medullaris thalami. The hippocampus is seen as an involution of the
parahippocampal gyrus into the inferior (temporal) horn of the lateral ventricle. The

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fimbria of the fornix, which contains axons of neurons in the hippocampus, is seen
attached to the hippocampus.

D. SECTION AT LEVEL OF BRAIN STEM (Atlas Figure 3-17)

At this level the cerebellum, mesencephalon, mamillary bodies, and optic chiasm are
seen. Rootlets of the oculomotor nerve (cranial nerve III) are seen coursing in the
mesencephalon. The cerebral peduncles, which are continuations of the internal
capsule, are located in the ventral part of the mesencephalon. Dorsal to the cerebral
peduncle is the substantia nigra.

The identification of brain structures in sagittal, axial, and coronal sections assumed
more importance with the introduction of imaging techniques (magnetic resonance
imaging [MRI]) as a diagnostic tool in neurology. In this procedure computerized
images of the brain are taken at a predetermined angle to detect the site and nature of
lesions in the brain. This is a highly specialized technique that requires a thorough
knowledge of the anatomy of the brain in sections. For the purpose of this
presentation, only a few representative MRI images will be described.

The first (Figure 2-22) is a midsagittal section of the brain and brain stem that shows
the medial surfaces of the frontal, parietal, and occipital lobes; the rostrum, genu,
body, and splenium of the corpus callosum; and the lateral and fourth ventricles,
thalamus, mesencephalon, pons, medulla, and cerebellum. Also seen in this section are
the vertebral, basilar, and anterior cerebral arteries; the internal cerebral vein, basal
veins, and great cerebral vein; some of the cerebrospinal fluid cisterns (cisterna magna
and medullary, suprasellar, and quadrigeminal cisterns); and the arachnoid
granulations.

Figure 2-20. Axial section of the brain at the level of the corpus callosum.

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Figure 2-21. Axial section of the brain at the level of the basal ganglia and
thalamus.

Figure 2-22. T2-weighted MRI of the brain in midsagittal cut. In this T2

sequence, cerebrospinal fluid spaces appear white, while brain substance is in

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shades of gray.

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The second (Figure 2-23) is an axial section through the thalamus that shows the
frontal, parietal, and occipital lobes. The third ventricle is in the midline separating the
two thalami. Within the thalamus the mamillothalamic tract is seen in cross section.
The caudate nucleus forms the lateral wall of the anterior horn of the lateral ventricle.
The anterior limb of the internal capsule separates the caudate nucleus and the
putamen. The posterior limb of the internal capsule separates the putamen and the
thalamus. The genu of the internal capsule lies between the anterior and posterior
limbs. The optic radiation is lateral to the atrium (trigone) of the lateral ventricle. The
columns of the fornix are above the third ventricle. In the interhemispheric fissure
rostrally are pericallosal branches of the anterior cerebral artery. The internal cerebral
veins and the straight and superior sagittal sinuses are seen caudally.

The third (Atlas Figure 9-7) image is a coronal section through the thalamus and third
ventricle. The body of the corpus callosum interconnects the two hemispheres. Dorsal
to the corpus callosum are pericallosal branches of the anterior cerebral artery. The
third ventricle separates the two thalami. Dorsal to the third ventricle are the internal
cerebral veins. The body of the caudate nucleus is in the lateral wall of the body of the
lateral ventricle. The insula (island of Reil) is deep within the lateral (sylvian) fissures.
Branches of the middle cerebral artery are within the lateral fissure. The inferior
(temporal) horns of the lateral ventricle are dorsal to the temporal lobe.

A complete set of MRI images in sagittal, axial, and coronal sections is included in the
Atlas.

TERMINOLOGY
Abducens nerve (Latin, “drawing away”).
The sixth cranial nerve, which was discovered by Eustachius in 1564, is so named
because it supplies the lateral rectus eye muscle, which directs the eye to the lateral
side away from the midline.

Accessory nerve.
The eleventh cranial nerve (accessory nerve of Willis) was described by Thomas Willis
in 1664. The name accessory was chosen because this nerve receives an additional
root from the upper part of the spinal cord (C-2–C-3 spinal roots).

Alzheimer's disease.
A degenerative brain disease (formerly known as senile dementia) characterized by
memory loss, cortical
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atrophy, senile plaques, and neurofibrillary tangles. Described by Alois Alzheimer, a
German neuropsychiatrist, in 1907.

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Figure 2-23. T2-weighted axial MRI through the thalamus.

Aneurysm (Greek aneurysma, “widening”).

A sac formed by dilatation of the wall of an artery, a vein, or the heart as a result of
weakening of the wall. The condition was known to Galen.

Aphasia (Greek a, “negative”; phasis, “speech”).

A defect in language communication, loss of speech. The modern knowledge of the
condition dates back to its description by Bouillard in 1825. In 1861 Broca associated
this condition with lesions in the inferior frontal gyrus on the left side of the brain and
called the condition aphemia. The term aphasia was introduced by Armand Trousseau
in 1864.

Arachnoid mater (Greek arachnoeides, “like a cobweb”).

The middle meningeal layer of the brain and spinal cord is so named because of
weblike trabeculae that extend from the arachnoid to the underlying pia mater. The
arachnoid mater was described by Bichat in 1800.

Atrium (Greek atrion, “court” or “hall”).

The atrium was a large area in the center of a Roman house. The term is used in
anatomic nomenclature to refer to a chamber that affords entrance to another
structure. The atrium of the lateral ventricle affords entrance to the occipital and
temporal horns of the lateral ventricle.

Broca's area.
The motor speech area in the inferior frontal gyrus of the left hemisphere. Named after

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Pierre-Paul Broca, a French anthropologist, anatomist, and surgeon who associated

lesions of this area with disturbance of speech function (aphasia) in 1861.

Brodmann's areas.
Fifty-two cortical areas defined on the basis of cytoarchitecture (cellular organization)
by Krobinian Brodmann, a German physician, between 1903 and 1908.

Cuneus (Latin, “wedge”).

The cuneus gyrus is a wedge-shaped lobule on the medial surface of the occipital lobe
between the parieto-occipital and calcarine sulci.

Dura mater (Latin durus, “hard”; mater, “mother”).

The outermost hard meningeal covering of the brain. The term is derived
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from the Arabic umm al-dimagh (“mother of the brain”). Believing that the meninges
were the mother of all membranes, the Arabs called the outermost meningeal layer the
thick mother and the innermost the thin mother. In 1127 Stephen of Antioch translated
these terms into Latin as dura mater and pia mater. Stephen, a monk, chose pia
(pious) rather than tenu to translate the term thin mother. The arachnoid membrane
(middle meningeal layer) was not known to the Arabs.

Facial nerve.
The seventh cranial nerve. Willis divided the seventh nerve into the portio dura (facial)
and the portio mollis (auditory). Soemmering separated the two and numbered them
separately (seventh and eighth cranial nerves).

Falx cerebelli, cerebri (Latin falx, “sickle”).

A sickle-shaped structure. The falx cerebelli and cerebri, dural folds separating the two
cerebellar and cerebral hemispheres, respectively, are sickle-shaped.

Flocculus (Latin, “tuft,” “small tangle of wool”).

A cerebellar lobule that with the nodulus forms the archicerebellum, which is involved
with the maintenance of posture. Flocculus was a vulgar Latin word for pubic hair. Its
use to name a brain structure illustrates the ancient practice of naming parts of the
brain for other parts of the body.

Fornix (Latin, “arch”).

An archlike pathway, below the corpus callosum, connecting mainly the hippocampal
formation and the mamillary body. The fornix was noted by Galen and described by
Vesalius. It was named by Thomas Willis the fornix cerebri.

Fusiform gyrus (Latin fusus, “spindle”; forma, “form”; Greek gyros, “circle”).
The fusiform gyrus of the temporal lobe has a spindlelike shape, tapering from the
middle toward each end. Also called the occipitotemporal gyrus.

Globus pallidus (Latin globus, “sphere” or “ball”; pallidus, “pale”).

The medial part of the lentiform nucleus of the basal ganglia.

Glomus (Latin, “a ball”).

The choroid plexus glomus is a ball-like enlargement of the choroid plexus in the
atrium (trigone) of the lateral ventricle.

Glossopharyngeal nerve (Greek glossa, “tongue”; pharynx, “throat”).

The ninth cranial nerve. Combined by Galen with the sixth nerve. Fallopius
distinguished it as a separate nerve in 1561. Thomas Willis included it as part of the
eighth nerve. Soemmering listed it as the ninth cranial nerve.

Gyrus rectus (Greek gyros, “circle”; Latin rectus, “straight”).

The gyrus rectus lies along the ventromedial margin of the frontal lobe medial to the
olfactory sulcus.

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Habenular nuclei (Latin habena, “a bridle rein or strap”).

The habenular nuclei in the caudal diencephalon near the pineal gland constitute part
of the epithalamus. The name resulted from the fact that early anatomists considered
the pineal gland the abode of the soul, likening it to a driver who directed the
operations of the mind via the habenula or reins.

Hemianopia (Greek hemi, “half”; an, “negative”; ops, “eye”).

Blindness in one-half of the field of vision. The term was introduced by Monoyer.
Hirschberg substituted the term hemianopsia.

Heschl's gyri.
The transverse temporal gyri, site of the primary auditory cortex. Described by Richard
Heschl, an Austrian anatomist, in 1855.

Homunculus (Latin, “a little man”).

A cortical representation of body parts in the motor and sensory cortices.

Huntington's chorea.
A degenerative brain disease caused by abnormal triplet codon repeats at chromosome
4p16.3 inherited in an autosomal dominant pattern. The clinical picture is
characterized by abnormal movements (Greek chorea, “dancing”) and
neuropsychological deficits. Named after George Sumner Huntington, an American
general practitioner who described the disease in 1872.

Hypoglossal nerve (Greek hypo, “beneath”; glossa, “tongue”).

The twelfth cranial nerve was named by Winslow. Willis included it with the ninth
cranial nerve. It was considered the twelfth nerve by Soemmering.

Island of Reil.
The insula of the cerebral cortex. It was noted by Johann Christian Reil, a Danish
physiologist, anatomist, and psychiatrist, in 1796 and described by him in 1809.

Limbic lobe (Latin limbus, “border”).

The limbic lobe is composed of structures on the medial surface of the cerebral
hemisphere bordering the corpus callosum and rostral brain stem.

Lingual (Latin, tongue) gyrus.

A gyrus in the occipital lobe on the medial surface of the hemisphere forming the
inferior lip of the calcarine sulcus.

Mamillary bodies (Latin, diminutive of mamma, “little breast, nipple”).

A pair of small round swellings on the ventral surface of the posterior hypothalamus.

Oculomotor nerve (Latin oculus, “eye”; motor, “mover”).

The third cranial nerve; affects movements of the eye.

Opercular gyrus (Latin operculum, “lid” or “cover”).

The opercular gyrus of the inferior frontal lobe forms a lid or cover over the lateral
(sylvian) fissure.

Optic chiasma (Greek optikos, “of or for sight”; chiasma, “a cross,” from the
letter chi, x).
The site of partial decussation (crossing) of the optic nerves. First described by Rufus
of Ephesus in the first century A.D. For many years it was thought that the chiasm was
responsible for coordinated eye movements.

Orbital gyrus.
Located on the inferior surface of the frontal lobe lateral to the olfactory sulcus.

Pia mater (Latin pia, “tender, soft”; mater, “mother”).

The innermost meningeal layer covering the brain and spinal cord. For further

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discussion of term, see dura mater (p. 42).

Putamen (Latin, “shell,” a cutting or paring, that which falls off in pruning or
trimming).
The outer part of the lentiform nucleus of the basal ganglia.

Rolandic sulcus (central sulcus).

The sulcus that separates the frontal and parietal lobes. Described by Luigi Rolando, an
Italian anatomist, in 1825. Named for Rolando by François Leuret in 1839.

Septum pellucidum (Latin septum, “dividing wall, partition”; pellucidus,

“translucent”).
A thin membrane between the corpus callosum and the fornix, separating the anterior
horns of the lateral ventricle. Described by Galen.

Splenium (Greek splenion, “bandlike structure,” a bandage or compress).

The posterior rounded end of the corpus callosum is so named because it is the thick
and swollen end of the corpus callosum, resembling a compress. Also named because
of its resemblance to the rolled-up leaf of a young fern; splenium was used by the
Romans as the name of a kind of fern.

Sylvian fissure (lateral fissure).

A prominent fissure on the lateral surface of the cerebral hemisphere between the
frontal and parietal lobes above and the temporal lobe below. Described by Francis de
la Boe Sylvius, a French anatomist, in 1641.

Tentorium cerebelli (Latin tentorium, “tent” from tendere, “to stretch,

something stretched out”).
A fold of dura mater stretched over the cerebellum like a tent. The term was adopted
about the end of the eighteenth century.
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Thalamus (Greek thalamos, “inner chamber,” the room occupied in a house by a

married couple).
A mass of gray matter on each side of the third ventricle. The name was coined by
Galen and reaffirmed by Willis in 1664.

Tonsil (Latin tonsilla, a general term for a small rounded mass).

The cerebellar tonsils are rounded masses in the posterior lobe of the cerebellum.
Downward extension of the cerebellar tonsils into the foramen magnum leads to
compression of the medulla oblongata and is life-threatening.

Trigeminal nerve (Latin tres, “three”; geminus, “twin”).

The fifth cranial nerve was described by Fallopius. So named because the nerve has
three divisions: ophthalmic, maxillary, and mandibular.

Trochlear nerve (Latin trochlearis, “resembling a pulley”).

The fourth cranial nerve supplies the superior oblique eye muscle, whose tendon angles
through a ligamentous sling like a pulley. Achillini and Vesalius included this nerve with
the third pair of cranial nerves. It was described as a separate root by Fallopius and
was named the trochlear nerve by William Molins, an English surgeon, in 1670.

Uncus (Latin “hook, hook-shaped structure”).

The medially curved rostral end of the parahippocampal gyrus resembles a hook, hence
the name.

Vagus (Latin vagari, “wanderer”).

The tenth cranial nerve is so named because of its long course and wide distribution.
This nerve was described by Marinus about A.D. 100. The name vagus was coined by
Domenico de Marchetti of Padua.

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Vermis (Latin “worm”).

The vermis of the cerebellum is named for its resemblance to the segmented body of a
worm. Galen was the first to liken it to a worm.

Wernicke's area.
The posterior part of the superior temporal gyrus, which is involved with
comprehension of spoken language. Lesions in this area are associated with receptive
aphasia. Named after Karl Wernicke, a German neuropsychiatrist, who described the
area in 1874.

SUGGESTED READINGS
Bergman RA et al: Atlas of Human Anatomy in Cross Section. Baltimore-Munich,
Urban & Schwarzenberg, 1991.

Gluhbegovic N, Williams TH: The Human Brain: A Photographic Guide. Hagerstown,

Harper & Row, 1980.

Haines DE: Neuroanatomy: An Atlas of Structures, Sections, and Systems.

Baltimore, MD, Urban & Schwarzenberg, 1983.

Jouandet ML, Gazzaniga MS: Cortical field of origin of the anterior commissure of
the rhesus monkey. Exp Neurol 1979; 66:381–397.

Maudgil DD: Changing interpretations of the human cortical pattern. Arch Neurol
1997; 54:769–775.

Naidich TP et al: Anatomic relationships along the low-middle convexity: I. Normal

specimens and magnetic resonance imaging. Neurosurgery 1995; 36:517–532.

Pryse-Phillips W: Companion to Clinical Neurology. Boston, Little, Brown, 1995.

Risse GL et al: The anterior commissure in man: Functional variation in a

multisensory system. Neuropsychologia 1978; 16:23–31.

Roberts M, Hanaway J: Atlas of the Human Brain in Sections. Philadelphia, Lea &
Febiger, 1970.

Shipps FC et al: Atlas of Brain Anatomy for C.T. Scans, 2nd ed. Springfield, IL,
Charles C Thomas, 1977.

Skinner HA: The Origin of Medical Terms, 2nd ed. Baltimore, MD, Williams &
Wilkins, 1961.

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Editors: Afifi, Adel K.; Bergman, Ronald A.

Title: Functional Neuroanatomy: Text and Atlas, 2nd Edition

Copyright ©2005 McGraw-Hill

> Table of Contents > Part I - Text > 3 - Spina l Cord

3
Spinal Cord

External Topography
Dermatomes and Myotomes
Meninges
Cross-Sectional Topography
Microscopic Anatomy
Gray Matter
White Matter
Spinal Cord Neurotransmitters and Neuropeptides
Spinal Reflexes
Micturition Pathway and Bladder Control
Functional Overview of the Spinal Cord
Blood Supply

KEY CONCEPTS

The spinal cord comprises 31 segments defined by 31 pairs of spinal nerves. Each spinal nerve
is formed by union of a dorsal (sensory) and a ventral (motor) root. The first cervical segment has
only a ventral root.

Dermatomes are areas of skin supplied by a single posterior (dorsal) nerve root. “Myotome”
refers to a group of muscles innervated by a single spinal cord segment.

The internal structure of the spinal cord consists of central, H-shaped, gray matter and
surrounding white matter. The former contains neurons, and the latter contains ascending and
descending fiber tracts.

Autonomic sympathetic neurons are located in thoracic and upper lumbar spinal cord segments,
whereas autonomic parasympathetic neurons are located in sacral spinal cord segments.

Alpha motor neurons in the ventral horn are somatotopically organized.

Posterior funiculus tracts convey conscious proprioceptive sensory modalities, especially those
actively explored by the individual perceived at cortical level.

Pain and thermal sensations are conveyed by the lateral and anterior spinothalamic tracts.

Corticospinal tracts are essential for skilled and precise movements.

Autonomic innervation of the urinary bladder is related to specific nerve cells in the lower
thoracic, upper lumbar, and midsacral region of the spinal cord. Somatic innervation of the urinary
bladder originates in the nucleus of Onufrowicz in the ventral horn of midsacral spinal cord
segments. Segmental control of bladder function is modified by suprasegmental influences in the
pons, midbrain, hypothalamus, and cerebral cortex.

The blood supply of spinal cord is provided by anterior and posterior spinal arteries derived
from vertebral and segmental (radicular) arteries. Some spinal cord segments are particularly
susceptible to reduction in blood supply.

EXTERNAL TOPOGRAPHY
The spinal cord of adult humans extends from the foramen magnum to the level of the first or second lumbar
vertebra. Approximately 45 cm long in males and 42 cm in females, it has a cylindrical shape in the upper
cervical and thoracic segments and an oval shape in the lower cervical and lumbar segments, which are sites

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of the brachial and lumbosacral nerve plexuses, respectively. In the early stages of fetal development, the
cord occupies the whole length of the vertebral canal; in the term newborn,
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it extends down to the lower border of the third lumbar vertebra; in late adolescence, the spinal cord attains
its adult position, terminating at the level of the intervertebral disk between the L-1 and L-2 vertebrae
(Figure 3-1). The level at which the cord terminates changes with development because the vertebral column
grows faster than the spinal cord. The length of the entire adult vertebral column is 70 cm. The spinal cord
exhibits two enlargements: cervical (third cervical to second thoracic segments) and lumbar (first lumbar to
third sacral segments). These are sites of neurons that innervate the upper and lower extremities,
respectively. The caudal end of the cord is tapered to form the conus medullaris, from which a pial-glial
filament, the filum terminale, extends and attaches to the coccyx to anchor the spinal cord. The spinal cord
is also anchored to the dura by two lateral series of denticulate ligaments, pial folds that stretch from the
surface of the cord to the dural sheath midway between the dorsal and ventral roots. Denticulate ligaments
serve as useful landmarks for the neurosurgeon in identifying the anterolateral segment of the cord when
performing operations such as cor-dotomies for the relief of intractable pain. There are 20 or 21 pairs of
denticulate ligaments extending between the first lumbar and first cervical vertebrae.

Figure 3-1. Schematic diagram showing the relationships of spinal cord segments and spinal nerves to
vertebral column levels.

The human spinal cord comprises 31 segments (8 cervical, 12 thoracic or dorsal, 5 lumbar, 5 sacral,
and 1 coccygeal), each of which, except the first cervical segment, has a pair of dorsal and ventral
roots and a pair of spinal nerves. The first cervical segment has only a ventral root. The dorsal and ventral
roots join in the intervertebral foramina to form the spinal nerves. Just proximal to its junction with the
ventral root in the intervertebral foramen, each dorsal root has an oval swelling: the dorsal root (spinal)
ganglion containing pseudounipolar sensory neurons. At the point where the dorsal nerve root enters the
spinal cord, glial supporting tissue from the spinal cord extends a short distance into the nerve root to meet
the Schwann cell and the collagenous supporting tissue of the peripheral nervous system. The junction zone
between the two types of tissues is quite sharp histologically. It is called the Obersteiner-Redlich space after
two Austrian neurologists, Heinrich Obersteiner and Emil Redlich. The 31 pairs of spinal nerves are divided
into 8 cervical nerves, 12 thoracic nerves, 5 lumbar nerves, 5 sacral nerves, and 1 coccygeal nerve (Figure
3-1). The fourth and fifth sacral nerves and the coccygeal nerve arise from the conus medullaris. Spinal
nerves leave the vertebral canal through the intervertebral foramina. The first cervical nerve emerges above
the atlas; the eighth cervical nerve emerges between the seventh cervical (C-7) and the first thoracic (T-1)

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vertebrae. All other spinal nerves exit beneath the corresponding vertebrae (Figure 3-1).

Because of the differential rate of growth of the spinal cord and vertebral column, spinal cord segment levels
do not correspond to those of the vertebral column (Table 3-1). Thus, in the cervical region, the tip of the
vertebral spine corresponds to the level of the succeeding cord segment; that is, the sixth cervical spine
corresponds to the level of the seventh spinal cord segment. In the upper thoracic region, the tip of the
spine is two segments above the corresponding cord segment; that is, the fourth thoracic spine corresponds
to the sixth cord segment. In the lower thoracic and upper lumbar regions, the difference between the
vertebral and cord level is three segments; that is, the tenth thoracic spine corresponds to the first lumbar
cord segment. Because of this, the root filaments of spinal cord segments have to travel progressively longer
distances from cervical to sacral segments to reach the corresponding intervertebral foramina from which the
spinal nerves emerge (Figure 3-1). The crowding of lumbosacral roots around the filum terminale is known
as the cauda equina.

Table 3-1. Relationship of Spinal Cord Segments and Vertebral Spines.

Cord segments Vertebral spines

C-1 C-1

C-7 C-6

T-6 T-4

L-1 T-10

S-1 T-12 to L-1

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DERMATOMES AND MYOTOMES

The area of skin supplied by a single posterior (dorsal) nerve root constitutes a dermatome. Familiarity
with dermatomal maps (Figure 3-2) is essential for localization of the level of lesion in the spinal cord.
Few dermatomes are particularly useful in localization of lesion (Table 3-2). A viral disorder that
characteristically presents with dermatomal distri-bution of pain and vesicular lesions is herpes zoster
(shingles). Groups of muscles innervated from a single spinal cord segment constitute a myotome.
Familiarity with clinically relevant myo-tomes is useful in localization of the level of lesion in the spinal cord
(Table 3-3).

MENINGES
The spinal cord is covered by three meningeal coats; these are the pia, arachnoid, and dura mater. The pia
mater is composed of an inner membranous layer, the intima pia, and an outer superficial layer, the epipia.
The intima pia is intimately adherent to the surface of the spinal cord. The epipia carries blood vessels that
supply and drain the spinal cord. It also forms the denticulate ligaments. The arachnoid is closely adherent
to the dura mater. The space between the dura and arachnoid (subdural space) is a very narrow (potential)
space visible with the aid of a microscope in histologic preparations in normal conditions. Bridging veins
course across this space. Rupture of these veins results in accumulation of blood and expansion of this
space, a condition known as subdural hematoma. The space between the arachnoid and pia (subarachnoid
space), in contrast, is wider and contains the cerebrospinal fluid. The spinal dura mater, unlike the dura
within the skull, is firmly attached to bone only at the margin of the foramen magnum. Elsewhere, the spinal
dura is separated from the vertebral periosteum by the epidural space. The spinal epidural space contains
adipose tissue and a venous plexus and is largest at the level of the second lumbar vertebra. The spinal
epidural space is used for injection of local anesthetics to produce paravertebral nerve block known as
epidural anesthesia for relief of pain during obstetrical delivery. The epidural space is also used to inject
drugs (e.g., cortisone) to relieve back pain. The spinal dura mater ensheathes the dorsal and ventral roots,
the dorsal root ganglia, and proximal portions of spinal nerves, and then it becomes continuous with the
epineurium of spinal nerves at the level of the intervertebral foramen. The spinal cord terminates at the
level of the L-1 and L-2 vertebrae, whereas the dura mater extends down to the level of the S-1 and S-2
vertebrae. Below the site of spinal cord termination (conus medullaris), a sac filled with cerebrospinal fluid
and devoid of spinal cord forms in the subarachnoid space. This sac is a favorable site for clinicians to
introduce a special spinal needle to obtain cerebrospinal fluid for examination or to inject drugs or dyes into
the subarachnoid space for purposes of treatment or diagnosis. This procedure is called lumbar puncture or
spinal tap.

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Figure 3-2. Dermatomal map showing body landmarks and corresponding spinal cord segments.

Table 3-2. Body Landmarks and Corresponding Dermatomes.

Body landmark Dermatome

Back of head C-2

Shoulder C-4

Thumb C-6

Middle finger C-7

Small finger C-8

Nipple T-4, T-5

Umbilicus T-10

Inguinal region L-1

Big toe L-4, L-5

Small toe S-1

Genitalia and perianal region S-4, S-5

CROSS-SECTIONAL TOPOGRAPHY
In cross section, the spinal cord is composed of a centrally placed butterfly- or H-shaped area of gray

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matter surrounded by white matter. The two wings of the butterfly are connected across the midline by the
dorsal and ventral
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gray commissures above and below the central canal, respectively (Figure 3-3). The gray matter of the cord
contains primarily the cell bodies of neurons and glia. The white matter of the cord contains primarily fiber
tracts.

Table 3-3. Clinically Relevant Myotomes.

Myotome Spinal cord segment

Deltoid C-5

Biceps C-6

Triceps C-7

Hypothenar muscle T-1

Quadriceps femoris L-4

Extensor hallucis L-5

Gastrocnemius S-1

Rectal sphincter S-3, S-4

The two halves of the spinal cord are separated by the dorsal (posterior) median septum and the ventral
(anterior) median fissure (Figure 3-3). The site of entrance of dorsal root fibers is marked by the
dorsolateral (posterolateral) sulcus; similarly, the site of exit of ventral roots is marked by the ventrolateral
(anterolateral) sulcus (Figure 3-3). These landmarks divide the white matter of each half of the cord into a
dorsal (posterior) funiculus, a lateral funiculus, and a ventral (anterior) funiculus (Figure 3-3). Furthermore,
in cervical and upper thoracic spinal cord segments, the dorsal (posterior) funiculus is divided into two
unequal parts by the dorsal (posterior) intermediate septum (Figure 3-3).

The H-shaped gray matter is also divided into a smaller dorsal (posterior) horn or column and a larger
ventral (anterior) horn or column. The thoracic and upper lumbar cord segments, in addition, exhibit a
wedge-shaped intermediolateral horn or column (Figure 3-3).

The spinal cord is asymmetric in about 75 percent of humans, with the right side being larger in 75 percent
of the asymmetries. The asymmetry is due to more descending corticospinal tract fibers on the larger side. It
has been shown that more fibers in the left medullary pyramid cross to reach the right half of the spinal cord
and more fibers from the right medullary pyramid remain uncrossed to descend in the right half of the spinal
cord. These two occurrences result in a larger complement of corticospinal fibers in the right half of the
cord. In essence, then, the right side of the spinal cord receives more fibers from the cortex than the left
side. This has no relation to handedness. The amount of uncrossed fibers may be related to the occurrence
of the ipsilateral hemiplegia (weakness) reported in patients with lesions in the internal capsule. If most
fibers do not cross, then the hemiplegia will be mostly ipsilateral.

MICROSCOPIC ANATOMY
The microscopic anatomy of the spinal cord varies in the different regions of the cord. The characteristics of
microscopic anatomy in the different regions help define the level of section (Figure 3-4). As one ascends
from low sacral segments to high cervical segments, the volume of white matter increases progressively
because the number of nerve fibers, both ascending to higher levels and descending to lower levels, is larger
in the high cervical sections and diminishes progressively at more caudal
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levels. Some tracts are not present at certain levels. The dorsal spinocerebellar tract appears first at the
second lumbar segment and is not present below this segment. This is because neurons that give rise to this
tract first appear at the level of L-2 and are not present below this level. The cuneate tract (fasciculus)
appears above the sixth thoracic spinal cord segment and is not pres-ent below this level. It follows that the
dorsal (posterior) intermediate sulcus, which separates the gracile and cuneate tracts, is only present above
the T-6 segment. Different spinal cord regions also demonstrate distinctive gray matter features. The

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intermedio-lateral cell column and the nucleus dorsalis of Clarke extend between the C-8 and L-2 segments
and are not seen either below or above these levels. The cervical and lumbar enlargements of the cord are
characterized by voluminous ventral horns because of the presence of motor neurons that supply limb
musculature at these two levels.

Figure 3-3. Photomicrograph of spinal cord showing division into gray and white matter, the sulci and
fissures, gray matter columns, and white matter funiculi.

Figure 3-4. Schematic diagram showing variations in spinal cord segments at different levels.

Gray Matter
A. OLDER TERMINOLOGY

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Prior to 1952, the organization of the gray matter of the spinal cord was presented in the following way.

z Dorsal horn The dorsal (posterior) horn or column receives axons of the dorsal root ganglia via the
dorsal roots and contains cell clusters concerned with sensory function. These cell clusters are the
posteromarginal nucleus, the substantia gelatinosa, and the nucleus proprius.

z Intermediolateral horn The intermediolateral horn or column is limited to the thoracic and upper lumbar
segments of the cord.

It contains preganglionic neurons of the sympathetic nervous system, the axons of which form the
preganglionic nerve fibers and leave the spinal cord via the ventral root. Although no distinct
intermediolateral horn is present in the sacral spinal cord, a dorsal outpouching of the ventral horn in
S-2 to S-4 spinal cord segments contains preganglionic parasympathetic neurons.

z Ventral horn The ventral horn or column contains multipolar motor neurons, axons of which constitute
the major component of the ventral root.

z Intermediate zone This zone contains the nucleus dorsalis of Clarke and a large number of
interneurons.

The preceding organizational pattern is illustrated diagrammatically in Figure 3-5.

B. REXED TERMINOLOGY
In 1952, Rexed investigated the cytoarchitectonics, or cellular organization, of the spinal cord in the cat and
found that cell clusters in the cord are arranged with extraordinary regularity into ten zones or laminae. His
observations subsequently have been confirmed in other species, including humans. Figure 3-6 is a
diagrammatic representation of the location of the ten laminae of Rexed. Table 3-4 compares the older
terminology with the more recent Rexed terminology.

Laminae I to IV are concerned with exteroceptive sensations, whereas laminae V and VI are concerned
primarily with proprioceptive sensations, although they respond to cutaneous stimuli. Lamina VII acts as a
relay between midbrain and cerebellum. Lamina VIII modulates motor activity, most probably via gamma
neurons. Lamina IX is the main motor area of the spinal cord. It contains large alpha and smaller gamma
motor neurons arranged in columns (dorsolateral, ventrolateral, ventromedial, and central). The axons of
these neurons supply extrafusal and intrafusal muscle fibers, respectively. Alpha motor neurons in lamina IX
of cord segments C-3 to C-5 constitute the phrenic nucleus. Axons of those neurons innervate the diaphragm
and thus are essential for breathing. From segments S-1, S-2 to S-4, a supplementary
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column of alpha motor neurons appears in lamina IX. This is the Onuf's (Onufrowicz) nucleus, which lies at
the most ventral border of the ventral horn. The nucleus is divided into a dorsomedial cell group innervating
the bulbocavernosus and ischiocavernosus muscles and a ventrolateral cell group innervating external anal
and urethral sphincters. The dorsomedial portion of Onuf's nucleus contains significantly more neurons in
males than in females. Motor neurons in Onuf's nucleus are characteristically spared in motor neuron disease
(amyotrophic lateral sclerosis), in marked contrast to motor neurons elsewhere in the spinal cord and brain
stem.

Figure 3-5. Cross-sectional diagram of the spinal cord showing the major nuclear groups within the
gray columns.

Alpha motor neurons in lamina IX are somatotopically organized in such a way that neurons supplying
flexor muscle groups are located dorsally, whereas neurons supplying extensor muscle groups are
located ventrally. In addition, neurons supplying trunk musculature are placed medially whereas neurons
supplying extremity musculature are placed laterally (Figure 3-7). Motor neurons in lamina IX receive direct
input from dorsal roots (for spinal reflexes) as well as from descending pathways concerned with motor

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control.

Physiologic studies have demonstrated two types of alpha motor neurons, tonic and phasic. Tonic neurons
are characterized by a lower rate of impulse firing and slower axonal conduction. They innervate the slow
muscle fibers. Phasic neurons exhibit fast axonal conduction and innervate the fast muscle fibers. No
anatomic criteria are available to distinguish tonic from phasic alpha motor neurons.

Figure 3-6. Schematic diagram of half of the spinal cord showing the location of Rexed laminae.

Physiologic studies also have demonstrated two types of gamma motor neurons, static and dynamic. The
static variety is related to the nuclear chain type of intrafusal muscle fiber, which is concerned with the
static response of the muscle spindle, whereas the dynamic variety is related to the nuclear bag type of
intrafusal muscle fiber, which is concerned with the dynamic response of the spindle. As is the case with
alpha motor neurons, no anatomic criteria are available to differentiate static from dynamic gamma motor
neurons.

In addition to alpha and gamma motor neurons, lamina IX contains interneurons. One of these interneurons,
the Renshaw cell, has received particular attention from neuroscientists. The Renshaw cell is interposed
between the recurrent axon collateral of an alpha motor neuron and the dendrite or cell body of the same
alpha motor neuron. The axon collateral of the alpha motor neuron excites the Renshaw cell. The axon of the
Renshaw cell inhibits (recurrent inhibition) the parent alpha motor neuron and other motor neurons. Through
this feedback loop, an alpha motor neuron may influence its own activity. Recent studies have shown that
Renshaw cell axons project to nearby as well as distant sites, including laminae IX, VIII, and VII. The
functional consequences of Renshaw cell inhibition are to curtail the motor output from a particular collection
of motor neurons and to highlight the output of motor neurons that are strongly activated. The inhibitory
neurotransmitter used by the Renshaw cells is probably glycine.

Table 3-4. Cellular Organization of Spinal Cord.

Rexed terminology Older terminology

Lamina I Posteromarginal nucleus

Lamina II Substantia gelatinosa

Laminae III, IV Nucleus proprius

Lamina V Neck of posterior horn

Lamina VI Base of posterior horn

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Lamina VII Intermediate zone, intermediolateral horn

Lamina VIII Commissural nucleus

Lamina IX Ventral horn

Lamina X Grisea centralis

Figure 3-7. Schematic diagram of the spinal cord showing somatotopic organization of ventral horn
(lamina IX) motor neurons.

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Quantitative studies of the dendritic organization of spinal motor neurons have shown that dendrites form
approximately 80 percent of the receptive area of a neuron. Although dendrites extend up to 1000 µm from
the cell body, the proximal third of each dendrite contains most of the synapses and thus is the most
effective in the reception and subsequent transmission of incoming stimuli. Lamina X surrounds the central
canal and contains neuroglia.

Neurons in the gray matter of the spinal cord are of two types, principal neurons and interneurons. The
former have been classified into two general categories on the basis of their axonal course. Tract
(projection) neurons have axons that contribute to the formation of a tract. Examples of such neurons
include the dorsal nucleus of Clarke, which gives rise to the dorsal spinocerebellar tract, and neurons in the
dorsal (posterior) horn that give rise to the spinothalamic tract. In contrast, root neurons have axons that
contribute to the formation of the ventral root. Examples of such neurons include alpha and gamma motor
neurons in the ventral (anterior) horn and the autonomic (sympathetic and parasympathetic) neurons in the
intermediolateral horn and S-2 to S-4 spinal cord segments, respectively.

White Matter
The white matter of the spinal cord is organized into three funic-uli (Figure 3-3):

1. Posterior (dorsal) funiculus

2. Lateral funiculus

3. Anterior (ventral) funiculus

Each of these funiculi contains one or more tracts or fasciculi (Tables 3-5 and 3-6). A tract is composed of
nerve fibers sharing a common origin, destination, and function. In general, the name of a tract denotes its
origin and destination; for example, the spino-cerebellar tract connects the spinal cord and cerebellum and
the corticospinal tract connects the cerebral cortex and spinal cord.

A. POSTERIOR FUNICULUS

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Nerve fibers in this funiculus are concerned with two general modalities related to conscious
proprioception. These are kinesthesia (sense of position and movement) and discriminative touch
(precise localization of touch, including two-point discrimination).

Lesions of this funiculus therefore will be manifested clinically as loss or diminution of the following
sensations:

1. Vibration sense

2. Position sense

3. Two-point discrimination

4. Touch

5. Form recognition

Table 3-5. Spinal Cord Ascending Tracts.

Tract name Origin Location Extent Termination Function

Gracile Ipsilateral Medial in Throughout Ipsilateral Conscious

dorsal root posterior spinal cord gracile nucleus proprioception
ganglion funiculus in medulla

Cuneate Ipsilateral Lateral in Above sixth Ipsilateral Conscious

dorsal root posterior thoracic cuneate proprioception
ganglion funiculus segment nucleus in
medulla

Dorsal spino- Ipsilateral Lateral Above Ipsilateral Unconscious

cerebellar nucleus funiculus second cerebellum proprioception
dorsalis of lumbar
Clarke segment

Ventral spino- Contralateral Lateral Throughout Contralateral Unconscious

cerebellar dorsal horn funiculus spinal cord cerebellum proprioception

Spinocervical Ipsilateral Lateral Throughout Ipsilateral Conscious

thalamic dorsal root funiculus spinal cord lateral cervical proprioception
(Morin's) ganglion nucleus

Lateral spino- Contralateral Lateral Throughout Ipsilateral Pain and

thalamic dorsal horn funiculus spinal cord thalamus thermal
(ventral sensations
posterolateral
nucleus)

Anterior Contralateral Lateral Throughout Ipsilateral Light touch

spinothalamic (largely) and spinal cord thalamus
dorsal horn anterior (ventral
funiculi posterolateral
nucleus)

Table 3-6. Spinal Cord Descending Tracts

Tract name Origin Location Extent Termination Function

Lateral Contralateral Lateral Throughout Ipsilateral Control of

corticospinal cerebral funiculus spinal cord ventral and skilled

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cortex dorsal horns movement,

modulation
of sensory
activity

Anterior Ipsilateral Anterior Variable Contralateral Control of

cortico-spinal cerebral funiculus ventral and skilled
(bundle of cortex dorsal horns movement,
Türck) (largely) modulation
of sensory
activity

Tract of Ipsilateral Lateral Throughout Ipsilateral Control of

Barnes cerebral funiculus spinal cord ventral and skilled
cortex dorsal horns movement,
modulation
of sensory
activity

Rubrospinal Contralateral Lateral Throughout Ipsilateral Control of

red nucleus funiculus spinal cord ventral horn movement
(midbrain)

Lateral Ipsilateral Lateral Throughout Ipsilateral Control of

vestibulo- lateral funiculus spinal cord ventral horn muscles that
spinal vestibular maintain
nucleus upright
posture and
balance

Medial Ipsi- and Anterior Cervical Ipsilateral Head

vestibulo- contralateral funiculus spinal cord ventral horn position in
spinal medial association
vestibular with
nuclei vestibular
stimulation

Reticulospinal Medullary and Lateral and Throughout Ipsilateral Control of

pontine anterior spinal cord ventral horn movement
reticular funiculi and inter- and posture,
formation, mediate zone modulation
bilaterally of sensory
activity

Tectospinal Contralateral Anterior Cervical Ipsilateral Head

superior funiculus spinal cord ventral horn position in
colliculus association
(midbrain) with eye
movement

Descending Ipsilateral Anterolateral Throughout Ipsilateral Control of

autonomic hypothalamus funiculus spinal cord intermedio- smooth
lateral cell muscles and
column and glands
sacral pre-
ganglionic
cell group

Monoaminergic Raphe Lateral and Throughout Ipsilateral Control of

nucleus, locus anterior spinal cord dorsal horn pain

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ceruleus, funiculi transmission

periaqueductal
gray

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The presence or absence of these different sensations is tested by the neurologist as follows:

1. Vibration is tested by placing a vibrating tuning fork over a bony prominence.

2. Position sense is tested by moving the tip of the patient's finger or toe dorsally and ventrally and
asking the patient (with eyes closed) to identify the position of the part moved.

3. Two-point discrimination is tested by simultaneously pricking or touching the patient in two adjacent
areas of skin. Under normal conditions, a person is able to recognize these two simultaneous stimuli as
separate stimuli if the distance between them is not less than 5 mm on the fingertips using pins and
not less than 10 cm on the shin using fingertips.

4. Touch is tested by placing a cotton ball gently over the skin.

5. Form recognition is tested by asking the patient to identify an object placed in the hand (with eyes
closed) based on weight, size, form, and texture perception.

The nerve fibers that contribute to the posterior funiculus have their cell bodies in the dorsal root ganglia.

Peripheral receptors contributing to this system are (1) cutaneous mechanoreceptors (hair follicle and touch
pressure receptors) that convey the sensations of touch, vibration, hair movement, and pressure and (2)
proprioceptive receptors (muscle spindle, Golgi tendon organ, and joint receptors). Muscle receptors (muscle
spindles and Golgi tendon organs) are the primary receptors conveying position sense. Joint receptors may
be concerned with signaling joint movement but not joint position.

Nerve fibers of the posterior funiculus are thickly myelinated and occupy the dorsolateral part of the dorsal
root. Those that enter the spinal cord below the sixth thoracic segment are located medially in the posterior
funiculus and form the gracile tract (tract of Goll). Fibers that enter the spinal cord above the sixth thoracic
segment are located more laterally and form the cuneate tract (Burdach column). Thus the nerve fibers in
the posterior funiculus are laminated or layered in such a way that those arising from the
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sacral region are most medial, whereas those from the cervical region are most lateral (Figure 3-8). It
should be pointed out that the lamination in the posterior funiculus is both segmental (sacral, lumbar,
thoracic, cervical) and modality oriented. Physiologic studies have shown that fibers conducting impulses
from hair receptors are superficial and are followed by fibers mediating tactile and vibratory sensations in
successively deeper layers.

The fibers forming the posterior funiculus ascend throughout the spinal cord and synapse on the posterior
(dorsal) column nuclei (nucleus gracilis and nucleus cuneatus) in the medulla oblongata. Axons of these
nuclei then cross in the midline to form the medial lemniscus, which ascends to the thalamus (ventral
posterolateral nucleus) and from there to the primary sensory (somesthetic) cortex (Figure 3-9).

Approximately 85 percent of ascending fibers in the posterior funiculus are primary afferents. These have
cell bodies in the dorsal root ganglia and are activated by stimulation of mechanoreceptors (unimodal
afferents). Approximately 15 percent of fibers in the posterior funiculus are nonprimary afferents. These
have cell bodies in the dorsal root ganglion, establish synapses in laminae III to V in the posterior (dorsal)
horns of the cervical and lumbar enlargements, and are activated by stimulation of both mechanoreceptors
and nociceptors (polymodal afferents).

Some of the fibers in the posterior funiculus send collateral branches that terminate on neurons in the
posterior horn gray matter. Such collaterals give the posterior funiculus a role in modifying sensory activity
in the posterior horn. As discussed later, this role is inhibitory to pain impulses.

Lesions in the posterior funiculus decrease the threshold to painful stimuli and augment all forms of
sensations conveyed by the spinothalamic (pain) pathways. Thus nonpainful stimuli become painful, and
painful stimuli are triggered by lower stimulation thresholds.

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Stimulation of the posterior funiculus has been used in the treatment of chronic pain. In one large study, 47
percent of treated patients responded initially to this stimulation, but the percentage dropped to 8 percent
after 3 years. None of the patients studied had complete relief from pain.

Reports in the literature describe lesions in the posterior funiculus in humans and animals without
concomitant deficit in the sensory modalities presumably carried by this system. This is explained by the
presence of another system, the spinocervical thalamic, located in the lateral funiculus, which may
compensate for some posterior funiculus deficits.

The role of the dorsal (posterior) column system in sensory transmission and appreciation has been studied
extensively in both humans and experimental animals (Table 3-7). Sensory stimuli conducted via the
posterior column are generally of three types: (1) those that are impressed passively on the organism, (2)
those that have temporal or sequential factors added to a spatial cue, and (3) those that cannot be
recognized without manipulation and active exploration by the digits. The first type, stimuli that are
impressed passively on the organism (e.g., vibrating tuning fork, two-point discrimination, touch with a
piece of cotton), are transmitted by the dorsal column. However, much the same information is transmitted
by a number of parallel pathways such as the spinocervical thalamic tract. Thus such passive types of
sensations remain intact in the absence of the dorsal column. The second type, stimuli with temporal or
sequential factors added to a spatial cue (e.g., determination of the direction of lines that are drawn on the
skin), are detected by the dorsal column. The dorsal column has the inherent function of transmission to
higher central nervous system centers information concerning the changes in a peripheral stimulus over a
period of time. The third type, stimuli that cannot be recognized without manipulation and active exploration
by the digits (e.g., detection of shapes and patterns), are appreciated only by the dorsal column.

In addition to its role in sensory transmission, the dorsal column has a role in certain types of motor control.
Many movements involving the extremities depend on sensory information that is fed back to the brain from
peripheral sensory organs such as muscle spindles, joint receptors, and cutaneous receptors. Many of these
feedback inputs travel via the dorsal column. The dorsal column transmits to the motor cortex of the brain
(via the thalamus) information necessary to plan, initiate, program, and monitor tasks that involve
manipulative movements by the digits. The thalamic nucleus (ventral posterolateral) that receives input from
the dorsal column system has been shown to project not only to the primary somesthetic (postcentral gyrus)
sensory cortex but also to the primary motor cortex in the precentral
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gyrus. In addition, the primary sensory cortex projects to the primary motor cortex.

Figure 3-8. Schematic diagram of the spinal cord showing spatial arrangement of fibers in the posterior
funiculus.

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Figure 3-9. Schematic diagram of the posterior column pathway.

A frequently reported observation in lesions of the posterior column is the discrepancy in loss of vibration
and position sense. A possible explanation for this differential loss is that different pathways are used for
transmission of the two modalities. In experimental animals it has been shown that cutaneous
mechanoreceptors in forelimbs and hindlimbs (conveying touch, vibration, hair movement, and pressure)
transmit their impulses via the dorsal columns (cuneate and gracile tracts, respectively) and the spino-
cervical thalamic tract (Figure 3-10). In contrast, proprioceptive sensations (from muscle spindle and Golgi
tendon organ [position sense] and joint receptors) from the forelimbs utilize the dorsal column (cuneate
tract), while those from the hindlimb travel with the gracile tract to the level of the dorsal nucleus of Clarke.
From there they leave the gracile tract, synapse in the nucleus dorsalis of Clarke, and travel with the dorsal
spinocerebellar fibers to terminate on the nucleus of Z (of Brodal and Pompeiano), a small collection of cells
in the most rostral part of nucleus gracilis in the medulla. From there the fibers join the medial lemniscus to
reach the thalamus (Figure 3-10).

Table 3-7. Dorsal Column System Function.

Dorsal
column

Type of stimulus Transmits Essential

for

Passively impressed (vibration, two-point discrimination, touch) Yes No

Temporal or sequential (direction of line drawn on skin) Yes Yes

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Actively explored and manipulated (detection of shapes and Yes Yes

patterns)

B. LATERAL AND ANTERIOR FUNICULI

Whereas the posterior funiculus (Table 3-5) contains only one ascending tract or fiber system (the posterior
column system), the lateral and anterior funiculi contain several ascending and descending tracts (Tables 3-5
and 3-6). Only those tracts with established functional or clinical relevance will be discussed.

C. ASCENDING TRACTS
All the following tracts have their cells of origin in dorsal root ganglia (Table 3-5).

1. Dorsal Spinocerebellar Tract.

This ascending fiber system conveys to the cerebellum proprioceptive impulses from receptors located in
muscles, tendons, and joints. The impulses arising in muscle spindles travel via Ia and II nerve fibers,
whereas those arising in Golgi tendon organs travel via Ib nerve fibers. Central processes of neurons in
dorsal root ganglia enter the spinal cord via the dorsal root and either ascend or descend in the posterior
funiculus for a few segments before reaching the spinal nucleus, or they may reach the nucleus directly.
Nerve cells, the axons of which form this tract, are located in the nucleus dorsalis of Clarke (also known as
Clarke's column, nucleus thoracicus, thoracic nucleus, Stilling column, or Stilling nucleus) within lamina VII
of Rexed (see Figure 3-12). This nucleus is not found throughout the extent of the spinal cord but is limited
to the spinal cord segments between the eighth cervical (C-8) and second lumbar (L-2). Because of this, the
dorsal spinocerebellar tract is not seen below the second lumbar segment. Nerve fibers belonging to this
system and entering below L-2 ascend to the L-2 level, where they synapse with cells located in the nucleus.
Similarly, nerve fibers entering above the upper limit of the nucleus ascend in the cuneate tract to reach the
accessory cuneate nucleus in the medulla oblongata, which is homologous to the nucleus dorsalis (Figure 3-
11). Fibers in this tract are segmentally laminated in such a way that fibers from lower limbs are placed
superficially. The fibers in this tract reach the cerebellum via the inferior cerebellar peduncle (restiform
body) (Figure 3-12) and terminate on the rostral and caudal portions of the vermis. The dorsal
spinocerebellar tract conveys to the cerebellum information pertaining to muscle contraction, including
phase, rate, and strength of contraction.

There is evidence to suggest that some of the fibers forming this tract arise from neurons in laminae V and
VI of Rexed, as well as from the nucleus dorsalis of Clarke.

2. Ventral Spinocerebellar Tract.

This fiber system (Figure 3-12) conveys impulses almost exclusively from Golgi tendon organs via Ib
afferents. Dorsal root fibers destined for this tract synapse with neurons in laminae V to VII of Rexed. Axons
arising from these neurons then cross to form the ventral spinocerebellar tract,
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which ascends throughout the spinal cord, medulla oblongata, and pons before entering the contralateral
cerebellum via the superior cerebellar peduncle (brachium conjunctivum). Thus the fibers of this tract cross
twice, once in the spinal cord and again before entering the cerebellum. Most fibers in this tract terminate in
the vermis and intermediate lobe, mostly homolateral to the limb of origin but also contralateral. The ventral
spinocerebellar tract transmits, to the cerebellum, information related to interneuronal activity and the
effectiveness of the descending pathways.

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Figure 3-10. Schematic diagram showing the different pathways for cutaneous and proprioceptive
sensations from fore- and hindlimbs.

Unlike the posterior column, which conveys conscious proprioception to the cerebral cortex, the dorsal and
ventral spinocerebellar tracts terminate in the cerebellum and thus convey unconscious proprioception.

In addition to the preceding classic spinocerebellar pathways, there are at least two other indirect pathways
from the spinal cord to the cerebellum:

1. The spino-olivo-cerebellar pathway, with an intermediate station at the inferior olive in the medulla
oblongata

2. The spino-reticulo-cerebellar pathway, with an intermediate synapse in the lateral reticular nucleus of
the medulla

The impulses traveling via the indirect spinocerebellar pathways reach the cerebellum after a longer latency
than that observed with the more direct spinocerebellar pathways. It is postulated that impulses traveling
via the classic direct pathway reach the cerebellum sooner and will condition it for the reception of impulses
arriving later via the indirect pathways.

3. Spinocervical Thalamic Tract (Morin's Tract).

Nerve fibers destined to form the spinocervical thalamic tract are central processes of dorsal root ganglia.
They enter the spinal cord with the thickly myelinated fibers of the medial division of the dorsal root. They
travel within the posterior funiculus for several segments before entering the posterior horn gray matter to
synapse on neurons there. Axons of neurons in the posterior horn ascend in the lateral funiculus to the upper

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two or three cervical segments, where they synapse on neurons of the lateral cervical nucleus. Axons of this
nucleus cross to the opposite lateral funiculus and ascend to the thalamus (Figure 3-10). The lateral cervical
nucleus is organized somatotopically (similar to the posterior column nuclei) and similarly receives an input
from the cerebral cortex.

Figure 3-11. Schematic diagram of the spinal cord showing the homology of the accessory cuneate
nucleus and the nucleus dorsalis of Clarke.

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The spinocervical thalamic tract accounts for the presence of kinesthesia and discriminative touch after total
interruption of the posterior funiculus. Although this tract has not been demonstrated in humans, its
presence has been assumed because of the persistence of posterior funiculus sensations after total posterior
funiculus lesions. Thus the older concept of the necessity of the posterior funiculus for discriminatory
sensation is being challenged. Instead, a newer concept is evolving that attributes to the posterior funiculus
a role in the discrimination of those sensations that an animal must explore actively and to the spinocervical
thalamic system a role in the discrimination of sensations that are impressed passively on the organism
(Table 3-7).

4. Lateral Spinothalamic Tract.

This ascending fiber tract is located medial to the dorsal and ventral spinocerebellar tracts (Figure 3-
13) and is concerned with transmission of pain and temperature sensations. Root fibers contributing to
this tract (C-fibers and A-delta fibers) have their cell bodies in dorsal root ganglia. They are unmyelinated
and thinly myelinated fibers that generally occupy the ventrolateral region of the dorsal root as it enters the
spinal cord. C-fibers conduct slowly at 0.5 to 2 m/s. A-delta fibers conduct faster at 5 to 30 m/s. Incoming
root fibers establish synapses in laminae I to VI of Rexed. A-delta and C-fibers terminate in laminae I to III;
A-delta fibers terminate in addition in deep layer V. Axons of neurons in these laminae in turn establish
synapses with neurons in laminae V to VIII. Axons of tract neurons in laminae V to VIII, as well as some
axons arising from neurons in lamina I, cross to the opposite lateral funiculus in the anterior white
commissure within one to two segments above their entry level to form the lateral spinothalamic tract. A
small number of fibers stay uncrossed. Fibers of sacral origin are located most laterally and those of cervical
origin more medially in the crossed tract. This segmental lamination is useful clinically in differentiating
lesions within the spinal cord from those compressing the spinal cord from outside. In the former, the
cervical fibers are affected early, whereas the sacral fibers are affected either late or not at all. This
condition, known clinically as sacral sparing, is characterized by preservation of pain and temperature
sensations in the sacral dermatomes and their loss or diminution in other dermatomes. In addition to this
segmental lamination, the lateral spinothalamic tract exhibits modality lamination, in which fibers conveying
pain sensations are located anteriorly and those conveying thermal sense are located most posteriorly
(Figure 3-14). This segregation of fibers in a modality pattern, however, is incomplete. Once formed, this
tract ascends throughout the length of the spinal cord and brain stem to reach the thalamus, where its axons
synapse on neurons in the ventral posterolateral nucleus. Third-order neurons project from there by means
of the posterior limb of the internal capsule to the primary somatosensory cortex (Figure 3-15).

Lesions of this tract result in loss of pain and thermal sensation in the contralateral half of the body
beginning one or two segments below the level of the lesion. In contrast to this pattern of pain and thermal

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loss, lesions of the dorsal root result in segmental (dermatomal) loss of sensation ipsilateral to the lesion,
whereas lesions of the crossing fibers in the anterior white commissure result in bilateral segmental loss of
pain and temperature sensation in dermatomes corresponding to the affected spinal segments. This last
pattern is often noted in syringomyelia, a disease in which the central canal of the spinal cord encroaches
on, among other sites, the anterior white commissure.

The lateral spinothalamic tract may be sectioned surgically for the relief of intractable pain. In this
procedure, known as cordotomy, the surgeon uses the ligamentum denticulatum of the spinal meninges as a
landmark and orients the knife anterior to the ligament to reach the tract. Because of the segregation of
pain and thermal fibers in the lateral spinothalamic tract, cordotomies can selectively ablate pain fibers,
leaving thermal sensations intact.

There has been increased interest in pain pathways and pain mechanisms in recent years. These extensive
studies have shown that the lateral spinothalamic tract is only one of several pathways carrying pain
impulses. Other pathways conveying this modality include a multisynaptic pathway associated with the
reticular system and a spinotectal pathway. These studies also have developed the concept of an inhibitory
input into the posterior horn from the thickly myelinated fibers of the dorsal root and posterior column. This
has led clinicians to stimulate these inhibitory fibers traveling in the posterior column in an attempt to
relieve intractable pain.

Out of these studies on pain mechanisms has evolved the gate-control theory of pain, proposed by Melzack
and Wall (Figure 3-16). According to this theory, two afferent inputs related to pain enter the spinal cord.
One input is via small fibers that are tonic and adapt slowly with a continuous flow of activity, thus keeping
the gate open. Impulses along these fibers will activate an excitatory mechanism that increases the effect of
arriving impulses. The second input is via large, thickly myelinated fibers that are phasic, adapt rapidly, and
fire in response to a stimulus. Both types of fibers project into lamina II of Rexed, which suggests that this
lamina is the modular center for pain. The thin fibers inhibit, whereas the thick fibers facilitate, neurons in
this lamina. Both types of fibers also project into laminae I and IV to VIII of Rexed, where tract cells are
located. Both thin and thick fibers facilitate neurons in these laminae. Furthermore, axons of neurons in
lamina II have a presynaptic
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inhibitory effect on both small and large axons projecting on tract neurons. These different relationships
(Figure 3-16) can be summarized as follows:

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Figure 3-12. Schematic diagram showing the formation, course, and termination of the dorsal
(posterior) and ventral (anterior) spinocerebellar tracts.

1. Ongoing activity that precedes a stimulus is carried by the tonic, slowly adapting fibers that tend to
keep the gate open.

2. A peripheral stimulus will activate both small and large fibers. The discharge of the latter initially will
fire the tract cells (T cells) through the direct route and then partially close the gate through their
action via lamina II (facilitation of presynaptic inhibition).

3. The balance between large- and small-fiber activation will determine the state of the gate. If the
stimulus is prolonged, large fibers will adapt, resulting in a relative increase in small-fiber activity that
will open the gate further and increase T-cell activity. However, if large-fiber activity is increased by a
proper stimulus (vibration), the gate will tend to close, and T-cell activity will diminish.

Since its publication, the gate-control theory has been modified and further clarified. It is now recognized
that inhibition occurs by both presynaptic and postsynaptic inputs from the periphery, as well as by
descending cortical influences. While it is generally agreed that a gate control for pain exists, its functional
role and detailed mechanism need further exploration.

Ongoing research in pain mechanisms has given rise in recent years to much interesting data, some of which
are summarized below:

1. Two types of pain receptors have been identified: unimodal nociceptors responding to nociceptive
stimuli and polymodal nociceptors responding to nociceptive, chemical, and mechanical stimuli.

2. Three types of spinothalamic neurons have been identified in the dorsal horn: low-threshold
mechanoreceptors in laminae VI to VII, high-threshold, nociceptive-specific nociceptors in lamina I, and
wide-dynamic-range neurons in laminae IV

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and V responding to both mechanoreceptor and nociceptor stimulation. The wide-dynamic-range
neurons receive inputs from both low-threshold mechanoreceptors and high-threshold nociceptors and
are probably concerned with visceral and referred pain.

Figure 3-13. Schematic diagram showing the formation of the lateral spinothalamic tract.

3. Only the nociceptor neurons are inhibited by serotonergic fibers from the nucleus raphe magnus of the
medulla.

4. Several neurotransmitter substances have been identified in the dorsal horn: norepinephrine and
serotonin in the substantia gelatinosa and substance P, somatostatin, and enkephalins in laminae I to
III. Substance P has been found to be excitatory, whereas enkephalins are inhibitory.

Figure 3-14. Schematic diagram showing the segmental and modality lamination of the lateral
spinothalamic tract. S, sacral; L, lumbar; T, thoracic (dorsal); C, cervical. Stippled area denotes
thermal fibers. Clear area denotes pain fibers.

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Figure 3-15. Schematic diagram of the formation, course, and termination of the lateral
spinothalamic tract.

5. C-fibers entering via the dorsal root terminate on lamina I, lamina II, and lamina III neurons. They
excite neurons in all these laminae via axodendritic synapses. Axons of lamina II neurons in turn inhibit
neurons of lamina I via axosomatic synapses.

6. A-delta fibers establish excitatory synapses on laminae II and IV neurons. Some terminate on laminae
I, III, and V. Since lamina II neurons inhibit lamina I neurons, repetitive stimulation of A-delta fibers
can inhibit lamina I neurons significantly. In common practice, this is probably what happens when pain
from a cut on the finger is reduced by local pressure (stimulation of A-delta fibers).

7. About 24 percent of sacral and 5 percent of lumbar originating fibers in the lateral spinothalamic tract
project to the ipsilateral thalamus.

5. Anterior Spinothalamic Tract.

This tract carries light touch stimuli. Fibers contributing to this tract in the dorsal root establish synapses in
laminae VI to VIII. Axons of neurons in these laminae cross in the anterior white commissure over several
segments and gather in the lateral and anterior funiculi to form the tract. Somatotopic organization in this
tract is similar to that in
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the lateral spinothalamic tract. The course of this tract in the spinal cord and brain stem is similar to that of
the lateral spinothalamic tract. Recent evidence about this tract suggests the following: (1) It conveys pain
impulses in addition to touch. (2) Some of its fibers ascend ipsilaterally all the way to the midbrain, where
they cross in the posterior commissure and project primarily on intralaminar neurons in the thalamus, with
some fibers reaching the periaqueductal gray matter in the midbrain. (3) It is believed to convey aversive
and motivational nondiscriminative pain sensations, in contrast to the lateral spinotha-lamic tract, which is
believed to convey the well-localized discriminative pain sensations. The existence of this tract as a separate
entity has been questioned. Most authors include this fiber system with the lateral spinothalamic tract.
Physiologists tend to refer to the two tracts as the anterolateral system.

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Figure 3-16. Schematic diagram of the gate-control theory of pain.

6. Other Ascending Tracts.

Other ascending tracts of less clinical significance include the spino-olivary, spinotectal, and spinocortical
tracts. The functional significance of these multisynaptic pathways is not very well delineated; they may play
a role in feedback control mechanisms.

D. DESCENDING TRACTS
Whereas all the ascending tracts originate in dorsal root ganglia neurons (Table 3-5), the descending tracts,
in contradistinction, originate from several sites (Table 3-6). As with the ascending tracts, only the
descending tracts of clinical or functional significance will be discussed.

1. Corticospinal Tract.
The corticospinal tract has the highest level of development in higher primates, especially in humans. The
cells of origin of this tract are located in the cerebral cortex. The primary motor cortex (Brodmann's area 4)
and the premotor cortex (area 6) contribute 80 percent of the tract. From their site of origin, axons of the
corticospinal tract descend throughout the whole length of the neuraxis (brain stem and spinal cord) (Figure
3-17). Approximately one million axons compose the corticospinal tract on each side. At the caudal end of
the medulla oblongata, the majority of corticospinal fibers cross (pyramidal decussation) to form the lateral
corticospinal tract, located in the lateral funiculus of the spinal cord (Figure 3-18). Fibers in the lateral
corticospinal tract are organized somatotopically. The cervical fibers are most medial, followed laterally by
the thoracic, lumbar, and sacral fibers (Figure 3-19). The uncrossed fibers remain in the anterior funiculus
as the anterior corticospinal tract (bundle of Türck) (Figure 3-18). They, in turn, cross at segmental levels to
terminate on contralateral motor neurons (Figure 3-18). A crossed component of the anterior corticospinal
tract has been described, however. It is located in the posterolateral part of the anterior funiculus close to
the ventral (anterior) horn. The crossed lateral corticospinal tract extends throughout the spinal cord. The
extent of the uncrossed component of the anterior corticospinal tract depends on its size, which is variable.
When large, it extends throughout the spinal cord. The crossed component of the anterior corticospinal tract
extends to the sixth or seventh cervical segments only. About 2 to 3 percent of the corticospinal fibers
remain uncrossed (Figure 3-18) in the lateral funiculus (tract of Barnes) and influence ipsilateral motor
neurons. Most fibers in the corticospinal tract are
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small in caliber, ranging in diameter from 1 to 4 µm. Only about 3 percent of the fiber population consists of
large-caliber fibers (<< 10 µm in diameter). The large-caliber fibers arise from the giant cells of Betz in the
motor cortex. In the spinal cord, corticospinal fibers project on interneurons in laminae IV to VII of Rexed.
There is evidence also for a direct projection of a small number of fibers on motor neurons (both alpha and
gamma) in lamina IX in monkeys and in humans. The impulses conveyed via the corticospinal tract are
facilitatory to flexor motor neurons. Lateral corticospinal tract fibers terminate on motor neurons located in
the lateral part of the ventral horn that supply distal limb musculature. Anterior (ventral) corticospinal tract
fibers terminate on motor neurons located in the medial part of the ventral horn that supply neck, trunk, and
proximal limb musculature (Figure 3-18). Stimulation of corticospinal tract fibers results in co-activation of
alpha and gamma motor neurons supplying the same muscle and thus simultaneous co-contraction of
extrafusal and intrafusal muscles. This co-contraction of the two types of muscles optimizes the sensitivity of

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the muscle spindle (intrafusal muscle) to changes in muscle length even under conditions of muscle
shortening. The termination of the corticospinal tract in laminae IV to VII (which also receive sensory
impulses from the periphery) suggests that this tract plays a role in modulation of sensory input to the
spinal cord. Evidence for corticospinal tract control of sensory function is provided by terminations of
corticospinal tract fibers on primary afferent fibers and sensory relay neurons in the posterior (dorsal) horn
of the spinal cord. Corticospinal tract terminals exert pre-synaptic inhibition on some primary afferents and
postsynaptic inhibition or excitation of sensory relay neurons. The presynaptic inhibition of primary afferents
determines what type of sensory information is allowed to reach higher levels even before this information is
relayed to sensory relay neurons in the dorsal horn or elsewhere. The postsynaptic inhibition or excitation of
sensory relay neurons in the dorsal horn modulates activity of neurons involved in the transmission of
somesthetic and proprio-ceptive information to the thalamus and cerebral cortex.

Figure 3-17. Schematic diagram of the corticospinal pathway.

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Figure 3-18. Schematic diagram showing the three divisions of the corticospinal tract and their
patterns of termination in the spinal cord.

Figure 3-19. Schematic diagram showing somatotopic organization of fibers in the lateral corticospinal
tract. C, cervical; T, thoracic; L, lumbar; S, sacral.

The corticospinal tract is essential for skill and precision in movement and the execution of discrete fine
finger movements. It cannot by itself, however, initiate these movements. Other corticofugal (cortically
originating) fibers are needed. An intact corticospinal tract is not essential for production of voluntary
movement but is necessary for speed and agility during these movements. It also serves to regulate sensory
relay processes and thus selects what sensory modality reaches the cerebral cortex.

Lesions of the corticospinal tract result in paralysis. If the lesion occurs above the level of the pyramidal
decussation, paralysis will be contralateral to the side of the lesion. If the corticospinal tract lesion is below
the decussation (i.e., in the spinal cord), the paralysis will be homolateral (ipsilateral) to the side of the
lesion. In addition to paralysis, lesions in the corticospinal tract result in a conglomerate of neurologic signs
that includes (1) spasticity (resistance to the initial phase of passive movement of a limb or muscle group),
(2) hyperactive myotatic reflexes (exaggerated response of knee-jerk and other deep tendon reflexes), (3)
Babinski sign (abnormal flexor reflex in which stroking the lateral aspect of the sole of the foot results in
dorsiflexion of the big toe and fanning out of the other toes), and (4) clonus (an alternating contraction of
antagonistic muscles resulting in a series of extension and flexion movements). Collectively, this
conglomerate of signs is referred to by clinicians as upper motor neuron signs. Usually, there is sparing of
muscles of the upper face, mastication, trunk, and respiration, presumably because these muscles are

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innervated bilaterally from the motor cortex.

2. Rubrospinal Tract.
Neurons of origin of the rubrospinal tract are located in the magnicellular posterior two-thirds of the red
nucleus in the midbrain. Fibers forming this tract cross in the ventral tegmental decussation of the midbrain
and descend throughout the whole length of the neuraxis to reach the lateral funiculus of the spinal cord in
close proximity to the corticospinal tract (Figure 3-20). They terminate in the same laminae as the
corticospinal tract and similarly facilitate flexor motor
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neurons. Because of the similarity in the site of termination of both tracts, and because the red nucleus
receives an input from the cortex, the rubrospinal tract has been considered by some as an indirect
corticospinal tract. The two tracts constitute the dorsolateral pathway for movement, in which the
corticospinal tract initiates movement and the rubrospinal corrects errors in movement. In most mammals,
the rubrospinal tract is the major output of the red nucleus. The significance of the rubrospinal tract has
diminished with evolution. In humans, the major output of the red nucleus is to the inferior olive.

Figure 3-20. Composite schematic diagram of the origin, course, and termination of the rubrospinal
tract.

3. Lateral Vestibulospinal Tract.

The neurons of origin of this tract lie in the lateral vestibular nucleus located in the pons. From their site of
origin, fibers descend uncrossed and occupy a position in the lateral funiculus of the spinal cord (Figure 3-
21). The fibers in this tract terminate on interneurons in laminae VII and VIII, with some direct terminations
on alpha motor neuron dendrites in the same laminae. The impulses conducted in this system facilitate
extensor motor neurons that maintain upright posture.

4. Medial Vestibulospinal Tract.

The neurons of origin of the medial vestibulospinal tract are located in the medial vestibular nucleus. From
their neurons of origin, fibers join the ipsilateral and contralateral medial longitudinal fasciculi, descend in
the anterior funiculus of the cervical cord segments, and terminate on neurons in laminae VII and VIII
(Figure 3-22). They exert a facilitatory effect on flexor motor neurons. The tract plays a role in control of
head position.

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Figure 3-21. Composite schematic diagram of the origin, course, and termination of the lateral
vestibulospinal tract.

5. Reticulospinal Tracts (Figure 3-23).

The neurons of origin of these tracts are located in the reticular formation of the pons and medulla
oblongata. The pontine reticulospinal tract is located in the anterior funiculus of the spinal cord, whereas the
medullary reticulospinal tract is located in the lateral funiculus. Both tracts descend predominantly
ipsilaterally, but both have, in addition, some crossed components. The pontine reticulospinal tract
facilitates extensor motor neurons, whereas the medullary reticulospinal tract facilitates flexor motor
neurons.

Figure 3-22. Schematic diagram of origin, course, and termination of the medial vestibulospinal tract.

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Figure 3-23. Schematic diagram of the origins and terminations of the pontine and medullary
reticulospinal tracts.

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Pontine originating fibers terminate in laminae VII and VIII of Rexed, whereas medullary originating fibers
terminate primarily in lamina VII. Some medullary originating fibers interact with motor neuron dendrites in
laminae VII and VIII. In addition to influencing motor neurons, reticulospinal fibers modify sensory activity
through their interaction with spinothalamic neurons in the dorsal horn.

6. Tectospinal Tract (Figure 3-24).

From their neurons of origin in the superior colliculus of the midbrain, fibers of this tract cross in the dorsal
tegmental decussation in the midbrain and descend throughout the neuraxis to occupy a position in the
anterior funiculus of the cervical spinal cord. Fibers of this tract terminate on neurons in laminae VI, VII,
and VIII. The function of this tract is not well understood; it is believed to play a role in the turning of the
head in response to light stimulation.

7. Descending Autonomic Pathway.

Fibers belonging to this descending system originate predominantly from the hypothalamus. They are small-
caliber fibers that follow a polysynaptic route and are scattered diffusely in the anterolateral funiculus of the
spinal cord. They project on neurons in the intermediolateral cell column. Lesions of this system result in
autonomic disturbances. If the lesion involves the sympathetic component of this system at or above the T-1
level, a characteristic syndrome known as Horner's syndrome, or Bernard-Horner syndrome, will result. This
syndrome is manifested by (1) miosis (small pupil), (2) pseudoptosis (minimal drooping of the eyelid), (3)
anhidrosis (absence of sweating) of the face, and (4) enophthalmos (slight retraction of the eyeball). All
these signs occur on the same side as the lesion and are due to interruption of sympathetic innervation to
the dilator pupillae, tarsal plate, sweat glands of the face, and retro-orbital fat, respectively.

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Figure 3-24. Schematic diagram of the origin and termination of the tectospinal tract.

8. Descending Monoaminergic Pathways.

Serotonergic fibers from the raphe nucleus of the medulla oblongata, noradrenergic fibers from the nucleus
locus ceruleus in the rostral pons and caudal midbrain, and enkephalinergic fibers from the periaqueductal
gray matter in midbrain descend in the lateral and anterior funiculi. They descend both ipsilateral and
contralateral to their site of origin.

Spinal Cord Neurotransmitters and Neuropeptides

Most primary sensory neurons in the dorsal horn release glutamate as a rapidly acting excitatory
neurotransmitter irrespective of the sensory modality conveyed by the afferent fiber. In addition to
glutamate, many small-diameter neurons in the dorsal horn also release neuropeptide transmitters, notably
substance P, somatostatin, and vasoactive intestinal peptides. These are believed to mediate slow synaptic
transmission. Other neurotransmitters and neuromodulators (peptide neurotransmitters) in the spinal cord
include norepinephrine, serotonin, enkephalin, neuropeptide Y, peptide histidyl isoleucine, and
cholecystokinin. Neuropeptides are most abundant in the dorsal horn, followed in decreasing intensity by the
intermediate zone and the anterior (ventral) horn. The lumbosacral region has more neuropeptides compared
with other regions of the spinal cord. While the exact function of most neuropeptides is not established with
absolute certainty, the following observations have been reported: Sub-stance P is the neurotransmitter of
primary nociceptive and non-nociceptive afferents in the dorsal horn. The marked reduction of substance P
immunoreactivity in lamina II in patients with
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profound analgesia in the familial dysautonomia (Riley-Day) syndrome supports a role for this neuropeptide
in pain transmission. Met-enkephalin and somatostatin (SST) in the dorsal horn inhibit release of substance
P from primary afferents and inhibit activity in dorsal horn neurons. Vasoactive intestinal peptide (VIP) is the
major neurotransmitter in visceral (especially pelvic) afferents and is found abundantly in lumbosacral
segments of the cord. Substance P, Met-enkephalin, and cholecystokinin (CCK) in the intermediate zone are
terminals from caudal raphe nuclei of the brain stem. Substance P and serotonin from the caudal raphe
nuclei participate in the modulation of motor neuron activity in the anterior horn. Norepinephrine from the
locus ceruleus has an inhibitory effect on nociceptive activity in the dorsal horn.

Spinal Reflexes
Motor neurons in the spinal cord are activated by (1) impulses from the periphery as part of reflex
mechanisms and (2) impulses from higher levels (cortical and subcortical) that modify local reflex
mechanisms. The spinal reflexes discussed below are of clinical significance.

A. MYOTATIC (STRETCH) REFLEX (Figure 3-25)

Stretching a muscle (by tapping its tendon) will activate the muscle spindle of the intrafusal muscle fiber
(primary annulospiral endings). Impulses from the activated muscle spindle will activate monosynaptically,
via Ia fibers, the homonymous (corresponding, ipsilateral) alpha motor neurons in the anterior horn of the
spinal cord. Impulses traveling via the axons of such alpha motor neurons will then reach the stretched
skeletal muscle and result in contraction of the muscle. Ia afferents will also make direct monosynaptic
excitatory connections with alpha motor neurons, which innervate muscles that are synergistic in action to
the muscle from which the Ia fiber originated. The activity in the Ia fibers will, in addition, inhibit

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disynaptically the motor neurons that supply the antagonistic muscle (reciprocal inhibition). This obviously
facilitates contraction of the homonymous muscle.

Figure 3-25. Schematic diagram of the components of the stretch reflex. Muscle stretch (1) will
activate Ia sensory nerve fibers (2), which will monosynaptically activate motor neurons. Axons of
activated motor neurons (3) will synapse on skeletal muscle fibers and produce contraction.

In humans, myotatic stretch reflexes can be elicited in the following sites and are part of a neurologic
examination:

Biceps jerk. This reflex is elicited by tapping the tendon of the biceps muscle. The biceps muscle will
contract, flexing the elbow.

Triceps Jerk. This reflex is elicited by tapping the tendon of the triceps muscle. As a result, the triceps
will contract and extend the elbow joint.

Radial jerk. Tapping the tendon of the brachioradialis muscle at the wrist will contract the
brachioradialis muscle and flex the wrist joint.

Knee jerk (quadriceps myotatic reflex). This reflex is elicited by tapping the tendon of the
quadriceps femoris muscle at the patella. The quadriceps muscle contraction extends the knee joint.

Ankle jerk. Tapping the tendon of the gastrocnemius muscle at the Achilles tendon will contract the
gastrocnemius and plantar flex the ankle.

B. INVERSE MYOTATIC REFLEX (Figure 3-26)

Severe tension in a muscle produced by stretch or contraction will stimulate nerve endings in its tendon
(Golgi tendon organ). Impulses from Golgi tendon organs travel via Ib nerve fibers. In the spinal cord, they
project upon inhibitory neurons, which in turn inhibit alpha motor neurons supplying the muscle under
tension (homonymous motor neurons). The result is relaxation of the muscle (lengthening reaction,
autogenic inhibition). At the same time, the Ib activity facilitates motor neurons that supply the antagonistic
muscle.

In reviewing the myotatic and inverse reflexes and their role in muscular activity, it becomes evident that
there are three controlling mechanisms.

One is a length-controlling mechanism subserved by the annulospiral endings of the intrafusal fiber. This
mechanism is sensitive to changes in length and mediates its effects via the Ia nerve fibers.

A second is a tension-controlling mechanism subserved by the Golgi tendon organ. This mechanism is
sensitive to tension in the muscle developed by either stretch or contraction of the muscle and is mediated
via the Ib nerve fibers.

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Figure 3-26. Schematic diagram of the components of the inverse myotatic reflex.

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A third is a follow-up control system in which extrafusal muscle fiber length follows intrafusal muscle fiber
length and is mediated through the gamma loop.

C. FLEXOR REFLEX (Figure 3-27)

The proper stimulus for eliciting this reflex is a nociceptive or painful one, such as pin prick, or one that
inflicts injury or damage to the skin or deeper tissues. The primary receptors for this reflex are the pain
(free nerve endings) receptors, although light touch receptors elicit a weaker and less sustained flexor
reflex. The purpose of this reflex is withdrawal of the injured part from the stimulus, thus the reflex is also
called the withdrawal reflex.

From the stimulated receptors, impulses travel by means of group III nerve fibers to the spinal cord, where
they establish polysynaptic relations (at least three or four interneurons) with a number of motor neurons.
The net effect of this circuitry is twofold: (1) facilitation of ipsilateral flexor motor neurons and (2) inhibition
of ipsilateral extensor motor neurons.

Efferent outflow of the activated motor neurons will effect contraction of flexor muscles (flexion) and
relaxation of antagonist extensor muscles in the stimulated part of the body.

D. CROSSED EXTENSION REFLEX (Figure 3-28)

This reflex is actually a byproduct of the flexion reflex. The incoming impulses from a nociceptive stimulus
will cross in the anterior commissure of the spinal cord and establish multisynaptic relationships with both
flexor and extensor motor neurons. Their effect on these motor neurons, however, is the reverse of that
described ipsilaterally: (1) facilitation of extensor motor neurons and (2) inhibition of flexor motor neurons.
As a result, the limb contralateral to the stimulated part of the body will be extended.

Thus, in response to a nociceptive stimulus, the ipsilateral limb will flex and the contralateral limb will
extend in preparation for withdrawal. Very strong nociceptive stimuli will spread activity in the spinal cord
through intersegmental reflexes to involve all four extremities. In response to a stimulus applied to one
extremity (hindlimb), a spinal cat will withdraw the stimulated limb, extend the opposite hindlimb and
ipsilateral forelimb, and flex the contralateral forelimb.

Micturition Pathway and Bladder Control

The urinary bladder receives efferent innervation from three sources: (1) sympathetic supply via the
hypogastric nerve, (2) parasympathetic supply via the pelvic nerve, and (3) somatic supply via the
pudendal nerve. The sympathetic preganglionic neurons are in the intermediolateral cell column in the upper
lumbar cord. Preganglionic axons leave the cord via the ventral root and synapse in paravertebral and
preaortic sympathetic ganglia. Postganglionic fibers travel in the hypogastric nerve to smooth muscles of
bladder wall and internal urethral sphincter. Parasympathetic preganglionic neurons are in the
intermediolateral-like cell column between the second and fourth sacral segments (S-2 and S-4).
Preganglionic axons join the pelvic splanchnic nerves (nervi erigentes) to terminal (vesical) ganglia and
innervate smooth muscles in the bladder wall and internal urethral sphincter. Somatic neurons are motor
neurons in the ventral-ventromedial part of the anterior (ventral) horn of S-2 to S-4 (nucleus of
Onufrowicz). Axons travel with the ventral root, join the pudendal nerve, and innervate the external urethral
sphincter.

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Figure 3-27. Schematic diagram of the components of the flexor reflex.

Afferent impulses from the bladder enter the cord via the same three nerves. Sympathetic afferents travel
via the hypogastric nerve, enter the cord at the upper lumbar level, and may extend rostrally up to the
fourth thoracic segment (T-4), but most are in the upper lumbar and low thoracic levels. Parasympathetic
afferents travel via the pelvic nerves and enter the cord between S-2 and S-4. Somatic afferents travel via
the pudendal nerves and enter the cord at S-2 to S-4 levels.

Bladder filling is associated with tonic activity in the sympathetic neurons and Onuf's nucleus. The former
results in relaxation of the detrusor muscle directly and indirectly (by inhibiting parasympathetic ganglion
cells in the vesical wall) and in contraction of the internal urethral sphincter. The latter results in contraction
of the external sphincter.

Bladder emptying (micturition) is associated with inhibition of sympathetic outflow, activation of

parasympathetic outflow (contraction of detrusor muscle), and inhibition of Onuf's nucleus (relaxation of
external sphincter).

Table 3-8 is a summary of the effects of the sympathetic, parasympathetic, and somatic (Onuf's) neurons on
detrusor muscle, internal sphincter, vesical ganglion cells, and external sphincter.

Descending pathways for micturition travel in the lateral funiculus just ventral to the denticulate ligament
and lateral corticospinal tract. They play a role in starting and stopping micturition and in inhibiting the
independent reflex activity of the sacral bladder center. The role of the corticospinal tracts in controlling
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the external sphincter and bladder contractions remains uncertain. In motor neuron disease (amyotrophic
lateral sclerosis), patients retain bladder control until very late in the disease despite the degeneration in
the corticospinal tract. Furthermore, the nucleus of Onufrowicz (Onuf's nucleus) is spared in motor neuron
disease.

Figure 3-28. Schematic diagram of the components of the crossed extensor reflex.

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Ascending pathways related to micturition also travel in the lateral funiculus ventral to the denticulate
ligament, in the region of the spinothalamic tract. They play a role in the conscious appreciation of the
desire to micturate.

Although the motor neuronal cell groups of bladder and sphincter are located in the spinal cord, the
coordination of urine storage and voiding takes place in the pons. This brain stem coordination is best seen
in patients with spinal cord injury above the sacral level. Such patients have great difficulty emptying the
bladder, because when the bladder contracts, the urethral sphincter also contracts (detrusor–sphincter
dyssynergia). Such a disorder never occurs in lesions rostral to the pons. In 1925, Barrington showed in the
cat that lesions in the dorsolateral pontine tegmentum result in inability to empty the bladder (urinary
retention). Tracing studies in the cat undertaken in 1979 showed that the Barrington area in the pons
projects to sacral autonomic neurons (parasympathetic bladder motor neurons between S-2 and S-4). The
pontine area described by Barrington is now recognized as the pontine micturition center (Barrington
nucleus, M-region). Another pontine area (L-region), ventral and lateral to the Barrington area, was found to
project to Onuf's nucleus (nucleus of Onufrowicz). This area is important during the filling phase of the
bladder and is called the pontine continence center.

Information about degree of bladder filling is conveyed by the hypogastric (sympathetic) and pelvic
(parasympathetic) nerves (primary afferents) to autonomic (sympathetic and parasympathetic) neurons in
the lumbosacral spinal cord, which in turn send secondary afferents that travel in the lateral funiculus and
lateral brain stem tegmentum to the periaqueductal gray area in the midbrain (mesencephalon). When the
bladder is filled to a degree that voiding is appropriate, the periaqueductal gray area activates neurons in
the pontine micturition center (Barrington nucleus), which in turn excites the sacral (S-2 to S-4)
preganglionic parasympathetic neurons and simultaneously inhibits (via GABA-ergic interneurons) Onuf's
nucleus. The combined effect on these two nuclear groups (parasympathetic preganglionic and Onuf's)
results in bladder wall contraction, relaxation of external urethral sphincter, and bladder emptying
(micturition).

Besides the pons and midbrain, the hypothalamus (medial preoptic area) and the cerebral cortex are
involved in micturition. Cortical areas involved in micturition are the right inferior frontal gyrus and the right
anterior cingulate gyrus. Positron emission tomography scanning has shown increased blood flow
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in the right dorsal pontine tegmentum and the right inferior frontal gyrus with micturition. Decreased blood
flow was found in the right anterior cingulate gyrus during urine withholding. These studies have shown that
cortical and pontine micturition sites are more active on the right side than on the left. A schema of the
segmental and suprasegmental control of micturition is shown in Figure 3-29.

Table 3-8. Spinal Cord Control of Urinary Bladder.

Neural system Detrusor Internal Vesical External

muscle urethral parasympathetic sphincter
sphincter ganglion cells

Sympathetic (T-11 to - + -
L-2)

Parasympathetic (S-2 + - +
to S-4)

Somatic (Onuf +
nucleus) (S-2 to S-4)

+,facilitatory; -,inhibitory.

FUNCTIONAL OVERVIEW OF THE SPINAL CORD

The spinal cord is organized into three major functional zones: the dorsal horn, the intermediate zone, and
the ventral horn.

1. The dorsal horn receives several varieties of sensory information from receptors in the skin surface
(exteroceptive), as well as from deeper-lying receptors in joints, tendons, and muscles (interoceptive).
Cell characteristics in the dorsal horn vary greatly with respect to the extent of their receptive fields

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and the degree of specificity of the modality received. Information received from the periphery is not
merely relayed in the dorsal horn but is modified by virtue of the various peripheral inputs received, as
well as by descending influences from the cerebral cortex and subcortical areas. The sum total of this
interaction in the dorsal horn is then mediated to motor neurons in lamina IX, to interneurons, or to
ascending tracts.

2. The intermediate zone similarly receives a variety of inputs from the dorsal root and dorsal horn, as
well as from cortical and subcortical areas. The information received here is integrated and modified
before being projected to other zones.

3. The ventral horn receives inputs from the dorsal root (monosynaptic reflex connections), the dorsal
horn, the intermediate zone, and the descending tracts. The descending tracts influence motor neurons
either directly or indirectly through interneurons in the intermediate zone. They selectively facilitate
flexor motor neurons (corticospinal, rubrospinal, medial vestibulospinal, and medullary reticulospinal
tracts) or extensor motor neurons (lateral vestibulospinal and pontine reticulospinal tracts). The output
from the ventral horn is via either alpha motor neurons to influence striated musculature or gamma
motor neurons to influence intrafusal muscle fibers.

Figure 3-29. Schema of segmental and suprasegmental control of micturition and continence. +
facilitatory; {-} inhibitory; (1) micturition pathways; (2) continence pathways. Blue lines, efferent
pathways; black lines, afferent pathways.

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BLOOD SUPPLY
The spinal cord receives its blood supply from the following arteries.

1. Subclavian via the following branches: vertebral, ascending cervical, inferior thyroid, deep
cervical, and superior intercostal

2. Aorta via the following branches: intercostal and lumbar arteries

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3. Internal iliac via the following branches: iliolumbar and lateral sacral

Branches of the subclavian artery supply the cervical spinal cord and the upper two thoracic segments; the
rest of the thoracic spinal cord is supplied by the intercostal arteries. The lumbosacral cord is supplied by
the lumbar, iliolumbar, and lateral sacral arteries. Intercostal arteries supply segmental branches to the
spinal cord down to the level of the first lumbar cord segment. The largest of these branches, the great
ventral radicular artery, enters the spinal cord between the eighth thoracic and fourth lumbar cord
segments. This large artery, also known as the arteria radicularis magna or artery of Adamkiewicz, usually
arises on the left side and may be responsible for most of the arterial blood supply of the lower half of the
spinal cord in some people.

The vertebral arteries give rise to anterior and posterior spinal arteries in the cranial cavity. The two
anterior spinal arteries unite to form a single anterior spinal artery that descends in the anterior median
fissure of the spinal cord. The posterior spinal arteries, smaller than the anterior, remain paired and descend
in the posterolateral sulci of the spinal cord. All other arteries send branches that enter the intervertebral
foramina, penetrate the dural sheath, and divide into anterior and posterior branches (radicular arteries)
that accompany the anterior and posterior nerve roots. These radicular arteries contribute to the three major
spinal cord arteries: the anterior spinal and the paired posterior spinal arteries. Since most of the radicular
arteries contributing to the anterior spinal artery are small, blood supply is mainly dependent on the 4 to 10
of these that are large, of which one or two are located in the cervical region usually at C-6, one or two in
the upper thoracic region, and one to three in the inferior thoracic and lumbosacral region, one of which
form the artery of Adamkiewicz. In contrast, the posterior spinal arteries receive from 10 to 20 well-
developed radicular arteries. In the lumbosacral cord, the posterior radicular arteries are vestigial and of no
clinical significance. Anastomoses between the anterior and posterior spinal arteries occur caudally around
the cauda equina. There are very few anastomoses at each segmental level.

The anterior spinal artery gives off a sulcal branch in the anterior median fissure. This branch turns either
right or left to enter the spinal cord; only in the lumbar and sacral cords are there both right and left
branches. The sulcal arteries are most numerous in the lumbar region and fewest in the thoracic region.
Sulcal arteries supply the anterior and intermediolateral gray horns, the central gray matter, and Clarke's
column, that is, all the gray matter except the dorsal horn. They also supply the bulk of the white matter of
the anterior and lateral funiculi. Thus the anterior two-thirds of the spinal cord is fed from the anterior
spinal artery; the remaining third, including the posterior funiculus and posterior horn, is supplied by the
two posterior spinal arteries. The outer rim of the spinal cord is supplied by coronal branches that arise from
the anterior spinal artery, pass laterally around the cord, and form imperfect anastomoses with the posterior
spinal artery branches (Figure 3-30).

Figure 3-30. Schematic diagram of segmental blood supply of spinal cord.

Certain segments of the spinal cord are more vulnerable than others to a compromise in blood flow. The
segments that are particularly vulnerable are T-1 to T-4 and L-1. These are regions of the spinal cord that
derive their blood supply from two different sources. At the level of T-1 to T-4, for example, the anterior
spinal artery becomes small, and its sulcal branches are not adequate to provide the necessary blood supply.
These segments are dependent for their blood supply on the radicular branches of the intercostal arteries. If
one or more of the intercostal vessels are compromised, the T-1 to T-4 spinal segments could not be
supplied adequately by the small sulcal branches of the anterior spinal artery. As a result, a segment or
several segments affected would be damaged.

Venous drainage of the spinal cord corresponds to the arterial supply with the following differences:

1. The venous network is denser on the posterior side of the cord compared with the arterial network,
which is more dense anteriorly.

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2. There is only one posterior spinal vein.

3. Anastomoses between the anterior and posterior spinal veins are more frequent than between the
arteries.

4. The territorial drainage from the anterior two-thirds of the spinal cord by the anterior spinal vein and
from the posterior one-third by the posterior spinal vein is generally maintained but not immutable.

5. Venous tributaries within and around the spinal cord are much more numerous than arterial tributaries,
so venous obstruction rarely damages the spinal cord. From the perispinal venous network, blood drains
into anterior and posterior radicular veins and then into dense longitudinal vertebral plexuses located
posteriorly and anteriorly in the epidural space. Blood then reaches the external vertebral venous
plexus through the intervertebral and sacral foramina.

TERMINOLOGY
Afferent (Latin afferre, “to carry to”).
Conveying impulses inward to a part or organ. Toward the spinal cord.

Arachnoid (Greek arachne, “like a cobweb, spider's web”).

The middle layer of the meninges between the outer dura and inner pia. Attached to the pia by a spider
web–like delicate network of fibers.

Autonomic (Greek autos, “self”; nomos, “law”).

Self-governing. The part of the nervous system concerned with visceral (involuntary) processes.
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Axon (Greek axon, “axis”).

The process of the nerve cell that transmits impulses away from the nerve cell.

Babinski, Josef-François-Felix (1857–1932).

French neurologist who described the Babinski sign in 1896 as the “phenomenon of the toes.” The sign or
components of it were noted earlier by Marshall Hall and Remak, but Babinski is credited with investigating
the phenomenon in depth, principally to differentiate organic from hysterical weakness. Babinski regarded
his work on spinal cord compression (not the “phenomenon of the toes”) to be his best.

Burdach column.
Cuneate tract, described in 1819 by Karl Frederich Burdach, German anatomist and physiologist.

Cauda equina (Latin “horse's tail”).

Bundle of lumbosacral nerve roots beyond the tip of the spinal cord that forms a cluster in the spinal canal
that resembles the tail of a horse.

Caudal (Latin “tail”).

Pertaining to cauda, toward the tail or posterior end.

Clarke's column.
After Jacob Clarke, English anatomist and neurologist who described the nucleus dorsalis in 1851.

Commissure (Latin “joining together”).

Axons that connect the two halves of the spinal cord or the two cerebral hemispheres.

Contralateral (Latin contra, “opposite”; latus, “side”).

Pertaining to or projecting to the opposite side.

Cordotomy.
Sectioning of the lateral spinothalamic tract for relief of intractable pain. The procedure was introduced by
Spiller in 1910. Since then the technique has been modified and improved. Percutaneous and open
cordotomies continue to be used to relieve pain in the contralateral side.

Cuneatus (Latin “wedge”).

The fasciculus cuneatus is so named because of its wedge shape and because it is short.

Decussation (Latin decussare, “to cross like an X”).

X-shaped crossing of nerve fiber tracts in the midline, as in pyramidal decussation.

Dendrite (Latin dendron, “a tree”).

The numerous processes of a nerve cell that branch like a tree and that transmit impulses toward the nerve
cell.

Denticulate (Latin denticulus, “a small tooth”).

The toothlike lateral projections of the pia mater in the spinal cord.

Dorsal (Latin dorsalis, from dorsum, “back”).

Pertaining to or situated near the back of an animal.

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Dura mater (Latin “hard mother”).

The thick and hard outermost layer of the meninges, so named because the Arabs believed the meninges
were the “mother” of all body tissues.

Exteroceptive (Latin “to take outside”).

To receive from outside. Exteroceptive receptors receive impulses from the outside.

Fasciculus (Latin “a small bundle”).

Small bundle of nerve fibers forming a tract, with a common origin and termination.

Funiculus (Latin funis, “cord”).

A bundle of white matter containing one or more fasciculi (tracts).

Ganglion (Greek “swelling, knot”).

A collection of nerve cells outside the central nervous system, as in dorsal root ganglia or autonomic
ganglia.

Gracilis (Latin “slender, thin”).

The fasciculus gracilis is so named because it is slender and long.

Inhibition (Latin inhibere, “to restrain or check”).

Arrest or restraint of a process.

Interoceptive.
Internal surface field of distribution of receptor organs.

Ipsilateral (Latin ipse, “self”; latus, “side”).

Pertaining or projecting to the same side.

Kinesthesia (Greek kinesis, “motion”; aisthesis, “sensation”).

Sense of perception of movement.

Lamina (Latin “thin layer”).

As in column of nerve cells in Rexed laminae.

Lesions (Latin laesia, laedere, “to hurt or injure”).

Morbid changes in tissue due to disease or injury.

Meninges (Greek plural of meninx, “membrane”).

The membranes covering the spinal cord and brain.

Myotatic (Greek myo, “muscle”; teinein, “to stretch”).

Performed or induced by stretching or extending muscle.

Nociceptive (Latin noceo, “to injure”; capio, “to take”).

Responds to painful injurious stimuli.

Nucleus (Latin nux, “a nut”).

Aggregation of nerve cells concerned with a particular function.

Paralysis (Greek paralusis, “to disable”).

Loss of voluntary movement.

Pia mater (Latin “soft, tender mother”).

The thin, delicate innermost meningeal layer.

Proprioception (Latin proprius, “one's own”; perception, “perception”).

The sense of position and movement.

Receptor (Latin recipere, “to receive”).

The sensory nerve ending or sensory organ that receives sensory stimuli.

Rubro (Latin ruber, “red”).

Rubrospinal tract originates from the red nucleus.

Somatic (Greek somatikos, “of the body”).

Pertaining to body as distinct from visceral; pertaining to viscera. Includes neurons and neural processes
related to skin, muscles, and joints.

Spinal cat.
An experimental cat preparation in which the spinal cord is disconnected from the brain stem and cerebral
cortex.

Stilling nucleus (column).

Described by Benedict Stilling (1810–1879), a German anatomist and surgeon who reported that it extended
from C-8 to L-3, L-4. Stilling published detailed accounts of the anatomy of the spinal cord, medulla, and
pons, including the solitary tract in the medulla. In his detailed anatomic studies, he used serial tissue
sections in three dimensions using the microtome, which he introduced in 1824. Stilling also described and

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differentiated almost all the cranial nerve nuclei recognized today.

Sulcus (Latin “groove”).

As in posterolateral and anterolateral sulci of the spinal cord.

Sympathetic (Greek sympathein, “self-responsive”).

Sympathetic division of the autonomic nervous system.

Synapse (Greek synapsis, “contact”).

Site of contact between processes of nerve cells (axon to axon, axon to dendrite), between neural process
and nerve cell, or between neural process and muscle.

Syndrome (Greek syndromos, “running together”).

A group of symptoms and signs that characterize a disease.

Syringomyelia (Greek syrinx, “a tube”; myelos, “marrow”).

Tubelike cavitation within the spinal cord.

Tactile (Latin tactilis, “touching”).

Pertaining to touch.

Tract of Goll.
Gracile tract, described in 1860 by the Swiss anatomist and neurologist, Goll.

Türck, Ludwig (1810–1868).

Austrian anatomist who described the anterior corticospinal tract in 1849. Other contributions include
description of the corticopontine fiber tract and the principle that nerve fiber degeneration occurs in the
direction
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in which physiologic impulses are conducted (ascending tract above the lesion and descending tracts below
the lesion).

Ventral (Latin ventralis, “belly”).

Pertaining to or toward the belly part of the body, as opposed to dorsal.

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Brodal A, Pompeiano O: The vestibular nuclei in the cat. J Anat (Lond) 1957; 91:438–454.

Broucker TD et al: Diffuse noxious inhibitory controls in man: Involvement of the spinoreticular tract.
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Davidoff RA: The dorsal columns. Neurology 1989; 39:1377–1385.

Davidoff RA: The pyramidal tract. Neurology 1990; 40:332–339.

Eyre JA et al: Evidence of activity-dependent withdrawal of corticospinal projections during human

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Guttmann L: Clinical symptomatology of spinal cord lesions. In Vinken PJ, Bruyn GW (eds): Handbook of
Clinical Neurology, vol 2. Amsterdam, North-Holland, 1978:178.

Hall JG: Supraspinal inhibition of spinal neurons responding to nociceptive stimulation. Neurosci Lett
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Hughes JT: Vascular disorders. In Pathology of the Spinal Cord, vol 6: Major Problems in Pathology.
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Jankowski E, Lindström S: Morphological identification of Renshaw cells. Acta Physiol Scand 1971;
81:428–430.

Kerr FWL, Fukushima T: New observations on the nociceptive pathways in the central nervous system. In
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58. New York, Raven Press, 1980:47.

Landgren S, Silfvenius H: Nucleus Z, the medullary relay in the projection path to the cerebral cortex of
group I muscle afferents from the cat's hind limb. J Physiol (Lond) 1971; 218:551–571.

Matsushita M et al: Anatomical organization of the spinocerebellar system in the cat as studied by
retrograde transport of horseradish peroxidase. J Comp Neurol 1979; 184:81–106.

Moberg E: The role of cutaneous afferents in position sense, kinesthesia, and motor function of the hand.
Brain 1983; 106:1–19.

Nathan PW et al: Sensory effects in man of lesions of the posterior columns and of some other afferent
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Nathan PW et al: The corticospinal tract in man: Course and location of fibers at different segmental
levels. Brain 1990; 113:303–324.

Priestley JV: Neuroanatomy of the spinal cord: Current research and future prospects. Paraplegia 1987;
25:198–204.

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125.

Scheibel ME, Scheibel AB: Inhibition and the Renshaw cell: A structural critique. Brain Behav Evol 1971;
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Schmahmann JD et al: The mysterious relocation of the bundle of Türck. Brain 1992; 115:1911–1924.

Schoenen J: The dendritic organization of the human spinal cord: The dorsal horn. Neuroscience 1982;
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Schoenen J: Dendritic organization of the human spinal cord: The motoneurons. J Comp Neurol 1982;
211:226–247.

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Terakawa H et al: Ipsilateral hemiparesis after putaminal hemorrhage due to uncrossed pyramidal tract.
Neurology 2000; 54:1801–1805.

Triggs WJ, Beric A: Sensory abnormalities and dysaesthesias in the anterior spinal artery syndrome.
Brain 1992; 115:189–198.

Van Keulen LCM: Axon trajectories of Renshaw cells in the lumbar spinal cord of the cat as reconstructed
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Editors: Afifi, Adel K.; Bergman, Ronald A.

Title: Functional Neuroanatomy: Text and Atlas, 2nd Edition

Copyright ©2005 McGraw-Hill

> Table of Contents > Part I - Text > 4 - Clinical Correlates of Spinal Cord Anatomy

4
Clinical Correlates of Spinal Cord Anatomy

Clinically Important Spinal Cord Structures

Motor Signs of Spinal Cord Disorders
Sensory Signs of Spinal Cord Disorders
Dorsal (Posterior) Column Signs
Lateral Spinothalamic Tract Signs
Sacral Sparing
Dorsal Root Signs
Anterior White Commissure Signs
Spinal Cord Syndromes
Segmental Lower Motor Neuron Syndrome
Hemisection (Brown-Séquard Syndrome)
Anterior Horn and Lateral Corticospinal Tract Syndrome (Motor Neuron Disease)
Lesions around Central Canal (Syringomyelia)
Combined System Degeneration Syndrome
Anterior Spinal Artery Syndrome
Transection
Conus Medullaris Syndrome
Cauda Equina Syndrome
Autonomic Syndromes

KEY CONCEPTS

Lesions in the thoracolumbar autonomic (sympathetic) neurons at or above T-2

result in ipsilateral Horner's syndrome.

Lesions in the sacral autonomic (parasympathetic) neurons between S-2 and S-

4 result in bladder and bowel dysfunction.

Lesions of the dorsal (posterior) column result in ipsilateral loss of kinesthesia

and discriminative touch at and below the level of spinal cord lesion.

Lesions of the lateral spinothalamic tract result in contralateral loss of pain and
temperature sensations beginning in dermatomes one or two segments below the
spinal cord lesion.

Sacral sparing helps differentiate intrinsic from extrinsic cord lesions.

Spinal cord lesions around the central canal characteristically present early
with bilateral segmental pain and thermal sensory loss.

Ascending and descending tracts in the posterior and lateral funiculi are
affected in Vitamin B 1 2 deficiency states as well as in a hereditary progressive
disorder, Friedreich's ataxia.

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The anterior two-thirds of the spinal cord is characteristically preferentially

involved in ischemic lesions.

Lesions of the conus medullaris are characterized by early sphincter

dysfunction and saddle anesthesia.

Lesions of the cauda equina manifest with ipsilateral sensory and lower motor
neuron–type signs of the affected nerve roots.

CLINICALLY IMPORTANT SPINAL CORD STRUCTURES

The following structures (Figure 4-1) are useful in clinical localization of spinal cord
disorders:

1. Descending tracts (motor function): Lateral corticospinal (pyramidal) tract

2. Ascending tracts (sensory function)

a. Dorsal (posterior) column (kinesthesia and discriminative touch)

b. Lateral spinothalamic tract (pain and temperature)

3. Neuronal populations

a. Anterior horn cells (somatic motor function)

b. Intermediolateral cell column (autonomic sympathetic function)

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c. Sacral autonomic neurons (autonomic parasympathetic function)

Figure 4-1. Schematic diagram of clinically important spinal cord structures

and effects of lesions in each.

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MOTOR SIGNS OF SPINAL CORD DISORDERS (Figure 4-1)

It is customary to classify motor signs of spinal cord disease into upper and lower motor
neuron signs:

1. Upper motor neuron signs (lesion of corticospinal tract)

a. Loss (paralysis) or diminution (paresis) of voluntary movement

b. Increase in muscle tone (spasticity)

c. Hyperreflexia (exaggerated deep tendon [myotatic] reflexes)

d. Clonus (repetitive involuntary alternating contractions of agonist and antagonist

muscle groups in response to sudden maintained stretching force)

e. Abnormal superficial plantar reflex (Babinski sign). The Babinski sign, described
by the French neurologist Josef-François-Felix Babinski as “the phenomenon of
the toes,” consists of dorsiflexion of the hallux and fanning of the toes in
response to painful stimulation of the sole of the foot.

All these signs occur ipsilateral and below the level of the spinal cord lesion.

2. Lower motor neuron signs (lesion of anterior horn cells)

a. Loss (paralysis) or diminution (paresis) of voluntary movement

b. Decrease in muscle tone (hypotonia)

c. Hyporeflexia (decrease) or areflexia (absence) of deep tendon (myotatic) reflexes

d. Fibrillations and/or fasciculations (spontaneous activity of muscle fibers at rest)

e. Muscle atrophy

All these signs occur ipsilateral and in muscles (myotomes) supplied by the affected
motor neurons.

3. Autonomic neuron signs

a. Intermediolateral (sympathetic) cell column (T-1 to L-2): Lesions in the

intermediolateral cell column at or above T-2 spinal cord segment are
associated with the following conglomerate of signs collectively known as the
Horner's syndrome: miosis (small pupil), pseudoptosis (minimal drooping of
eyelids), anhidrosis (absence of sweating over the face), and enophthalmos
(slight retraction of eyeball)

All these signs occur ipsilateral to the lesion in the spinal cord. Johann Friedrich
Horner, a Swiss ophthalmologist, is credited with the first complete description of
this syndrome in humans, although Claude Bernard described the same ocular
changes in animals 7 years earlier. (The syndrome is also known as the Bernard-
Horner syndrome.)

b. Sacral autonomic (parasympathetic) neurons (S-2 to S-4): Lesions in the

sacral autonomic area are associated with urinary incontinence and bowel
incontinence.

SENSORY SIGNS OF SPINAL CORD DISORDERS

Dorsal (Posterior) Column Signs (Figures 4-1 and 4-2)

Lesions in the dorsal column are usually associated with diminution or loss of

1. Vibration sense

2. Position sense

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3. Two-point discrimination

4. Deep touch

All these signs occur ipsilateral to the affected posterior column in dermatomes at and
below the level of the spinal cord lesion.

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Lateral Spinothalamic Tract Signs (Figures 4-1 and 4-3)

Figure 4-2. Schematic diagram showing the pattern of sensory deficit resulting from a
lesion in the posterior column.

Lesions affecting the lateral spinothalamic tract are associated with diminution or loss
of

1. Pain sensations

2. Temperature sensations

Deficits in pain and temperature sensations occur contralateral to the affected tract in
dermatomes beginning one or two segments below the level of the spinal cord lesions.

Sacral Sparing
Because of the pattern of lamination of nerve fibers in the spinothalamic tract (sacral
fibers lateral, cervical fibers medial), extrinsic cord lesions (such as a tumor in the

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meninges that compresses the spinal cord from the outside) will affect sacral fibers early,
whereas intrinsic spinal cord lesions (such as a tumor arising within the spinal cord) will
affect cervical fibers early and sacral fibers late or not at all (sacral sparing).

Dorsal Root Signs (Figure 4-4)

Lesions affecting one or more dorsal roots are associated with diminution or loss of all
sensory modalities (anesthesia) ipsilateral and in dermatomes supplied by the involved
dorsal root(s).

Figure 4-3. Schematic diagram showing the pattern of sensory deficit resulting from a
lesion in the lateral funiculus involving the lateral spinothalamic tract.

Anterior White Commissure Signs (Figure 4-5)

Lesions in the anterior white commissure are associated with bilateral diminution or loss of
pain and temperature (sensory modalities that cross in the anterior white commissure)
sensations in dermatomes supplied by the involved spinal cord segments. Although fibers
carrying light touch also travel in the anterior white commissure, no deficit in light touch
occurs because this sensory modality is also represented in the posterior column.

SPINAL CORD SYNDROMES

The following clinicopathologic syndromes are encountered in clinical practice.

Segmental Lower Motor Neuron Syndrome (Figure 4-6)

Lesions of spinal motor neurons in the anterior horn are associated with a lower motor

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neuron syndrome (paralysis, hypotonia, areflexia, muscle atrophy, fasciculations) ipsilateral

to the cord lesion and in muscles (myotomes) supplied by the affected spinal
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cord segments. This syndrome is commonly seen in the disease poliomyelitis.

Figure 4-4. Schematic diagram showing the distribution of sensory deficit resulting
from a lesion in the dorsal root.

Hemisection (Brown-Séquard Syndrome) (Figure 4-7)

This syndrome is named after the neurologist Charles Edouard Brown-Séquard, who first
described the syndrome. The following signs will be detected in hemisection of the spinal
cord. The nuclear groups or tracts giving rise to these signs are listed.

1. Ipsilateral signs. Signs ipsilateral to the spinal cord lesion are

a. Corticospinal tract signs. The following upper motor neuron signs occur at and
below the level of the hemisection:

1. Muscle paralysis

2. Spasticity

3. Hyperactive myotatic reflexes

4. Babinski sign

5. Clonus

b. Posterior column signs. These include loss of the following sensations at and

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below the level of the hemisection:

1. Vibration

2. Position

3. Two-point discrimination

4. Deep touch

Figure 4-5. Schematic diagram showing the distribution of sensory

deficit resulting from a lesion in the anterior white commissure.

c. Ventral horn signs. The following lower motor neuron signs are found in muscles
(myotomes) supplied by the affected spinal cord segment(s):

1. Muscle paralysis

2. Muscle atrophy

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Figure 4-6. Schematic diagram showing the site of the lesion in

segmental lower motor neuron syndrome and associated neurologic
signs.

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3. Loss of myotatic reflexes

Figure 4-7. Schematic diagram showing the site of the lesion in spinal
cord hemisection and associated neurologic signs.

4. Fibrillations and fasciculations

5. Hypotonia

2. Contralateral signs. Signs contralateral to the spinal cord lesion are lateral
spinothalamic tract signs. Loss of pain and thermal sense in the contralateral half of

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the body in dermatomes beginning one or two segments below the level of
hemisection.

3. Bilateral signs. Segmental loss of pain and thermal sense in dermatomes one or two
segments below the level of the hemisection due to interruption of spinothalamic fibers
crossing in the anterior white commissure.

Anterior Horn and Lateral Corticospinal Tract Syndrome

(Motor Neuron Disease) (Figure 4-8)
This syndrome is known clinically as motor neuron disease or amyotrophic lateral sclerosis.
This disorder is also known as Lou Gehrig's disease. It is a degenerative disease affecting
the anterior horn and the lateral corticospinal tract bilaterally. It is thus manifested by a
combination of lower and upper motor neuron signs, including paralysis, muscular atrophy,
fasciculation and fibrillation, exaggerated myotatic reflexes, and a Babinski sign. This is a
progressive condition that involves the spinal cord as well as motor nuclei of cranial nerves
in the brain stem. For unexplained reasons, motor neurons in the brain stem controlling eye
movements and sacral neurons controlling sphincter function are usually spared. Life
expectancy is usually three to five years after onset.

Figure 4-8. Schematic diagram showing the spinal cord structures involved in motor
neuron disease and associated neurologic signs.

Lesions Around Central Canal (Syringomyelia) (Figure 4-

9)
Lesions in or around the central canal will encroach initially on the fibers conveying
pain and temperature in the anterior white commissure. The effect of such
encroachment will be segmental and bilateral loss of temperature and pain sensations in the
corresponding dermatomes. Such a
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lesion is characteristic of the clinical condition known as syringomyelia. This type of lesion
usually affects the cervical spinal segments but may affect other segments of the spinal
cord as well. In some patients, the lesion (syrinx) may extend to the brain stem
(syringobulbia). In most instances, the original lesion may progress to involve, in addition
to the anterior white commissure, the anterior, lateral, and/or posterior columns of the
spinal cord, with symptoms and signs corresponding to the affected structures.

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Figure 4-9. Schematic diagram showing the site of the lesion in syringomyelia and
associated neurologic signs.

Combined System Degeneration Syndrome

In this syndrome, there is bilateral but selective degeneration of some of the posterior
and lateral column tracts with loss of kinesthesia and discriminative touch, as well as
upper motor neuron signs (Figure 4-10). It is seen in patients with pernicious anemia
(vitamin B 1 2 deficiency). In a hereditary form of this syndrome, known as Friedreich's ataxia
(after the German pathologist Nikolaus Friedreich, who described the condition), the
spinocerebellar tracts are also involved bilaterally in the degenerative process.

Figure 4-10. Schematic diagram showing the affected spinal cord tracts in combined
system degeneration and associated neurologic signs.

Anterior Spinal Artery Syndrome (Figure 4-11)

This syndrome is due to occlusion of the anterior spinal artery that supplies the
anterior two-thirds of the spinal cord. The syndrome is characterized by abrupt onset

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of symptoms and signs. Flaccid (lower motor neuron) paralysis (spinal shock) occurs within
minutes or hours below the level of the lesion and is associated with impaired bowel and
bladder functions. Dissociated sensory loss characterized by loss of pain and temperature
sensations (lateral spinothalamic tract lesion) and preservation of kinesthesia and
discriminative touch sensations (sparing of posterior column) occurs below the level of the
spinal cord lesion. With time, upper motor neuron signs predominate (withdrawal of
supraspinal inhibition). Some patients develop painful dysesthesia about 6 to 8 months after
onset of neurologic symptoms. This is attributed either to sparing of spinoreticulothalamic
tract or to alteration of central nervous system interpretation of sensory input as a result of
the imbalance produced by an intact posterior column and impaired lateral spinothalamic
sensory input.

Transection
The following signs will be detected in transection of the spinal cord, as occurs in transverse
myelitis due to a demyelinating lesion as in multiple sclerosis or to trauma, inflammation, or
ischemia.

A. SPINAL SHOCK
Complete transection of the spinal cord results in disturbances of motor, sensory, and
autonomic functions. The manifestations of such a lesion in the immediate and early stages
(2 to 3 weeks) differ from those in later stages.

1. Motor manifestations. In the immediate and early stages following transection, there is
flaccid and bilateral paralysis of all muscles (myotomes) innervated by segments of the
spinal cord affected by the transection, as well as those myotomes below the level of
the transection. The flaccid paralysis of muscles below the level of the lesion, however,
will change into the spastic (upper motor neuron) variety in later stages. Flaccid
paralysis of muscles innervated by the affected spinal cord segments is attributed to
injury of motor neurons in the anterior horn or their ventral roots. The early flaccid
paralysis below the level of the lesion is attributed to the sudden withdrawal of a
predominantly facilitating or excitatory influence from supraspinal centers. The spastic
type of paralysis that follows later is attributed to release of segmental reflexes below
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the level of the lesion from supraspinal inhibitory influences. This spastic paralysis
results in the development of flexor spasms that eventually change into extensor
spasms. During the stage of flexor spasm, the patient's paralyzed limbs are kept in
almost permanent hip and knee flexion (paraplegia-in-flexion). In the extension spasm
stage, the limbs are kept extended at the knee and ankle (paraplegia-in-extension).
Experience with war victims has shown that paraplegia-in-flexion occurs in complete
(whole segment[s]) cord transection, whereas paraplegia-in-extension occurs in
incomplete (partial) cord lesion.

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Figure 4-11. Schematic diagram showing the extent of the spinal cord lesion in
the anterior spinal artery syndrome and associated neurologic signs.

2. Sensory manifestations. All sensations are lost bilaterally at and below the level of the
transection. In addition, there is a hyperpathic zone at the border of the lesion and for
one or two dermatomes above it. In this hyperpathic zone, the patient complains of
pain of a burning character.

3. Bladder function. In the immediate and early stages following transection, all volitional
or reflex functions of the urinary bladder are lost, resulting in urinary retention. This
may last from 8 days to 8 weeks. Subsequently, a state of automatic bladder emptying
develops. In this state, once a sufficient degree of bladder distension occurs, sensory
receptors in the bladder wall evoke reflex contraction of the detrusor muscle, thus
emptying the bladder.

4. Bowel function. Similar to bladder function, the immediate and early effect of cord
transection is paralysis of bowel function and fecal retention. This is changed in later
stages to intermittent automatic reflex defecation.

5. Sexual function. Erection and ejaculatory functions are lost in males in the immediate
and early stages. Later on, reflex erection and ejaculation appear as a component of
the automatic activity of the isolated cord and are evoked by extrinsic and intrinsic
stimuli. In the female, there may be temporary cessation of menstruation and
irregularities in the menstrual cycle.

Conus Medullaris Syndrome

Lesions of the conus (usually tumors) are characterized by early sphincter dysfunction,
urinary incontinence, loss of voluntary emptying of the bladder, increased residual
urine volume, and absent sensation of the urge to urinate. In addition, constipation and
impairments in erection and ejaculation occur. Symmetric loss of sacral sensations (saddle
anesthesia) along the distribution of S-2 to S-4 dermatomes is found. Pain is unusual, but
dull aching pain may occur over the region of the tumor. Usually there is no motor deficit
until S-1 and L-5 roots are involved. Loss of ankle jerk may then be the early sign.

Cauda Equina Syndrome

Lesions of the cauda equina give rise to symptoms and signs related to the affected
nerve roots. In general, there is early occurrence of radicular pain in dermatomes
supplied by the affected roots. Lower motor neuron–type paresis or paralysis occurs in
muscles supplied by the affected nerves. In high cauda equina lesions, for example,
affecting the L-2 to L-4 nerves, on the right side, the patient will have ipsilateral wasting
and weakness of quadriceps and adductor thigh muscles and absent knee jerk. Sensory loss
will be evident in L-2 to L-4 dermatomes. If the tumor compresses the spinal cord, upper
motor neuron–type signs will be present. For example, in L-2 to L-4 tumor, there will be
ipsilateral Babinski sign, ankle clonus, and weakness of dorsiflexion of foot. Sphincter
disturbances are usually late occurrences in cauda equina lesions.

Clinical differentiation between lesions of the conus medullaris and cauda equina is often
difficult. In general, however, lesions of the conus medullaris are associated with early
sphincter disturbance and symmetric loss of sacral sensations. Pain is unusual in conus
lesions. In contrast, cauda equina lesions are associated with early radicular pain and late
sphincter disturbance.

Autonomic Syndromes
A. RESPIRATORY DYSFUNCTION
Three patterns of respiratory insufficiency may occur in spinal cord lesions. The first is

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reduction in respiratory vital capacity due to weakness of the diaphragm and intercostal
muscles as a result of interruption of the descending motor pathways. The second is
reduction in CO 2 responsivity without reduction in vital capacity and without overt weakness
of the diaphragm or chest wall muscles. The basis of this phenomenon is presumed to
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be interruption of ascending ventrolateral quadrant nerve fibers, which augment the
response of the respiratory center to CO 2 . The third is a combination of the preceding two
syndromes, namely, reduced vital capacity from muscle weakness as well as reduced
responsivity to CO 2 . This deficit may indicate interruption of both ascending and descending
pathways.

B. AUTONOMIC RESPIRATORY DYSFUNCTION SYNDROME

Interruption of the ventrolateral white matter of the cervical region causes a distinct
autonomic respiratory dysfunction syndrome. The full syndrome consists of (1) respiratory
arrest or sleep apnea (core sign) and variable onset of one or more of the following: (2)
hypotension, (3) hyponatremia, (4) inappropriate antidiuretic hormone secretion, (5)
hypohidrosis, and (6) urinary retention. The syndrome may appear suddenly or within hours
following cordotomy. It may last days to weeks.

C. AUTONOMIC DYSFUNCTION SYNDROME

This is an episodic autonomic dysreflexia syndrome seen in the chronic stages after cord
section rostral to T-5. In this syndrome, a specific stimulus (usually distension of bladder or
rectum) sets off excessive sweating (especially rostral to the level of the lesion), cutaneous
flushing, hypertension, pounding headache, and reflex bradycardia.

TERMINOLOGY
Amyotrophic lateral sclerosis.
Progressive degenerative central nervous system disorder characterized by muscle
weakness and wasting combined with pyramidal tract signs. The pathology primarily affects
spinal and cranial nerve motor neurons and the corticospinal (pyramidal) tract. The
condition is also known as motor neuron disease, Charcot syndrome, progressive muscular
atrophy, Aran-Duchenne disease, and Lou Gehrig's disease.

Babinski sign.
An upper motor neuron sign consisting of dorsiflexion of the big toe and fanning out of the
rest of the toes in response to stimulation of the sole of the foot. Described in detail by
Josef-François-Felix Babinski, French neurologist, in 1896.

Brown-Séquard syndrome.
A spinal cord syndrome characterized by ipsilateral loss of pyramidal and posterior column
signs and contralateral spinothalamic signs, due to cord hemisection. Described by Charles
Edouard Brown-Séquard, Eurasian and Irish American neurologist, in 1850.

Clonus (Greek klonos, “turmoil”).

Repetitive involuntary contractions of agonist and antagonist muscles in response to
stretch. A sign of upper motor neuron disease.

Fasciculations.
Local, spontaneous, contraction of a group of muscle fibers, usually visible under the skin
due to denervation. The term was introduced by Derek Denny Brown, English neurologist.

Fibrillations.
Spontaneous contraction of a single muscle fiber not visible by the naked eye but recorded
by electromyography. A sign of denervation.

Friedreich's ataxia.
Progressive hereditary degenerative central nervous system disorder characterized by
combination of posterior column, lateral corticospinal, and spinocerebellar tracts signs.
Described by Nikolaus Friedreich, German pathologist in 1863.

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Horner's syndrome.
Drooping of the eyelid (ptosis), constriction of the pupil (miosis), retraction of the eyeball
(enophthalmos), and loss of sweating on the face (anhidrosis) comprise a syndrome
described by Johann Friedrich Horner, Swiss ophthalmologist, in 1869. The syndrome is due
to interruption of descending sympathetic fibers. The syndrome was described in animals by
Francois du Petit in 1727. Claude Bernard in France in 1862, and E. S. Hare in England in
1838 gave precise accounts of the syndrome before Horner

Hyperpathic (Greek hyper, “above or excessive”; pathia, “pain”).

Abnormally exaggerated subjective response to painful stimuli

Hypohidrosis (Greek hypo, “below”; hidros, “sweat”).

Decreased sweating, as seen in the face in those with Horner's syndrome

Inappropriate antidiuretic hormone secretion.

Excessive secretion of antidiuretic hormone (ADH) by the posterior pituitary gland leading
to excessive urine output, and hyponatremia associated with serum hypoosmolarity and
urine hyperosmolarity.

Kinesthesia (Greek kinesis, “motion”; aisthesis, “sensation”).

Sense of perception of movement

Lou Gehrig.
Renowned first base player for the New York Yankees from 1923–1939. Had a lifetime
batting average of .340 with a record 23 grand slams. Died of amyotrophic lateral sclerosis.
Other famous personalities afflicted with the disease include actor David Niven, senator
Jacob Javits, heavyweight boxer Ezzard Charles, physicist Stephen Hawking, photographer
Eliot Porter, and composer Dmitri Shostakovich.

Paraplegia (Greek para, “beside”; plege, “stroke”).

Paralysis of the legs.

Saddle anesthesia.
Sensory deficit in the anal, perianal, and genital regions; buttocks; and posterior upper
thighs due to a lesion in the second to the fourth sacral segments of the spinal cord or their
roots.

Syringobulbia (Greek syrinx, “pipe, tube”; bolbos, “bulb”).

Extension of syringomyelic cavity from the spinal cord to the brain stem.

Syringomyelia (Greek syrinx, “pipe, tube”; myelos, “marrow”).

Longitudinal cystic cavitation within the spinal cord of developmental or acquired etiology.
Clinical signs were described by Sir William Withey Gull, English physician, in 1862. The
term was introduced by Hans Chiari, Austrian pathologist in 1888.

Syrinx (Greek syrinx, “pipe, tube”).

Fluid-filled space longitudinal cavitation of the spinal cord or brain stem of developmental
or acquired etiology.

SUGGESTED READINGS
Biller J, Brazis PW: The localization of lesions affecting the spinal cord. In Brazis PW, et
al (eds): Localization in Clinical Neurology. Boston, Little, Brown, 1985:63.

Guttman L: Clinical symptomology of spinal cord lesions. In Vinken RJ, Bruyn GW (eds):
Handbook of Clinical Neurology, vol 2. Amsterdam, North-Holland, 1978:178.

Nathan PW et al: Sensory effects in man of lesions of the posterior columns and of some
other afferent pathways. Brain 1986; 109:1003–1041.

Triggs WJ, Beric A: Sensory abnormalities and dysaesthesias in the anterior spinal

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artery syndrome. Brain 1991; 115:189–198.

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Editors: Afifi, Adel K.; Bergman, Ronald A.

Title: Functional Neuroanatomy: Text and Atlas, 2nd Edition

Copyright ©2005 McGraw-Hill

> Table of Contents > Part I - Text > 5 - Medulla Oblongata

5
Medulla Oblongata

Gross Topography
Ventral (Anterior) Surface
Dorsal (Posterior) Surface
Fourth Ventricle
Internal Structure
Level of Motor (Pyramidal) Decussation
Level of Sensory (Lemniscal) Decussation
Area Postrema
Level of Inferior Olive
Medullary Reticular Formation
Inferior Cerebellar Peduncle (Restiform Body)
Cranial Nerve Nuclei of the Medulla
Hypoglossal Nerve (Cranial Nerve XII)
Accessory Nerve (Cranial Nerve XI)
Vagus Nerve (Cranial Nerve X)
Glossopharyngeal Nerve (Cranial Nerve IX)
Vestibulocochlear Nerve (Cranial Nerve VIII)
Nucleus Solitarius
The Medulla and Cardiovascular Control
The Medulla and Respiratory Function
Neurogenic Pulmonary Edema
The Medulla and Sneezing
The Medulla and Swallowing
Neuroanatomy of Vomiting
Neuroanatomy of Yawning
Neurotransmitters and Neuropeptides
Blood Supply of the Medulla

KEY CONCEPTS

The ventral surface of the medulla oblongata shows the pyramids, the pyramidal decussation, and the
inferior olives.

The dorsal surface of the medulla shows the clava (gracile nucleus), the cuneate tubercle (cuneate
nucleus), and the hypoglossal and vagal trigones (surface markings of the hypoglossal nucleus and dorsal
motor nucleus of the vagus, respectively).

At the pyramidal decussation, 75 to 90 percent of corticospinal fibers decussate to form the lateral
corticospinal tract.

Dorsal column nuclei receive input from the dorsal column (gracile and cuneate tracts) as well as
from the cerebral cortex and other suprasegmental sites.

The output of the dorsal column nuclei projects to the thalamus via the medial lemniscus.

The proximity of the spinal trigeminal nucleus to the spinothalamic tract in the medulla is responsible
for the crossed sensory deficit (ipsilateral face and contralateral body) described in patients with
medullary lesions.

The medial lemniscus conveys dorsal column sensations (kinesthesia and discriminative touch) to the
thalamus.

The accessory (lateral) cuneate nucleus is homologous to the nucleus dorsalis (Clarke's nucleus) in
the spinal cord and thus is part of the spinocerebellar system of unconscious proprioception.

The area postrema in the caudal fourth ventricle belongs to the group of circumventricular organs
devoid of blood-brain barrier.

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The inferior olivary complex serves as a relay between cortical and subcortical areas and the
cerebellum.

The inferior cerebellar peduncle (restiform body) links the spinal cord and medulla with the
cerebellum.

Lesions of the hypoglossal nucleus or nerve result in ipsilateral tongue atrophy, fasciculations, and
weakness. The protruded tongue deviates toward the weak atrophic side.

Vascular occlusion of the anterior spinal artery in the medulla produces crossed motor or sensory
syndromes characterized by ipsilateral tongue paralysis and contralateral loss of kinesthesia and
discriminative touch (medial lemniscus) and/or the contralateral upper motor neuron syndrome
(pyramid).

The accessory nerve has two components: the spinal, which supplies the sternocleidomastoid and the
upper part of the trapezius muscles, and the cranial, which forms the recurrent laryngeal nerve of the
vagus and supplies the intrinsic muscles of the larynx.

The vagus nerve has two motor nuclei (the dorsal motor nucleus and the nucleus ambiguus) and two
sensory nuclei (the nucleus solitarius and the spinal trigeminal nucleus).

The glossopharyngeal nerve has two motor nuclei (the nucleus ambiguus and the inferior salivatory
nucleus) and two sensory nuclei (the nucleus solitarius and the spinal trigeminal nucleus).

Two regions in the medulla are concerned with respiratory function: dorsal in the nucleus solitarius
and ventral in the nuclei ambiguus and retroambiguus.

Two regions in the medulla oblongata are linked to swallowing: a dorsal region in and near the
nucleus solitarius and a ventral region around the nucleus ambiguus.

A vomiting center has been identified in the dorsolateral medullary reticular formation, and a
chemoreceptor trigger zone for vomiting has been identified in the area postrema.

The medulla oblongata is divided into four vascular territories: paramedian, olivary, lateral, and
dorsal.

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GROSS TOPOGRAPHY

Ventral (Anterior) Surface

The anterior median fissure of the spinal cord continues on the ventral (anterior) surface of the medulla
(Figure 5-1). On each side of this fissure are the medullary pyramids. These pyramids carry descending
corticospinal fibers from the cerebral cortex to the lateral and anterior corticospinal tracts in the spinal cord and
carry corticobulbar fibers to cranial nerve nuclei in the brain stem. In the lower part of the medulla, the
corticospinal fibers in the pyramid partly cross to the opposite side to form the lateral corticospinal tract. This
decussation, or crossing, forms the basis for the motor control of one cerebral hemisphere over the contralateral
half of the body and is known as the motor or pyramidal decussation. The pyramids are bounded laterally by the
anterolateral (ventrolateral) sulcus, a continuation of the same structure in the spinal cord. Lateral to this sulcus,
approximately in the middle of the medulla, are the inferior olives. Lateral to each olive is the posterolateral
(dorsolateral) sulcus. Rootlets of the hypoglossal nerve (cranial nerve XII) exit between the pyramids and olives in
the anterolateral sulcus. Rootlets of the accessory (cranial nerve XI), vagus (cranial nerve X), and
glossopharyngeal (cranial nerve IX) cranial nerves exit lateral to the olives.

Dorsal (Posterior) Surface

The posterior (dorsal) median sulcus and the posterolateral (dorsolateral) sulcus of the spinal cord continue on the
dorsal surface of the medulla (Figure 5-2). Between these two surface landmarks are the rostral prolongations of
the gracile and
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cuneate tracts and their nuclei.

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Figure 5-1. Schematic diagram showing the major structures seen on the ventral surface of the medulla
oblongata.

Figure 5-2. Schematic diagram showing the major structures seen on the dorsal surface of the brain stem.

On the dorsal surface of the medulla, the gracile and cuneate nuclei form protuberances known as the clava
and cuneate tubercles, respectively. Lateral to the cuneate tubercle, between it and the posterolateral sulcus,
is the tuberculum cinereum, which represents the surface marking of the spinal nucleus of the trigeminal nerve
(cranial nerve V).

Fourth Ventricle
A. FLOOR
The caudal part of the floor of the fourth ventricle is formed by the dorsal surface of the medulla oblongata
(Figure 5-3). The rostral part of the floor is formed by the pons. The medullary and pontine parts of the floor form
a diamond-shaped structure. The medullary part of the floor has the following surface landmarks.

1. Posterior Median Fissure.

This fissure is a continuation of the posterior median sulcus of the spinal cord.

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Figure 5-3. Schematic diagram showing the major structures seen in the floor of the fourth ventricle.

2. Hypoglossal Trigone.
This trigone is a protuberance of the nucleus of the hypoglossal nerve (cranial nerve XII) into the floor of the
fourth ventricle.

3. Vagal Trigone.
Lateral to the hypoglossal trigone is a protuberance of the dorsal motor nucleus of the vagus nerve (cranial nerve
X) into the floor of the fourth ventricle.

The pontine part of the floor contains the facial colliculus, which represents the surface markings of the
subependymal bundle of the facial nerve (cranial nerve VII), making a loop around the nucleus of the abducens
nerve (cranial nerve VI).

Between the rostral (pontine) and caudal (medullary) parts of the floor of the fourth ventricle is an intermediate
zone containing the stria medullaris, a fiber bundle which courses laterally. This is the surface landmark of the
arcuatocerebellar bundle of fibers running from the arcuate nucleus of the medulla oblongata to the cerebellum.

B. ROOF
Three structures form the roof of the fourth ventricle: the anterior medullary velum, the cerebellum, and the tela
choroidea (Figure 5-4). The tela choroidea is formed by the neural ependyma (the original posterior [inferior]
medullary velum) covered by a mesodermal pia mater.

From the tela choroidea in the posterior part of the roof of the fourth ventricle, the choroid plexus projects as two
vertical and two lateral ridges, forming a T-shaped structure with a double vertical stem.

C. LATERAL BOUNDARIES
The lateral boundaries of the fourth ventricle (see Figure 5-3) are formed from rostral to caudal by the following
structures.

1. Brachium Conjunctivum.
This structure connects the cerebellum and the midbrain.

2. Restiform Body.
This structure connects the medulla oblongata and the cerebellum.

3. Clava and Cuneate Tubercles.

These are the surface markings of the gracile and cuneate nuclei, respectively.

The lateral angles of the fourth ventricle are the lateral recesses.

INTERNAL STRUCTURE
The internal structure of the medulla is best understood when examined at three caudorostral representative
levels: the level of
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motor (pyramidal) decussation, the level of sensory (lemniscal) decussation, and the level of the inferior olive.

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Figure 5-4. Schematic diagram showing structures that form the roof and floor of the fourth ventricle.

Level of Motor (Pyramidal) Decussation

The two main distinguishing features of this level (Figure 5-5) are the pyramidal decussation and the dorsal
column nuclei.

A. PYRAMIDAL DECUSSATION
Although the concept of the control of one side of the body by the contralateral hemisphere (law of cruciate
conduction) has existed since the time of Hippocrates, the actual crossing of the pyramids was not observed until
1709; it was described in the following year. This description was ignored, however, until Gall and Spurzheim
called attention to it in 1810. Many anat-omists denied the existence of the pyramidal decussation until 1835,
when Cruveilhier traced the pyramidal bundles to the opposite side.

The pyramids contain two types of descending cortical fibers: corticospinal and corticobulbar. The
corticospinal fibers are somatotopically organized. The fibers of the lower extremities are more lateral than
are those of the upper extremities. As they descend in the medulla oblongata, corticobulbar fibers leave the
pyramid to project on the nuclei of cranial nerves. Near the caudal border of the medulla, roughly 75 to 90
percent of the corticospinal fibers in the pyramid decussate to the opposite side to form the lateral corticospinal
tract. The rest of the corticospinal fibers descend homolaterally to form the anterior corticospinal tract. It has
been observed that the left pyramid decussates first in 73 percent of humans; this, however, bears no relationship
to the handedness of an individual. The corticospinal fibers that convey impulses to the neck and upper extremity
musculature cross first. These fibers are separate from and rostral to those conveying impulses to the lower
extremities; they are also more superficially located and are identified in the lower medulla in close proximity to
the odontoid process of the second cervical vertebra. Because of this anatomic location, fractures of the odontoid
process or mass lesions in that location result in paralysis of the muscles of the upper extremities but may spare
the muscles of the lower extremities. By contrast, paralysis of an ipsilateral arm and a contralateral leg
(hemiplegia cruciata) can result from a lesion in the lower medulla that injures the crossed fibers to the arm as
well as the uncrossed fibers to the leg (Figure 5-6).

The pyramidal decussation constitutes the anatomic basis for the voluntary motor control of one-half of the body
by the opposite cerebral hemisphere. As the pyramidal fibers decussate, the fibers of the medial longitudinal
fasciculus are displaced laterally.

B. DORSAL COLUMN NUCLEI

In the dorsal (posterior) column two nuclei appear: the nucleus gracilis in the tractus gracilis and the nucleus
cuneatus in the tractus cuneatus. They are collectively referred to as the dorsal column nuclei. The gracile nucleus
appears and disappears caudal to the cuneate nucleus. Caudally, both the nuclei and the tracts capping them are
seen; rostrally, only the nuclei are seen. The surface projections of these two nuclei into the dorsal (posterior)
surface of the medulla form the clava and cuneate tubercles.

The dorsal column nuclei are organized for the spatial origin of afferent fibers. Afferent fibers from C-1 to T-7
project to the nucleus cuneatus, whereas fibers below T-7 project to the nucleus
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gracilis. It has been shown in animal experiments that overlapping terminations are more extensive and irregular
in the gracile nucleus than in the cuneate nucleus, with less autonomous terminal representation of individual
dorsal roots.

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Figure 5-5. Photograph of caudal medulla oblongata at the level of the motor (pyramidal) decussation
showing major structures seen at this level.

Figure 5-6. Schematic diagram of the pattern of motor decussation to the upper and lower extremity motor
neurons showing how a rostral lesion A can result in bilateral upper extremity paralysis without lower
extremity paralysis, whereas a more caudal lesion B can result in hemiplegia cruciata. A, arm; T, trunk; L,
leg.

The dorsal column nuclei are not homogeneous cell masses. They contain several different types of nerve cells,

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and on the basis of the distribution of these cells and their afferent and efferent connections, the dorsal column
nuclei are divided into two distinct areas (Table 5-1): a core region and a reticular zone. The core region includes
the middle and caudal parts of each dorsal column nucleus. The reticular zone surrounds the core region and
consists of the rostral and deeper portions of the dorsal column nuclei.

Activity in the dorsal column nuclei is controlled by peripheral afferent inputs and is modulated by input from the
cerebral cortex and other suprasegmental sites (reticular formation, caudate nucleus, cerebellum). In general,
descending afferents are restricted in their distribution to the reticular zone.

Peripheral afferent inputs from cutaneous mechanoreceptors that are activated by mechanical stimulation
(touch, pressure, vibration, hair movement) in both forelimbs and hindlimbs are transmitted to the core
region of the dorsal column nuclei by primary afferents in the dorsal column. From the dorsal column nuclei, this
information reaches the thalamus (ventral posterolateral [VPL] nucleus) via the medial lemniscus. This primary
pathway accounts for roughly 20 percent of the fibers in the dorsal column. Collateral branches from these
primary afferents in the dorsal column synapse on second-order sensory neurons in the posterior horn of the
spinal cord.

The second-order (sensory) neurons then travel in the spinocervical thalamic tract, synapse on neurons in
the lateral cervical nucleus, and from there join the medial lemniscus to reach the VPL nucleus of the
thalamus. The existence of two pathways by which information from peripheral mechanoreceptors reaches the
thalamus (dorsal column and spinocervical thalamic tract) explains the preservation of sensations related to these
mechanoreceptors (touch, pressure, vibration) after a dorsal column lesion.

Proprioceptive pathways from joint (Golgi tendon organ) and muscle (spindle) receptors convey joint movement
and position sense, respectively, and are more complicated than the cutaneous mechanoreceptor pathways.
Afferents from upper extremity proprioceptors travel in the dorsal column (cuneate tract) and synapse on relay
cells in the cuneate nucleus and from there travel via the medial lemniscus to the thalamus. Afferents from lower
extremity proprioceptors, in contrast, reach the thalamus via two pathways. Those from some joint receptors
(rapidly adapting) travel through the dorsal column (gracile tract) to the dorsal column nuclei (gracile nucleus)
and from there project to the thalamus via the medial lemniscus. Afferents from muscle spindles and slowly
adapting joint receptors leave the gracile tract and synapse on cells of the dorsal (Clarke's) nucleus in the spinal
cord. Second-order neurons then travel via the dorsolateral fasciculus to nucleus of Z, a small collection of cells
situated in the medulla in the most rostral part of the nucleus gracilis. Fibers from this nucleus cross the midline
to join the medial lemniscus to reach the thalamus. The differential channeling of cutaneous and proprioceptive
information presumably is responsible for the differential loss of vibration and position senses in some patients
with spinal cord lesions.

Descending afferents to the dorsal column nuclei arise mainly from the primary somatosensory cortex with
contributions from the secondary somatosensory cortex and the primary motor and premotor cortices. This input
is somatotopically organized so that forelimb cortical areas project on the cuneate nucleus and hindlimb cortical
areas project on the gracile nucleus. Cortical inputs to the dorsal column nuclei travel via the internal capsule and
reach the nuclei via the pyramid. They project on interneurons in the reticular zone. Activation of descending
cortical input generally inhibits, via interneurons, the excitation of relay neurons.

Neurons in the dorsal column nuclei are influenced by facilitatory as well as inhibitory inputs (Figure 5-7).
Inhibition is mediated by reticular zone interneurons and is both presynaptic and postsynaptic. Presynaptic
inhibition is mediated by interneurons that form axoaxonic synapses on the terminals of dorsal column afferents.
These terminals in turn form excitatory synapses on relay neurons. Postsynaptic inhibition, in contrast, is
mediated by interneurons that form axodendritic and axosomatic synapses on relay neurons. Interneurons in the
reticular zone are excited by primary as well as postsynaptic fibers in the dorsal column. In
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turn, interneurons modulate the transmission of impulses from dorsal column afferents to relay neurons.

Table 5-1. Dorsal Column Nuclei

Core region Reticular zone

Location Middle and caudal Rostral and deeper

Neuron Type Relay Interneurons and relay

Input Posterior column (long ascending primary Posterior column (second-order

fibers) postsynaptic fibers, and dorsolateral
fasciculus)

Output Ventral posterolateral nucleus of thalamus Diffusely to thalamus, brain stem

nuclei, cerebellum

Primary Cutaneous (distal extremities) Cutaneous (distal and proximal

receptors extremities and axial)

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Other Joint and muscle proprioceptors (minority) Muscle and joint

receptors

Receptive Small Large

fields

Other Selective response to activation of a Input from cortical areas and reticular
particular cutaneous receptor excited by formation
specific stimuli

The main efferent projection of the dorsal column nuclei is the medial lemniscus, which terminates in the
thalamus. Other projections, which have been confirmed recently, include those to the inferior olive, tectum,
spinal cord, and cerebellum. The cerebellar fibers originate mainly from the cuneate nucleus with minor
contributions from the gracile nucleus. The function of these extrathalamic connections is not well understood.

C. SPINAL TRIGEMINAL NUCLEUS

Another feature seen at the level of the motor decussation is the spinal nucleus of the trigeminal nerve. This
nuclear mass occupies a dorsolateral position in the medulla and is capped by the descending (spinal) tract of the
trigeminal nerve. The spinal trigeminal nucleus extends throughout the medulla oblongata and descends caudally
to the level of C-3 in the cervical spinal cord. It is continuous caudally with the substantia gelatinosa of the spinal
cord and rostrally with the main sensory nucleus of the trigeminal nerve in the pons. The spinal tract and nucleus
of the trigeminal nerve are concerned with exteroceptive sensations (pain, temperature, and light touch) from the
ipsilateral face. The spinal nucleus is divided into three parts along its rostrocaudal extent. The caudal part, the
caudal nucleus, extends from the obex of the medulla oblongata rostrally to the substantia gelatinosa of the spinal
cord, with which it is continuous caudally. It mediates pain and temperature sensations from the ipsilateral side of
the face. Rostral to the obex is the nucleus interpolaris, which is distinct cytologically from the nucleus caudalis;
it mediates dental pain. Rostral to the interpolar nucleus and just caudal to the main sensory nucleus of the
trigeminal is the nucleus oralis, which mediates tactile sensations from the oral mucosa.

Figure 5-7. Schematic diagram depicting the major input and output of the posterior column nuclei, as well
as their internal circuitry.

Fibers of the spinal tract of the trigeminal nerve that originate from the mandibular region of the face project
down to the third and fourth cervical segments. Those from the perioral region of the face project to lower
medullary levels. Those originating between the mandible and the perioral region terminate in the upper cervical
region. Evidence in support of this “onion-skin” distribution pattern is found in patients in whom the spinal tract of
the trigeminal nerve is cut (tractotomies) to relieve pain. Thus, tractotomies that spare the lower medulla spare
pain and temperature sensations around the mouth. In contrast to the onion-skin pattern of distribution of
exteroceptive sensations on the face described by Dejerine in 1914, some observations suggest that all fibers
carrying pain impulses from the face, not only those from the mandible, reach lower cervical levels. Pain neurons
in the spinal trigeminal nucleus, like their counterparts in the spinal cord, have been classified physiologically into
high-threshold (HT), low-threshold (LT), and wide-dynamic-range (WDR) neurons. Specific thermoreceptive

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neurons have been localized on the outer rim of the nucleus. Axons of neurons in the spinal trigeminal nucleus
cross the midline to form the ventral trigeminothalamic tract which projects on neurons in the ventral
posteromedial (VPM) nucleus of the thalamus. From there, facial sensations are transmitted to the face area of the
primary somatosensory cortex. Within the trigeminothalamic tract, fibers from the ophthalmic branch (V 1 ) of the
trigeminal nerve are located most lateral and those from the mandibular branch (V 3 ) are most medial. In addition
to the major input from exteroreceptors in the face, the spinal trigeminal nucleus has been shown to receive an
input from the nucleus locus ceruleus in the pons and to send fibers back to the locus ceruleus. The input
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from the locus ceruleus is inhibitory. It should be pointed out that the spinal tract of the trigeminal conveys, in
addition to exteroceptive sensations from the face, general somatic fibers belonging to the facial (cranial nerve
VII), glossopharyngeal (cranial nerve IX), and vagus (cranial nerve X) nerves.

D. OTHER TRACTS
The following ascending tracts are also seen at the level of the motor decussation. The spinothalamic tracts
traverse the medulla in close proximity to the spinal nucleus and tract of the trigeminal nerve (Figure 5-5).
Lesions of the medulla in this location therefore produce sensory loss of pain and temperature sensation on the
face ipsilateral to the medullary lesion (spinal tract and nucleus of the trigeminal nerve) as well as loss of the
same sensations on the body contralateral to the medullary lesion (spinothalamic tract). Although the lateral and
anterior spinothalamic tracts retain their spinal cord positions in the caudal medulla, the position of the anterior
spinothalamic tract in the rostral medulla has not been definitively delineated in humans, and its fibers probably
run along with the lateral spinothalamic tract. As in the spinal cord, several lines of evidence support segregation
of pain and thermal fibers within the lateral spinothalamic tract in the medulla oblongata. Thus, a superficial
lesion in the medulla that only involves the dorsal portion of the lateral spinothalamic tract could result in isolated
loss of thermal sensation.

The spinal cord positions of the dorsal and ventral spinocerebellar tracts remain unchanged in the medulla (Figure
5-5).

Other ascending and descending tracts encountered in the spinal cord traverse the medulla on their way to higher
or lower levels.

Level of Sensory (Lemniscal) Decussation

A. MEDIAL LEMNISCUS
The distinguishing feature of the level of sensory decussation (Figure 5-8) is the crossing of second-order
neurons of the dorsal column system. Axons of relay neurons in the dorsal column nuclei course
ventromedially (internal arcuate fibers) and cross to the opposite side (sensory decussation) above the pyramids
to form the medial lemniscus. In the decussation, fibers derived from the gracile nucleus come to lie ventral to
those derived from the cuneate nucleus. The medial lemniscus thus carries the same modalities of sensation
carried by the dorsal column. The medial lemniscus projects on neurons in the VPL nucleus of thalamus. VPL, in
turn, projects to the primary somatosensory cortex. Lesions in the medial lemniscus result in a loss of kinesthesia
and discriminative touch contralateral to the side of the lesion in the medulla. The sensory decussation provides
part of the anatomic basis for the sensory representation of half of the body in the contralateral hemisphere. The
other part is provided by the crossing of the spinothalamic system in the spinal cord.

B. MEDIAL LONGITUDINAL FASCICULUS

The medial longitudinal fasciculus (MLF), displaced dorsolaterally by the pyramidal decussation, is pushed farther
upward
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by the sensory decussation so that it comes to lie dorsal to the medial lemniscus (Figure 5-8). It retains this
position throughout the extent of the medulla oblongata. Descending fibers in this bundle are derived from various
brain stem nuclei. Vestib-ular fibers in the bundle are derived from the medial and inferior vestibular nuclei. The
pontine reticular formation contrib-utes the largest number of descending fibers. Smaller groups of fibers arise
from Cajal's interstitial nucleus in the rostral midbrain.

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Figure 5-8. Photograph of medulla oblongata at the level of sensory (lemniscal) decussation showing major
structures seen at this level.

C. ACCESSORY CUNEATE NUCLEUS

A group of large neurons situated dorsolateral to the cuneate nucleus is known as the accessory (lateral or
external) cuneate nucleus. Although this nucleus shares its name with the cuneate nucleus, it does not
belong functionally to the dorsal column system; it is part of the dorsal spinocerebellar system. Fibers of the
dorsal spinocerebellar system entering the spinal cord above the level of C-8 (upper extent of the dorsal
[Clarke's] nucleus) ascend with the posterior column fibers and terminate on neurons of the accessory cuneate
nucleus. Second-order neurons from the accessory cuneate nucleus course dorsolaterally as dorsal external
arcuate fibers and reach the cerebellum (cuneocerebellar fibers) via the restiform body. Like the spinocerebellar
system, the cuneocerebellar tract is concerned with unconscious proprioception. Neurons in the accessory cuneate
nucleus have been shown to receive fibers from the glossopharyngeal (cranial nerve IX) and vagus (cranial nerve
X) nerves as well as from the vasopressor and cardioacceleratory areas of the posterior hypothalamus. Stimulation
of the accessory cuneate nucleus has been shown to produce bradycardia and hypotension. This response has
been shown to be due to vagal stimulation. It has been suggested that hypertension triggers the accessory
cuneate nucleus, via cardiovascular reflexes, to produce bradycardia and hypotension.

D. ARCUATE NUCLEI
A group of neurons on the anterior (ventral) aspect of the pyramid is known as the arcuate nucleus. The arcuate
nuclei increase in size significantly in rostral levels of the medulla and become continuous with the pontine nuclei
in the pons. The afferent and efferent connections of the arcuate nuclei are identical to those of the pontine
nuclei. Their major input is from the contralateral cerebral cortex; their major output is to the homolateral and
contralateral cerebellum via the restiform body. The arcuatocerebellar fibers reach the restiform body via two
routes (Figure 5-9). One route courses along the outer surface of the medulla (ventral external arcuate fibers);
the other route courses along the midline of the medulla and turns laterally in the floor of the fourth ventricle,
forming the stria medullaris of the floor of the fourth ventricle.

Area Postrema
In the floor of the caudal fourth ventricle, just rostral to the obex, is the area postrema, which is formed of
astroblast-like cells, arterioles, sinusoids, and some apolar or unipolar neurons. It is one of several central
nervous system areas that lack a blood-brain barrier. Collectively referred to as the circumventricular organs,
they include, in addition to the area postrema, the subfornical organ, subcommissural organ, pineal gland, median
eminence, neurohypophysis, and organum vasculosum. All except the area postrema are unpaired midline
structures that are related to the diencephalon. Stimulation of the area postrema in experimental animals induces
vomiting, suggesting the presence of a chemosensitive emetic center in this area.

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Figure 5-9. Schematic diagram illustrating the course of arcuatocerebellar fibers within the medulla
oblongata.

Level of Inferior Olive

The distinguishing feature of the level of the inferior olive (Figure 5-10) of the medulla is the appearance of the
inferior olivary nuclei, which are convoluted laminae of gray matter dorsal to the pyramids. They project from the
ventrolateral surface of the medulla as olive-shaped structures (Figure 5-1). The inferior olivary nuclear complex
consists of three nuclear groups:

1. Principal olive (the largest of the complex)

2. Dorsal accessory olive

3. Medial accessory olive

The olivary complex in humans is estimated to contain 0.5 million neurons. The complex is surrounded by a mass
of fibers known as the amiculum olivae.

The inferior olives receive fibers from the following sources (Figure 5-11):

1. Cerebral cortex via the corticospinal tract to both principal olives.

2. Basal ganglia to both principal olives via the central tegmental tract.

3. Mesencephalon from the periaqueductal gray matter of the midbrain and the red nucleus to the homolateral
principal olive via the central tegmental tract.

4. In the medulla oblongata, the dorsal column nuclei project to the contralateral accessory olive. The inferior
and medial vestibular nuclei project to both inferior olives. The two inferior olives are interconnected.

5. In the cerebellum, the deep cerebellar nuclei (dentate and interposed nuclei) project to the principal and
accessory inferior olives via the superior cerebellar peduncle.

6. From the spinal cord, to the accessory olives of both sides via the spino-olivary tract.

The major output of the inferior olivary complex is to the cerebellum (olivocerebellar tract). Olivocerebellar fibers
arise from both olivary complexes but come primarily from the
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contralateral complex. They pass through the hilum of the olive, traverse the medial lemniscus, and course
through the opposite olive to enter the restiform body on their way to the cerebellum. Olivocerebellar fibers
constitute the major component of the restiform body and are localized in the ventromedial part. Olivocerebellar
fibers originating from the accessory olives and the medial parts of the principal olives project onto the vermis of
the cerebellum, whereas fibers originating from the rest of the principal olive project to the cerebellar
hemispheres. The deep cerebellar nuclei also receive fibers from the olivocerebellar tract.

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Figure 5-10. Photograph of medulla oblongata at the inferior olive level showing major structures seen at
this level.

Figure 5-11. Schematic diagram showing major sources of input to the inferior olive.

Thus, the inferior olivary complex is a relay station between the cortex, subcortical structures, the spinal
cord, and the cerebellum.

The ascending and descending fiber tracts, as well as the nuclear complexes encountered in more caudal levels of
the medulla, are present at this level. The cranial nerve nuclei of the medulla are discussed in “Cranial Nerve
Nuclei of the Medulla,” below.

MEDULLARY RETICULAR FORMATION

The medullary reticular formation is characterized by a great number of neurons of various sizes and shapes
intermingled with a complex network of fibers. It spans the area between the pyramids (ventrally) and the floor of
the fourth ventricle (dorsally). It is phylogenetically old and in lower forms constitutes the major part of the
central nervous system. Caudally, the reticular formation appears at about the level of the pyramidal decussation.
Rostrally, it is continuous with the reticular formation of the pons. Physiologically, the reticular formation is a
polysynaptic system that is rich in collateral fibers for the dispersion of impulses. The cellular organization,
connections, and functions of the medullary reticular formation are discussed in Chapter 32.

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INFERIOR CEREBELLAR PEDUNCLE (RESTIFORM BODY)

The brain stem and cerebellum are connected by three peduncles:

1. The inferior cerebellar peduncle (Figures 5-3 and 5-12) between the medulla and the cerebellum

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2. The middle cerebellar peduncle (brachium pontis) between the pons and the cerebellum

3. The superior cerebellar peduncle (brachium conjunctivum) between the cerebellum and the midbrain

The inferior cerebellar peduncle (restiform body) is located on the dorsolateral border of the medulla
oblongata. It appears rostral to the clava and cuneate tubercles and forms a distinct bundle at about the
midolivary level. The fiber tracts contained within the inferior cerebellar peduncle include the following afferent
and efferent (medullary and spinal originating or destined) tracts:

1. Olivocerebellar tract (the largest component of this peduncle) connecting the inferior olive and cerebellum

2. Dorsal spinocerebellar tract from the nucleus dorsalis (Clarke's nucleus) to the cerebellum

3. Reticulocerebellar tract connecting the reticular formation with the cerebellum

Figure 5-12. Composite schematic diagram of the components of the inferior cerebellar peduncle
(restiform body).

4. Cuneocerebellar tract from the accessory cuneate nucleus to the cerebellum (homologous to the dorsal
spinocerebellar tract)

5. Arcuatocerebellar tract from the arcuate nucleus to the cerebellum

6. Cerebello-olivary tract from the cerebellum to the inferior olive

7. Trigeminocerebellar tract from the spinal nucleus of the trigeminal nerve (medulla) and the principal nucleus
of the trigeminal nerve (pons) to the cerebellum

8. Fibers from the perihypoglossal nuclei (concerned with eye movement) to the cerebellum

A small inner (medial) part of the restiform body is known as the juxtarestiform body. It contains the following
fiber tracts:

1. Cerebelloreticular tract from the cerebellum to the reticular formation

2. Cerebellovestibular tract from the cerebellum to the vestibular nuclei

3. Vestibulocerebellar, secondary vestibular fibers form the vestibular nuclei to the cerebellum

4. Direct vestibular nerve fibers to the cerebellum (with no synapse in the vestibular nuclei)

5. Cerebellospinal tract (from the cerebellum to motor neurons of the cervical spinal cord)

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Lesions in the inferior cerebellar peduncle result in the following symptoms and signs:

1. Ataxia (lack of coordination of movement) with a tendency to fall toward the side of the lesion

2. Nystagmus (involuntary rapid eye movement)

3. Muscular hypotonia

CRANIAL NERVE NUCLEI OF THE MEDULLA

The following cranial nerves have their nuclei in the medulla oblongata: (1) hypoglossal (cranial nerve XII), (2)
accessory (cranial nerve XI), (3) vagus (cranial nerve X), (4) glossopharyngeal (cranial nerve IX), and (5)
vestibulocochlear (cranial nerve VIII).

Hypoglossal Nerve (Cranial Nerve XII)

The hypoglossal nerve contains primarily somatic motor nerve fibers that innervate the intrinsic and extrinsic
muscles of the tongue. It also contains afferent proprioceptive fibers from the muscle spindles of tongue muscles.
The central termination of afferent proprioceptive fibers in the hypoglossal nerve is not known with certainty. The
nucleus of the solitary tract and the hypoglossal nucleus have been reported to receive these afferents.

The nucleus of the hypoglossal nerve extends throughout the medulla oblongata except for its most rostral and
caudal levels. It is divided into cell groups that correspond to the tongue muscles they supply. The surface
markings of the nucleus in the floor of the fourth ventricle are known as trigonum hypoglossi. The nucleus
receives both crossed and uncrossed corticoreticulobulbar fibers. The root fibers of the nerve course in the
medulla oblongata lateral to the medial lemniscus and emerge on the ventral surface of the medulla between the
pyramid and the inferior olive (Figure 5-13).

Figure 5-13. Schematic diagram of the origin and intramedullary course of rootlets of the hypoglossal nerve.

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A number of nuclear masses in close proximity to the hypoglossal nerve (cranial nerve XII) nucleus are believed to
be reticular neurons; they do not contribute fibers to the hypoglossal nerve. They are known as perihypoglossal or
satellite nuclei (nucleus intercalatus, nucleus prepositus, and Roller's nucleus). They receive input from the (1)
cerebral cortex, (2) vestibular nuclei, (3) accessory oculomotor nuclei, and (4) paramedian pontine reticular
formation.

The output of these nuclei terminates in (1) cranial nerve nuclei involved in extraocular movement (oculomotor,
trochlear, abducens), (2) the cerebellum, and (3) the thalamus.

The perihypoglossal nuclei and their connections are part of a complex circuitry related to eye movements.

Lesions in the hypoglossal nerve or nucleus result in lower motor neuron paralysis of the tongue musculature
homolateral to the lesion (Figure 5-14A), which is manifested by the following symptoms:

1. Decrease or loss of movement of the homolateral half of the tongue

2. Atrophy of muscles in the homolateral half of the tongue

3. Fasciculations of muscles in the homolateral half of the tongue

4. Deviation of the protruding tongue to the atrophic side (by action of the normal genioglossus muscle)

Lesions involving the rootlets of the hypoglossal nerve and the adjacent medial lemniscus within the medulla
result in the signs of hypoglossal nerve lesion detailed above and contralateral hemisensory loss of kinesthesia
and discriminative touch (Figure 5-14B). Extremely rare, sensory loss follows a dermatomal pattern
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reflecting the arrangement of posterior column fibers in the medial lemniscus (sacral fibers most ventral, cervical
fibers most dorsal).

Figure 5-14. Schematic diagram illustrating lesions of the hypoglossal nerve in its extra- and intramedullary
course, and the resulting clinical deficits of each.

Lesions involving the rootlets of the hypoglossal nerve and the adjacent pyramid within the medulla are
manifested by the signs and symptoms of a hypoglossal nerve lesion and contralateral upper motor neuron
paralysis (Figure 5-14C).

Intramedullary vascular lesions or tumors that involve the hypoglossal, cranial accessory, vagus, and
glossopharyngeal nerves and contralateral hemiparesis constitute Jackson's syndrome.

Intra- or extramedullary lesions that involve the hypoglossal, vagus, and glossopharyngeal nerves constitute
Tapia's syndrome.

Accessory Nerve (Cranial Nerve XI)

The accessory nerve (Figure 5-15) has two roots: spinal and cranial. The spinal root arises from the
accessory nucleus, a collection of motor neurons in the anterior horn of the upper five or six cervical spinal
segments and the caudal part of the medulla. From their cells of origin, the rootlets course dorsolaterally and exit
from the lateral part of the spinal cord between the dorsal and ventral roots. The spinal root of the accessory
nerve enters the cranial cavity through the foramen magnum and leaves it through the jugular foramen. The
spinal root contains somatic motor fibers that supply the sternocleidomastoid and trapezius (upper part) muscles.

The cranial root arises from the caudal pole of the nucleus ambiguus in the medulla oblongata. This root emerges
from the lateral surface of the medulla, joins rootlets of the vagus nerve (forming its recurrent laryngeal branch),
and supplies the intrinsic muscles of the larynx. Thus, the cranial root of the accessory nerve is in essence part of
the vagus nerve.

The recurrent laryngeal nerve is also known as Galen's nerve after Galen of Pergamon (A.D. 130–200), who took
pride in his discovery that the recurrent laryngeal nerves control the voice. Some scholars argue that the function
of the recurrent laryngeal nerve was described centuries before Galen.

The following are manifestations of unilateral lesions of the accessory nerve:

1. Downward and outward rotation of the scapula ipsilateral to the lesion

2. Moderate sagging of the ipsilateral shoulder

3. Weakness on turning the head to the side opposite the lesion

4. No observable abnormality of head position in repose

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The first two signs are due to impaired function of the trapezius muscle, and the third is due to impaired function
of the sternocleidomastoid muscle.

Vagus Nerve (Cranial Nerve X)

The vagus nerve (Figure 5-16), a mixed nerve containing both afferent and efferent fibers, is associated with four
nuclei in the medulla oblongata. The efferent components of the nerve are related to two medullary nuclei.

A. DORSAL MOTOR NUCLEUS OF THE VAGUS

The dorsal motor nucleus of the vagus is a column of cells dorsolateral or lateral to the hypoglossal nucleus
and extending both rostrally and caudally a little beyond the hypoglossal nucleus. Axons of neurons in this
column course ventrolaterally in the medulla and emerge from the lateral surface of the medulla between the
inferior olive and the inferior cerebellar peduncle. Axons arising from this nucleus are preganglionic
parasympathetic fibers that convey general visceral efferent impulses to the viscera in the thorax and abdomen.
Postganglionic fibers arise from terminal ganglia situated within or on the innervated viscera in the thorax and
abdomen. The dorsal motor nucleus of the vagus receives fibers from the vestibular nuclei; thus, excessive
vestibular stimulation
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(e.g., motion sickness) results in nausea, vomiting, and a change in heart rate.

Figure 5-15. Schematic diagram illustrating the neurons of origin of the accessory nerve, and muscles
supplied by the nerve.

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Figure 5-16. Schematic diagram of the components of the vagus nerve and the areas they supply.

B. NUCLEUS AMBIGUUS
The nucleus ambiguus is also known as the ventral motor nucleus of the vagus. It is a column of cells situated
about halfway between the inferior olive and the nucleus of the spinal tract of the trigeminal nerve. Axons of
neurons in this nucleus course dorsomedially and then turn ventrolaterally to emerge from the lateral surface of
the medulla between the inferior olive and the inferior cerebellar peduncle. These axons convey special visceral
efferent impulses to the branchiomeric muscles of the pharynx and larynx (pharyngeal constrictors, cricothyroid,
intrinsic muscles of the larynx, levator veli palatini, palatoglossus, palatopharyngeus, and uvula). In addition to
the vagus nerve, the nucleus ambiguus contributes efferent fibers to the glossopharyngeal (cranial nerve IX) and
accessory (cranial nerve XI) nerves.

The afferent components of the vagus nerve are related to two medullary nuclei:

1. Nucleus of the spinal tract of the trigeminal nerve. This nucleus receives general somatic afferent fibers from
the external ear, external auditory canal, and external surface of the tympanic membrane. The neurons of
origin of these fibers are in the superior (jugular) ganglion of the vagus nerve. The general somatic afferent
component of the vagus nerve is small, and its ganglion contains relatively few neurons. Somatic afferent
fibers in the vagus nerve descend in the spinal trigeminal tract and synapse in the nucleus of the spinal tract
of the trigeminal nerve.

2. Nucleus solitarius. This nucleus receives two types of visceral afferent fibers.

a. General visceral afferent fibers. These fibers convey general visceral sensations from the pharynx,
larynx, trachea, and esophagus as well as the thoracic and abdominal viscera.

b. Special visceral afferent fibers. These fibers convey taste sensations from the region of the epiglottis.

The neurons of origin of both types of afferent fibers reside in the inferior (nodosum) ganglion of the vagus. The
central processes of neurons in this ganglion enter the lateral surface of the medulla oblongata, course
dorsomedially, and form the tractus solitarius, which projects on cells of the nucleus solitarius. Neurons in the
latter nucleus are organized so that those receiving general visceral afferent fibers are located in the caudal and
medial part of the nucleus, whereas those receiving special visceral afferent fibers (taste) are located in the
rostral and lateral part. Caudally, the two solitary nuclei merge to form the commissural nucleus of the vagus
nerve. In addition to the vagus nerve, the nucleus solitarius receives general visceral afferent fibers from the
glossopharyngeal nerve (cranial nerve IX) and special visceral (taste) afferent fibers from the glossopharyngeal
(cranial nerve IX) and facial (cranial nerve VII) nerves.

The vagus nerve emerges from the medulla in a series of rootlets lateral to the inferior olive. The rootlets come to
form a single root that leaves the skull through the jugular foramen.

Bilateral lesions of the vagus nerve are fatal as a result of complete laryngeal paralysis and asphyxia.

Unilateral vagal lesions result in ipsilateral paralysis of the soft palate, pharynx, and larynx. This is manifested by
hoarseness of
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the voice, dysphagia (difficulty swallowing), and dyspnea (difficulty breathing).

Glossopharyngeal Nerve (Cranial Nerve IX)

The glossopharyngeal nerve (Figure 5-17), which is also a mixed nerve (containing both afferent and efferent
components), is associated with four nuclei in the medulla. The efferent components of the glossopharyngeal

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nerve are related to two nuclei.

A. NUCLEUS AMBIGUUS
Axons that travel with the glossopharyngeal nerve arise from neurons in the rostral part of the nucleus ambiguus
and supply special visceral efferent fibers to the stylopharyngeus muscle, which elevates the pharynx during
swallowing and speech. This efferent component of the glossopharyngeal nerve is small.

B. INFERIOR SALIVATORY NUCLEUS

The inferior salivatory nucleus is a group of neurons that are difficult to distinguish from reticular neurons in the
dorsal aspect of the medulla. The axons of neurons in this nucleus leave the medulla from its lateral surface. They
are preganglionic general visceral efferent fibers that convey secretomotor impulses to the parotid gland. They
travel via the lesser petrosal nerve to the otic ganglion, from which postganglionic fibers supply the parotid gland.
Dry mouth in response to fear and anxiety, and salivation in response to food odor reflect inputs to the inferior
salivatory nucleus from the hypothalamus and olfactory system, respectively.

The afferent components of the glossopharyngeal nerve are related to the same two nuclei associated with the
vagus nerve:

1. Nucleus of the spinal tract of the trigeminal nerve. This nucleus receives general somatic afferent fibers from
the retroauricular region. Neurons of origin of these fibers are located in the superior ganglion within the
jugular foramen.

2. Nucleus solitarius. This nucleus receives two types of visceral afferent fibers.

a. General visceral afferent fibers. These fibers convey tactile, pain, and thermal sensations from the
mucous membranes of the posterior third of the tongue, the tonsils, and the eustachian tube.

b. Special visceral afferent fibers. These fibers convey taste sensations from the posterior third of the
tongue.

Neurons of origin of the visceral afferent fibers are located in the inferior (petrosal) ganglion. Within the medulla,
they form the tractus solitarius and project on the nucleus solitarius in a manner similar to that described above
for the vagus nerve.

The glossopharyngeal nerve also contains a special afferent branch, the carotid sinus nerve. This branch
innervates the carotid body and carotid sinus, which are chemoreceptor and baroreceptor centers. Elevation of
carotid arterial pressure stimulates the carotid sinus nerve, which upon reaching the medulla sends collaterals to
the dorsal motor nucleus of the vagus. General visceral
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efferent components of the vagus nerve then reach ganglion cells in the wall of the heart to slow the heart rate
and reduce blood pressure. This glossopharyngeal-vagal reflex is especially sensitive in elderly people. Therefore,
extreme care should be taken in manipulating the carotid sinus region in the neck of an elderly person.

Figure 5-17. Schematic diagram of the components of the glossopharyngeal nerve and the structures they

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supply.

Unilateral lesions of the glossopharyngeal nerve are manifested by the following signs:

1. Loss of the pharyngeal (gag) reflex homolateral to the nerve lesion. This reflex is elicited by stimulation of
the posterior pharyngeal wall, the tonsillar area, or the base of the tongue. Normally, tongue retraction is
associated with elevation and constriction of the pharyngeal musculature.

2. Loss of the carotid sinus reflex homolateral to the nerve lesion.

3. Loss of taste in the homolateral posterior third of the tongue.

4. Deviation of the uvula to the unaffected side.

Glossopharyngeal neuralgia (Reichert syndrome, tympanic plexus neuralgia) due to a lesion in the
glossopharyngeal nerve is characterized by paroxysms of severe pain in the throat, posterior tongue, and ear
triggered by swallowing or tongue movements.

Vestibulocochlear Nerve (Cranial Nerve VIII)

The vestibular component of the vestibulocochlear nerve is discussed in Chapter 7. The two vestibular nuclei that
appear at rostral levels of the medulla are the inferior vestibular nucleus and the medial vestibular nucleus.

The inferior vestibular nucleus is located medial to the restiform body and is characterized in histologic
preparations by the presence of dark-staining bundles of fibers coursing through it. The medial vestibular nucleus,
which is located medial to the inferior nucleus, is poorly stained in myelin preparations because of the relatively
few fibers it contains.

Nucleus Solitarius
The nucleus solitarius is divided into two zones (Figure 5-18). The caudal and medial zone is concerned with
general visceral sensation and primarily cardio-respiratory function. The rostral and lateral zone is concerned with
special visceral (taste) function. Caudally, the two medial parts of the solitary nuclei merge to form the
commissural nucleus.

The gustatory (taste) zone receives taste sensations via three cranial nerves: The facial nerve (cranial nerve VII)
conveys taste sensations from the anterior two-thirds of the tongue, the glossopharyngeal nerve (cranial nerve
IX) conveys taste sensations from the posterior third of the tongue, and the vagus nerve (cranial nerve X)
conveys taste sensations from the epiglottis. The output of the gustatory zone is to the posterior thalamus
(ventral posterior medial nucleus), which in turn projects to the primary gustatory cortex.

The zone concerned with general visceral sensations receives input via two cranial nerves: the glossopharyngeal
(cranial nerve IX) and the vagus (cranial nerve X). Neurons in this zone project to the nucleus ambiguus, the
dorsal motor nucleus of the vagus, centers within the medullary reticular formation concerned with cardiovascular
and respiratory function, the intermediolateral cell column in the spinal cord, and the parabrachial pontine
nucleus. From the parabrachial pontine nucleus, visceral sensory information is relayed to the amygdala and
hypothalamus. Lesions in the nucleus or tractus solitarius and their connections with the area postrema have been
associated in humans and experimental animals with a change in feeding behavior characterized by early satiety
and poor appetite. The nucleus solitarius is coextensive with the physiologically defined medullary respiratory
center, which includes the nucleus ambiguus and surrounding portions of the reticular formation. Cells of the
medullary respiratory center are activated by vagal impulses and by changes in their chemical environment (CO 2
accumulation). The caudal zone of the nucleus solitarius, along with the dorsal motor nucleus of the vagus and the
medial reticular formation, has been implicated in the genesis of neurogenic pulmonary edema.

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Figure 5-18. Schematic diagram showing major inputs and outputs of the nucleus solitarius.

The Medulla and Cardiovascular Control

The nucleus solitarius, along with the dorsal motor nucleus of the vagus, the caudal, and the rostral ventrolateral
medulla, comprise the brain stem nuclei involved in cardiovascular control. They receive direct projections from
the sensorimotor cortex. The cortical input to these nuclei provides the basis for cortical influences on the
baroreceptor reflex and sympathetic vasomotor mechanisms for control of blood pressure. Lesions in the nucleus
solitarius have been shown to result in arterial blood pressure elevation. Neurons in the caudal ventrolateral
medulla receive baroreceptor input and send inhibitory projections to the rostral ventrolateral medulla. Lack of
activity in caudal ventrolateral medullary neurons has been associated with development of hypertension. The
rostral ventrolateral medulla is critical for the tonic and reflexic regulation of blood pressure.

The Medulla and Respiratory Function

Experimental studies have identified two medullary regions related to respiratory function. The dorsal
respiratory group in the nucleus solitarius contains primary inspiratory
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neurons that project to the nucleus ambiguus and to spinal cord neurons that supply the diaphragm. The ventral
respiratory group in the nucleus ambiguus and nucleus retroambiguus contains inspiratory and expiratory neurons.
The inspiratory neurons are driven by the nucleus solitarius. Neurons in the ventral respiratory group project to
spinal cord neurons that supply the intercostal and abdominal muscles.

There is a paucity of information about centers of respiration in the brain stem in humans. Structures implicated
in apnea in humans include the nucleus solitarius, the nucleus ambiguus, the nucleus retroambiguus, the dorsal
motor nucleus of the vagus, the region of the medial lemniscus, the region of the spinothalamic tract, and the
medullary reticular formation, all bilaterally.

Discrete unilateral lesions in the nucleus ambiguus and the adjacent reticular formation in humans have been
reported to result in failure of automatic respiratory function (sleep apnea, Ondine's curse). Lesions that also
involve the nucleus solitarius result in failure of both automatic and voluntary respiration.

Neurogenic Pulmonary Edema

The specific pathways for neurogenic pulmonary edema have not been identified with certainty. Based primarily on
experimental data, hypothalamic and medullary sites have been reported to be the origin of neurogenic pulmonary
edema.

Clinical reports of neurogenic pulmonary edema from focal lesions support a caudal brain stem site for the
induction of pulmonary edema. These cases include focal puncture wounds of the medulla, posterior fossa stroke,
localized brain stem hemorrhage, bulbar poliomyelitis, and multiple sclerosis. Recent high-resolution brain
imaging studies have suggested an anatomic substrate for neurogenic pulmonary edema in the caudal brain stem
that includes the nucleus solitarius, the dorsal motor nucleus of the vagus, and the medial medullary reticular
formation. Both indirect evidence and direct evidence support the nucleus solitarius as the effector site inducing
neurogenic pulmonary edema. The caudal portion of the nucleus solitarius appears phylogenetically only in air-
breathing animals and contains the neuronal pools involved in the regulation of ventilation. The nucleus is also the
site of termination of afferent fibers from the lung (via cranial nerves IX and X) and from chemoreceptors and

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baroreceptors of the carotid sinus. Efferent fibers from the ventral lateral zone of the nucleus solitarius terminate
in the thoracic region of the spinal cord. The caudal zone of the nucleus plays well-defined roles in the regulation
of other peripheral cardiovascular functions, particularly systemic vascular pressure.

The Medulla and Sneezing

The sneezing reflex is triggered by a variety of stimuli, the most common of which is stimulation of the nasal
mucosa (trigeminal nerve sensory endings) by mechanical or chemical stimuli. Other stimuli include exposure to
bright or blue light (solar sneeze) and male orgasm. The latter two stimuli elicit sneezing via pathways that
converge on the sneezing center. The sneezing center is in the medulla oblongata at the ventromedial margin of
the descending tract and nucleus (spinal nucleus) of the trigeminal nerve and includes the adjacent reticular
formation and nucleus solitarius. The sneezing reflex has two phases: nasal and respiratory.

The afferent limb of the nasal phase consists of the ethmoidal (cranial nerve V) and olfactory (cranial nerve I)
nerves, which project to the sneezing center in the medulla oblongata. The efferent limb consists of preganglionic
fibers to the greater petrosal nerve (cranial nerve VII) and the sphenopalatine ganglion (cranial nerve VII), which
innervate glands and blood vessels in the nose, resulting in nasal secretion and edema, further stimulation of the
nasal mucosa, and more impulses to the sneezing center.

The respiratory phase of the sneezing reflex commences when a critical number of inspiratory and expiratory
neurons are recruited by the sneezing center. Recruitment of these neurons increases activity in the vagus,
phrenic, and intercostal nerves to the appropriate musculature. Manifestations of this phase consist of the
following sequence of events: eye closure, deep inspiration, pharyngeal closure, forceful expiration, dilation of the
glottis, explosive air release through the mouth and nose, and expulsion of mucus and irritants.

Sneezing disorders consist of those of excessive sneezing (more common) and the inability to sneeze (less
common). Inability to sneeze has been reported in psychiatric disorders and in medullary neoplasms affecting the
sneezing center.

The Medulla and Swallowing

Swallowing is a complex motor sequence that involves more than 25 pairs of muscles in the mouth, pharynx,
larynx, and esophagus. Swallowing is a primitive reflex. The human fetus can swallow by the twelfth week of
gestation, before cortical and subcortical structures have developed. Swallowing has even been reported to occur
in anencephalic fetuses. The process of swallowing involves three functionally distinct phases: oral,
pharyngolaryngeal, and esophageal. In the oral phase, food is broken into sufficiently small pieces for transport
through the pharynx and esophagus and the food is propelled into the pharynx after mastication. The oral phase is
entirely voluntary and can be interrupted at any time. The pharyngolaryngeal phase propels the bolus to the
esophagus while coordinating the protection of the respiratory tract by means of inhibition of respiration, closure
of the palatopharyngeal isthmus, and constriction of the larynx. The esophageal phase involves both striated and
smooth esophageal muscles and propels the food to the stomach. The pharyngolaryngeal and esophageal phases
are controlled involuntarily, by neurons in the medullary reticular formation.

Stimulation studies suggest that two regions in the medulla are involved in swallowing: both areas constitute
the central pattern generator (CPG). The dorsal swallowing group (DSG), located within the nucleus solitarius
and the adjacent reticular formation, contains the generator neurons which trigger, shape, and time the sequential
or rhythmic swallowing pattern. The ventral swallowing group (VSG), located in the ventrolateral medulla adjacent
to the nucleus ambiguus, contains the switching neurons, which distribute the swallowing drive to the various
motor neuronal pools involved in swallowing. The ventral swallowing group of neurons is driven by the dorsal
swallowing group (Figure 5-19). The swallowing centers in the medulla are influenced by peripheral stimuli from
sensory receptors and by descending suprasegmental input. The peripheral fields from which swallowing can be
evoked include the posterior tongue and the oropharyngeal region. The most important afferent impulses are
carried in the glossopharyngeal and vagus nerves. Descending pathways that modify swallowing arise from the
prefrontal cortex, the limbic system, the hypothalamus, the midbrain, and the pons. Descending influences can be
either excitatory or inhibitory. Descending pathways are important in the process of learning to integrate orofacial
movements in the oral phase but are not essential in the coordination of the pharyngeal and esophageal phases.
Swallowing continues in humans and experimental animals with lesions in the descending pathways.

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Figure 5-19. Schematic diagram of the swallowing central pattern generator and its afferent and efferent
connections. Roman numerals indicate cranial nerves. DSG, dorsal swallowing group; VSG, ventral swallowing
group; C-1–C-3, motor neurons at cervical spinal segments 1–3.

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Neuroanatomy of Vomiting
Vomiting or emesis is an instinctive defense reaction caused by somatoautonomic reflexes integrated in the
medulla oblongata. Vomiting may be induced by a variety of triggers: motion, adverse drug reactions,
trauma, toxin ingestion, among others. A chemoreceptor trigger zone for vomiting is present in the area
postrema, an area in the floor of the fourth ventricle devoid of blood-brain barrier. Chemoreceptors in the area
postrema detect emetic agents in the blood and relay the information to the adjacent nucleus solitarius. Ablation
of the area postrema abolishes the response to emetic agents in the blood stream. In addition to the input from
area postrema, the nucleus solitarius receives inputs from taste receptors via cranial nerves VII, IX, and X;
autonomic input from the intestine via cranial nerve X (parasympathetic) and splanchnic nerves (sympathetic);
and from the vestibular system. The nucleus solitarius projects to a central pattern generator, which coordinates
the sequence of behaviors during vomiting, to a group of cranial nerve nuclei that control jaw, mouth, and tongue
movements (trigeminal, facial, and hypoglossal), to nuclei that control respiratory and abdominal muscles that
participate in the expulsive phase of vomiting (dorsal motor nucleus of vagus, nucleus ambiguus, anterior horn of
spinal cord), and to the hypothalamus. The previous concept of a “vomiting center” in the medulla has now been
replaced by the concept of the presence of a group of loosely organized neuronal groups that may be activated in
sequence by a central pattern generator.

Neuroanatomy of Yawning
Yawning is a phylogenetically old, stereotyped event that occurs alone or in association with stretching, penile
erection, or both. It is characterized by gaping and facial mimics that are accompanied by a long inspiration
followed by a shorter expiration. The neural structures necessary for yawning are presumably located in the
medulla oblongata close to respiratory and vasomotor centers. Yawning can be triggered by a variety of stimuli,
including seeing someone yawn, being involved in a boring task, and thinking about it. Yawning is influenced by
several neurotransmitters and neuropeptides. Oxytocinergic neurons in the paraventricular nucleus of the
hypothalamus mediate the expression of yawning via connections to the hippocampus, pons, and medulla
oblongata. Yawn-producing neurons in the paraventricular nucleus are activated by dopamine, excitatory amino
acids, and oxytocin. They are inhibited by opioid peptides. Several links exist among neurotransmitters and
neuropeptides involved in yawning, suggesting that multiple pathways influence yawning. The details of these
pathways are not yet worked out.

Neurotransmitters and Neuropeptides

The following neurotransmitters and neuropeptides have been identified in the medulla oblongata: acetylcholine,
norepinephrine, serotonin, enkephalin, substance P, somatostatin, cholecystokinin, and neuropeptide Y (Table 5-
2).

BLOOD SUPPLY OF THE MEDULLA

The medulla oblongata receives its blood supply from the following arteries:

1. Vertebral

2. Anterior spinal

3. Posterior spinal

4. Posterior inferior cerebellar artery (PICA)

The medulla is divided into the following four vascular territories: paramedian, olivary, lateral, and dorsal
(Figure 5-20).

The paramedian territory receives its blood supply from the vertebral and/or anterior spinal arteries. It includes
the pyramid, the medial lemniscus, the medial longitudinal fasciculus, and the hypoglossal nucleus and nerve. The
olivary territory receives an inconstant blood supply from the vertebral artery. It includes
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most of the inferior olivary complex. The lateral territory receives a constant blood supply from the vertebral
artery and a variable supply from the posterior inferior cerebellar artery. It includes the dorsal motor nucleus of
the vagus, the nucleus solitarius and tract, vestibular nuclei, the nucleus ambiguus, the spinal trigeminal nucleus
and tract, the lateral spinothalamic tract, the restiform body, and the olivocerebellar pathway. The dorsal territory
is supplied rostrally by the posterior inferior cerebellar artery and caudally by the posterior spinal artery. This
includes the vestibular nuclei, the dorsal column nuclei and tracts, and part of the restiform body.

Table 5-2. Medulla Oblongata: Neurotransmitters and Neuropeptides

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Hypoglossal Dorsal Nucleus Nucleus Spinal Reticular Raphe

nucleus motor ambiguus solitarius trigeminal formation nucleus
nucleus nucleus
of
vagus

Acetylcholine X X X

Norepinephrine X

Serotonin X

Enkephalin X X X X

Substance P X X X

Somatostatin X

Cholecystokinin X

Neuropeptide Y X

Figure 5-20. Schematic diagram of vascular territories of the medulla oblongata.

TERMINOLOGY
Accessory nerve.
The eleventh cranial nerve (accessory nerve of Willis) was described by Thomas Willis in 1664. The name
accessory was used because this nerve receives an additional root from the upper part of the spinal cord.

Arcuate nucleus (Latin arcuatus, “bow-shaped”).

The arcuate nucleus in the medulla oblongata is an archlike structure lateral and inferior to the pyramid.

Area postrema.
One of the circumventricular organs devoid of a blood-brain barrier. Located in the floor of the fourth ventricle.

Ataxia (Greek a, “negative”; taxis, “order”).

Without order, disorganized. Incoordination of movement frequently seen in cerebellar disease. The term was
used by Hippocrates and Galen for disordered action of any type, such as irregularity of pulse.

Brachium (Latin, Greek brachion, “arm”).

Any structure resembling an arm.

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Brachium conjunctivum (Latin, Greek brachion, “arm”; conjunctiva, “connecting”).

An armlike bundle of fibers that connect the cerebellum and midbrain.

Brachium pontis.
An armlike bundle of fibers that link the pons and the cerebellum.

Cinereum (Latin cinerius, “ashen-hued,” for the gray matter of the brain).
The term tuberculum cinereum refers to the spinal trigeminal nucleus.

Clava (Latin, “stick”).

The surface marking of the nucleus gracilis on the dorsal surface of the medulla oblongata.

Cruveilhier, Jean (1791–1874).

A French surgeon and pathologist who traced the crossing of the pyramids at the pyramidal decussation.

Cuneate (Latin, “wedge”).

The cuneate fasciculus and cuneate tubercle are so called because of their wedgelike shape.

Dejerine, Joseph-Jules (1849–1917).

A French neurologist who increased knowledge about cerebral localization, clinical neurology, and the alexias.

Dysphagia (Greek dys, “difficult”; phagien, “to eat”).

Difficulty swallowing.

Dyspnea (Greek dyspnoia, “difficulty breathing”).

Difficulty breathing.

Galen, Claudius (A.D. 130–200).

Founder of Galenic medicine. Described the Great Vein of Galen and several cranial nerves. He described the
function of the recurrent laryngeal nerve by cutting the nerve in the pig. His many contributions guided medical
practice for over a thousand years.

Gall, F. J. (1758–1828).
A Viennese physician and neuroanat-omist who founded the discipline of phrenology and cerebral localization.

Glossopharyngeal (Greek glossa, “tongue”; pharynx, “throat”).

The ninth cranial nerve. Included by Galen with the sixth nerve. Fallopius distinguished it as a separate nerve in
1561. Thomas Willis included it as part of the eighth nerve. Soemmering listed it as the ninth cranial nerve.

Gracile (Latin, “slender, thin”).

The fasciculus gracilis and nucleus gracilis are so named because they are slender and long.

Gustatory (Latin gustatorius, “pertaining to the sense of taste”).

Hemiplegia cruciata (alternate brachial diplegia).

Paralysis of one arm and the contralateral leg caused by a lesion within the pyramidal decussation at a point
below the decussation of fibers destined for the arm and above the decussation of fibers destined for the leg.

Hypoglossal nerve (Greek hypo, “beneath”; glossa, “tongue”).

The twelfth cranial nerve was so named by Winslow. Willis included it with the ninth cranial nerve. It was named
the twelfth nerve by Soemmering.

Jackson's Syndrome.
Paralysis of the hypoglossal, cranial accessory, vagus, glossopharyngeal nerves and contralateral hemiparesis,
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associated with intramedullary lesions. First described by John Hughlings in a case of tongue paralysis from
intramedullary hemorrhage.

Lemniscal decussation.
Crossing of axons of the posterior column nuclei in the medulla oblongata to form the medial lemniscus. Also
known as sensory decussation.

Locus ceruleus (Latin, “place, dark blue”).

A pigmented norad-renergic nucleus in the rostral pons that is dark blue in sections.

Motor decussation.
The crossing of most of the pyramidal fibers in the caudal medulla oblongata to form the lateral corticospinal
tract. Also called the pyramidal decussation

Nucleus ambiguus (Latin, “changeable or doubtful”).

The boundaries of the nucleus ambiguus are indistinct.

Nystagmus (Greek nystagmos, “drowsiness, nodding”).

Nodding or closing of the eyes in a sleepy person. Today the term refers to involuntary rhythmic oscillation of the
eyes.

Ondine's curse.
A syndrome characterized by the cessation of breathing in sleep because of failure of the medullary automatic
respiratory center. Named after the story of the 1939 play “Ondine” by the French playwright Jean Giraudoux in
which a water nymph or mermaid (Ondine in French) made a pact with the mermaid king that if her human lover

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was unfaithful, he will lose all automatic functions (not only automatic breathing) and forfeit his life.

Onion-skin (peel) pattern.

A pattern of sensory loss in the face that is complete centrally around the nose and mouth but shades off
peripherally and occurs with a rostral spinal trigeminal nucleus and tract lesion. This pattern was described by
Dejerine in 1914. The onion-skin segmental distribution reflects the rostral-caudal somatotopic arrangement of
the cutaneous distribution of the spinal trigeminal nucleus, with the perioral area being rostral and the lateral face
being caudal in the nucleus.

Pyramidal decussation.
Crossing of pyramidal fibers in the caudal medulla to form the lateral corticospinal tract. Also called motor
decussation.

Restiform body (Latin restis, “rope”; forma, “form”).

The restiform body (inferior cerebellar peduncle) is shaped like a rope. This body was described by Humphrey
Ridley, an English anatomist, in 1695.

Sensory decussation.
Crossing of axons of the posterior column nuclei (gracilis and cuneatus) in the medulla oblongata to form the
medial lemniscus. Also known as the lemniscal decussation.

Splanchnic nerves (Greek splanchnikos, “pertaining to the viscera”).

The sympathetic nerves to the abdominal viscera. Originally investigated by Scarpa. The term appeared in English
in 1694.

Spurzheim, Johann Caspar (1776–1832).

A French physician. A student of and collaborator with F. J. Gall in the discipline of phrenology and cerebral
localization. With Gall, he called attention in 1810 to the crossing of the pyramids, which had been described in
1709.

Tapia's syndrome.
Paralysis of the hypoglossal, vagus, and glossopharyngeal nerves by intra- or extramedullary lesions. Described in
1904 by Antonio Garcia Tapia, a Spanish otolaryngologist in a patient who suffered occupational injury as a
matador.

Tela choroidea (Latin tela, “a web”; chorion, “membrane”; eidos, “form”).

A membrane of pia and ependyma that includes the choroid plexus. Found in the lateral ventricles, the roof of the
third ventricle, and the posterior roof of the fourth ventricle.

Tractotomy.
A surgical operation that involves severing a specific nerve fiber tract in the central nervous system, usually to
relieve pain.

Trigeminal nerve (Latin tres, “three”; geminus, “twin”).

The fifth cranial nerve was described by Fallopius. So named because the nerve has three divisions: ophthalmic,
maxillary, and mandibular.

Trigone (Latin, “triangular area”).

The hypoglossal and vagal trigones are so named because of their triangular shape.

Vagus (Latin vagari, “wanderer”).

The tenth cranial nerve is so named because of its long course and wide distribution. The nerve was described by
Marinus in about A.D. 100. The name vagus was coined by Domenico de Marchetti of Padua.

Velum (Latin, “curtain or veil”).

A term used for various thin membranes or veils in the brain, such as the superior medullary velum and inferior
medullary velum, that constitute the roof of the fourth ventricle.

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Zemlan FP, Pfaff DW: Topographical organization in medullary reticulospinal systems as demonstrated by the
horseradish peroxidase technique. Brain Res 1979; 174:161–166.

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Editors: Afifi, Adel K.; Bergman, Ronald A.

Title: Functional Neuroanatomy: Text and Atlas, 2nd Edition

Copyright ©2005 McGraw-Hill

> T ab le of C onte nts > Pa r t I - Te xt > 6 - M edu lla O blong ata : C linica l C or rela tes

6
Medulla Oblongata: Clinical Correlates

Medial Medullary Syndrome (Dejerine's Anterior Bulbar Syndrome)

Lateral Medullary Syndrome
Babinski-Nageotte Syndrome
Dorsal Medullary Syndrome
Collet-Sicard Syndrome
Pseudobulbar Palsy

KEY CONCEPTS

Vascular lesions of the medulla oblongata are designated by the anatomic region affected rather than by the arte-
rial supply.

The clinical signs of the medial medullary syndrome include contralateral weakness of the upper motor neuron
type, contralateral loss of kinesthesia and discriminative touch, and ipsilateral tongue weakness of the lower motor
neuron type.

The clinical signs of the lateral medullary syndrome include loss of pain and temperature sense in the ipsilateral
face and the contralateral half of the body, ipsilateral loss of the gag reflex, hoarseness, dysphagia, dysarthria,
ataxia, vertigo, ipsilateral Horner's syndrome, nystagmus, and ocular lateropulsion.

The clinical signs of combined lateral and medial medullary syndromes constitute the Babinski-Nageotte
syndrome.

The clinical signs of the dorsal medullary syndrome include ipsilateral ataxia, nystagmus, vomiting, and vertigo.

The Collet-Sicard syndrome results from an extra-axial lesion affecting cranial nerves IX to XII.

Bilateral interruption of the corticobulbar or corticoreticulobulbar fibers results in the pseudobulbar syndrome.

Vascular lesions in the medulla oblongata are best suited to anatomicoclinical correlation. In the past, these syndromes
were designated by the artery of supply (e.g., anterior spinal artery syndrome, posterior inferior cerebellar artery
syndrome, vertebral artery syndrome). Because of variations in the source of blood supply, however, these syndromes are
currently designated by the anatomic region affected by the lesion. Two such syndromes are particularly illustrative: the
medial medullary syndrome and the lateral medullary syndrome.

MEDIAL MEDULLARY SYNDROME (DEJERINE'S ANTERIOR BULBAR SYNDROME)

The medial medullary syndrome (Figure 6-1) is caused by occlusion of the anterior spinal artery or the paramedian branches of
the vertebral artery. The affected area usually includes the following structures:

1. Medial lemniscus

2. Pyramid

3. Rootlets of the hypoglossal nerve or its nucleus within the medulla

The neurologic signs resulting from the involvement of these areas are as follows:

1. Contralateral loss of kinesthesia and discriminative touch resulting from involvement of the medial lemniscus

2. Contralateral paralysis of the upper motor neuron type (weakness, hyperactive reflexes, Babinski's sign,clonus, and
spasticity) with sparing of the face caused by involvement of the pyramid

3. Lower motor neuron paralysis of the homolateral half of the tongue (weakness, atrophy, and fibrillation) and deviation of
the protruded tongue to the atrophic side caused by involvement of the hypoglossal nucleus or nerve

The medial medullary syndrome may occur bilaterally, resulting in bilateral upper motor neuron weakness or paralysis (with
facial sparing), bilateral paralysis of the tongue of the lower motor neuron type, and bilateral loss of kinesthesia and
discriminative touch.

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Figure 6-1. Schematic diagram of medullary structures involved in the medial medullary syndrome, and the resulting
clinical manifestations.

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LATERAL MEDULLARY SYNDROME

The lateral medullary syndrome (Figure 6-2) is caused by occlusion of the vertebral artery or, less frequently, the medial
branch of the posterior inferior cerebellar artery when this artery supplies the lateral medulla. It is also known as the posterior
inferior cerebellar artery (PICA) syndrome or Wallenberg's syndrome. The affected area usually includes the following
structures:

1. Spinal nucleus of the trigeminal nerve and its tract

2. Adjacent spinothalamic tract

3. Nucleus ambiguus or its axons

4. Base of the inferior cerebellar peduncle (restiform body)

5. Vestibular nuclei

6. Descending sympathetic fibers from the hypothalamus

7. Olivocerebellar fibers

The neurologic signs and symptoms resulting from the involvement of these areas include the following:

1. Loss of pain and temperature sensations from the ipsilateral face as a result of involvement of the spinal nucleus of
the trigeminal nerve and its tract.

2. Loss of pain and temperature sensation over the contralateral half of the body because of involvement of the
spinothalamic tract.

3. Loss of the gag reflex, difficulty swallowing (dysphagia), hoarseness, and difficulty in articulation (dysarthria) caused by
paralysis of muscles supplied by the nucleus ambiguus ipsilateral to the medullary lesion.

4. Ipsilateral loss of coordination (ataxia) resulting from involvement of the base of the inferior cerebellar peduncle.

5. Hallucination of turning (vertigo) resulting from involvement of the vestibular nuclei.

Figure 6-2. Schematic diagram of medullary structures involved in the lateral medullary syndrome, and the resulting
clinical manifestations.

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6. Horner's syndrome caused by involvement of the descending sympathetic fibers from the hypothalamus. This syndrome

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consists of a small pupil (miosis), slight drooping of the upper eyelid (ptosis), and warm dry skin of the face (anhidrosis),
all ipsilateral to the lesion.

7. Vomiting, nystagmus, and nausea resulting from involvement of the vestibular nuclei.

8. Hiccuping that is of uncertain cause but usually is attributed to involvement of the respiratory center in the reticular
formation of the medulla.

9. Ocular lateropulsion occurs almost universally in this syndrome. It consists of a tendency toward saccadic eye movement
overshoot or hypermetria toward the side of the lesion and a tendency toward hypometria away from the lesion. Ocular
lateropulsion is believed to result from involvement of olivocerebellar fibers related to ocular movement traveling in the
lateral medulla or to a concomitant cerebellar lesion.

10. Difficulty pursuing contralateral moving targets as a result of involvement of the vestibular pathways to nuclei of
extraocular movement.

Although credit for the description of the lateral medullary syndrome in 1895 is often given to Adolph Wallenberg, as evidenced
by the term Wallenberg's syndrome, the Swiss physician Gaspard Vieusseux provided an account in 1810, reporting in detail
his own stroke to the Medical and Surgical Society of London.

Clinical manifestations of the lateral medullary syndrome may vary depending on the caudal-rostral level of the lesion.
Dysphagia, hoarseness, and ipsilateral facial paresis are more common in patients with lesions in the rostral medulla. Gait
ataxia, vertigo, and nystagmus are more common in patients with caudal medullary lesions. The ipsilateral facial paresis
reported in rostral medullary lesions is attributed to involvement of aberrant cortico-bulbar fibers in the medulla or extension
of the medullary lesion to the pons.

The sensory pattern in the lateral medullary syndrome has been shown to vary with the rostral-caudal and lateral-medial
extent of the lesion. The following sensory patterns (Figure 6-3) have been described (Table 6-1):

1. Loss of pain and thermal sense in the ipsilateral face and contralateral body (classical pattern). This pattern has been
reported in 26 percent of patients. The lesion is in the posterolateral part of the caudal-middle medulla and involves the
spinothalamic tract and spinal trigeminal tract and nucleus.

2. Loss of pain and thermal sense in the face bilaterally and in the contralateral body. This pattern occurs in 24 percent of
patients. The lesion is usually large in the posterolateral and ventromedial parts of the middle-rostral medulla. In addition
to the spinothalamic tract and spinal trigeminal tract and nucleus, the trigeminothalamic tract (secondary trigeminal) is
involved.

3. Loss of pain and thermal sense in the contralateral face and body. This pattern reportedly occurs in 18 percent of
patients. The lesion spares most of the posterolateral part of the medulla and selectively involves the spinothalamic and
trigeminothalamic tracts.

4. Loss of pain and thermal sense in the contralateral body. The face is spared. This pattern occurs in 20 percent of
patients. The lesion is small and superficial in the lateral medulla, involving only the spinothalamic tract.

5. Loss of pain and thermal sense in the ipsilateral face. This pattern has been reported to occur in 8 percent of patients.
The lesion is usually small, more posteriorly localized, and involves only the spinal trigeminal tract and nucleus.

6. No sensory loss. This pattern has been reported in 4 percent of patients. The lesion is small and spares all sensory
structures.

Dissociation of spinothalamic sensation (loss of thermal sense and maintenance of pain sensation) in the contralateral body has
been reported in the lateral medullary syndrome. This pattern is attributed to a small superficial lesion that transects the
lateral spinothalamic tract, thus affecting thermal fibers and sparing pain fibers.

Proprioceptive (vibration, position) deficits have been reported in lateral medullary syndrome when the lesion is in the caudal
medulla and involves the posterior column nuclei.

Figure 6-3. Lateral medullary syndrome patterns.

Table 6-1. Lateral Medullary Syndrome Patterns of Sensory Deficits (Pain and Thermal Sense)

Face Body Involved structures

Pattern Ipsilateral Contralateral Bilateral Ipsilateral Contralateral Spinothalamic Spinal Trigeminothala

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tract trigeminal tract

tract and
nucleus

1 X X X X

2 X X X X X

3 X X X X

4 ` X X

5 X X

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Chronic facial pain has been reported in some patients with lateral medullary syndrome. This rare manifestation has been
attributed to a lesion that affects the rostral spinal trigeminal nucleus (pars oralis and interpolaris) and tract, and that spares
the caudal spinal trigeminal nucleus (pars caudalis), where most nociceptor neurons are located. Deafferentation of the pars
caudalis results in abnormal neuronal activity, which is transmitted to the thalamus and beyond, leading to chronic neuropathic
pain.

Besides Wallenberg's syndrome, occlusion of the medial branch of PICA can present with a pseudolabyrinthine syndrome
characterized by cerebellar and vestibular signs (vertigo, dysmetria, ataxia, and axial lateropulsion) that overshadow the
medullary signs. Occlusion of the medial branch of the posterior inferior cerebellar artery also may result in a silent infarct
that is detected only at autopsy. There are no clinical reports of occlusion of the lateral branch of the posterior inferior
cerebellar artery. Silent infarcts have been reported as a chance autopsy finding.

BABINSKI-NAGEOTTE SYNDROME
The Babinski-Nageotte syndrome, also known as medullary tegmental paralysis, is a combined lateral and medial
medullary syndrome. The lesion is at the pontomedullary junction. Manifestations include ipsilateral Horner's syndrome
(autonomic sympathetic fibers); ipsilateral weakness of the soft palate, pharynx, larynx (nucleus ambiguus), and tongue
(hypoglossal nucleus); loss of taste in the posterior third of the tongue (nucleus solitarius); cerebellar ataxia (restiform body)
and nystagmus (vestibular nuclei); and contralateral hemiparesis (pyramid) and hemianesthesia (medial lemniscus).

DORSAL MEDULLARY SYNDROME

The dorsal medullary syndrome is caused by occlusion of the medial branch of the posterior inferior cerebellar artery.
Affected structures include the vestibular nuclei and the restiform body (inferior cerebellar peduncle). The associated
neurologic signs include the following:

1. Ipsilateral limb or gait ataxia resulting from involvement of the restiform body

2. Vertigo, vomiting, and ipsilateral gaze-evoked nystagmus resulting from involvement of the vestibular nuclei

COLLET-SICARD SYNDROME
Described by the French otolaryngologist Frederick Collet in 1915 and two years later by the French radiologist and
neurologist Jean-Athenase Sicard, this syndrome consists of loss of taste in the posterior third of the tongue, paralysis of
vocal cords and palate, weakness of sternomastoid and trapezius muscles, and hemianesthesia of palate, tongue, and
pharyngeal wall, all ipsilateral to the lesion. The syndrome is associated with unilateral extra-axial injury of the
glossopharyngeal (cranial nerve IX), vagus (cranial nerve X), accessory (cranial nerve XI), and hypoglossal (cranial nerve XII)
nerves.

PSEUDOBULBAR PALSY
Pseudobulbar palsy is a clinical syndrome caused by the interruption of the corticobulbar fibers to motor nuclei of the
cranial nerves. Most cranial nerve nuclei in the brain stem receive bilateral inputs from the cerebral cortex arising
primarily from the precentral cortex. The majority of these fibers reach cranial nerve nuclei via the reticular formation
(corticoreticulobulbar system). Some cranial nerve nuclei, however, receive corticobulbar fibers directly. These nuclei include
the sensory and motor trigeminal nuclei, the nucleus solitarius, the facial motor nucleus, the spinal accessory (supraspinal)
nucleus, and the hypoglossal nucleus.

Bilateral interruption of the indirect corticoreticulobulbar or direct corticobulbar fibers in the brain stem results in the
syndrome of pseudobulbar palsy. The neurologic manifestations of this syndrome include the following:

1. Weakness (upper motor neuron variety) of muscles supplied by the corresponding cranial nerve nuclei

2. Inappropriate outbursts of laughter and crying

TERMINOLOGY
Anhidrosis (Greek an, “negative”; hidros, “sweat”).
Absence or deficiency of sweating.

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Babinski's sign.
An upper motor neuron lesion sign characterized by dorsiflexion of the big toe and fanning out of the rest of the toes upon
painful stimulation or stroking of the sole. The sign was described “as the phenomenon of the toes” by Josef-François-Felix
Babinski (1857–1932), a French neurologist, in 1896. The phenomenon had previously been noted by Hall and Remak. Babinski
investigated the phenomenon in depth in papers published between 1896 and 1903.

Clonus (Greek klonos, “turmoil”).

Alternate muscular contraction of agonist and antagonist muscle groups in rapid succession in response to sudden stretching of
the muscle tendon. Usually seen in an upper motor neuron lesion caused by the loss of
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suprasegmental inhibition of the local spinal reflex arc. The term was originally used by Greek physicians for the convulsing
movements of epileptics.

Dejerine, Joseph-Jules (1849–1917).

A French neurologist who described, among other syndromes, the medial medullary syndrome.

Dysmetria (Greek dys, “difficult”; metron, “measure”).

Improper measuring of distance, disturbed control of range of movement. A sign of cerebellar disease.

Fibrillation.
Local involuntary contraction of muscle that is invisible under the skin and is recorded by electromyography after the
placement of a recording needle in the muscle. A sign of denervation.

Hemianesthesia (Greek hemi, “half”; an, “negative”; aisthesis, “sensation”).

Loss of feeling or sensation in half the body.

Hemiparesis (Greek hemi, “half”; paresis, “relaxation”).

Weakness of one side of the body.

Hiccup.
An involuntary spasmodic contraction of the diaphragm that causes a beginning of inspiration, which is suddenly checked by
closure of the glottis, causing a characteristic sound. Also called singultus.

Horner's syndrome.
Drooping of the eyelid (ptosis), constriction of the pupil (miosis), retraction of the eyeball (enophthalmos), and loss of
sweating on the face (anhidrosis) constitute a syndrome described by Johann Friedrich Horner, a Swiss ophthalmologist, in
1869. The syndrome is due to interruption of descending sympathetic fibers. Also known as Bernard-Horner syndrome and
oculosympathetic palsy. The syndrome was described in animals by François du Petit in 1727. Claude Bernard in France in
1862 and E. S. Hare in Great Britain in 1838 gave precise accounts of the syndrome before Horner.

Lateropulsion (Latin latero, “side”; pellere, “to drive”).

An involuntary tendency to go to one side. A characteristic sign of a cerebellar or lateral medullary lesion.

Nageotte, Jean (1866–1948).

A French neurologist who with Babinski described the combined lateral and medial medullary syndrome (medullary tegmental
paralysis).

Nucleus ambiguus (Latin, “changeable, doubtful”).

So called because its boundaries are indistinct.

Nystagmus (Greek nystagmos, “drowsiness, nodding”).

Nodding or closing of the eye in a sleepy person. The modern use of the term refers to involuntary rhythmic oscillation of the
eyes.

Wallenberg's (lateral medullary) syndrome.

Also known as the lateral bulbar syndrome and the posterior inferior cerebellar artery syndrome. A syndrome consisting of
vertigo, vomiting, hiccups, dysarthria, dysphagia, hoarseness, ataxia, Horner's syndrome, and crossed sensory loss. The
syndrome was described in detail by Adolph Wallenberg, a German neurologist, in 1895. An earlier account of the syndrome
was provided by the Swiss physician Gaspard Vieusseux in 1810.

SUGGESTED READINGS
Amarenco P et al: Infarction in the territory of the medial branch of the posterior inferior cerebellar artery. J Neurol
Neurosurg Psychiatry 1990; 53:731–735.

Arai M: Isolated thermoanesthesia associated with a midlateral medullary infarction. Neurology 2002; 58:1695–1696.

Brazis PW: The localization of lesions affecting the brainstem. In Brazis PW et al (eds): Localization in Clinical Neurology.
Boston, Little, Brown, 1985:225–238.

Brochier T et al: Dorsolateral infarction of the lower medulla: Clinical MRI study. Neurology 1999; 52:190–193.

Fitzek S et al: Mechanisms and predictors of chronic facial pain in lateral medullary infarction. Ann Neurol 2001; 49:493–
500.

Kim JS et al: Spectrum of lateral medullary syndrome. Correlation between clinical findings and magnetic resonance
imaging in 33 subjects. Stroke 1994; 25:1405–1410.

Kim JS et al: Patterns of sensory dysfunction in lateral medullary infarction. Clinical–MRI correlation. Neurology 1997;
49:1557–1563.

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Milandre L et al: Bilateral infarction of the medullary pyramids. Neurology 1990; 40:556.

Norrving B, Cronquist S: Lateral medullary infarction: Prognosis in an unselected series. Neurology 1991; 41:244–248.

Pryse-Phillips W: Companion to Clinical Neurology. Boston, Little, Brown, 1995.

Romano J, Merritt HH: The singular affection of Gaspard Vieusseux: An early description of the lateral medullary syndrome.
Bull Hist Med 1941; 9:72–79.

Sacco RL et al: Wallenberg's lateral medullary syndrome: Clinical-magnetic resonance imaging correlations. Arch Neurol
1993; 50:609–614.

Troost BT: Signs and symptoms of stroke syndromes of the brain stem. In Hofferberth B et al (eds): Vascular Brain Stem
Diseases. Basel, Karger, 1990:112–124.

Vieusseux G: An early description of the lateral medullary syndrome. Bull Hist Med 1941; 9:72–79.

Vuilleumier P et al: Infarction of the lower brainstem: Clinical, aetiological and MRI-topographical correlations. Brain 1995;
118:1013–1025.

Waepse W, Wichmann W: Oculomotor disturbances during visual vestibular interactions in Wallenberg's lateral medullary
syndrome. Brain 1990; 113:821–846.

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Editors: Afifi, Adel K.; Bergman, Ronald A.

Title: Functional Neuroanatomy: Text and Atlas, 2nd Edition

Copyright ©2005 McGraw-Hill

> Table of Contents > Part I - Text > 7 - Pons

7
Pons

Gross Topography
Ventral Surface
Dorsal Surface
Microscopic Structure
Basis Pontis (Ventral)
Tegmentum (Dorsal)
Pontine Reticular Formation
Parabrachial and Pedunculopontine Nuclei
Parabrachial Nucleus
Pedunculopontine Nucleus
Cranial Nerve Nuclei
Cochleovestibular Nerve (Cranial Nerve VIII)
Facial Nerve (Cranial Nerve VII)
Abducens Nerve (Cranial Nerve VI)
Trigeminal Nerve (Cranial Nerve V)

KEY CONCEPTS

The ventral surface of the pons shows the basilar artery in the
pontine sulcus and four cranial nerves: the abducens at the medullary
pontine junction, the facial and cochleovestibular in the cerebellopontine
angle, and the trigeminal at the midpontine level.

The dorsal surface of the pons forms the rostral floor of the fourth
ventricle, in which the facial colliculi are seen. Coronal sections of the
pons reveal two components: a ventral and phylogenetically newer basis
pontis and a dorsal and phylogenetically older tegmentum.

The basis pontis contains pontine nuclei and the following nerve
fiber bundles: corticospinal, corticobulbar, and corticopontocerebellar
(the largest).

The tegmentum contains the following nerve fiber bundles: medial

lemniscus, trigeminal lemniscus, spinothalamic, trap-ezoid body, central
tegmental tract, medial longitudinal fasciculus, tectospinal, and
descending sympathetic fibers.

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The parabrachial nucleus plays an important role in autonomic

regulation. The pedunculopontine nucleus plays roles in locomotion,
motor learning, reward system, arousal, and saccadic eye movements.

Cochlear nerve fibers terminate selectively on neurons in the dorsal

or ventral cochlear nuclei.

Reciprocal feedback circuits exist throughout the extent of the

auditory pathways.

Reflex eye and neck movements to sound are carried out via two
pathways: from the inferior colliculus to the superior colliculus and then
via the tectobulbar and tectospinal tracts to the nuclei of eye and neck
muscles and from the superior olive to the abducens nucleus and then
via the medial longitudinal fasciculus to the nuclei of extraocular
movements.

Vestibular nerve fibers terminate selectively on four ves-tibular

nuclei: medial (Schwalbe's principal), inferior (spinal), lateral (Deiters'),
and superior (Bechterew's). Some fibers project directly to the
cerebellum.

The output of vestibular nuclei is to the following areas: spinal cord,

cerebellum, thalamus, nuclei of extraocular movement, vestibular
cortex, and vestibular end organ.

Vestibular projections to the nuclei of extraocular movement play

important roles in controlling conjugate eye movements.

The sensory facial nuclei are the spinal trigeminal nucleus

(exteroceptive sensation) and the nucleus solitarius (taste).

The motor facial nuclei are the facial motor nucleus (somatic motor)
and the superior salivatory nucleus (visceral motor).

Cortical input to the facial motor nucleus is bilateral to the upper

face motor neurons and only contralateral to the lower face motor
neurons.

Characteristic conglomerate clinical signs occur in lesions of the

facial nerve at or distal to the stylomastoid foramen, distal to the
geniculate ganglion, and proximal to the geniculate ganglion.

Lesions of the abducens nerve outside the neuraxis result in

ipsilateral lateral rectus paralysis. Lesions of the abducens nucleus
result in paralysis of ipsilateral lateral gaze.

The motor nucleus of the trigeminal nerve supplies the muscles of

mastication, the tensor tympani, the tensor palati, the mylohyoideus,
and the anterior belly of the digastric.

The sensory nuclei of the trigeminal nerve are the spinal (pain,
temperature, touch), principal (main) sensory (touch), and

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mesencephalic (proprioception).

Dorsal and ventral trigeminothalamic tracts link the main sensory

and spinal trigeminal nuclei, respectively, with the thalamus.

Blood supply to the pons is provided by the basilar artery via three
branches: paramedian, short circumferential, and long circumferential.

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GROSS TOPOGRAPHY
The pons is the part of the brain stem that lies between the medulla oblongata
caudally and the midbrain rostrally. The cerebral peduncles and the superior
pontine sulcus mark its rostral boundary, the middle cerebellar peduncles
(brachium pontis) mark its lateral boundary, and the inferior pontine sulcus
marks its caudal boundary. The dorsal surface of the pons is covered by the
cerebellum.

Ventral Surface
The ventral surface (Figure 7-1) of the pons forms a bulge known as the
pontine protuberance. In the middle of this protuberance is the pontine
sulcus, which contains the basilar artery. Several cranial nerves leave the ventral
surface of the pons. The abducens nerve (cranial nerve VI) emerges from the
boundary between the pons and the medulla oblongata. In the angle between the
caudal pons, the rostral medulla, and the cerebellum (the cerebellopontine
angle), the facial (cranial nerve VII) and cochleovestibular (cranial nerve VIII)
nerves appear. From the lateral and rostral parts of the pons emerge the two
components of the trigeminal nerve (cranial nerve V): the larger sensory portion
(portio major) and the smaller motor portion (portio minor). The crowding of the
facial and cochleovestibular nerves in the cerebellopontine angle explains the
early involvement of these two nerves in tumors (acoustic neuromas) that arise in
this angle.

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Figure 7-1. Schematic diagram of the ventral surface of the brain stem
showing the major structures on the ventral surface of the pons.

Dorsal Surface
The dorsal surface (see Figure 5-3) of the pons forms the rostral portion of
the floor of the fourth ventricle. This part of the floor features the facial
colliculi, one on each side of the midline sulcus (median sulcus). These colliculi
represent the surface landmarks of the genu of the facial nerve and the
underlying nucleus of the abducens nerve.

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MICROSCOPIC STRUCTURE
Coronal sections of the pons reveal a basic organizational pattern made of two
parts: a ventral basis pontis and a dorsal tegmentum.

Basis Pontis (Ventral)

The basis pontis (Figure 7-2) corresponds to the pontine protuberance described
in “Gross Topography,” earlier. It contains the pontine nuclei and multidirectional
nerve fiber bundles.

The multidirectional nerve fiber bundles in the basis pontis belong to three
fiber systems.

1. Corticospinal fibers from the cerebral cortex to the spinal cord pass through
the basis pontis and continue caudally as the pyramids of the medulla
oblongata.

2. Corticobulbar fibers from the cerebral cortex to the cranial nerve nuclei of
the brain stem. Some of these fibers project directly on the nuclei of cranial
nerves (corticobulbar); the majority, however, synapse on an intermediate
reticular nucleus before reaching the cranial nerve nucleus

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(corticoreticulobulbar). Corticobulbar and corticoreticulobulbar fibers usually

arise from both cerebral hemispheres.

3. Corticopontocerebellar fibers constitute the largest group of fibers in the

basis pontis. This fiber system originates from wide areas of the cerebral
cortex, projects on ipsilateral pontine nuclei, and crosses the midline on its
way to the cerebellum via the middle cerebellar peduncle. It is estimated
that in humans this fiber system contains approximately 19 million fibers on
each side. The number of pontine neurons in humans is estimated to be
approximately 23 million in each half of the pons. Thus, the ratio of
corticopontine fibers to pontine neurons is approximately 1:1. Although the
corticopontine projection is believed to arise from wide areas of the cerebral
cortex, it arises principally from the prerolandic and postrolandic
sensorimotor cortices with minor to moderate contributions from the parietal
and temporal association cortices, the premotor and prefrontal association
cortices, and the cingulate gyrus. The fact that cortical input to the pontine
nuclei arises chiefly from primary cortical areas suggests that the
corticopontocerebellar fiber system is concerned with the rapid correction of
movements. The functional significance of the cingulopontine fiber
connection is not known, but it may represent the anatomic substrate for
the effect of emotion on motor function. The input from the association
cortices suggests a role for this fiber system in behavioral and cognitive
processes. A cortical region usually projects to more than one cell column of
the pontine nuclei, and some pontine columns receive projections from more
than one cortical region. Like the corticoolivocerebellar system, the
corticopontocerebellar system is somatotopically organized. Thus, the
prerolandic cortex (primary motor cortex) projects to medial pontine nuclei,
the postrolandic cortex (primary somatosensory cortex) to lateral pontine
nuclei, the arm area of the sensorimotor cortex to dorsal pontine nuclei, and
the leg area to ventral pontine nuclei. The projection from the cingulate
gyrus also has been shown to be somatotopically organized, with the
anterior cingulate cortex projecting to the medial pontine nuclei and the
posterior cingulate cortex projecting to the lateral pontine nuclei.

The pontocerebellar projection is primarily crossed; however, it has been

estimated that 30 percent of the pontine projection to the cerebellar vermis and
10 percent of the projection to the cerebellar hemisphere are ipsilateral. The
density of projection to the cerebellar hemispheres is three times that to the
vermis. Like the corticopontine projection, the pontocerebellar projection is
somatotopically organized, with the caudal half of the pons projecting to the
anterior lobe of the cerebellum and the rostral half projecting to the posterior
lobe.

The basilar portion of the pons is the phylogenetically newer part and is present
only in animals with well-developed cerebellar hemispheres.

Tegmentum (Dorsal)
The tegmentum is the phylogenetically older part of the pons and is
composed largely of the reticular formation. Lesions that destroy more than
25 percent of the tegmentum may result in loss of consciousness. In the basal
part of the tegmentum, the medial lemniscus (which maintains a vertical
orientation on each side of the midline in the medulla) becomes flattened in a
mediolateral

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direction (Figure 7-3). Fibers originating from the cuneate nucleus are located
medially; gracile fibers are laterally placed. Lateral to the medial lemniscus lies
the trigeminal tract, which conveys sensations of pain, temperature, touch, and
proprioception from the contralateral face. The spinothalamic tract is lateral to
the trigeminal tract and carries pain and temperature sensations from the
contralateral half of the body. Thus, in the basal part of the tegmentum lies the
specific sensory lemniscal system, which includes the medial lemniscus,
trigeminal lemniscus, and spinotha-lamic tract.

Figure 7-2. Schematic diagram of the pons showing its major divisions into
tegmentum and basis pontis, and types of fiber bundles traversing the basis
pontis.

Intermingled with the ascending fibers of the lemniscal system are transversely
oriented fibers of the trapezoid body. These fibers arise from the cochlear nuclei,
course through the tegmentum, and gather in the lateral portion of the pons to
form the lateral lemniscus. This fiber system will be discussed later in connection
with the cochlear division of the cochleovestibular nerve (cranial nerve VIII).

Dorsal to the medial lemniscus is the central tegmental tract, which originates in
the basal ganglia and midbrain and projects on the inferior olive. It shifts
position in the tegmentum of the pons and lies dorsal to the lateral part of the
medial lemniscus in the caudal pons (Figure 7-3).

The medial longitudinal fasciculus and the tectospinal tract retain the same dorsal
and paramedian positions they occupied in the medulla just beneath the floor of
the fourth ventricle (Figure 7-3).

Other tracts coursing through the tegmentum of the pons include the rubrospinal
tract medial to the spinal trigeminal nucleus and the ventral spinocerebellar tract
medial to the restiform body. The ventral spinocerebellar tract enters the

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superior cerebellar peduncle to reach the cerebellum. The tegmentum of the pons
also contains descending sympathetic fibers from the hypothalamus; these fibers
are located in the lateral part of the tegmentum. Interruption of these fibers
produces Horner's syndrome (Chapter 5). Corticobulbar fibers and corticoreticulo-
bulbar fibers on their way from the basis pontis to cranial nerve nuclei also pass
through the tegmentum (Figure 7-2).

In the rostral pons, lying dorsally in the tegmentum, is the nucleus locus ceruleus
(group A-6 of primates). It contains on each side an average of 16,000 to 18,000
melanin-containing neurons that are involved in Parkinson's disease, Alzheimer's
disease, and Down syndrome. It is the major source of the widespread
noradrenergic innervation to most central nervous system regions. This nucleus is
subdivided into four subnuclei: central (largest), anterior (rostral end), the
nucleus subceruleus (caudal and ventral), and a small posterior and dorsal
nucleus. The nucleus spans a rostral-caudal distance of 11 to 14 mm. Rostrally,
the nucleus begins at the level of the inferior colliculus (midbrain), where it is
situated ventral and lateral to the cerebral aqueduct (aqueduct of Sylvius) in the
periaqueductal gray matter of the midbrain. Caudally, at the junction of the
cerebral aqueduct and the fourth ventricle, the nucleus is displaced laterally. The
number of cells in the nucleus increases from rostral to caudal. Two projection
bundles emanate from the nucleus: a dorsal ascending bundle to the
hypothalamus, hippocampus, neocortex, and cerebellum and a descending bundle
to the spinal cord. Cell loss in the nucleus is generalized in Parkinson's disease,
whereas it is limited to the rostral portion of the nucleus (which projects mainly
to the cerebral cortex) in Alzheimer's disease and Down syndrome.

Figure 7-3. Schematic diagram of the pons showing the major tracts
traversing the tegmentum.

PONTINE RETICULAR FORMATION

The pontine reticular formation constitutes the major part of the tegmental
portion of the pons and is a rostral continuation of the medullary reticular
formation. The organization and connections of the pontine reticular formation
are discussed in Chapter 32. Lesions involving the pontine reticular nuclei in the

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tegmentum and corticospinal fibers in the basis pontis are associated with the
syndrome of anosognosia for hemiplegia in which the patients are unaware of
their motor deficit. A similar syndrome occurs in lesions of the nondominant
parietal lobe.

PARABRACHIAL AND PEDUNCULOPONTINE

NUCLEI

Parabrachial Nucleus
At the level of the isthmus, in the dorsolateral pons, between the lateral edge of
the brachium conjunctivum (superior cerebellar peduncle) and the lateral
lemniscus, is the parabrachial nucleus, a synaptic station for gustatory (taste)
pathways. In humans the parabrachial nucleus has been shown to have
neuromelanin-containing catecholamine neurons. The pigmented neurons in the
nucleus are rather small (compared with neuromelanin-containing neurons in the
locus ceruleus or the substantia nigra), and their granules have a very delicate
appearance; this may explain why pigmented neurons in this nucleus have been
overlooked in reports on the distribution of catecholamine neurons in the human
brain. In humans the parabrachial
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nucleus is subdivided into lateral and medial segments. Pigmented neurons are
more abundant in the lateral segment. Pigmented neurons in the parabrachial
nucleus undergo a significant reduction in number in patients with Parkinson's
disease. The parabrachial nucleus has fiber connections with the hypothalamus,
amygdala, stria terminalis, and brain stem nuclei, including the nucleus of the
solitary tract and the dorsal raphe nucleus. It is believed that the parabrachial
nucleus plays an important role in autonomic regulation, and its involvement in
parkinsonism may explain the autonomic disturbances that occur in that disease.
Studies in animals and man suggest that the parabrachial nucleus is a relay
station in the brainstem pathway for taste.

Pedunculopontine Nucleus
Between the spinal lemniscus, brachium conjunctivum, and medial lemniscus is
the parabrachial pedunculopontine nucleus.

The pedunculopontine nucleus is the brain stem control center for somatic motor
and cognitive behaviors, including locomotion, motor learning, and the reward
system. Accumulated evidence points to a role for the nucleus in the sleep–wake
arousal system and the muscle coordination mechanism as well as in oculomotor
function including initiation of saccadic eye movements. The nucleus contains two
populations of neurons, cholinergic and glutamatergic. The complex and widely
distributed efferents of the cholinergic population allow the nucleus to participate
in a variety of functions. The glutamatergic population projects caudally to the
pontine and medullary reticular formation responsible for locomotion. It receives
direct excitatory cortical input from multiple motor-related areas of the frontal
lobe and an inhibitory input from the basal ganglia (internal segment of globus
pallidus and substantia nigra pars reticulata). The nucleus sends direct excitatory
output to the basal ganglia (mainly to subtha-lamic nucleus and substantia nigra
pars compacta, with a smaller projection to both segments of globus pallidus)
and to the intralaminar nuclei of thalamus. The nucleus sends indirect output to
the spinal cord (via the gigantocellular reticular nucleus of the medulla
oblongata) (Figure 7-4). The nucleus is believed to possibly have two functional

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roles: (1) relay between the cerebral cortex and spinal cord serving as control
center for interlimb coordination in locomotion and (2) modulatory center that
receives excitatory drive from the cerebral cortex and governs activity of
dopaminergic neurons in the substantia nigra pars compacta, thus influencing
motor learning and the reward system as well as voluntary motor control.

CRANIAL NERVE NUCLEI

Cochleovestibular Nerve (Cranial Nerve VIII)

The cochleovestibular nerve has two divisions: cochlear and vestibular. The two
divisions travel together from the peripheral end organs in the inner ear to the
pons, where they separate; each then establishes its own distinct connections.

A. COCHLEAR DIVISION
The cochlear division (Figure 7-5) of the cochleovestibular nerve is the
larger of the two divisions. Nerve fibers in the cochlear nerve are central
processes of bipolar neurons in the spiral ganglion located in the modiolus of the
inner ear. The peripheral processes of these bipolar neurons are linked to the
hair cells of the auditory end organ in the organ of Corti. As fibers of the cochlear
nerve reach the caudal part of the pons, they enter its lateral surface caudal and
lateral to the vestibular division and project on the dorsal and ventral cochlear
nuclei. The dorsal cochlear nucleus, situated on the dorsolateral surface of the
restiform body, receives fibers originating in the basal turns of the cochlea
(mediating high-frequency sound). The ventral cochlear nucleus, situated on the
ventrolateral aspect of the restiform body, receives fibers from apical turns of the
cochlea (mediating low-frequency sound). The total number of neurons in the
cochlear nuclei far exceeds the total number of cochlear nerve fibers, and so each
fiber is believed to project on several neurons.

Figure 7-4. Afferent and efferent connections of the pedunculopontine

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nucleus. PPN, pedunculopontine nucleus; GPi, internal segment of globus

pallidus; SNr, substantia nigra pars reticulata; STN, subthalamic nucleus;
SNc, substantia nigra pars compacta; GPe, external segment of globus
pallidus.

Second-order neurons from the cochlear nuclei course through the tegmentum of
the pons to form the three acoustic striae: dorsal, ventral, and intermediate. The
dorsal acoustic stria is formed by axons of neurons in the dorsal cochlear
nucleus, the ventral acoustic stria (trapezoid body) is formed by axons from the
inferior cochlear nucleus, and the intermediate acoustic stria originates in the
inferior and superior cochlear nuclei.

The ventral acoustic stria (the trapezoid body) is the largest of the three striae.
Fibers in this stria project on neurons in the superior olivary complex and the
nucleus of the trapezoid body. The superior olivary nuclear complex is embedded
in the trapezoid body. It includes the lateral and medial superior olivary nuclei.
The olivary nuclei are elongated cell masses of which the medial superior olivary
nucleus is much better developed in humans, whereas the lateral superior olivary
nucleus and the nucleus of the trapezoid body are poorly developed. The nucleus
of the trapezoid body consists of small cells situated at the caudal half of the
superior olivary nucleus. The two superior olivary nuclei and the nucleus of the
trapezoid body are surrounded by a zone of cells of varying sizes and shapes
known collectively as the periolivary nuclei. It was originally believed that the
periolivary nuclei are exclusively involved in descending auditory pathways, but it
has been established that these
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cells are involved in descending as well as ascending auditory projections.
Functions of the superior olivary complex include: (1) processing of cochlear
signals via the ascending auditory pathway, (2) detection of interaural sound
intensity, and (3) providing feedback control of cochlear mechanism through the
olivocochlear bundle.

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Figure 7-5. Schematic diagram of the auditory pathways.

Afferents to the superior olivary complex from nonauditory areas have been
described from serotoninergic and noradrenergic brain stem nuclei. Compared to
the auditory afferents, the serotoninergic and noradrenergic afferents are sparse.
An input from the trigeminal ganglion to the superior olivary nuclear complex has
also been described. Third-order neurons from the superior olivary complex, the
nucleus of the trapezoid body, and the periolivary nuclei contribute mainly to the
contralateral lateral lemniscus, with some projection to the homolateral lateral
lemniscus. The lateral lemniscus also receives fibers from the dorsal and
intermediate acoustic striae. Fibers in the lateral lemniscus project on the
nucleus of the lateral lemniscus. The nucleus of the lateral lemniscus is an
elongated strand of cells embedded within the lateral lemniscus at the isthmus
level. Two subnuclei are recognized: dorsal and ventral. Subsequent stations in
the auditory system include synapses in the inferior colliculus and the medial
geniculate body.

The inferior colliculus is the most important relay station in the ascending and
descending auditory projections. It consists of a large compact central nucleus
and a more diffuse laterally situated zone. The majority of ascending auditory
fibers to the inferior colliculus terminate in the central nucleus. The lateral zone
of the inferior colliculus receives afferents from the central nucleus as well as

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from the nucleus of the lateral lemniscus. There is evidence that the ipsilateral
medial superior olivary nucleus and the contralateral lateral superior olivary
nucleus send excitatory projections to the central nucleus of the inferior
colliculus, whereas the ipsilateral lateral superior olivary nucleus sends inhibitory
projections to the central nucleus. Only a limited number of fibers belonging to
the ascending auditory projection bypass the inferior colliculus to reach the
medial geniculate body directly. These fibers usually arise from the cochlear
nuclei and the nucleus of the lateral lemniscus. The two inferior colliculi are
connected to each other by the commissure of the inferior colliculus and to the
medial geniculate nucleus by the brachium of the inferior colliculus (inferior
quadrigeminal brachium).

The final station is the primary auditory cortex (transverse Heschl's gyri) in the
temporal lobe. The auditory projection (auditory radiation) from the medial
geniculate body to the primary auditory cortex traverses the sublenticular portion
of the internal capsule. From the level of the inferior colliculus onward to the
primary auditory cortex, the auditory projection is subdivided into “core” and
“belt” projections. The core projection terminates in the primary auditory cortex;
the belt projection terminates
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in cortical areas surrounding the primary auditory cortex. The core and belt
projections also have distinct zones of origin within the inferior colliculus, where
the central nucleus is related to the core projection, whereas the lateral zone is
related to the belt projection. Tonotopic localization exists throughout the
auditory system.

In addition to this “classic” auditory pathway, evidence suggests the existence of

another multisynaptic auditory pathway through the reticular formation. The
evidence for a reticular pathway is based on several experimental observations.

1. Reticular thalamic neurons project to the medial geniculate nucleus.

2. The nucleus of the lateral lemniscus and the inferior colliculus are connected
with the mesencephalic reticular formation.

3. Auditory-responding cells have been identified in the mesencephalic

reticular formation and the pretectum.

4. An increase in 2-deoxy-D-glucose metabolism throughout the auditory

pathways has been obtained by means of electric stimulation of the
mesencephalic reticular formation.

Several fiber bundles of the auditory system decussate at various levels:

1. In the pontine tegmentum, the superior, middle, and inferior acoustic striae
decussate and link the right and left cochlear nuclear complexes.

2. The olivocochlear bundle (efferent bundle of Rasmussen), which will be

discussed below, also decussates in the pontine tegmentum.

3. The nuclei of the lateral lemniscus are connected via Probst's commissure,
which passes through the brachium conjunctivum and the most rostral part
of the pontine tegmentum. Probst's commissure also carries fibers from the
nuclei of the lateral lemniscus to the contralateral inferior colliculus.

4. At the midbrain level, the two inferior colliculi communicate via the

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commissure of the inferior colliculus. This commissure also carries fibers

passing from the inferior colliculus to the medial geniculate body.

The auditory system is characterized by the presence of several inhibitory

feedback mechanisms that consist of descending pathways linking the
different cortical and subcortical auditory nuclei. Thus, a system of descending
fibers links the primary auditory cortex, the medial geniculate body, the inferior
colliculus, the nucleus of the lateral lemniscus, the superior olivary nuclear
complex, and the cochlear nuclei. However, the most important feedback
mechanism is served by the olivocochlear bundle, also known as the efferent
bundle of Rasmussen (Figure 7-6). This bundle of fibers arises from cholinergic
neurons of the periolivary nuclei and projects on hair cells in the organ of Corti.
It has both crossed and uncrossed components which differentially innervate the
two types of hair cells.

The crossed bundle originates from large cells in the ventromedial part of the
periolivary area, courses dorsally in the pontine tegmentum, bypasses the
nucleus of the abducens nerve, and crosses to the contralateral side to terminate
by large synaptic terminals abutting the basal parts of the outer hair cells. The
uncrossed component is smaller and originates from small neurons in the vicinity
of the lateral superior olivary nucleus. It terminates by en passant synapses on
primary afferent cochlear fibers just beneath the inner hair cells. Both
components initially join the vestibular division of the cochleovestibular nerve
(cranial nerve VIII), but at the vestibulocochlear anastomosis, they leave it and
travel with the cochlear division as far as the hair cells of the organ of Corti.
Stimulation of the olivocochlear bundle suppresses the receptivity of the organ of
Corti, and thus activity in the auditory nerve. A variety of functions have been
proposed for the olivocochlear bundle. These include: (1) a protective effect on
the cochlea against loud sound, (2) frequency selectivity, (3) selective auditory
attention that permits detection of new signals and understanding of speech in a
noisy background.

Figure 7-6. Schematic diagram showing the origins and course of the
olivocochlear bundle.

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The hair cells of the organ of Corti transduce mechanical energy into nerve
impulses and exhibit a graded generator potential. Spike potentials appear in the
cochlear nerve.

Cochlear nerve fibers respond to both displacement and velocity of the basilar
membrane of the organ of Corti. Displacement of the basilar membrane toward
the scala vestibuli produces inhibition, whereas displacement toward the scala
tympani produces excitation. A single fiber in the cochlear nerve may respond to
both displacement and velocity.

Reflex movements of the eyes and neck toward a sound source are mediated
via two reflex pathways. The first runs from the inferior colliculus to the
superior colliculus and from there via tectobulbar and tectospinal pathways to the
nuclei of eye muscles and the cervical musculature. The other pathway runs from
the superior olive to the abducens nerve (cranial nerve VI) nucleus and then via
the medial longitudinal fasciculus to the nuclei of cranial nerves of extraocular
muscles.

Other reflex pathways include those between cochlear nuclei and the ascending
reticular activating system, which give rise to the auditory-evoked startle
response, and those between the ventral cochlear nuclei and the motor nuclei of
the trigeminal and facial nerves. The latter pathways constitute reflex arcs that
link the organ of Corti with the tensor tympani and stapedius muscles. Thus, in
response to sounds of high intensity, these muscles reflexly contract and dampen
the vibration of the ear ossicles.

B. VESTIBULAR DIVISION
Vestibular nerve fibers are central processes of bipolar cells in Scarpa's ganglion.
Peripheral processes of these bipolar cells are distributed to the vestibular end
organ in the three semicircular canals, the utricle, and saccule. The semicircular
canals are concerned with angular acceleration (detecting a simultaneous
increase in velocity and direction when one is rotating or turning); the utricle and
saccule are concerned with linear acceleration (detecting a change in velocity
without a change in direction, the gravitational effect). The superior portion of
Scarpa's ganglion
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receives fibers from the anterior and horizontal semicircular canals, the utricle
and saccule. The inferior portion of the ganglion receives fibers from the
posterior semicircular canal and the saccule (Figure 7-7). The vestibular nerve
accompanies the cochlear nerve from the internal auditory meatus to the pons,
where it enters the lateral surface at the pontomedullary junction medial to the
cochlear nerve.

Within the pons, vestibular nerve fibers course in the tegmentum between
the restiform body and the spinal trigeminal complex. The major portion of
these fibers projects on the four vestibular nuclei; a smaller portion goes directly
to the cerebellum via the juxtarestiform body. In the cerebellum, these fibers
terminate as mossy fibers on neurons in the flocculonodular lobe and the uvula.
There are four vestibular nuclei: medial, inferior, lateral, and superior. The
medial nucleus (principal nucleus [Schwalbe's nucleus]) appears in the medulla
oblongata at the rostral end of the inferior olive and extends to the caudal part of
the pons. The inferior nucleus (spinal nucleus) lies between the medial nucleus
and the restiform body. The inferior nucleus, which is characterized in histologic
sections by myelinated fibers that traverse it from the vestibular nerve, extends

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from the rostral extremity of the gracile nucleus to the pontomedullary junction.
The lateral nucleus (Deiters' nucleus), which is characterized in histologic
sections by the presence of large multipolar neurons, extends from the
pontomedullary junction to the level of the abducens nerve (cranial nerve VI)
nucleus. The superior nucleus (Bechterew's nucleus) is smaller than the other
nuclei and lies dorsal and medial to the medial and lateral nuclei. The number of
neurons in the vestibular nuclei far exceeds the number of vestibular nerve
fibers. Vestibular nerve fibers project only to limited regions within each
vestibular nucleus. In addition to input from the vestibular nerve, the vestibular
nuclei receive fibers from: (1) the spinal cord, (2) the cerebellum, and (3) the
vestibular cortex (Figure 7-8). The output from the vestibular nuclei is to: (1) the
spinal cord, (2) the cerebellum, (3) the thalamus, (4) the nuclei of the
extraocular muscles, (5) the vestibular cortex, and (6) the vestibular end organ.

Figure 7-7. Schematic diagram showing the origin and termination of the
vestibular nerve.

The vestibular projection to the spinal cord (Figure 7-9) is through the lateral
vestibulospinal tract (from the lateral vestibular nucleus) and the medial
vestibulospinal tract (from the medial vestibular nucleus) via the descending
component of the medial longitudinal fasciculus. The lateral vestibulospinal tract
facilitates extensor motor neurons, whereas the medial tract facilitates flexor
motor neurons. The medial vestibulospinal tract sends fibers to the dorsal motor
nucleus of the vagus. This explains the nausea, sweating, and vomiting that occur
after stimulation of the vestibular end organ.

Projections from the vestibular nuclei to the cerebellum (Figure 7-9) travel
via the juxtarestiform body along with the primary vestibulocerebellar
fibers. These projections arise from the superior, inferior, and medial vestibular
nuclei and terminate mainly ipsilaterally (but also bilaterally) on neurons in the

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flocculonodular lobe, the uvula, and the nucleus fastigii. Cerebellovestibular

connections are much more abundant than are vestibulocerebellar connections.

Vestibulothalamic projections arise from the medial, lateral, and superior

vestibular nuclei and project bilaterally on several thalamic nuclei (ventral
posterolateral, centrolateral, lateral geniculate, and posterior group). They reach
their destinations via several pathways (lateral lemniscus, brachium
conjunctivum, reticular formation), with a few traveling via the medial
longitudinal fasciculus.

Vestibular projections to the nuclei of extraocular muscles travel via the

ascending component of the medial longitudinal fasciculus. They arise from all
four vestibular nuclei and project on nuclei of the oculomotor (cranial nerve III),
trochlear (cranial nerve IV), and abducens (cranial nerve VI) nerves. The crossed
component of this system exerts an excitatory effect, whereas the uncrossed
component exerts an inhibitory effect, on nuclei of extraocular movement.

A projection from the vestibular nuclei to the primary vestibular cortex in the
temporal lobe probably reaches the vestibular cortex via relays in the thalamus.

A projection to the vestibular end organ has been described. Axons travel with
the vestibular nerve and terminate in a bilateral
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fashion on hair cells in cristae of the semicircular canal and the maculae of the
utricle and saccule. In contrast to the olivocochlear bundle, which exerts an
inhibitory effect on the cochlear end organ, this bundle is excitatory to the
vestibular end organ.

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Figure 7-8. Schematic diagram showing the major inputs to the vestibular
nuclei.

The vestibular output to the nuclei of extraocular muscles plays an

important role in the control of conjugate eye movements (Figure 7-9). This
control is mediated via two pathways: the ascending component of the medial
longitudinal fasciculus and the reticular formation. Reflex conjugate deviation of
the eyes in a specific direction, which is known as nystagmus, has two
components: a slow component away from the stimulated vestibular system and a
fast component toward the stimulated side. In clinical medicine, the term
nystagmus refers to the fast component. Although the mechanism of the slow
component is fairly well understood in terms of neuronal connections, the same
cannot be said of the fast component, which is believed to represent a corrective
attempt to return the eyes to a neutral position. Stimulation of the right
horizontal semicircular canal (turning to the right in a Bárány chair or pouring
warm water in the right ear) or the right medial, lateral, or inferior vestibular
nucleus results in a reflex conjugate horizontal deviation of the eyes (horizontal
nystagmus) with a slow component to the left and a fast component to the right.
Bilateral stimulation of the anterior semicircular canal results in upward
movement of the eyes, while stimulation of the posterior canal produces

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downward movement. Sectioning of the medial longitudinal fasciculus rostral to

the abducens nuclei abolishes these primary oculomotor responses. Nystagmus,
however, can still result from labyrinthine stimulation, confirming that pathways
essential for nystagmus probably pass via the reticular formation. Stimulation of
the superior vestibular nucleus produces vertical nystagmus.

Lesions of the medial longitudinal fasciculus (MLF) rostral to the abducens

nucleus interfere with normal conjugate eye movements. In this condition, which
is known as internuclear ophthalmoplegia or the MLF syndrome, there is paralysis
of adduction ipsilateral to the MLF lesion and horizontal monocular nystagmus of
the abducting eye (Figure 7-10). This condition is known to occur in multiple
sclerosis and vascular disorders of the pons. Experimental evidence has shown
that this type of lesion interrupts MLF fibers destined for the part of the
oculomotor nuclear complex that innervates the medial rectus; this explains the
loss of adduction.

There is no satisfactory explanation for the monocular horizontal nystagmus of

the abducting eye. Two theories have been proposed to explain this phenomenon.
The first suggests that nystagmus is due to the utilization of convergence
mechanisms to adduct the ipsilateral eye. This induces adduction of the
contralateral eye, which then jerks back to the position of fixation. The second
theory suggests that the medial longitudinal fasciculus carries facilitatory fibers
to the ipsilateral medial rectus neurons and inhibitory fibers to the contralateral
medial rectus neurons. In lesions of the medial longitudinal fasciculus, failure of
inhibition of adduction in the contralateral eye thus
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causes an abducting (corrective) nystagmus in that eye. The term “internuclear
ophthalmoplegia” (ataxic nystagmus, Lhermitte syndrome, Bielschowsky-Lutz-
Cogan syndrome) was coined by Lhermitte, a French neurologist. Lutz, a Cuban
ophthalmologist, defined two varieties of this syndrome: (1) anterior, in which
the lateral rectus functions normally but the medial rectus is paralyzed on the
side of the MLF lesion and (2) posterior, in which the lateral rectus is paralyzed
but the medial rectus functions normally. The validity of this division of the
syndrome is not certain.

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Figure 7-9. Schematic diagram showing the efferent connections of the

vestibular nuclei. MLF, medial longitudinal fasciculus.

Figure 7-10. Schematic diagram showing the effects of lesions in the medial
longitudinal fasciculus (MLF) on conjugate eye movements. Zigzag arrows

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indicate nystagmus.

Facial Nerve (Cranial Nerve VII)

The facial nerve (Figure 7-11) is a mixed nerve with both sensory and motor
components. This nerve is responsible for our individuality, the facial expressions
that characterize each of us.

A. SENSORY COMPONENTS
The facial nerve carries two types of sensory afferents: exteroceptive fibers
from the external ear and taste fibers from the anterior two-thirds of the
tongue.

Figure 7-11. Schematic diagram showing the nuclei of origin, course, and
areas of supply of the facial nerve (cranial nerve VII).

The exteroceptive fibers from the external ear are peripheral processes of
neurons in the geniculate ganglion. Central processes project on neurons in the
spinal trigeminal nucleus (similar to fibers from the same area carried by the
glossopharyngeal [cranial nerve IX] and vagus [cranial nerve X] nerves).

The taste fibers have their neurons of origin in the geniculate ganglion.
Peripheral processes of these neurons reach the taste buds in the anterior two-
thirds of the tongue; central processes enter the brain stem with the nervus
intermedius and project on neurons in the gustatory part of the nucleus
solitarius, along with fibers carried by the glossopharyngeal (from the posterior

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third of the tongue) and vagus (from the epiglottic region) nerves. The sensory
and gustatory fibers, along with the visceral motor component, form a separate
lateral root of the facial nerve, the nervus intermedius (Wrisberg's nerve).

B. MOTOR COMPONENTS
The facial nerve carries two types of motor fibers: somatic and
secretomotor.

1. Somatic Motor Fibers

Somatic motor fibers supply the muscles of facial expression and the stapedius,
the stylohyoid, and the posterior belly of the digastric. These fibers arise from
the facial motor nucleus in the pontine tegmentum. From their neurons of origin,
fibers course dorsomedially and then rostrally in the tegmentum and form a
compact bundle near the abducens (cranial nerve VI) nucleus in the floor of the
fourth ventricle (the facial colliculus). They bend (genu) laterally over the
abducens nucleus and turn ventrolaterally to emerge at the lateral border of the
pons. This peculiar course of the somatic motor component of the facial nerve
fibers in the tegmentum results from the migration of facial motor neurons from a
dorsal position in the floor of the fourth ventricle caudally and ventrally, pulling
their axons with them. The migration of the facial motor nucleus is explained by
neurobiotaxis, in which neurons tend to migrate toward major sources of stimuli.
In the case of the facial motor nucleus, this migration brings it closer to the
trigeminal spinal nucleus and its tract. Visceral motor and sensory components of
the facial nerve do not make a loop around the abducens
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nucleus. Instead, they form a separate lateral root of the facial nerve, the nervus
intermedius.

The motor nucleus of the facial nerve is organized into longitudinally oriented
motor columns (subnuclei) concerned with specific facial muscles: the medial,
dorsal, intermediate, and lateral subnuclei. Motor neurons that supply upper
facial muscles are located in the dorsal part of the nucleus, those innervating
lower facial muscles are primarily located in the lateral part of the nucleus, and
those supplying the platysma and the posterior auricular muscles are in the
medial part of the nucleus.

The facial motor nucleus receives fibers from the following sources:

a. Cerebral cortex
Corticofacial fibers originate from areas of face representations in the
primary motor, supplementary motor, premotor, rostral, and caudal
cingulate cortices. These fibers travel as direct corticobulbar or indirect
corticoreticulobulbar fibers. The cortical input to the facial nucleus is bilateral to
the part of the nucleus that supplies the upper facial muscles and only
contralateral to the part that innervates the perioral musculature. In lesions
affecting one hemisphere, only the lower facial muscles contralateral to the lesion
are affected (Figure 7-12). This is referred to as central (supranuclear) facial
paresis, in contradistinction to peripheral facial paralysis or paresis (resulting
from lesions of the facial motor nucleus or the facial nerve), in which all the
muscles of facial expression ipsilateral to the lesion are affected. Two types of
central facial paresis (palsy) have been described: voluntary and involuntary
(mimetic). Voluntary central facial palsy results from lesions involving the

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contralateral corticobulbar or corticoreticulobulbar fibers. Mimetic or emotional

innervation of the muscles of facial expression is involuntary and of uncertain
origin. It allows contraction of the lower facial muscles in response to genuine
emotional stimuli. Certain neural lesions can produce mimetic central facial
paralysis without voluntary central facial paralysis. More extensive lesions
produce combined voluntary and mimetic central facial paralysis.

Figure 7-12. Schematic diagram illustrating the concept of central facial

paresis.

Recent experimental evidence provides an alternative explanation for the sparing

of the upper facial musculature in patients with central (hemispheral) lesions.
Sparse data from human studies coupled with the results of experimental studies
in a variety of mammals, including monkeys, have shown that (1) the bilateral
cortical input to facial motor neurons that innervate upper facial muscles is
sparse, (2) motor neurons of the facial nucleus that innervate the lower facial
muscles receive significant and bilateral cortical input which is threefold heavier
on the contralateral side, and (3) cortical innervation of the ipsilateral lower
facial motor subnucleus is considerably heavier than that of the ipsilateral upper
facial motor subnucleus. On the basis of these findings, it has been proposed that
the deficit of facial muscles seen after unilateral hemispheral lesions reflects the
extent to which direct cortical innervation of facial motor neuron is lost. Thus,
motor neurons innervating the upper face would be little affected because they
do not receive much direct cortical input. Also, lower facial motor neurons

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contralateral to the lesion would suffer loss of function because they are most
dependent on direct contralateral cortical innervation and because the remaining
ipsilateral cortical projection apparently is insufficient to drive them. The small
loss of cortical input to lower facial motor neurons ipsilateral to the lesion is
compensated by the remaining, much more intense, input from the intact
hemisphere. Alternately, it is possible that the lower facial muscles ipsilateral to
the lesion display some mild weakness, but this is obscured by the much more
profound contralateral weakness. The course of corticobulbar fibers to the facial
nucleus in humans remains uncertain. Histologic studies in human autopsy
material at the turn of the 20th century described
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an “aberrant bundle” separating from the corticospinal tract at the midbrain and
upper pons and coursing along the tegmental border adjacent to the lemniscal
fibers. These observations were subsequently confirmed using more reliable
staining methods. Recent studies have described three possible trajectories for
the corticofacial fibers: (1) via the “aberrant bundle,” (2) separating from the
corticospinal tract in the caudal basis pontis and coursing dorsally to the facial
nucleus in the pontine tegmentum, and (3) forming a loop into the medulla
oblongata before reaching the facial nucleus. These trajectories would explain the
occurrence of central facial palsy in lesions affecting the pontine tegmentum and
basis pontis and those associated with the lateral medullary syndrome.

b. Basal ganglia
This input to the facial motor nucleus explains the movement of paretic facial
muscles in response to emotional stimulation. Patients with central facial
paralysis who are unable to move the lower facial muscles voluntarily may be
able to do so reflexly in response to emotional stimulation.

c. Superior olive
This input is part of a reflex involving the facial and auditory nerves. It explains
the grimacing of facial muscles that occurs in response to a loud noise.

d. Trigeminal system
This input is also reflex in nature, linking the trigeminal and facial nerves. It
underlies the blinking of the eyelids in response to corneal stimulation.

e. Superior colliculus
This input via tectobulbar fibers is reflex in nature and provides for closure of the
eyelids in response to intense light or a rapidly approaching object.

2. Secretomotor (Visceral Motor) Fibers.

These fibers arise from the superior salivatory nucleus in the tegmentum of the
pons. They are preganglionic fibers that leave the brain stem with the nevus
intermedius (Wrisberg's nerve) and synapse in collateral ganglia. Fibers destined
for the lacrimal gland leave the nervus intermedius and travel in the greater
superficial petrosal and the nerve of the pterygoid canal (vidian nerve) before
synapse in the pterygopalatine ganglion, from which postganglionic
parasympathetic fibers travel in the maxillary, zygomatic, zygomaticotemporal,
and lacrimal nerves to reach the lacrimal gland. Fibers destined for the
submandibular and sublingual glands join the chorda tympani and the lingual

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nerves and synapse in the submandibular ganglion, from which postganglionic

parasympathetic fibers arise. Because fibers for the lacrimal, submandibular, and
sublingual glands leave the brain stem together, lesions of the facial nerve
proximal to the geniculate ganglion may result in aberrant growth of regenerating
fibers so that fibers destined to innervate the lacrimal glands reach the
submandibular and sublingual salivary glands. This aberrant growth is responsible
for the phenomenon of “crocodile tears,” in which the presence of food in the
mouth is followed by lacrimation rather than salivation.

C. FACIAL NERVE LESIONS

Signs of facial nerve paralysis (Bell's palsy) vary with the location of the lesion
(Figure 7-13). Bell's palsy is named after Sir Charles Bell (1774–1842), a British
anatomist, physiologist, surgeon, and neurologist who was also a pioneer in the
study of facial expression.

Figure 7-13. Schematic diagram showing lesions in the facial nerve at

different sites and the resulting clinical manifestations of each.

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1. Proximal to Geniculate Ganglion

Lesions of the facial nerve proximal to the geniculate ganglion result in the
following signs:

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1. Paralysis of all the muscles of facial expression

2. Loss of taste in the anterior two-thirds of the ipsilateral half of the

tongue

3. Impaired salivary secretion

4. Impaired lacrimation

5. Hyperacusis (hypersensitivity to sound as a result of paralysis of the

stapedius muscle)

6. Crocodile tears in some patients with aberrant growth of regenerating fibers

2. Distal to Geniculate Ganglion

Lesions of the facial nerve distal to the geniculate ganglion but proximal to the
chorda tympani result in the following ipsilateral signs:

1. Paralysis of all the muscles of facial expression

2. Loss of taste in the anterior two-thirds of the tongue

3. Impaired salivary secretion

4. Hyperacusis

Lacrimation is not affected by this type of lesion, since the fibers destined for the
lacrimal gland leave the nerve proximal to the level of the lesion.

3. Stylomastoid Foramen
Lesions of the facial nerve at the sty-lomastoid foramen (where the motor fibers
destined for the muscles of facial expression leave the cranium) result only in
paralysis of the muscles of facial expression that are ipsilateral to the lesion.

Abducens Nerve (Cranial Nerve VI)

The abducens nerve (Figure 7-14) is a purely motor nerve that innervates the
lateral rectus muscle. The abducens nucleus is located in a paramedian site in the
tegmentum of the pons, in the floor of the fourth ventricle. It extends from the
rostral limit of the lateral vestibular nucleus to the rostral portion of the
descending vestibular nucleus. The abducens nucleus has two populations of
neurons: large (motor neurons) and small (interneurons).

Axons of the large neurons (motor neurons) form the abducens nerve and supply
the lateral rectus muscles. Axons of the small neurons (interneurons) join the
contralateral medial longitudinal fasciculus and terminate on neurons in the
oculomotor nucleus that supply the medial rectus muscle (medial rectus
subnucleus). Axons of the abducens nerve course through the tegmentum and
basis pontis and exit on the ventral surface of the pons in the groove between
the pons and the medulla oblongata (Figure 7-14). The abducens nucleus (Figure
7-14) receives fibers from (1) the cerebral cortex (corticoreticulobulbar fibers),
(2) the medial vestibular nucleus via the medial longitudinal fasciculus, (3) the
paramedian pontine reticular formation (PPRF), and (4) the nucleus prepositus
hypoglossi. The corticobulbar input is bilateral, the inputs from the PPRF and the
nucleus prepositus are uncrossed, and the input from the medial vestibular

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nucleus is predominantly uncrossed. Direct afferent fibers from Scarpa's ganglion

to the abducens nucleus have been described.

Figure 7-14. Schematic diagram showing sources of modulating inputs into

the abducens (cranial nerve VI) nucleus and intrapontine course of the
abducens nerve.

Figure 7-15. Schematic diagram showing the clinical manifestations

resulting from lesions in the abducens nucleus (B) and nerve (A).

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Lesions of the abducens nerve result in paralysis of the ipsilateral lateral

rectus muscle and diplopia (double vision) on attempted horizontal gaze
toward the side of the paralyzed muscle (Figure 7-15A); the two images are
horizontal, and the distance between them increases as the eyes move in the
direction of action of the paralyzed muscle. The abducens nerve has a long
intracranial course and therefore is commonly affected in intracranial diseases of
varying etiologies and sites. In contrast to lesions of the abducens nerve, lesions
of the abducens nucleus do not result in paralysis of abduction but instead in
paralysis of horizontal gaze ipsilateral to the lesion; this is manifested by the
failure of both eyes to move on attempted ipsilateral horizontal gaze (Figure 7-
15).

Paralysis of lateral gaze after abducens nucleus lesions is explained by

involvement of the large neurons that supply the ipsilateral lateral rectus muscle
and the small neurons (interneurons) that supply the contralateral medial rectus
neurons (medial rectus subnucleus) within the oculomotor nucleus (Figure 7-16).
The
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notion that pontine reticular neurons are responsible for paralysis of adduction no
longer appears tenable. Tritiated amino acids injected into the paramedian
pontine reticular formation do not reveal terminations in the oculomotor nucleus
but instead in the abducens nucleus and the interstitial nucleus of the medial
longitudinal fasciculus, which is believed to be involved in vertical (downward)
gaze. The pontine center for lateral gaze and the abducens nucleus probably
constitute a single entity. The PPRF (pontine center for lateral gaze) is a
physiologically defined neuronal pool that is rostral to the abducens nucleus. It is
composed of caudal and rostral parts. The caudal part is connected to the
ipsilateral abducens nucleus. Stimulation of the caudal part results in conjugate
horizontal deviation of the eyes. The rostral part is connected to the rostral
interstitial nucleus of the MLF (RiMLF), which in turn projects to the ipsilateral
oculomotor nucleus by pathways other than the MLF. Stimulation of the rostral
PPRF results in vertical gaze. Lesions in the caudal PPRF abolish conjugate lateral
gaze, whereas lesions in the rostral PPRF abolish vertical gaze. Extensive lesions
in PPRF result in paralysis of both horizontal and vertical gaze.

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Figure 7-16. Schematic diagram illustrating the basis of lateral gaze

paralysis in abducens nucleus lesions.

Abducens nerve rootlets along their course within the pons may be involved in a
variety of intraaxial vascular lesions.

1. Lesions in the basis pontis involving the corticospinal fibers and the rootlets
of the abducens nerve result in alternating hemiplegia manifested by
ipsilateral lateral rectus paralysis (and diplopia) as well as an upper motor
neuron paralysis of the contralateral half of the body (Figure 7-17A).

2. Lesions in the pontine tegmentum involving the abducens rootlets and the
medial lemniscus result in ipsilateral lateral rectus paralysis (and diplopia)
and contralateral loss of kinesthesia and discriminative touch (Figure 7-
17B).

3. More dorsal lesions involving the abducens nucleus, the medial longitudinal
fasciculus, and the curving rootlets of the facial nerve produce paralysis of
horizontal gaze and peripheral-type facial paralysis, both ipsilateral to the
lesion (Figure 7-17C).

4. Small lacunar infarct involving sixth nerve fascicles within the pons produce
isolated abducens nerve palsy.

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Figure 7-17. Schematic diagram of lesions of the abducens nerve

(cranial nerve VI) and nucleus and the resulting clinical manifestations.

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Unilateral and bilateral duplications of the abducens nerve have been reported. In
some cases, the nerve emerged from the brain stem as a single trunk and split
into two branches in the
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subarachnoid space before reaching the cavernous sinus. In other cases, the
nerve exited the brain stem as two separate branches. In both situations, the two
branches usually merge within the cavernous sinus.

Trigeminal Nerve (Cranial Nerve V)

The trigeminal nerve is the largest of the twelve cranial nerves. It transmits
sensory information from the head and neck and provides innervation to the
muscles of mastication, the tensor tympani, tensor palati, myelohyoid, and
anterior belly of the digastric. The trigeminal nerve has two roots: a smaller
(portio minor) efferent root and a larger (portio major) afferent root. The motor
root is composed of as many as 14 separately originating rootlets that are joined
about 1 cm from the pons. At the pons, the first division of the trigeminal
sensory root (V1) usually is located in a dorsomedial position adjacent to the
motor root and the third division (V3) is in a caudolateral position. V3, however,
may vary from being directly lateral to directly caudal to V1. Aberrant sensory
roots exist in about 50 percent of individuals and may explain the persistence of
facial pain (trigeminal neuralgia) after surgical sectioning of the sensory root.
Aberrant sensory rootlets enter the sensory root within 1 cm of the pons and
contribute mainly to V1. Some rootlets between the motor and sensory roots may
join either root farther away from the pons. Anastomosis between the motor and
sensory roots has been described and may explain the failure of sensory root
sectioning to relieve facial pain.

A. EFFERENT ROOT
The efferent root of the trigeminal nerve arises from the motor nucleus of the
trigeminal nerve in the tegmentum of the pons. The efferent root supplies the
muscles of mastication and the tensor tympani, the tensor palati, the mylohyoid,
and the anterior belly of the digastric. The motor nucleus receives fibers from the
cerebral cortex (corticobulbar) and the sensory nuclei of the trigeminal nerve.
The cortical projections to trigeminal motor neurons are bilateral and symmetric
via direct corticobulbar and indirect corticoreticulobulbar fibers. Lesions affecting
the motor nucleus or efferent root result in paralysis of the lower motor neuron
type of the muscles supplied by this root.

B. AFFERENT ROOT
The afferent root (Figure 7-18) of the trigeminal nerve contains two types of
afferent fibers.

1. Proprioceptive Fibers.
Proprioceptive fibers from deep structures of the face travel via the efferent and
afferent roots. They are peripheral processes of unipolar neurons in the
mesencephalic nucleus of the trigeminal nerve located at the rostral pontine and
caudal mesencephalic levels. This nucleus is unique in that it is homologous to
the dorsal root ganglion yet is centrally placed. Proprioceptive fibers to the
mesencephalic nucleus convey pressure and kinesthesia from the teeth,
periodontium, hard palate, and joint capsules as well as impulses from stretch
receptors in the muscles of mastication. The output from the mesencephalic

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nucleus is destined for the cerebellum, the thalamus, the motor nuclei of the
brain stem, and the reticular formation. The mesencephalic nucleus is concerned
with mechanisms that control the force of the bite.

2. Exteroceptive Fibers
Exteroceptive fibers are general somatic sensory fibers that convey pain,
temperature, and touch sensations from the face and the anterior aspect of the
head. The neurons of origin of these fibers are situated in the semilunar
(gasserian) ganglion. The peripheral processes of neurons in the ganglion are
distributed in the three divisions of the trigeminal nerve: ophthalmic, maxillary,
and mandibular. The central processes of these unipolar neurons enter the lateral
aspect of the pons and distribute themselves as follows.

Figure 7-18. Schematic diagram showing the cells of origin and course of
the sensory root of the trigeminal nerve (cranial nerve V).

Some of these fibers descend in the pons and medulla and run down to the level
of the second or third cervical spinal segment as the descending (spinal) tract of
the trigeminal nerve. They convey pain and temperature sensations. Throughout
their caudal course these fibers project on neurons in the adjacent nucleus of the
descending tract of the trigeminal nerve (spinal trigeminal nucleus). The spinal
trigeminal nucleus is divided into three parts on the basis of its cytoarchitecture:
(1) an oral part, which extends from the entry zone of the trigeminal nerve in the
pons to the level of the rostral third of the inferior olivary nucleus in the medulla
oblongata and receives tactile sensibility from oral mucosa, (2) an interpolar
part, which extends from the caudal extent of the oral part to just rostral to the
pyramidal decussation in the medulla oblongata and receives dental pain, and (3)

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a caudal part, which extends from the pyramidal decussation down to the second
or third cervical spinal segments and receives pain and temperature sensations
from the face.

Axons of neurons in the spinal trigeminal nucleus cross the midline and form the
ventral secondary ascending trigeminal tract, which courses rostrally to terminate
in the thalamus. During their rostral course these second-order fibers send
collateral branches to several motor nuclei of the brain stem (hypoglossal [cranial
nerve XII], vagus [cranial nerve X], glossopharyngeal [cranial nerve IX], facial
[cranial nerve VII], and trigeminal [cranial nerve V]) to establish reflexes. The
spinal tract of the trigeminal nerve is concerned mainly with the transmission of
pain and temperature sensations. It sometimes is cut surgically at a low level
(trigeminal tractotomy) to relieve intractable pain. These operations may relieve
pain but leave touch sensation intact. The spinal tract of the trigeminal nerve
also carries somatic afferent fibers traveling
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with other cranial nerves (facial [cranial nerve VII], glossopharyngeal [cranial
nerve IX], and vagus [cranial nerve X]), as was outlined previously.

Other incoming fibers of the trigeminal nerve bifurcate on entry into the
pons into ascending and descending branches. These fibers convey touch
sensation. The descending branches join the spinal tract of the trigeminal nerve
and follow the course that was outlined above. The shorter ascending branches
project on the main sensory nucleus of the trigeminal nerve. From the main
sensory nucleus, second-order fibers ascend ipsilaterally and contralaterally as
the dorsal ascending trigeminal tract to the thalamus. Some crossed fibers also
travel in the ventral ascending trigeminal tract. Once they are formed, both
secondary trigeminal tracts (dorsal and ventral) lie lateral to the medial
lemniscus between it and the spinothalamic tract. Since fibers that convey touch
sensation bifurcate on entry to the pons and terminate on both the spinal and the
main sensory trigeminal nuclei, touch sensations are not abolished when the
spinal trigeminal tract is cut (trigeminal tractotomy). A schematic summary of
the afferent and efferent trigeminal roots and their nuclei is shown in Figure 7-
19. Studies of trigeminothalamic fibers have revealed that the bulk of these
fibers arise from the main sensory nucleus and the interpolaris segment of the
spinal nucleus. Most of these fibers terminate in the contralateral thalamus
(ventral posterior medial [VPM] nucleus) with few terminations ipsilaterally.
Other efferents of the trigeminal nuclei include projections to the ipsilateral
cerebellum via the inferior cerebellar peduncle (from the spinal and main sensory
nuclei), the spinal cord dorsal horn (bilaterally) from the spinal nucleus, and the
cerebellum (from the mesencephalic nucleus).

Trigeminal neuralgia (tic douloureux) is a disabling painful sensation in the

distribution of the branches of the trigeminal nerve. The pain is paroxysmal,
stabbing, or like lightning in nature and usually is triggered by eating, talking, or
brushing the teeth. Several methods of treatment, including drugs, alcohol
injection of the nerve, electrocoagulation of the ganglion, and surgical
interruption of the nerve or spinal tract in the medulla oblongata (trigeminal
tractotomy), have been tried with varying degrees of success.

C. TRIGEMINAL REFLEXES
Collaterals from the secondary ascending trigeminal tracts establish synapses
with the following cranial nerve nuclei to establish reflex responses:

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1. The motor nucleus of the trigeminal to elicit the jaw reflex

2. The facial motor nuclei on both sides, resulting in a bilateral blink reflex,
the corneal reflex (direct and consensual), in response to unilateral corneal
stimulation. The reflex is elicited by gently touching the cornea (usually with
a cotton wisp). The afferent limb of the reflex is the trigeminal nerve and
the descending (spinal) tract of the trigeminal nerve. Collateral branches of
the spinal tract synapse in the oral or interpolar parts of the spinal nucleus
of the trigeminal nerve. Connections are then made via the reticular
formation with the facial nuclei bilaterally. Trigeminal fibers establish three
types of synapses with facial nuclei: (1) disynaptic with the ipsilateral facial
nerve nucleus, (2) polysynaptic with the ipsilateral facial nucleus, and (3)
indirect and polysynaptic with the contralateral facial nerve nucleus.

3. The nucleus ambiguus, the respiratory center of the reticular formation, and
the spinal cord (phrenic nerve nuclei and anterior horn cells to intercostal
muscles), resulting in the sneezing reflex in response to stimulation of the
nasal mucous membrane

4. The dorsal motor nucleus of the vagus as part of the vomiting reflex

5. The inferior salivatory nucleus for the salivatory reflex

6. The hypoglossal nucleus for reflex movements of the tongue in response to

tongue stimulation

7. The superior salivatory nucleus, resulting in tears in response to corneal

irritation, the tearing reflex

Figure 7-19. Composite schematic diagram of the afferent and efferent

roots of the trigeminal nerve (cranial nerve V) and their nuclei.

D. BLOOD SUPPLY
The blood supply of the pons (Figures 7-20 and 7-21) is derived from the
basilar artery. Three groups of vessels provide blood to specific regions of

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the pons: the paramedian and the short and long circumferential.

The paramedian vessels (four to six in number) arise from the basilar artery and
enter the pons ventrally, supplying the medial basis pontis and the tegmentum.
Pontine nuclei, corticospinal tract bundles within the basis pontis, and the medial
lemniscus are among the structures supplied by these vessels.

Short circumferential arteries arise from the basilar artery, enter the brachium
pontis, and supply the ventrolateral region of the basis pontis.

Long circumferential arteries include the anterior inferior cerebellar artery

(AICA), the internal auditory artery, and the superior cerebellar artery. The AICA
supplies the lateral tegmentum of the lower two-thirds of the pons as well as the
ventrolateral cerebellum. The internal auditory artery, which may arise from the
AICA or the basilar artery, supplies the auditory, vestibular,
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and facial cranial nerves. The superior cerebellar artery supplies the dorsolateral
pons, brachium pontis, brachium conjunctivum, and dorsal reticular formation.
Occasionally the ventrolateral pontine tegmentum is also supplied by this vessel.

Figure 7-20. Schematic diagram of vascular territories in the rostral pons.

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Figure 7-21. Schematic diagram of vascular territories in the caudal pons.

TERMINOLOGY
Abducens nerve (Latin, “drawing away”).
The sixth cranial nerve, discovered by Eustachius in 1564, is so named because it
supplies the lateral rectus muscle, whose function is to direct the eye to the
lateral side away from the midline.

Acoustic neuroma.
A tumor of the eighth cranial nerve characterized by deafness and vertigo. May
involve adjacent structures in the brain stem. Described by Harvey Cushing, an
American neurosurgeon, in 1917.

Alternating hemiplegia.
Paresis of the cranial nerves ipsilateral to a brain stem lesion and of the trunk
and limbs contralateral to the lesion.

Alzheimer's disease.
A degenerative disease of the brain formerly known as senile dementia.
Characterized by memory loss, cortical atrophy, senile plaques, and
neurofibrillary tangles. Described by Alois Alzheimer, a German
neuropsychiatrist, in 1907.

Bárány chair test.

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A test of labyrinthine function in which the subject, wearing opaque lenses, is

rotated while seated on a chair with the head tilted 30 degrees forward to bring
the horizontal semicircular canal into the true horizontal plane. Rotation normally
elicits horizontal nystagmus opposite to the direction of rotation.

Bechterew's nucleus.
The superior nucleus of the vestibular nerve. Described by Vladimir Bechterew, a
Russian neurologist, in 1908.

Bell's palsy.
Facial paralysis ipsilateral to a facial nerve lesion. Described by Sir Charles Bell,
a Scottish anatomist and surgeon, in 1821.

Brachium conjunctivum (Latin, Greek brachion, “arm”; conjunctiva,

“connecting”).
An armlike bundle of fibers that connect the cerebellum and midbrain.

Brachium pontis (Latin, Greek, brachion, “arm”; pontis, “bridge”).

An armlike bundle of fibers that connect the pons and cerebellum.

Central facial palsy.

Weakness of the lower facial muscles contralateral to a lesion in the cerebral
cortex or corticobulbar fibers.

Cerebellopontine angle.
The angle between the medulla oblongata, pons, and cerebellum. Contains the
seventh (facial) and eighth (cochleovestibular) cranial nerves.

Cochlea (Latin, “snail shell”).

So named because it has a spiral form resembling a snail shell.

Conjugate eye movement (Latin conjugatus, “yoked together”).

The lateral deviation of the two eyes in parallel.

Corneal reflex.
Blinking in response to corneal stimulation. The afferent limb of the reflex is via
the trigeminal nerve, and the efferent limb is via the facial nerve.

Crocodile tears (Bogorad syndrome).

Shedding of tears while eating as a result of aberrant innervation of facial nerve
fibers so that fibers destined to innervate the lacrimal glands reach the
submandibular and sublingual glands. Named after F. A. Bogorad, a Russian
physiologist who suggested the name and the physiologic mechanism in 1928.
The phenomenon had been described by Hermann Oppenheim, a German
neurologist, in 1913.

Deiters' nucleus.
The lateral vestibular nucleus. Described by Otto Friedrich Karl Deiters, a German
anatomist, in 1865.

Diplopia (Greek diplos, “double”; ops, “eye”).

The perception of two images of a single object. Double vision resulting from
extraocular muscle weakness.

Down syndrome.
A genetic syndrome caused by trisomy of chromosome 21 or translocation of
chromosomal material. Characterized by unique facial features, mental
retardation, skeletal abnormalities, congenital cardiac lesions, and a single

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transverse palmar crease. Described by James Langdon Haydon Down, an English

physician, in 1866.

Efferent bundle of Rasmussen.

The olivocochlear efferent bundle in the pons extends from the periolivary nuclei
to the hair cells of the organ of Corti. Suppresses the receptivity of the cochlear
end organ. Described by Theodor Rasmussen, a Canadian neurosurgeon, in 1946.

Facial colliculus (Latin colliculus, “small elevation”).

An elevation in the floor of the fourth ventricle overlying the genu of the facial
nerve and the abducens nucleus.

Facial nerve.
The seventh cranial nerve. Willis divided the seventh nerve into a portio dura
(facial) and a portio mollis (auditory). Soemmering separated the two and
numbered them separately.

Gasserian ganglion.
The sensory trigeminal (semilunar) ganglion was named after Johann Gasser, an
Austrian anatomist, by one of his students in 1765. Gasser had described the
ganglion in his thesis.

Heschl's gyri (Greek gyros, “circle”).

The transverse gyri in the temporal lobe are the sites of the primary auditory
cortex. Named after Richard Heschl, an Austrian anatomist who described them in
1855.

Horner's syndrome.
Drooping of the eyelids (ptosis), constriction of the pupil (miosis), retraction of
the eyeball (enophthalmos), and loss of sweating on the face (anhidrosis)
constitute this syndrome described by Johann Friedrich Horner, a Swiss
ophthalmologist, in 1869. The syndrome is due to interruption of descending
sympathetic fibers. Also known as Bernard-Horner syndrome and
oculosympathetic palsy. Described in animals by Francois du Petit in 1727.
Claude Bernard in France in 1862 and E. S. Hare in Great Britain in 1838 gave
precise accounts of the syndrome before Horner did.

Hyperacusis (Greek hyper, “above”; akousis, “hearing”).

Abnormal sensitivity to loud sounds. Commonly seen in persons with facial nerve
lesions and subsequent paralysis of the stapedius muscle.

Internuclear ophthalmoplegia (MLF syndrome).

A condition characterized by paralysis of ocular adduction ipsilateral to the
medial longitudinal fasciculus lesion and monocular nystagmus in the
contralateral abducting eye.

Isthmus (Greek isthmos, “a narrow connection between two large bodies

or spaces”).
The narrowest portion of the hindbrain. It is situated between the pons and the
midbrain.

Jaw reflex.
Contraction of the masseter and the temporalis muscle in response to a tap just
below the lower lip. The afferents and efferent limbs of the reflex are via the
trigeminal nerve. The reflex is evident in upper motor neuron lesions.

Juxtarestiform body (Latin juxta, “near, close by”; restis, “rope”; forma,

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“shape”).
A bundle of nerve fibers in close proximity to the restiform body (inferior
cerebellar peduncle). Carries vestibular and reticular fibers from and to the
cerebellum.
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Lateral lemniscus (Latin from Greek lemniskos, “ribbon”).

A fiber bundle carrying second- and third-order auditory fibers in the brain stem.

Locus ceruleus (Latin, “place, dark blue”).

A pigmented noradrenergic nucleus in the rostral pons that is dark blue in
sections.

Modiolus (Latin, “nave, hub”).

The central pillar (axis) of the cochlea. Described and named by Eustachius in
1563. Its structure suggests the hub of the wheel with radiating spokes (lamina
spiralis) attached to it.

Nervus intermedius (Wrisberg's nerve).

Lateral root of the facial nerve containing visceral motor and sensory
components. Named by Heinrich August Wrisberg, a German anatomist.

Nucleus prepositus.
One of the perihypoglossal reticular nuclei in the medulla oblongata. Related to
ocular movement.

Nystagmus (Greek nystagmos, “drowsiness, nodding”).

Nodding or closing of the eyes in a sleepy person. The term now refers to
involuntary rhythmic oscillation of the eyes.

Organ of Corti.
The cochlear receptor organ in the inner ear. Described by Marchese Alfonso
Corti, an Italian histologist, in 1851.

Parkinson's disease.
A degenerative disease of the brain characterized by postural tremor and rigidity
from loss of dopaminergic neurons in the substantia nigra. Described by James
Parkinson, an English physician, in 1817 under the name of shaking palsy.

Pons (Latin, “bridge”).

A bridge between the medulla oblongata, midbrain, and cerebellum. Described by
Eustachius and Varolius. The illustrations of Eustachius were superior to those of
Varolius but were not published until 1714, whereas those of Varolius were
published in 1573; hence the name pons varolii.

Probst's commissure.
A bundle of fibers connecting the nuclei of the lateral lemniscus with each other
and with the inferior colliculus.

Restiform body (Latin restis, “rope”; forma, “form”).

A body (inferior cerebellar peduncle) shaped like a rope. Described by Humphrey
Ridley, an English anatomist, in 1695.

Saccule (Latin sacculus, “little bag or sac”).

One of the vestibular end organs in the inner ear. Detects linear displacement of
the body.

Salivatory reflex.

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Salivation in response to trigeminal stimulation. The afferent limb of the reflex is

via the trigeminal nerve; the efferent limb is via the glossopharyngeal nerve.

Scarpa's ganglion (Greek ganglion, “knot”).

A structure containing bipolar cells that give rise to the vestibular nerve. Located
in the internal auditory meatus. Described by Antonius Scarpa, an Italian surgeon
and anatomist, in 1779.

Schwalbe's nucleus.
The medial vestibular nucleus. Described by Gustav Schwalbe (1844–1916), a
German anatomist.

Semilunar ganglion (Latin semi, “half”; luna, “moon”).

Resembling a crescent or half moon. The semilunar (gasserian) ganglion of the
trigeminal nerve lies on the medial end of the petrous bone.

Sneezing (nasal) reflex.

Sneezing in response to a nasal tickle. The afferent limb of the reflex is via the
trigeminal nerve; the efferent limbs are via the vagus, phrenic, and intercostal
nerves.

Spiral ganglion.
The sensory ganglion of the cochlear nerve. Contains bipolar cells.

Tearing reflex.
Production of tears in response to corneal stimulation. The afferent limb of the
reflex is via the trigeminal nerve; the efferent limb is via the facial nerve.

Tegmentum (Latin, a “covering”).

The dorsal parts of the pons and midbrain.

Trapezoid body (Latin trapezoides, “table-shaped”).

The ventral acoustic stria in the tegmentum of the pons constitutes the trapezoid
body.

Trigeminal nerve (Latin tres, “three”; geminus, “twin”).

The fifth cranial nerve was described by Fallopius. So named because it has three
divisions: ophthalmic, maxillary, and mandibular.

Trigeminal neuralgia (tic douloureux, Fothergill's syndrome).

Paroxysmal attacks of severe facial pain in the trigeminal sensory distribution.
Described by John Fothergill, an English physician, in 1773.

Trigeminal tractotomy.
Cutting of the spinal trigeminal tract in the brain stem to relieve severe
intractable facial pain.

Utricle (Latin utriculus, “small sac”).

A sensory vestibular end organ that detects linear displacement of the body.

Vomiting reflex.
Vomiting in response to stimulation of the pharyngeal wall. The afferent limb of
the reflex is via the trigeminal nerve; the efferent limb is via the vagus nerve.

SUGGESTED READINGS
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Atilla H et al: Isolated sixth nerve palsy from pontine infarct. Acta Neurol
Belgica 2000; 100:246–247.

Brodal P: The pontocerebellar projection in the Rhesus monkey: An

experimental study with retrograde axonal transport of horseradish
peroxidase. Neuroscience 1979; 4:193–208.

Burton H, Craig AD: Distribution of trigeminothalamic projection cells in cat

and monkey. Brain Res 1979; 161:515–521.

Carpenter MB, Batton RR: Abducens internuclear neurons and their role in
conjugate horizontal gaze. J Comp Neurol 1980; 189:191–209.

Fisher CM: Ataxic hemiparesis: A pathologic study. Arch Neurol 1978;

35:126–128.

Gacek RR: Location of abducens afferent neurons in the cat. Exp Neurol
1979; 64:342–353.

Gudmundsson K et al: Detailed anatomy of the intracranial portion of the

trigeminal nerve. J Neurosurg 1971; 35:592–600.

Haymaker W: The Founders of Neurology. Springfield, IL, Charles C. Thomas,

1953.

Hu JW, Sessle BJ: Trigeminal nociceptive and non-nociceptive neurons: Brain

stem intranuclear projections and modulation by orofacial, periaqueductal
gray and nucleus raphe magnus stimuli. Brain Res 1979; 170:547–552.

Jenny AB, Saper CB: Organization of the facial nucleus and corticofacial
projection in the monkey: A reconsideration of the upper motor neuron facial
palsy. Neurology 1987; 37:930–939.

Jones BE: Elimination of paradoxical sleep by lesions of the pontine

gigantocellular tegmental field in the cat. Neurosci Lett 1979; 13:285–293.

Korte GE, Mugnaini E: The cerebellar projection of the vestibular nerve in the
cat. J Comp Neurol 1979; 184:265–278.

Kotchabhakdi N et al: The vestibulothalamic projections in the cat studied by

retrograde axonal transport of horseradish peroxidase. Exp Brain Res 1980;
40:405–418.

Kushida CA et al: Cortical asymmetry of REM sleep EEG following unilateral

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pontine hemorrhage. Neurology 1991; 41:598–601.

Lang W et al: Vestibular projections to the monkey thalamus: An

autoradiographic study. Brain Res 1979; 177:3–17.

Loewy AD et al: Descending projection from the pontine micturition center.

Brain Res 1979; 172:533–538.

Matsumura M et al: Organization of somatic motor inputs from the frontal

lobe to the pedunculopontine tegmental nucleus in the macaque monkey.
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Schmahmann JD, Pandya DN: Anatomic organization of the basilar pontine

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tomographic demonstration. Arch Neurol 1982; 39:660–661.

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brainstem. Brain 2001; 124:1866–1876.

Venna N, Sabin TD: Universal dissociated anesthesia, due to bilateral brain-

stem infarcts. Arch Neurol 1985; 42:918–922.

Vilensky JA, Van Hoesen GW: Corticopontine projections from the cingulate
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Editors: Afifi, Adel K.; Bergman, Ronald A.

Title: Functional Neuroanatomy: Text and Atlas, 2nd Edition

Copyright ©2005 McGraw-Hill

> Table of Contents > Part I - Text > 8 - Pons: Clinical Correlates

8
Pons: Clinical Correlates

Basal Pontine Syndromes

Caudal Basal Pontine Syndromes
Rostral Basal Pontine Syndrome
Pure Motor and Ataxic Hemiparesis
Dysarthria–Clumsy Hand Syndrome
The Locked-in Syndrome
Crying and Laughter
Tegmental Pontine Syndromes
The Medial Tegmental Syndrome
The One-and-a-Half Syndrome
Dorsolateral Tegmental Pontine Syndrome
Caudal Tegmental Pontine Syndromes
Mid-Tegmental Pontine Syndrome (Grenet Syndrome)
Rostral Tegmental Pontine Syndrome (Raymond-Cestan-Chenais
Syndrome)
Extreme Lateral Tegmental Pontine Syndrome (Marie-Foix Syndrome)
Ocular Bobbing and Dipping
REM Sleep
Central Neurogenic Hyperventilation
The Pons and Respiration

KEY CONCEPTS

Manifestations of the Millard-Gubler syndrome consist of ipsilateral

facial nerve palsy and contralateral hemiplegia. In some patients the
abducens nerve may be involved ipsilateral to the lesion.

Manifestations of the Gellé syndrome consist of ipsilateral deafness

and vertigo, with or without facial palsy, and contralateral hemiparesis.

Manifestations of the Brissaud-Sicard syndrome consist of ipsilateral

facial hemispasm and contralateral hemiparesis.

Manifestations of the rostral basal pontine syndrome consist of

ipsilateral trigeminal nerve palsy (motor and sensory) and contralateral
hemiplegia.

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The medial tegmental syndrome is manifested by ipsilateral

abducens and facial nerve palsies and contralateral loss of kinesthesia
and discriminative touch.

The one-and-a-half syndrome is manifested by ipsilateral horizontal

gaze paralysis and internuclear ophthalmoplegia.

The dorsolateral pontine tegmental syndrome is manifested by

dissociated sensory loss (loss of pain and temperature sense with
preservation of kinesthesia and discriminative touch) over the ipsilateral
face and contralateral trunk and extremities.

Foville syndrome is manifested by ipsilateral facial nerve palsy,

ipsilateral horizontal gaze paralysis, and contralateral hemiparesis.

Manifestations of the Grenet syndrome consist of bilateral facial and

contralateral trunk thermoanalgesia, ipsilateral paralysis of muscles of
mastication, ataxia and tremor, and contralateral hemiparesis.

The Raymond-Cestan-Chenais syndrome is manifested by ipsilateral

internuclear ophthalmoplegia and ataxia and contralateral hemiparesis
and hemisensory loss.

The Marie-Foix syndrome is manifested by ipsilateral ataxia and

contralateral hemiparesis with or without hemisensory loss.

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Figure 8-1. Schematic diagram of the structures involved in the caudal

pontine syndrome (Millard-Gubler) and the resulting clinical manifestations.

Vascular lesions of the pons are best suited to anatomicoclinical correlations. The
following syndromes are particularly illustrative.

BASAL PONTINE SYNDROMES

Basal pontine syndromes are caused by lesions in the basal part of the pons,
affecting the rootlets of cranial nerves and corticospinal tract bundles in the basis
pontis.

Caudal Basal Pontine Syndromes

A. MILLARD-GUBLER SYNDROME
The manifestations of this syndrome, as originally described by Millard and
Gubler in 1856, include ipsilateral facial paralysis of the peripheral type and
contralateral hemiplegia of the upper motor neuron type (Figure 8-1). Frequently,
the lesion may extend medially and rostrally to include the rootlets of the sixth
nerve (Figure 8-2). In this situation, the patient also manifests signs of
ipsilateral sixth nerve paralysis. Current textbook definitions of the Millard-Gubler
syndrome concur on the presence of contralateral hemiplegia of the upper motor
neuron type in association with ipsilateral facial nerve or abducens nerve paresis
or both and with occasional involvement of the medial lemniscus.

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B. GELLÉ SYNDROME
Described in 1901, the Gellé syndrome consists of ipsilateral deafness,
vertigo, variable facial nerve palsy, and contralateral hemiparesis. The
lesion is in the caudal ventrolateral pons involving the cochleovestibular (cranial
nerve VIII) nerve and corticospinal tract fibers with variable involvement of the
facial nerve.

C. BRISSAUD-SICARD SYNDROME
Described in 1906, the Brissaud-Sicard syndrome consists of ipsilateral facial
hemispasm and contralateral hemiparesis. The lesion is in the caudal ventral
pons involving facial nerve (cranial nerve VII) rootlets and corticospinal tract
fibers.

Rostral Basal Pontine Syndrome

If the basal pontine lesion occurs more rostrally, at the level of the
trigeminal nerve (Figure 8-3), the manifestations include ipsilateral
trigeminal signs (sensory and motor) and a contralateral hemiplegia of the upper
motor neuron variety.

Pure Motor and Ataxic Hemiparesis

Discrete lesions in the basis pontis have been reported to result in pure motor
hemiparesis or ataxic hemiparesis. Pure motor hemiparesis is secondary to
involvement of corticospinal tract fascicles within the basis pontis. Ataxic
hemiparesis is due to involvement of corticospinal tract fascicles along with
pontocerebellar fascicles in the basis pontis.

Dysarthria–Clumsy Hand Syndrome

Vascular lesions of the basis pontis at the junction of the upper third and lower
two-thirds of the pons have been associated
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with the dysarthria–clumsy hand syndrome. This syndrome is characterized by
central (supranuclear) facial weakness, severe dysarthria and dysphagia, hand
paresis, and clumsiness.

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Figure 8-2. Schematic diagram of the structures involved in medial and

rostral extensions of the caudal basal pontine syndrome and the resulting
clinical manifestations.

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Figure 8-3. Schematic diagram showing structures involved in the rostral

basal pontine syndrome and the resulting clinical manifestations.

The Locked-in Syndrome

The locked-in syndrome is a severely disabling basal pontine syndrome that is
due to an infarct in the ventral half of the pons. In this syndrome there is
paralysis of all motor activity as a result of involvement of corticospinal tracts in
the basis pontis and aphonia (loss of voice) caused by the involvement of
corticobulbar fibers coursing in the basis pontis. Vertical gaze and blinking are
spared and are the only means by which such patients communicate. Such
patients have been described as “corpses with living eyes.”

Crying and Laughter

Discrete unilateral or bilateral vascular lesions in the basis pontis have been
associated with pathologic crying and, rarely, laughter. These episodes consist of
a sudden onset of involuntary crying (rarely laughter) lasting about 15 to 30
seconds. Such emotional “incontinence” may herald a brain stem stroke, be part
of it, or follow the onset of a stroke by a few days. The anatomic basis for the
emotional incontinence in pontine lesions has not been established. Most cases of
pathologic crying or laughter are associated with bilateral frontal or parietal
lesions with pseudobulbar palsy. Some investigators have postulated that lesions
in the basis pontis interrupt an inhibitory corticobulbar pathway to the pontine
tegmental center for laughing and crying, essentially releasing that center from

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cortical inhibition.

TEGMENTAL PONTINE SYNDROMES

Tegmental pontine syndromes are caused by lesions in the tegmentum of the
pons that affect cranial nerve nuclei or rootlets and long tracts in the
tegmentum.

The Medial Tegmental Syndrome

Structures affected in the medial tegmental syndrome include the nucleus
and rootlets of the abducens nerve (cranial nerve VI), the genu of the facial
nerve, and the medial lemniscus (Figure 8-4). The manifestations of the lesion
therefore include ipsilateral sixth nerve paralysis and a lateral gaze paralysis,
ipsilateral facial paralysis of the peripheral variety, and contralateral loss of
kinesthesia and discriminative touch.

The One-and-a-Half Syndrome

The one-and-a-half syndrome is characterized by ipsilateral lateral gaze
paralysis resulting from involvement of the abducens nucleus and
internuclear ophthalmoplegia (paralysis of adduction of the eye ipsilateral to the
lesion and nystagmus of the abducting eye) as a result of involvement of the
medial longitudinal fasciculus. The vascular lesion is discrete in the dorsal
paramedian tegmentum, involving the abducens nucleus and the medial
longitudinal fasciculus (type I one-and-a-half syndrome, Figure 8-5). Type II one-
and-a-half syndrome is associated with cavernous sinus thrombosis that affects
two of its contents: abducens nerve and internal carotid artery. The clinical
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picture is that of abducens nerve palsy and cerebral hemisphere (gaze center)
infarction (Figure 8-6)

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Figure 8-4. Schematic diagram showing structures involved in the tegmental

pontine syndrome and the resulting clinical manifestations.

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Figure 8-5. One-and-a-half syndrome, type I. MLF, medial longitudinal

fasciculus.

Dorsolateral Tegmental Pontine Syndrome

Vascular lesions in the dorsolateral pontine tegmentum that affect structures
supplied by the anterior inferior cerebellar artery (AICA) on one side coupled
with a vascular lesion in the dorsolateral medulla that affects structures supplied
by the posterior inferior cerebellar artery (PICA) on the other side have been
reported to produce dissociated sensory loss (loss of pain and temperature sense
with preservation of vibration and position sense) enveloping the entire body,
accompanied by truncal and limb ataxia without weakness. The dissociated
sensory loss is due to simultaneous and bilateral involvement of the
spinothalamic tracts and the trigeminal system with sparing of the lemniscal
system. The ataxia is due to involvement of cerebellar-destined fibers coursing in
the tegmentum or, alternatively, the cerebellum itself.

Caudal Tegmental Pontine Syndromes

A. FOVILLE'S SYNDROME (RAYMOND-FOVILLE
SYNDROME)
Foville's syndrome is characterized by an ipsilateral peripheral type of facial
nerve palsy and horizontal gaze palsy and contralateral hemiparesis. The
lesion usually is in the caudal pons and involves the corticospinal tract

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(contralateral hemiparesis), the paramedian pontine reticular formation (PPRF),

and/or the abducens nucleus (conjugate gaze palsy), as well as the nucleus or
fascicles of the facial nerve (facial muscle weakness).

B. MUSICAL HALLUCINOSIS
Lateral or paramedian lesions in the tegmentum of the caudal pons have been
associated with musical hallucinosis. The musical melodies or sounds are usually
familiar. The lesion usually involves one or more of the following auditory
structures: acoustic striae (including the trapezoid body), superior olivary
nucleus, lateral lemniscus. In addition, the lesion involves trigeminal nerve fibers
destined to the tensor tympani muscle and facial nerve fibers to the stapedius
muscle, both of which travel in caudal pons. The hallucinations are attributed to
release of auditory memories by disinhibition of reticular pathways from nucleus
raphe pontis to sensory centers in the thalamus and cerebral cortex.

Mid-Tegmental Pontine Syndrome (Grenet

Syndrome)
Described by Grenet in 1856, this syndrome consists of thermoanalgesia in
both sides of the face and the contralateral trunk, ipsilateral trigeminal
(cranial nerve V) nerve motor involvement (paralysis of muscles of mastication),
ataxia and tremor, and contralateral hemiparesis. The lesion is in mid-pons
tegmentum and involves the trigeminal nucleus and trigeminothalamic fibers,
superior cerebellar peduncle, and spinothalamic tract, and it extends ventrally to
involve corticospinal fibers.

Rostral Tegmental Pontine Syndrome (Raymond-

Cestan-Chenais Syndrome)
In the Raymond-Cestan-Chenais syndrome the lesion is in the rostral pons
and involves the medial lemniscus, medial longitudinal
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fasciculus, spinothalamic tract, and cerebellar fibers. The manifestations are
internuclear ophthalmoplegia (medial longitudinal fasciculus), ipsilateral ataxia
(cerebellar fibers), and hemisensory loss (medial lemniscus and spinotha-lamic
tract). With ventral extension, there may be contralateral hemiparesis due to
corticospinal tract involvement.

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Figure 8-6. One-and-a-half syndrome, type II.

Extreme Lateral Tegmental Pontine Syndrome

(Marie-Foix Syndrome)
In the Marie-Foix syndrome there is ipsilateral cerebellar ataxia and
contralateral hemiparesis with or without hemisensory loss. The lesion in the
rostral extreme lateral pons involves the brachium pontis (ataxia), the
spinothalamic tract (hemisensory loss), and the corticospinal tract (hemiparesis).
The full clinical picture of the Marie-Foix syndrome has rarely been reported and
includes ipsilateral cranial nerve palsies, Horner's syndrome, hemiataxia, palatal
myoclonus, and contralateral spinothalamic sensory loss.

Ocular Bobbing and Dipping

A variety of oscillatory eye movement abnormalities have been described in
patients with pontine vascular lesions. These abnormalities have been referred to
as ocular bobbing, inverse ocular bobbing, ocular dipping, and inverse ocular
dipping on the basis of the predominant oscillatory abnormality.

REM Sleep
The pons is also necessary and sufficient to generate rapid eye movement (REM)
sleep. In humans, bilateral pontine damage may prevent REM sleep.

Central Neurogenic Hyperventilation

Reports in humans suggest that medial tegmental pontine lesions, possibly
affecting the PPRF bilaterally, are associated with the syndrome of central
neurogenic hyperventilation. This syndrome is characterized by sustained
tachypnea that persists despite an elevated arterial PO 2 and pH and a low arterial

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PCO 2 . It has been hypothesized that a pontine lesion of this type disinhibits
inhibitory pontine influences on medullary respiratory neurons.

The Pons and Respiration

Respiration is of two types: voluntary and automatic. Selective loss of voluntary
respiration occurs in patients with lesions of the basis pontis. Selective loss of
voluntary or automatic respiration also has been described as part of the locked-
in syndrome.

Automatic respiratory pathways are presumed to be initiated in limbic cortex and

involve diencephalic structures, the reticular system of the brain stem, the lateral
or dorsal pons, the medullary nuclei mediating automatic respirations, and
respiratory neurons of the spinal cord. Selective loss of automatic respiration
occurs in patients with Ondine's curse, lesions of the medulla oblongata, or
bilateral high cervical cord lesions.

TERMINOLOGY
Ataxia (Greek an, “negative”; taxis, “order”).
Without order, disorganized. Incoordination of movement seen in cerebellar
disease. The term was used by Hippocrates and Galen for disordered action of
any type, such as irregularity of pulse.

Brissaud, Edward (1852–1909).

French neuropsychiatrist who trained under Charcot and later deputized for him
at the Salpêtrière hospital in Paris. He described the Brissaud-Sicard pontine
syndrome and many other syndromes. Died of brain tumor.
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Dysarthria (Greek dys, “difficult”; arthroun, “to utter distinctly”).

Imperfect articulation of speech caused by a disturbance of muscular control.

Dysphagia (Greek dys, “difficult”; phagien, “to eat”).

Difficulty swallowing.

Foville syndrome (Raymond-Foville syndrome).

A syndrome of alternating hemiplegia caused by vascular lesions in the
tegmentum of the caudal pons. Characterized by ipsilateral facial nerve palsy and
conjugate gaze paralysis and contralateral hemiparesis. Described by Achille-
Louis-François Foville in 1858.

Internuclear ophthalmoplegia (MLF syndrome).

A condition characterized by paralysis of ocular adduction ipsilateral to a medial
longitudinal fasciculus (MLF) lesion and monocular nystagmus in the contralateral
abducting eye.

Marie-Foix syndrome.
A vascular pontine syndrome characterized by ipsilateral cerebellar ataxia and
contralateral hemiparesis with or without hemisensory loss. Described in 1913 by
Pierre Marie, a French neurologist, and his student, Charles Foix.

Millard-Gubler syndrome (caudal basal pontine syndrome).

A vascular syndrome of the caudal basis pontis characterized by ipsilateral facial
nerve palsy and contralateral hemiplegia. The syndrome may include abducens
nerve palsy. Described by Auguste Millard and Adolphe-Marie Gubler, French

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physicians, in 1856.

Ocular bobbing.
Saccadic repetitive fast movement of the eyes downward with a slow return to
the primary position. Seen in patients with severe pontine dysfunction, who are
usually unresponsive. Described by C. M. Fisher in 1964.

Ocular dipping (inverse ocular bobbing).

Spontaneous eye movement in comatose patients with slow downward movement
and a fast return to the primary position. The reverse of ocular bobbing. Seen in
patients with disorders of the pons, basal ganglia, or cerebral cortex.

Ondine's curse.
A syndrome characterized by cessation of breathing in sleep because of failure of
the medullary automatic center. Named after the story of Ondine, a water nymph
who punished her unfaithful husband by depriving him of the ability to breathe
while asleep.

Raymond-Cestan-Chenais syndrome.
A vascular syndrome of the rostral tegmentum of the pons characterized by
internuclear ophthalmoplegia, ipsilateral ataxia, and contralateral mild
hemiparesis and hemisensory loss. Described by Fulgence Raymond, Etienne
Jacques-Marie-Raymond Cestan, and L. G. Chenais, French physicians, in 1903.

Sicard, Jean-Athenase (1872–1929).

French neurologist who, with his mentor Brissaud, described the pontine
Brissaud-Sicard syndrome. He also contributed to the description of the
medullary Collet-Sicard syndrome and the Sicard-Hagueman syndrome (Meige
syndrome, Breughel syndrome, orofacial dystonia).

Tachypnea (Greek tachys, “swift”; pnoia, “breath”).

Excessive rapidity of respiration.

SUGGESTED READINGS
Asfora WT et al: Is the syndrome of pathological laughing and crying a
manifestation of pseudobulbar palsy? J Neurol Neurosurg Psychiatry 1989;
52:523–525.

Ash PR, Keltner JL: Neuro-ophthalmic signs in pontine lesions. Medicine

(Baltimore) 1979; 58:304–320.

Bassetti C et al: Isolated infarcts of the pons. Neurology 1996; 46:165–175.

Brazis PW: The localization of lesions affecting the brainstem. In Brazis PW et

al (eds): Localization in Clinical Neurology. Boston, Little, Brown, 1985:225–
238.

Carter JE, Rauch RA: One-and-a-half syndrome, type II. Arch Neurol 1994;
51:87–89.

Deleu D et al: Dissociated ipsilateral horizontal gaze palsy in one-and-a-half

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syndrome: A clinicopathologic study. Neurology 1988; 38:1278–1280.

Fisher CM: Ocular bobbing. Arch Neurol 1964; 11:543–546.

Fisher CM: Some neuro-ophthalmologic observations. J Neurol Neurosurg

Psychiatry 1967; 30:383–392.

Fisher CM: Ataxic hemiparesis: A pathologic study. Arch Neurol 1978;

35:126–128.

Goebel HH et al: Lesions of the pontine tegmentum and conjugate gaze

paralysis. Arch Neurol 1971; 24:431–440.

Jaeckle KA et al: Central neurogenic hyperventilation: Pharmacologic

intervention with morphine sulfate and correlative analysis of respiratory,
sleep, and ocular motor dysfunction. Neurology 1990; 40:1715–1720.

Kushida CA et al: Cortical asymmetry of REM sleep EEG following unilateral

pontine hemorrhage. Neurology 1991; 41:598–601.

Matlis A et al: Radiologic-clinical correlation, Millard-Gubler syndrome. AJNR

1994; 15:179–181.

Munschauer FE et al: Selective paralysis of voluntary but not limbically

influenced automatic respiration. Arch Neurol 1991; 48:1190–1192.

Pryse-Phillips W: Companion to Clinical Neurology. Boston, Little, Brown,

1995.

Rothstein TL, Alvord EC: Posterior internuclear ophthalmoplegia: A

clinicopathologic study. Arch Neurol 1971; 24:191–202.

Schielke E et al: Musical hallucinations with dorsal pontine lesions. Neurology

2000; 55:454–455.

Silverman IE et al: The crossed paralyses. The original brain-stem syndromes

of Millard-Gubler, Foville, Weber, and Raymond Cestan. Arch Neurol 1995;
52:635–638.

Stiller J et al: Brainstem lesions with pure motor hemiparesis. Computed

tomographic demonstration. Arch Neurol 1982; 39:660–661.

Tatemichi TK et al. Pathological crying: A pontine pseudobulbar syndrome.

Ann Neurol 1987; 22:133.

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Troost BT: Signs and symptoms of stroke syndromes of the brain stem. In
Hofferberth B et al (eds): Vascular Brain Stem Diseases. Basel, Karger,
1990:112.

Venna N, Sabin TD: Universal dissociated anesthesia due to bilateral brain-

stem infarcts. Arch Neurol 1985; 42:918–922.

Wall M, Wray SH: The one-and-a-half syndrome: A unilateral disorder of the

pontine tegmentum: A study of 20 cases and review of the literature.
Neurology 1983; 33:971–980.

Yarnell PR: Pathological crying localization. Ann Neurol 1987; 22:133–134.

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Editors: Afifi, Adel K.; Bergman, Ronald A.

Title: Functional Neuroanatomy: Text and Atlas, 2nd Edition

Copyright ©2005 McGraw-Hill

> Table of Contents > Part I - Text > 9 - Mesencephalon (Midbrain)

9
Mesencephalon (Midbrain)

Gross Topography
Ventral View
Dorsal View
Microscopic Structure
General Organization
Inferior Colliculus Level
Superior Colliculus Level
Light Reflex
Afferent Pathway
Efferent Pathway
Accommodation-Convergence Reflex
Mesencephalic Reticular Formation
Vertical Gaze
Control of Saccadic Eye Movement
Smooth Pursuit Eye Movements
Blood Supply
Inferior Colliculus Level
Superior Colliculus Level
Pretectal Level

KEY CONCEPTS

In cross section the mesencephalon is divided into three regions: the tectum, the
tegmentum, and the basal portion.

The inferior colliculus receives inputs from the lateral lemniscus, medial geniculate body,
primary auditory cortex, and cerebellar cortex.

The output of the inferior colliculus is to the medial geniculate body, nucleus of the
lateral lemniscus, superior colliculus, and cerebellum.

Axons of trochlear neurons form the trochlear nerve, the smallest cranial nerve and the
only one that decussates before exiting the neuraxis from the dorsal surface of the midbrain.

In the cerebral peduncle, corticospinal fibers occupy the middle three-fifths, flanked on
each side by corticopontine fibers.

The substantia nigra receives inputs from the neostriatum, cerebral cortex, globus
pallidus, subthalamic nucleus, and midbrain reticular formation.

The output of the substantia nigra is to the neostriatum, limbic cortex, globus pallidus,
red nucleus, subthalamic nucleus, thalamus, superior colliculus, midbrain reticular formation,
and amygdala.

On the basis of its projection sites, the mesencephalic dopaminergic system is subdivided
into mesostriatal, mesoallocortical, and mesoneocortical subdivisions.

The superior colliculus receives inputs from the cerebral cortex, retina, spinal cord, and
inferior colliculus.

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The output of the superior colliculus is to the spinal cord, pontine nuclei, reticular
formation of the midbrain, and thalamus.

The pretectal area is involved in the pupillary light reflex and vertical gaze.

Input to the red nucleus comes mainly from the deep cerebellar nuclei and the cerebral
cortex.

The output of the red nucleus is mainly to the spinal cord, cerebellum, reticular
formation, and inferior olive.

Somatic motor neurons of the oculomotor nucleus are organized into subnuclei that
correspond to the eye muscles supplied by the oculomotor nerve. All these subnuclei supply
ipsilateral muscles except the superior rectus subnucleus, which supplies the contralateral
superior rectus muscle, and the levator palpebrae subnucleus, which supplies both levator
palpebrae muscles.

Lesions of the oculomotor nerve within the midbrain result in oculomotor nerve palsy and
either contralateral tremor (if the red nucleus is concomitantly involved) or contralateral
upper motor neuron paralysis (if the cerebral peduncle is involved).

Accessory oculomotor nuclei include Cajal's interstitial nucleus, rostral interstitial nucleus
of the medial longitudinal fasciculus (RiMLF), Darkschewitsch's nucleus, and nucleus of the
posterior commissure.

The periaqueductal (central) gray region is concerned with modulation of pain,

vocalization, control of reproductive behavior, modulation of medullary respiratory centers,
aggressive behavior, and vertical gaze.

Constriction of the pupil ipsilateral to light stimulation constitutes the direct light reflex;
constriction of the pupil contralateral to light stimulation constitutes the consensual light
reflex.

In an Argyll Robertson pupil, light reflex is lost while accommodation convergence is

preserved.

The midbrain reticular formation is involved in wakefulness and sleep.

The neural substrates for vertical gaze consist of the ocular motor neurons of cranial
nerves III and IV, the rostral interstitial nucleus of the medial longitudinal fasciculus,
interstitial nucleus of Cajal, nucleus of the posterior commissure, the posterior commissure,
the mesencephalic reticular formation, and the medial longitudinal fasciculus.

Saccadic eye movements are controlled by cortical inputs to the brain stem pulse
generators either directly or indirectly via the superior colliculus. Brain stem pulse
generators for horizontal saccades are in the paramedian pontine reticular formation, and for
vertical saccades they are in the midbrain (RiMLF).

Smooth pursuit eye movements are controlled by input from cortical areas 8, 19, 37, and
39 to the dorsolateral pontine nucleus and the nucleus reticularis tegmenti pontis and
cerebellum.

The midbrain receives the bulk of its blood supply from the basilar artery via the
paramedian, superior cerebellar, and posterior cerebral branches.

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GROSS TOPOGRAPHY

Ventral View
The inferior surface of the mesencephalon (midbrain) is marked by the divergence of two massive
bundles of fibers—the cerebral peduncles—which carry corticofugal fibers to lower levels (Figure 9-1).
Caudally, the cerebral peduncles pass into the basis pontis; rostrally, they continue into the internal
capsule. Between the cerebral peduncles lies the interpeduncular fossa, from which exits the
oculomotor nerve (cranial nerve III). The trochlear nerve (cranial nerve IV) emerges from the dorsal

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aspect of the mesencephalon, curves around, and appears at the lateral borders of the cerebral
peduncles. The optic tract passes under the cerebral peduncles before the peduncles disappear into
the substance of the cerebral hemispheres.

Dorsal View
The dorsal surface of the mesencephalon features four elevations (corpora quadrigemina) (see Figure
5-2). The rostral and larger two are the superior colliculi; the caudal and smaller two are the inferior
colliculi. The trochlear nerves emerge just caudal to the inferior colliculi.

MICROSCOPIC STRUCTURE

General Organization
Three subdivisions are generally recognized in sections of the mesencephalon (Figure 9-2).

1. The tectum is a mixture of gray and white matter dorsal to the central gray matter. It includes
the superior and inferior colliculi (quadrigeminal plates). The term quadrigeminal plate was
coined by Vesalius to refer to the tectum. Anatomists of that time wanted to name the superior
and inferior colliculi after the Latin equivalents for the testes and buttocks. The overlying pineal
gland, which looked like a pinecone to the Greeks, was mistaken for a penis. This was too
explicit for Vesalius, who renamed the tectum the quadrigeminal plate.

Figure 9-1. Schematic diagram of the ventral surface of the midbrain and pons showing
major midbrain structures encountered on this surface.

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2. The tegmentum, the main portion of the mesencephalon, lies inferior to the central gray matter
and contains ascending and descending tracts, reticular nuclei, and well-delineated nuclear
masses.

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Figure 9-2. Cross-sectional diagram of the midbrain showing its major subdivisions.

3. The basal portion includes the cerebral peduncles, a massive bundle of corticofugal fibers on the
ventral aspect of the mesencephalon, and the substantia nigra, a pigmented nuclear mass that
lies between the dorsal surface of the cerebral peduncle and the tegmentum. The term basis
pedunculi has been used to refer to the basal portion of the mesencephalon, which includes the
cerebral peduncle and substantia nigra. The term crus cerebri has been used to refer to the
massive bundle of corticofugal fibers (cerebral peduncle) on the ventral aspect of the
mesencephalon. Not frequently, the term cerebral peduncle is erroneously used to refer to the
mesencephalon below the tectum (tegmentum and basal portion).

The components of these subdivisions are discussed below under two characteristic levels of the
mesencephalon: the inferior colliculus and the superior colliculus. The inferior colliculus level is
characterized in histologic sections by the decussation of the superior cerebellar peduncle and by the
fourth nerve (trochlear) nucleus. The superior colliculus level is characterized by the red nucleus, the
third nerve (oculomotor) nucleus, and the posterior commissure.

Inferior Colliculus Level

A. TECTUM
The nucleus of the inferior colliculus occupies the tectum at the level of the inferior colliculus. This
nucleus is an oval mass of small and medium-size neurons organized into three parts: (1) main
laminated mass of neurons, called the central nucleus, (2) a thin dorsal cellular layer, the pericentral
nucleus, and (3) a group of neurons that surround the central nucleus laterally and ventrally, the
external nucleus. The central nucleus is the major relay nucleus in the auditory pathway. High-
frequency sounds are represented in the ventral part, and low-frequency sounds in the dorsal part of
the nucleus (similar to that in the cochlea). The pericentral nucleus receives only contralateral
monaural input and serves to direct auditory attention. The external nucleus is related primarily to
acousticomotor reflexes. The inferior colliculus has the following afferent and efferent connections.

1. Afferent Connections (Figure 9-3)

Fibers come from the following sources.

1. Lateral lemniscus. These fibers terminate on the ipsi- and contralateral inferior colliculi.
Some lateral lemniscus fibers bypass the inferior colliculus to reach the medial geniculate
body.

2. Contralateral inferior colliculus.

3. Ipsilateral medial geniculate body. This connection serves as a feedback mechanism in the
auditory pathway.

4. Cerebral cortex (primary auditory cortex).

5. Cerebellar cortex via the anterior medullary velum.

2. Efferent Connections
The inferior colliculus projects to the following areas (Figure 9-4).

1. Medial geniculate body via the brachium of the inferior colliculus. This pathway is concerned
with audition.

2. Contralateral inferior colliculus.

3. Superior colliculus. This pathway establishes reflexes for turning the neck and eyes in response
to sound.

4. Nucleus of the lateral lemniscus and other relay nuclei of the auditory system for feedback.

5. Cerebellum. The inferior colliculus is a major center for the transmission of auditory impulses to
the cerebellum via the anterior medullary velum. The inferior colliculus thus is a relay nucleus in
the auditory pathway to the cerebral cortex and cerebellum. In addition, the inferior colliculus

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plays a role in the localization of the source of sound.

Figure 9-3. Schematic diagram showing the major afferent connections of the inferior
colliculus.

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Figure 9-4. Schematic diagram showing the major efferent connections of the inferior colliculus.

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B. TEGMENTUM
At the level of the inferior colliculus, the tegmentum of the mesencephalon contains fibers of passage
(ascending and descending tracts) and nuclear groups.

1. Fibers of Passage
The following fiber tracts pass through the mesencephalon (Figure 9-5).

a. Brachium conjunctivum (superior cerebellar peduncle)

The brachium conjunctivum is a massive bundle of fibers arising in the deep cerebellar nuclei. These
fibers decussate in the tegmentum of the midbrain at this level. A few proceed rostrally to terminate
on the red nucleus; the others form the capsule of the red nucleus and continue rostrally to terminate
on the ventrolateral nucleus of the thalamus.

b. Medial lemniscus
The medial lemniscus lies lateral to the decussating brachium conjunctivum and above the substantia
nigra. This fiber system, which conveys kinesthesia and discriminative touch from more caudal levels,
continues its course toward the thalamus. Fibers in the medial lemniscus are somatotopically
organized, with cervical fibers being most medial and sacral fibers most lateral.

c. Trigeminal lemniscus
The trigeminal lemniscus is composed of the ventral secondary trigeminal tracts and travels close to
the medial lemniscus on its way to the thalamus.

d. Spinothalamic tract
The spinothalamic tract conveys pain and temperature sensations from the contralateral half of the
body and lies lateral to the medial lemniscus. Mingled with the spinothalamic fibers are the spinotectal
fibers on their way to the tectum. Fibers in the spinothalamic tract are somatotopically organized,
with cervical fibers being most medial and sacral fibers most lateral.

e. Lateral lemniscus
The lateral lemniscus conveys auditory fibers and occupies a position lateral and dorsal to the
spinothalamic tract.

f. Medial longitudinal fasciculus

The medial longitudinal fasciculus maintains its position dorsally in the tegmentum in a paramedian
position.

g. Central tegmental tract

The central tegmental tract conveys fibers from the basal ganglia and midbrain to the inferior olive
and occupies a dorsal position in the tegmentum, ventrolateral to the medial longitudinal fasciculus.

h. Rubrospinal tract
The rubrospinal tract conveys fibers from the red nucleus to the spinal cord and inferior olive and is
located dorsal to the substantia nigra.

C. NUCLEAR GROUPS
The following nuclei are seen at the level of the inferior colliculus (Figure 9-6).

1. Mesencephalic Nucleus
The mesencephalic nucleus of the trigeminal nerve is homologous in structure to the dorsal root
ganglion but is uniquely placed within the central nervous system. It contains unipolar neurons with
axons (the mesencephalic root of the trigeminal nerve) which convey proprioceptive impulses from the
muscles of mastication and the periodontal membranes. As these fibers approach the nucleus, they

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gather in a bundle close to the nucleus: the mesencephalic tract.

2. Nucleus of the Trochlear Nerve (Cranial Nerve IV)

The nucleus of the trochlear nerve lies in the V-shaped ventral part of the central gray matter.
Axons of this nerve arch around the central gray matter, cross in the anterior medullary velum,
and emerge from the dorsal aspect of the mesencephalon (Figure 9-7). These axons supply the
superior oblique
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eye muscle. The trochlear nerve is thus unique in two respects: It is the only cranial nerve that
crosses before emerging from the brain stem, and it is the only cranial nerve that emerges on the
dorsal aspect of the brain stem. Because of decussation, lesions of the trochlear nucleus result in
paralysis of the contralateral superior oblique muscle, whereas lesions of this nerve after it emerges
from the brain stem result in paralysis of the ipsilateral superior oblique muscle. The superior oblique
muscle has three actions: primary of intorsion, secondary of depression, and tertiary of abduction. It
thus acts by intorsion of the abducted eye and depression of the adducted eye. Patients with trochlear
nerve lesions complain of vertical diplopia (double vision) that is especially marked in looking
contralaterally downward while descending stairs and usually is corrected by head tilt (toward the
normal nerve) to compensate for the action of the paralyzed muscle. Tilting the head toward the
paretic nerve increases double vision. The trochlear nucleus receives contralateral and probably some
ipsilateral corticobulbar fibers and vestibular fibers from the medial longitudinal fasciculus that are
concerned with coordination of eye movements. Vestibular fibers to the trochlear nucleus originate
from the superior and medial vestibular nuclei. The fibers from the superior vestibular nucleus are
ipsilateral and inhibitory; those from the medial vestibular nucleus are contralateral and excitatory.

Figure 9-5. Schematic diagram of the midbrain at the inferior colliculus level, showing the major
ascending and descending tracts.

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Figure 9-6. Schematic diagram of the midbrain at the inferior colliculus level showing major
nuclear groups seen at this level.

Figure 9-7. Schematic diagram of the midbrain showing origin, intra-axial course of the trochlear
nerve, and the extraocular muscle supplied by the nerve.

3. Interpeduncular Nucleus
The interpeduncular nucleus, which is indistinct in humans, is a poorly understood nuclear group in
the base of the tegmentum between the cerebral peduncles. It receives fibers mainly from the
habenular nuclei (in the diencephalon) through the habenulointerpeduncular tract and sends fibers to
the dorsal tegmental nucleus through the pedunculotegmental tract.

4. Nucleus Parabrachialis Pigmentosus

The nucleus parabrachialis pigmentosus, which lies between the substantia nigra and the
interpeduncular nucleus, is a ventral extension of the ventral tegmental area of Tsai.

5. Dorsal Tegmental Nucleus

The dorsal tegmental nucleus lies dorsal to the medial longitudinal fasciculus (MLF) in the central gray
matter in close proximity to the dorsal raphe nucleus. It receives fibers from the interpeduncular

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nucleus and projects on autonomic nuclei of the brain stem and the reticular formation.

6. Ventral Tegmental Nucleus

The ventral tegmental nucleus lies ventral to the MLF in the midbrain tegmentum. Cells in this nucleus
are rostral continuations of the superior central nucleus of the pons. This nucleus receives fibers from
the mamillary bodies in the hypothalamus. The dorsal and ventral tegmental nuclei are part of a
circuit concerned with emotion and behavior.

7. Pedunculopontine (Nucleus Tegmenti Pedunculopontis) and

Lateral Dorsal Tegmental Nuclei
These two cholinergic nuclei lie within the tegmentum of the caudal mesencephalon (inferior colliculus
level) and rostral pons dorsolateral to and
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overlapping the lateral margin of the rostral superior cerebellar peduncle, between that peduncle and
the lateral lemniscus. Neurons of the pedunculopontine nucleus are affected in patients with
progressive supranuclear palsy, a degenerative central nervous system disease. It projects to the
thalamus and the pars compacta of the substantia nigra. This nucleus lies in a region from which
walking movements can be elicited on stimulation (locomotor center).

8. Nucleus Supratrochlearis (Dorsal Raphe Nucleus)

The nucleus supratrochlearis lies in the ventral part of the periaqueductal (central) gray matter
between the two trochlear nuclei. It sends serotonergic fibers to the substantia nigra, neostriatum
(caudate and putamen), and neocortex.

9. Parabigeminal Area
The parabigeminal area is an oval collection of cholinergic neurons ventrolateral to the nucleus of the
inferior colliculus and lateral to the lateral lemniscus. It receives fibers from superficial layers of the
superior colliculus and projects bilaterally back into superficial layers of the superior colliculus. Cells
in this area play a role, along with the superior colliculus, in processing visual information. They
respond to visual stimuli and are activated by both moving and stationary visual stimuli.

10. Nucleus Pigmentosus (Locus Ceruleus)

The nucleus pigmentosus is seen in the rostral pons and caudal mesencepha-lon. It contains 30,000 to
35,000 neurons. At the level of the inferior colliculus it is situated at the edge of the central gray
matter. It is made up of four subnuclei: central (largest); anterior (rostral end); ventral (caudal and
ventral), also known as the nucleus subceruleus; and posterior dorsal (small). Its pigmented cells
contain melanin granules, which are lost in patients with Parkinson's disease. The neurons of the locus
ceruleus provide noradrenergic innervation to most central nervous system regions. Axons of the
neurons in the locus ceruleus are elaborately branched and ramify practically throughout the brain.
These axons reach their destinations via three major ascending tracts: the central tegmental tract,
the dorsal longitudinal fasciculus, and the medial forebrain bundle. Through these tracts, the locus
ceruleus innervates the thalamus, hypothalamus, and basal telencephalon. In addition, the locus
ceruleus projects to the cerebellum (via the brachium conjunctivum), to the spinal cord and to
sensory nuclei of the brain stem. This nucleus is believed to play a role in the regulation of respiration
as well as in the rapid eye movement (REM) stage of sleep.

D. BASAL PORTION
At the level of the inferior colliculus, the basal portion of the mesencephalon includes the cerebral
peduncles and the substantia nigra.

1. Cerebral Peduncle
The cerebral peduncle (Figure 9-8) is a massive fiber bundle that occupies the most ventral part
of the mesencephalon. It is continuous with the internal capsule rostrally and merges caudally
into the basis pontis. This massive fiber bundle carries corticofugal fibers from the cerebral cortex to
several subcortical centers. The middle three-fifths of the cerebral peduncle is occupied by the
corticospinal tract, which is continuous caudally with the pyramids. Fibers destined to the arm are
medially located, those to the leg are laterally placed, and trunk fibers lie in between. The
corticopontine fibers occupy the areas of the cerebral peduncle on each side of the corticospinal tract.
The medially located corticopontine fibers constitute the frontopontine projection; the laterally located
fibers constitute the parieto-occipito-temporo-pontine projections. Corticopontine fibers originate in
wide areas of the cerebral cortex, synapse on pontine nuclei, and enter the contralateral cerebellar

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hemisphere via the middle cerebellar peduncle (brachium pontis). The corticobulbar fibers destined for
cranial nerve nuclei occupy a dorsomedial position among the corticospinal fibers. According to some
studies, the cerebral peduncle in humans has two groups of corticobulbar tracts. Those in the medial
portion of the peduncle descend to the pontine neurons responsible for gaze; those in the lateral
portion descend to the motor nuclei of cranial nerves V, VII, and XII and the nucleus ambiguus.

Figure 9-8. Schematic diagram of the midbrain showing the major subdivisions of the cerebral
peduncle.

2. Substantia Nigra
The substantia nigra was first identified by Felix Vicq d'Azyr, a French physician in 1786. It was then
considered to be part of the oculomotor nerve because of its proximity to oculomotor nerve rootlets.
The substantia nigra is a pigmented mass of neurons sandwiched between the cerebral peduncles and
the tegmentum. It is composed of two zones: a dorsal zona compacta containing melanin pigment and
a ventral zona reticulata containing iron compounds. Dendrites of neurons in the zona compacta
arborize in the zona reticulata. The pars lateralis represents the oldest part of this nucleus. The
neuronal population of the substantia nigra consists of pigmented and nonpigmented neurons.
Pigmented neurons outnumber nonpigmented neurons two to one. The neurotransmitter in pigmented
neurons is dopamine. Nonpigmented neurons are either cholinergic or GABAergic. There is a
characteristic pattern of neuronal loss in the substantia nigra in different disease states (Table 9-1).
Both pigmented and nonpigmented neurons are lost in patients with Huntington's chorea. Only
pigmented (dopaminergic) neurons, especially those in the center of the substantia nigra, are lost in
idiopathic Parkinson's disease. In the postencephalitic type of Parkinson's disease, pigmented
(dopaminergic) neurons are lost uniformly. In Parkinson's disease–dementia complex, there is a
uniform loss of both pigmented and nonpigmented neurons. Finally, in multiple system atrophy,
pigmented neurons are lost in medial and lateral nigral zones. Nigral neurons (variable number) show
abnormal (reduced) immunostaining for complex I of the mitochondrial electron transport system in
patients with Parkinson's disease. This reduction is believed to be related to the pathogenesis of the
disease. The neural connectivity of the substantia nigra suggests an important role in the regulation
of motor activity. Lesions of the substantia nigra are almost always seen in Parkinson's disease, which
is characterized by
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tremor, rigidity, and slowness of motor activity. The known afferent and efferent connections of the
substantia nigra are outlined below.

Table 9-1. Substantia Nigra: Pattern of Cell Loss in Disease.

Type of cell Huntington's Idiopathic Postencephalitic Parkinson's Multiple

disease Parkinson's Parkinson's dementia system
disease disease complex atrophy

Pigmented X X X X X
neurons

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Nonpigmented X X
neurons

Distribution

Uniform X X
loss

Central loss X

Medial X

Lateral X

a. Afferent connections (Figure 9-9)

(1) Neostriatu
The neostriatal input to the substantia nigra is the largest and projects primarily to the pars
reticulata with a smaller input to the pars compacta. It arises from the associative region of the
neostriatum primarily from the caudate nucleus. The neurotransmitter is gamma-aminobutyric acid
(GABA). The striatonigral fibers are topographically organized so that the head of the caudate nucleus
projects to the rostral third of the substantia nigra, while the putamen projects to all the other parts
of the nigra.

(2) Cerebral Cortex

The corticonigral projection is not as massive as was previously believed. Most of these fibers are
fibers of passage, and relatively few of them terminate on nigral neurons.

(3) Globus Pallidus

The input to the substantia nigra from the globus pallidus arises from the external (lateral) segment.
It is composed of GABAergic fibers that terminate mainly on pars reticulata, with some in the pars
compacta.

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Figure 9-9. Schematic diagram showing the major afferent and efferent connections of the
substantia nigra.

(4) Subthalamic Nucleus

The subthalamic nucleus projects in a patchy manner to pars reticulata. The transmitter is glutamine.

(5) Tegmentonigral Tracts

The tegmentonigral tracts arise from the midbrain raphe nuclei, which have serotonin and
cholecystokinin, and from the pedunculopontine nucleus, which is cholinergic.

b. Efferent connections (Figure 9-9)

(1) Nigrostriate Fibers

Nigrostriate fibers from the pars compacta project to the neostriatum (caudate and putamen) and
are dopaminergic. The nigrostriate projection is somatotopically organized so that neurons in the
lateral part of the pars compacta of the substantia nigra project to the putamen, whereas the caudate
nucleus receives its nigral input mainly from the medial part. The nigrostriate projections terminate
on the associative sensorimotor and limbic striatum. The sites of origin of the projections to the
caudate and putamen are segregated in the pars compacta. Cells in the pars compacta project to the
caudate nucleus or the putamen but not to both. Dopaminergic nigral projections to the neostriatum
terminate on distal dendrites of medium spiny (projection) neurons. They facilitate neostriatal
neurons that project to the pars reticulata of the substantia nigra and the internal (medial) segment
of the globus pallidus and inhibit neostriatal neurons that project to the external (lateral) segment of
the globus pallidus.

(2) Nigrocortical Tract

The nigrocortical fibers originate in the medial zona compacta and the adjacent ventral tegmental
area, course through the medial forebrain bundle, and terminate in the limbic cortex. The involvement
of this pathway in parkinsonism may explain the akinesia seen in that disease. Another projection
from the substantia nigra and the ventral tegmental area terminates in the neocortex. The function of
this projection is not known but may be related to cognition.

(3) Nigropallidal Tract

Nigropallidal projections are more abundant in the associative pallidal territory compared with the

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sensorimotor territory.

(4) Nigrorubral Tract

A projection to the red nucleus from the substantia nigra has been described in experimental animals.

(5) Nigrosubthalamic Tract

The connections between the substantia nigra and subthalamic nucleus are reciprocal.

(6) Nigrothalamic Tract

The nigrothalamic GABAergic tract runs from the pars reticulata to the ventral anterior, ventral
lateral, and dorsomedial nuclei of the thalamus.

(7) Nigrotegmental Tract and Nigrocollicular Tract

The nigrotegmental and nigrocollicular tracts originate from separate regions of the pars reticularis of
the substantia nigra. They are both GABAergic. The nigrotegmental tract links the substantia
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nigra with the reticular formation and with the spinal cord via the reticulospinal projection. The
nigrocollicular tract links the substantia nigra with the superior colliculus and secondarily with the
control of ocular movement as well as with the spinal cord (tectospinal tract). Through its connections
with the basal ganglia and the superior colliculus and reticular formation, the substantia nigra acts as
a link through which the basal ganglia exert an effect on spinal and ocular movements.

(8) Nigroamygdaloid Tract

The nigroamygdaloid tract originates from dopaminergic neurons in the zona compacta and the pars
lateralis of the substantia nigra and projects on the lateral and central amygdaloid nuclei.

The nigral origin of many of these efferent fiber systems requires further exploration. The GABAergic
outputs from the pars reticulata of the substantia nigra to the thalamus, superior colliculus, and
reticular formation are believed to play a role in suppressing the progression of epileptic discharge. A
marked increase in metabolic activity in the substantia nigra has been reported to occur during
epileptic discharge. Nigrothalamic, nigrotectal, and nigrotegmental pathways originate from separate
regions in the pars reticulata.

E. MESENCEPHALIC DOPAMINERGIC CELL GROUPS

Besides the pars compacta of the substantia nigra, two other cell groups in the mesencephalic
tegmentum are dopaminergic: the ventral tegmental area of Tsai in close proximity to the medial
substantia nigra and the retrorubral cell group (substantia nigra, pars dorsalis) in close proximity to
the red nucleus. The pars compacta of the substantia nigra in humans (area A-9 of primates) is
closely associated, and merges with the immediately adjacent dopamine cell groups of the ventral
tegmental area, the most prominent of which is the nucleus parabrachialis pigmentosus. The ventral
tegmental area corresponds to area A-10, and the retrorubral nucleus corresponds to area A-8.

Studies in primates and humans have identified three subdivisions of the mesencephalic
dopaminergic system on the basis of their projection sites. One subdivision is related to the
striatum (mesostriatal subdivision) and terminates on the caudate nucleus, putamen, globus pallidus,
and nucleus accumbens. The second subdivision is related to the allocortex (mesoallocortical
subdivision) and terminates on the amygdala, olfactory tubercle, septal area, and piriform cortex. The
third subdivision is related to the neocortex (mesoneocortical) and terminates in all neocortical areas
(frontal, temporal, parietal, and occipital cortices). Recently, a dopaminergic projection to the
cerebellar cortex from the ventral tegmental area of Tsai was described, possibly as part of the
hypothalamo-tegmental-cerebellar hypothalamic loop.

The term mesostriatal is used to describe the first subdivision in preference to the term nigrostriatal
system, since evidence suggests that both the ventral tegmental area and the substantia nigra
contribute to this projection. A reduction in dopaminergic neurotransmission in this system is
associated with parkinsonism. Hyperactivity of this system has been implicated in Huntington's
chorea. Hyperactivity in the mesoallocortical subdivision is believed to play a role in the
symptomatology of psychotic disorders, whereas a reduction in function may contribute to the
cognitive abnormalities found in patients with Parkinson's disease.

Very little is known about the functional role of the mesoneocortical system. Some researchers have
suggested a role in human cognition. A decrease in dopamine in this system may explain cognitive
impairments in patients with Parkinson's disease. A decrease in dopamine in the visual cortex has

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been implicated in photosensitive epilepsy (Table 9-2).

Two types of response mode have been demonstrated in mesencephalic dopamine neurons: (1) a
phasic mode response to reward and reward-predicting stimuli that have to be processed by the
subject with high priority and (2) a tonic mode response involved in maintaining states of behavioral
alertness. Thus, the dopamine system is involved in both the setting and the maintenance of levels of
alertness through the phasic and tonic mode responses.

Superior Colliculus Level

A. TECTUM
The nucleus of the superior colliculus occupies the tectum at the level of the superior colliculus. The
superior colliculus is a laminated mass of gray matter that plays a role in visual reflexes and control
of eye movement. The laminated appearance results from alternating strata of white and gray matter.
Superficial layers of the superior colliculus contain cells aligned in an orderly fashion with well-defined
visual receptive fields and apparently represent a map of visual space. In contrast, the deep layers
contain cells whose activity is related to the goal points of saccadic eye movements. It thus appears
that a sensory map of the visual space in the superficial layers is transformed in the deeper layers
into a motor map on which a vector from an initial eye position to a goal eye position is represented.
The vector is then translated into command signals for saccade generators such as the paramedian
pontine reticular formation (PPRF).

1. Afferent Connections
Afferent connections to the superior colliculus (Figure 9-10) come from the following sources.

a. Cerebral Cortex
Corticocollicular fibers arise from all over the cerebral cortex, but most abundantly from the
occipital (visual) cortex. Fibers originating from the frontal lobe are concerned with conjugate
eye movements and reach the superior colliculus by a transtegmental route. Occipitotectal fibers are
concerned with reflex scanning eye movements in pursuit of a passing object and reach the colliculus
via the brachium of the superior colliculus. Corticotectal fibers are ipsilateral. Occipitotectal and
frontotectal fibers terminate in the superficial and middle layers of the superior colliculus.
Temporotectal fibers (from the auditory cortex), in contrast, project into deep collicular layers.

b. Retina
Retinal fibers project on the same layer of the superior colliculus as do those of the cerebral cortex.
In contrast to cortical fibers, fibers from the retina are bilateral, with a preponderance of contralateral
input. Retinal fibers reach the superior colliculus by way of the brachium of the superior colliculus;
they leave the optic
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tract proximal to the lateral geniculate body. Retinotectal fibers arise from homonymous portions of
the retina of each eye, but crossed fibers are the most numerous. The contralateral homonymous
halves of the visual field are thus represented in each superior colliculus. The retinotectal fibers are
retinotopically organized so that upper retinal quadrants of the contralateral visual fields are in the
medial parts of the superior colliculus and lower retinal quadrants are in the lateral parts of the
colliculus. Peripheral visual fields are represented in the caudal superior colliculus, and central visual
fields are rostrally placed in the colliculus.

Table 9-2. Disorders of the Mesencephalic Dopaminergic System

Subdivision Hypoactivity Hyperactivity

Mesostriatal Parkinson's disease Huntington's chorea

Mesoallocortical Cognitive impairment

(Parkinson's disease) Psychotic disorders

Mesoneocortical Cognitive impairment

(Parkinson's disease) Undetermined

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Photosensitive epilepsy
(visual cortex)

Figure 9-10. Schematic diagram showing the major afferent connections of the superior

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colliculus.

c. Spinal cord
Spinotectal fibers ascend in the anterolateral part of the cord (with the spinothalamic tract) to reach
the superior colliculus. They belong to a multisynaptic system that conveys pain sensation.

d. Inferior colliculus
The input from the inferior colliculus and a number of other auditory relay nuclei is part of a reflex arc
that turns the neck and eyes toward the source of a sound.

Other inputs to the superior colliculus have been reported to arise from the midbrain tegmentum,
central (periaqueductal) gray matter, substantia nigra (pars reticulata), and spinal trigeminal nucleus.

2. Efferent Connections
Efferent connections (Figure 9-11) leave the superior colliculus via the following tracts.

Figure 9-11. Schematic diagram showing the major efferent connections of the superior
colliculus.

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a. Tectospinal tract
From their neurons of origin in the superior colliculus, fibers of the tectospinal tract system cross
in the dorsal tegmental decussation in the midbrain tegmentum and descend as part of or in
close proximity to the medial longitudinal fasciculus to reach the cervical spinal cord and terminate on
Rexed's laminae VII and VIII. They are concerned with reflex neck movement in response to visual
stimuli.

b. Tectopontocerebellar tract
The tectopontocerebellar tract descends to the ipsilateral pontine nuclei, which also receive fibers
from visual and auditory cortex. This tract is believed to convey visual impulses from the superior
colliculus to the cerebellum via the pontine nuclei.

c. Tectoreticular tract
The tectoreticular tract projects profusely and bilaterally on reticular nuclei in the midbrain as well as
on the accessory oculomotor nuclei.

d. Tectothalamic tract
The tectothalamic tract projects to the lateral posterior nucleus of the thalamus, the lateral
geniculate, and the pulvinar. The pulvinar receives extensive projections from superficial layers of the
superior colliculus and relays them to extrastriate cortical areas 18 and 19. Input to the lateral
geniculate nucleus arises from superficial layers of the superior colliculus and is relayed to the striate
cortex.

As with the afferent connections of the superior colliculus, the efferent connections originate from
different laminae of the superior colliculus. In general, the ascending tectothalamic projections
originate from superficial laminae, whereas the descending tectospinal, tectopontine, and
tectoreticular projections originate in deeper laminae.

Unilateral lesions of the superior colliculus in animals have been associated with the following
functional deficits: relative neglect of visual stimuli in the contralateral visual field, heightened
responses to stimuli in the ipsilateral visual field, and deficits in perception involving spatial
discrimination and the tracking of moving objects.

Stimulation of the superior colliculus results in contralateral conjugate deviation of the eyes. Since
there are no demonstrable direct connections of the superior colliculus to the nuclei of extraocular
movement, this effect may be mediated via connections to the rostral interstitial nucleus of the medial
longitudinal fasciculus (RiMLF) and the PPRF.

Most collicular neurons respond only to moving stimuli, and most also show directional selectivity.

B. PRETECTAL AREA
Rostral to the superior colliculus at the mesencephalic-diencephalic junction is the pretectal area
(pretectal nucleus). This area is an important station in the reflex pathway for the pupillary light
reflex and vertical gaze. It receives fibers from the retinas and projects fibers bilaterally to both
oculomotor nuclei. Several nuclei in the pretectal region have been identified, including the nucleus of
the optic tract, along the dorsolateral border of the pretectum at its junction with the pulvinar, and
the pretectal olivary nucleus, which is seen best at the level of the caudal posterior commissure.

Experiments in which the pretectal area and/or the posterior commissure were ablated suggest
strongly that these structures are essential for vertical gaze. This may explain the paralysis of vertical
gaze in patients with pineal tumors, which compress these structures. In humans, a group of signs
and symptoms resulting from a lesion in the pretectal area are referred to as the pretectal syndrome.
Synonyms include the sylvian aqueduct syndrome, the dorsal midbrain syndrome, Koerber-Salus-
Elschnig syndrome, the pineal syndrome, and Parinaud's syndrome. The conglomerate signs and
symptoms that constitute this syndrome include vertical gaze palsies, pupillary abnormalities
(anisocoria, light-near dissociation), conversion retraction nystagmus, lid retraction (Collier's sign),
inappropriate conversion (pseudoabducens palsy), impaired convergence, skewed eye deviation in the
neutral position, papilledema, and lid flutter. This syndrome has been reported in a variety of clinical
states, including brain tumors (pineal, thalamic, midbrain, third ventricle), hydrocephalus, stroke,
infection, trauma, and tentorial herniation.

C. TEGMENTUM
At the level of the superior colliculus, the tegmentum contains fibers of passage and nuclear groups.

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1. Fibers of Passage
The fibers of passage include all the fiber tracts encountered at the level of the inferior colliculus
except the lateral lemniscus, which terminates on inferior colliculus neurons and is not seen at
superior colliculus levels. The brachium conjunctivum fibers, which decussate at inferior colliculus
levels, terminate in the red nucleus at this level or form the capsule of the red nucleus on their way
to the thalamus. The other tracts discussed under “Inferior Colliculus Level” above maintain
approximately the same positions at this level.

2. Nuclear Groups
The nuclear groups include the red nucleus, the oculomotor nucleus, and accessory oculomotor nuclei
(Figure 9-12).

a. Red nucleus
The red nucleus, so named because in fresh preparations its rich vascularity gives it a pinkish hue, is
a prominent feature of the tegmentum at this level. It is composed of a rostral, phylogenetically
recent small cell part (parvicellular) and a caudal, phylogenetically older large cell part
(magnicellular). The rostral part is well developed in humans. The nucleus is traversed by the
following fiber systems: (1) the superior cerebellar peduncle (brachium conjunctivum), (2) the
oculomotor nerve (cranial nerve III) rootlets, and (3) the habenulointerpeduncular tract. Of the three
systems, only the brachium conjunctivum projects on this nucleus; the other two are related to the
red nucleus only by proximity. The red nucleus has the following afferent and efferent connections.

(1) Afferent Connections

Afferent connections that are most documented come from two sources (Figure 9-13).

(a) Deep Cerebellar Nuclei

The cerebellorubral fibers arise from the dentate, globose, and emboliform nuclei of the
cerebellum. They travel via the brachium conjunctivum, decussate in the tegmentum of the
inferior colliculus, and project partly to the contralateral red nucleus. Fibers from the dentate nucleus
terminate on the rostral (parvicellular) part of the red nucleus which projects to the inferior olive,
while fibers from the globose and emboliform nuclei project on the caudal part (magnicellular) of the
nucleus, which projects to the spinal cord. Interruption of the cerebellorubral fiber system results in a
volitional type of tremor that is manifested when the extremity is in motion (e.g., attempting to reach
for an object). The triangular area bounded by the red nucleus, the inferior olive (in the medulla
oblongata), and the dentate nucleus of the cerebellum is known as Mollaret's triangle. Lesions that
interrupt connectivity among these three structures result in spontaneous rhythmic movement of the
palate (palatal myoclonus).

(b) Cerebral Cortex

Corticorubral fibers arise mainly from the motor and premotor cortices and project mainly to the
ipsilateral red nucleus. This projection is somatotopically organized. Projections from the medial part
of area 6 (supplementary motor area MII) are crossed and end in the magnicellular region of the
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nucleus. Projections from the precentral (motor) cortex are ipsilateral to the magnicellular part of the
nucleus and correspond to the somatotopic origin of the rubrospinal fibers. The corticorubral and
rubrospinal tracts are considered an indirect corticospinal fiber system. The corticorubral input to the
red nucleus establishes primarily axodendritic synapses. Deafferentation experiments have shown that
after cerebellar ablation the cerebral input to the red nucleus establishes axosomatic synapses to
replace the deafferented cerebellar input.

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Figure 9-12. Schematic diagram of the midbrain at the superior colliculus level, showing its
major nuclear groups.

Figure 9-13. Schematic diagram showing the major afferent connections of the red nucleus.

The two afferent connections mentioned above are the best established. Other possible afferent tracts
include tectorubral from the superior colliculus and the pallidorubral from the globus pallidus.

(2) Efferent Connections

Efferent connections project to the following areas (Figure 9-14).

(a) Spinal Cord

Rubrospinal fibers arise from the caudal part (magnicellular) of the nucleus, cross in the ventral

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tegmental decussation, and descend to the spinal cord. They project on the same spinal cord laminae
as does the corticospinal tract. Like the corticospinal tract, the rubro-spinal tract facilitates flexor
motor neurons and inhibits extensor motor neurons. Because of their common termination and the
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fact that the red nucleus receives cortical input, the rubrospinal tract has been considered an indirect
corticospinal tract. In most mammals, the red nucleus sends its major output to the spinal cord and
clearly subserves a motor function. The projection to the spinal cord has diminished with evolution,
and in humans the red nucleus sends its major output to the inferior olive. In turn, the inferior olive
is connected to the cerebellum.

Figure 9-14. Schematic diagram showing the major efferent connections of the red nucleus.

(b) Cerebellum
In most mammals the rubrocerebellar fibers are collaterals from the rubrospinal tract. In the upper
pons some rubrospinal fibers leave the descending tract and accompany the superior cerebellar
peduncle to the cerebellum. In the cerebellum these fibers terminate on cells of the interposed nuclei
(emboliform and globose).

(c) Reticular Formation

Rubroreticular fibers are also offshoots from the rubrospinal tract. They separate from the descending
tract in the medulla oblongata and terminate in the ipsilateral lateral reticular nucleus. The lateral
reticular nucleus in turn projects to the cerebellum. Thus, a feedback circuit is established between
the cerebellum, the red nucleus, the lateral reticular nucleus, and back to the cerebellum.

(d) Inferior Olive

The rubro-olivary tract arises in the rostral small cell part (parvicellular) of the nucleus and projects
to the ipsilateral inferior olive via the central tegmental tract. The inferior olive in turn projects to the
cerebellum, thus establishing another feedback circuit between the cerebellum, the red nucleus, the
inferior olive, and back to the cerebellum. The rubro-olivary tract in humans is more important than is
the rubrospinal tract.

(e) Other Projections

Other efferent projections include fibers to Darkschewitsch's nucleus, the Edinger-Westphal nucleus,
the mesencephalic reticular formation, the tectum, the pretectum, principal sensory and spinal

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trigeminal nuclei, and the facial motor nucleus.

Thus, the red nucleus is a synaptic station in neural systems concerned with movement, linking the
cerebral cortex, cerebellum, and spinal cord.

Lesions of the red nucleus result in contralateral tremor.

b. Oculomotor nucleus
The oculomotor nucleus lies dorsal to the medial longitudinal fasciculus (MLF) at the level of the
superior colliculus. It is composed of a lateral somatic motor cell column and a medial visceral cell
column. It is approximately 10 mm in length. This nucleus receives fibers from the following sources.

(1) Cerebral Cortex

Corticoreticulobulbar fibers are bilateral but come mainly from the contralateral hemisphere.

(2) Mesencephalon
Mesencephalic projections to the oculomotor nucleus originate from Cajal's interstitial nucleus, the
rostral interstitial nucleus of the medial longitudinal fasciculus (RiMLF), and the pretectal olivary
nucleus. Fibers from Cajal's interstitial nucleus course in the posterior commissure and project mainly
on the contralateral oculomotor nucleus. Interruption of these fibers results in paralysis of upward
gaze. The RiMLF is just rostral to Cajal's interstitial nucleus. The projection from the RiMLF to the
oculomotor nucleus is mainly ipsilateral. Lesions of the RiMLF lead to paralysis of downard gaze.
Physiologic studies have shown that neurons in Cajal's interstitial nucleus and the RiMLF are active
just before vertical eye movements. Cajal's interstitial nucleus and the RiMLF project fibers to the
somatic motor cell column of the oculomotor nucleus, whereas the pretectal area projects mainly to
the Edinger-Westphal nucleus of the visceral cell column. The pretectal area receives fibers from both
retinas and projects to both oculomotor nuclei. This connection plays a role in the pupillary light
reflex.

(3) Pons and Medulla

Pontine and medullary projections to the oculomotor nucleus arise from the vestibular nuclei, the
nucleus prepositus, and the abducens nucleus. The vestibular projections originate in the superior and
medial vestibular nuclei. Projections from the medial vestibular nuclei via the MLF are bilateral, while
those from the superior vestibular nucleus, via the MLF, are ipsilateral. Other fibers from the superior
vestibular nucleus that are not contained in the MLF cross in the caudal midbrain and project to the
superior rectus and the inferior oblique subnuclei of the oculomotor complex. The projection from the
abducens nucleus arises from interneurons, is crossed, and reaches the oculomotor nucleus via the
MLF along with vestibular fibers. The connection between the abducens and oculomotor nuclei
provides the anatomic substrate for the coordination between the lateral rectus and medial rectus
muscles in conjugate horizontal gaze. The nucleus prepositus projects ipsilaterally to the oculomotor
complex and may be involved in vertical eye movement.

(4) Cerebellum
Cerebello-oculomotor fibers to the somatic motor cell column arise from the contralateral dentate
nucleus and are concerned with the regulation of eye movements. In addition, the cerebellum exerts
an influence on autonomic neurons of the oculomotor nucleus. Short-latency (direct) as well as long-
latency (indirect) responses have been elicited in the Edinger-Westphal nucleus after stimulation of
the interposed and fastigial cerebellar nuclei. This connection is believed to course in the brachium
conjunctivum and plays a role in pupillary constriction and accommodation. The short-latency
connection is facilitatory, whereas the long-latency connection is inhibitory.

The somatic motor cell column is organized into subgroups (Figure 9-15) for each of the eye
muscles supplied by the oculomotor nerve. From the most rostral extension of the oculomotor
nucleus to its middle third are the Edinger-Westphal nuclei and the inferior rectus subnuclei. Inferior
rectus subnuclei extend rostrally like a peninsula and are the only subnuclei seen in the most rostral
part of the nucleus. A discrete lesion of the oculomotor nucleus at its most rostral level may result in
an isolated inferior rectus paresis with or without pupillary abnormalities.

The inferior oblique subnuclei are the most laterally placed subnuclei in the middle and caudal thirds
of the nuclear complex.
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Superior rectus subnuclei are medially located in the middle and caudal thirds of the nucleus and are
the only subnuclei in the third nuclear complex that supply contralateral eye muscles (superior rectus
muscle). All other subnuclei supply corresponding ipsilateral eye muscles. The superior rectus

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subnucleus is adjacent to and caudal to the inferior rectus subnucleus. A lesion slightly caudal to a
lesion that produces an isolated inferior rectus palsy can affect the inferior and superior rectus
subnuclei, producing an ipsilateral inferior rectus and contralateral superior rectus paresis. The medial
rectus subnuclei are located primarily in the ventral oculomotor nuclear complex in close proximity to
the MLF. The levator palpebrae subnucleus is a single central nucleus in the caudal third of the
nucleus. Axons from the neurons of this single nucleus divide into right and left bundles to supply the
two levator palpebrae muscles. Discrete lesions in individual subnuclei of the oculomotor nuclear
complex have been reported (using magnetic resonance imaging) with isolated unilateral inferior
rectus paresis, bilateral inferior rectus paresis and unilateral superior rectus weakness, and isolated
unilateral inferior rectus and contralateral superior rectus weakness.

Figure 9-15. Simplified schematic diagram of the rostrocaudal arrangement of oculomotor

subnuclei. EW, Edinger-Westphal; IR, inferior rectus; SR, superior rectus; L, levator; IO, inferior
oblique; MR, medial rectus; MLF, medial longitudinal fasciculus.

Axons of neurons in the somatic motor column course through the tegmentum of the midbrain, pass
near or through the red nucleus, and emerge from the interpeduncular fossa medial to the cerebral
peduncle. In their course in the midbrain tegmentum, oculomotor nerve fascicles are organized so
that fascicles to the inferior oblique are most laterally placed, followed from lateral to medial by
superior rectus, medial rectus, inferior rectus, and pupillary fascicles. The levator palpebrae fascicles
lie dorsally close to those of the medial rectus. Discrete lesions involving one or more of these
fascicles may result in partial oculomotor nerve paresis.

The oculomotor nerve leaves the brain stem between the superior cerebellar artery and the posterior
cerebral artery. Once it leaves the brain stem, this nerve courses anteriorly in the subarachnoid space
until it pierces the dura covering the roof of the cavernous sinus. In the anterior part of the cavernous
sinus, the oculomotor nerve divides into superior and inferior divisions. The superior division
innervates the levator palpebrae superioris and superior rectus muscles. The inferior division
innervates the inferior rectus, medial rectus, and inferior oblique muscles and the iris sphincter. The
inferior oblique muscle lowers the eye when one is looking medially, and the superior and inferior
rectus muscles elevate and lower the eye, respectively, when one is looking laterally. The medial
rectus adducts the eye. The levator palpebrae elevate the lid.

The visceral cell column includes the Edinger-Westphal nucleus and Perlia's nucleus. The Edinger-
Westphal nucleus is concerned with the light reflex. Perlia's nucleus is probably concerned with
accommodation but has not been identified in humans.

The axons of neurons in the visceral cell column accompany those of the somatic motor column as far
as the orbit. In the orbit they part company, and the visceral axons project to the ciliary ganglion.
Postganglionic fibers from the ciliary ganglion innervate the sphincter pupillae and ciliaris muscles.
Lesions in this component of the oculomotor nerve result in a dilated pupil that is unresponsive to
light or accommodation.

Lesions of the oculomotor nerve outside the brain stem (Figure 9-16A) result in (1) paralysis of the
muscles supplied by the nerve, manifested by drooping of the ipsilateral eyelid (ptosis) and deviation
of the ipsilateral eye downward and outward by the action of the intact lateral rectus and superior
oblique muscles (supplied by the abducens and trochlear nerves, respectively), (2) double vision
(diplopia), and (3) paralysis of the sphincter pupillae and ciliaris muscles, manifested by an ipsilateral

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dilated pupil that is unresponsive to light and accommodation.

Lesions at the interpeduncular fossa (Figure 9-16B) involving the cerebral peduncle and the rootlets of
the oculomotor nerve result in (1) deviation of the ipsilateral eye downward and outward, with
drooping of the eyelid, (2) diplopia, (3) ipsilateral loss of light and accommodation reflexes, (4)
dilatation of the ipsilateral pupil, and (5) contralateral upper motor neuron paralysis.

Lesions in the mesencephalon involving the red nucleus and the rootlets of the oculomotor nerve
(Figure 9–16C) are manifested by (1) deviation of the ipsilateral eye downward and outward,
with drooping of the eyelid,
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(2) diplopia, (3) ipsilateral loss of light and accommodation reflexes, (4) dilatation of the ipsilateral
pupil, and (5) contralateral tremor.

Figure 9-16. Schematic diagram showing lesions of the oculomotor nerve in its intra- and extra-
axial course and their respective clinical manifestations.

Following lesions in the oculomotor nerve, atypical movements of the pupil, lid, or eye can occur due
to aberrant nerve degeneration. This phenomenon is referred to as oculomotor synkinesis. In most of
these cases, the oculomotor nerve lesion is extra-axial. Occasional oculomotor synkinesis has been
reported in ischemic intra-axial lesions.

The relationship of the oculomotor nerve to the posterior cerebral and superior cerebellar arteries
makes this nerve vulnerable to aneurysms in those vessels. Rupture of these aneurysms is usually
manifested by the sudden onset of headache and signs of oculomotor nerve lesion.

It is worth noting that the parasympathetic fibers concerned with the pupillary light reflex travel on
the superficial aspect of the oculomotor nerve in its cisternal portion and thus are the most
susceptible to extrinsic compression by extraneural masses such as posterior communicating artery
aneurysms. Conversely, in the majority of cases of vascular ischemic disease of the nerve, such as
diabetes mellitus, which affect centrally located fibers, the pupillary fibers are spared. The blood
supply of the oculomotor nerve dips deep into the nerve, and thus interruption of the blood supply
adversely affects deeper fibers and spares the more superficial ones concerned with the pupillary light
reflex. The pupillary fibers are also of the small unmyelinated type and are relatively resistant to
ischemia.

The sparing of parasympathetic pupillary fibers in ischemic disease and their dysfunction in
compressive disease are not, however, absolute. In 3 to 5 percent of aneurysms, the pupil may be
spared. Pupil-sparing oculomotor nerve palsy is not, however, unique to nerve involvement outside
the brain stem (in the subarachnoid space or cavernous sinus). These palsies also have been reported
with intra-axial (within the midbrain) lesions. Many, however, are associated with other neurologic
signs (e.g., tremor), suggesting the involvement of adjacent structures such as the red nucleus. Few
cases of pupil-sparing oculomotor nerve palsy from intra-axial lesions have been reported without

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another associated neurologic sign. Such cases are explained by isolated involvement of the
appropriate nerve fascicles by the ischemic process.

c. Accessory oculomotor nuclei

The accessory oculomotor nuclei include the following nuclei (see Figure 9-12).

(1) Interstitial Nucleus of Cajal

The interstitial nucleus of Cajal is located rostral to the Edinger-Westphal nucleus and caudal to
the rostral interstitial nucleus of the medial longitudinal fasciculus. It contains two
subpopulations of neurons. One subpopulation is related to integration of vertical gaze, and the other
is concerned with eye-head coordination. The nucleus receives inputs from burst neurons in the
rostral interstitial nucleus of the medial longitudinal fasciculus and from the vestibular nuclei. It
projects fibers (via the posterior commissure) to the ocular motor nuclei (cranial nerves III and IV)
and the contralateral interstitial nucleus of Cajal. It also sends fibers to the reticular formation and
both RiMLF.

(2) Rostral Interstitial Nucleus of the Medial Longitudinal Fasciculus

The RiMLF is located dorsomedial to the red nucleus, rostral to the oculomotor nucleus, and ventral to
the periaqueductal gray matter. Synonyms include the nucleus of the prerubral field and the nucleus
of the field of Forel. The nucleus contains burst neurons that fire with both upward and downward eye
movements. The nucleus receives inputs from the frontal eye fields; raphe nucleus interpositus, which
gates activity of burst neurons; nucleus of the posterior commissure; superior colliculus; and the
nucleus fastigii of the cerebellum. The two RiMLF nuclei are interconnected. The nucleus projects to
ocular motor neurons (cranial nerves III and IV). Each RiMLF projects simultaneously to motor
neurons that move each eye in the same direction (e.g., inferior rectus muscle of one eye and the
superior oblique muscle of the other eye). Projections to motor neurons that innervate elevator
(upgaze) muscles are bilateral, with crossing occurring within the cranial nerve nucleus (cranial nerve
III). Projections to motor neurons that innervate depressor (downgaze) muscles are ipsilateral. The
RiMLF also projects to the interstitial nucleus of Cajal.

(3) Darkschewitsch's Nucleus

Darkschewitsch's nucleus lies dorsal and lateral to the somatic motor cell column of the oculomotor
nerve. It projects to the nuclei of the posterior commissure but does not project to the oculomotor
nuclear complex.

(4) Nucleus of the Posterior Commissure

This nucleus is located within the posterior commissure. It has connections with pretectal and
posterior thalamic nuclei. Lesions involving nuclei of the posterior commissure and crossing fibers
from Cajal's interstitial nuclei produce bilateral eyelid retraction and impairment of vertical eye
movement.

The accessory oculomotor nuclei are directly or indirectly connected with the oculomotor complex.
Cajal's interstitial nucleus also sends fibers to the spinal cord via the MLF.

D. CENTRAL (PERIAQUEDUCTAL) GRAY

The central gray region of the mesencephalon surrounds the aqueduct of Sylvius and contains
scattered neurons, several nuclei, and some fine myelinated and unmyelinated fibers. The
oculomotor, accessory oculomotor, and trochlear nuclei, as well as the mesencephalic nucleus of the
trigeminal nerve, lie at the edge of this region. The dorsal longitudinal fasciculus (fasciculus of
Schütz) is a periventricular ascending and descending fiber system that courses in the central gray
matter. It arises in part from the hypothalamus and contains autonomic fibers. It generally connects
the hypothalamus with the periaqueductal gray and with autonomic nuclei in the pons and medulla.
The neuropeptide enkephalin has been identified in the central gray matter. Stimulation of certain
sites within the central gray matter release enkephalins, which act on serotonergic neurons in the
medulla oblongata, which in turn project on primary afferent axons (concerned with pain conduction)
in the dorsal horn of the spinal cord to produce analgesia. Stimulus-produced analgesia has been
achieved by stimulation of ventrolateral regions of the central gray matter. In contrast, stimulation of
the rostral and lateral central gray matter facilitates pain sensations.

In addition to its role in central analgesic mechanisms, the central (periaqueductal) gray region has
been implicated in vocalization, control of reproductive behavior, modulation of medullary respiratory
centers, aggressive behavior, and vertical gaze. The peri-aqueductal gray, along with deep layers of
the superior colliculus, have been shown to be involved in different components of aversive states.

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Escape behavior and defensive or fear-like behavior are elicited by stimulation of these areas. The
periaqueductal gray receives information about urinary bladder filling and thus is involved in the
central process of micturition. Through connections to the hypothalamus and rostral medulla, the
periaqueductal gray has been implicated in the process of penile erection. Afferents to this region
arise from the hypothalamus, the amygdala, the brain stem reticular formation, the locus ceruleus,
and the spinal cord. Immunoreactivity to a variety of neuropeptides has been demonstrated in
periaqueductal neurons; these neuropeptides include enkephalin, substance P, cholecystokinin,
neurotensin, serotonin, dynorphin, and somatostatin.

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LIGHT REFLEX
Stimulation of the retina by light sets off a reflex with the following afferent and efferent pathways
(Figure 9-17).

Afferent Pathway
From the retina the impulse travels via the optic nerve and optic tract to the pretectal area. After
synapsing on neurons of the pretectal area, the impulse travels via the posterior commissure to both
Edinger-Westphal nuclei in the oculomotor complex.

Efferent Pathway
From the Edinger-Westphal nucleus, parasympathetic preganglionic fibers travel with the somatic
motor component of the oculomotor nerve as far as the orbit. In the orbit, the parasympathetic fibers
project on neurons in the ciliary ganglion. Postganglionic fibers arise from the ciliary ganglion (short
ciliary nerves) and innervate the sphincter pupillae and ciliaris muscles.

Thus, when light is thrown on one retina, both pupils respond by constricting. The response of
the ipsilateral pupil is the direct light reflex, whereas that of the contralateral pupil is the
consensual light reflex. A consensual light reflex is possible because of the projection of the pretectal
area to both oculomotor nuclei.

Lesions of the optic nerve (Figure 9-18) abolish both direct and consensual light reflexes in response
to light stimulation of the ipsilateral retina. Lesions of the oculomotor nerve (Figure 9-19) abolish the
direct light reflex but not the consensual light reflex in response to light stimulation of the ipsilateral
retina.

Figure 9-17. Schematic diagram showing the afferent and efferent pathways of the pupillary
light reflex.

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Figure 9-18. Schematic diagram showing the effects of optic nerve lesions on the direct and
consensual pupillary light reflexes.

The Marcus Gunn phenomenon is a paradoxical dilatation of both pupils that occurs when light is
shone in the symptomatic eye (optic nerve lesion) after having been shone in the normal eye. When
light is shone in the normal eye, both pupils constrict (direct and consensual light reflexes). When
light is then swung to the symptomatic eye, less light reaches the oculomotor nucleus
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because of the optic nerve lesion (optic neuropathy). The oculomotor nucleus senses the less intense
light and shuts off the parasympathetic response, resulting in paradoxical pupillary dilatation (Figure
9-20).

Adie's pupil, or tonic pupil, is characterized by a widely dilated pupil and a sluggish, prolonged
pupillary contraction in reaction to light. When it is constricted, the pupil takes a long time to dilate.
The affected pupil is larger than the normal pupil, but in darkness it may be smaller, since the normal
pupil is free to dilate widely. Adie's pupil shows a more definite response to accommodation. It results
from pathology in the ciliary ganglion within the orbit. The etiology of Adie's pupil is unknown, but
believed to be due, in part, to redirection of regenerating parasympathetic fibers. Normally, 90
percent of parasympathetic nerves in the ciliary ganglion innervate the ciliary body and the remaining
10 percent innervate the iris sphincter. When the ciliary ganglion is damaged, the pupil becomes
dilated and unresponsive to light or accommodation. During recovery reinnervation takes place in a
random fashion. As a result, 90 percent of the parasympathetic fibers that previously innervated the
pupil now innervate the ciliary body. When light is shone in the eye, 90 percent of the
parasympathetic instruction to constrict the pupil is dissipated in the ciliary body, leaving only 10
percent for pupillary constriction.

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Figure 9-19. Schematic diagram showing the effects of oculomotor nerve lesions on the direct
and consensual pupillary light reflexes.

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Figure 9-20. Schematic diagram showing response to light stimulation of the Marcus Gunn pupil.

ACCOMMODATION-CONVERGENCE REFLEX
The accommodation-convergence reflex involves the following processes:

1. The assumption of a convex shape by the lens is secondary to contraction of the ciliary muscle,
which causes relaxation of the suspensory ligament. This is a process of accommodation of the
lens, which thickens to keep the image in sharp focus.

2. Contraction of both medial recti muscles for convergence brings the eyes into alignment.

3. Pupillary constriction occurs as an aid in regulating the depth of focus for sharper images.

The accommodation-convergence reflex occurs when the eyes converge voluntarily to look at a nearby
object or make a reflex response to an approaching object.

The pathway of the accommodation-convergence reflex has not been well delineated. It is
believed, however, that afferent impulses from the retina reach the occipital cortex and that the
efferent pathway from the occipital cortex reaches the oculomotor complex after synapsing in the
pretectal nucleus and/or superior colliculus. In the oculomotor complex, Perlia's nucleus has been
assumed to play a role in convergence (Figure 9-21). The pathway for the accommodation-

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convergence reflex is thus different from that of the light reflex. This is supported clinically by a
condition known as the Argyll Robertson pupil, in which the light reflex is lost while the
accommodation-convergence reflex persists. The site of the lesion in this condition has not been
established with certainty, but its etiology is known to be syphilis of the nervous system.

MESENCEPHALIC RETICULAR FORMATION

The mesencephalic reticular formation is a continuation of the pontine reticular nuclei and
merges rostrally with the zona incerta. The major output from the mesencephalic reticular
formation ascends to the diencephalon and cerebral cortex and is involved in wakefulness and sleep.

The reticular nuclei of the mesencephalon and other brain stem areas are discussed in the chapter on
reticular formation, wakefulness, and sleep.

VERTICAL GAZE
Whereas control of lateral gaze is a function of the pons, the rostral midbrain at the mesencephalic-
diencephalic junction is critical in the mediation of vertical gaze.

The following structures are important for vertical eye movements:

1. Motor neurons in the oculomotor (cranial nerve III) and trochlear (cranial nerve IV) nuclei that
supply ocular muscles
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involved in vertical eye movements: superior rectus, inferior rectus, inferior oblique (cranial
nerve III), and superior oblique (cranial nerve IV).

Figure 9-21. Schematic diagram showing the afferent and efferent pathways of the
accommodation-convergence reflex.

2. RiMLF. This nucleus constitutes the neural substrate for vertical eye movements. It contains
burst neurons that fire on upward and downward gaze. Although the RiMLF is the key
substrate for vertical eye movements, vertical burst neurons also reside in the mesencephalic
reticular formation.

Bilateral lesions in the RiMLF abolish all vertical (up and down) eye movements. Unilateral
lesions result in defect in downward gaze. The difference in outcome between bilateral and
unilateral lesions is consistent with bilateral projections of the nucleus to elevator motor neurons
and ipsilateral projections to the depressor motor neurons.

3. Interstitial nucleus of Cajal (INC). The INC is the neural integrator for vertical gaze. Bilateral
lesions in the nucleus result in limitations in the range of vertical gaze and in gaze holding.

Because of the projections of the INC to ocular motor neurons (cranial nerves III and IV) and to
the opposite INC via the posterior commissure, a lesion in one INC becomes in effect a bilateral
lesion.

Reflex eye movements in response to head turning (oculocephalic response) are mediated by
vestibular originating fibers destined to the oculomotor and trochlear nuclear complexes via the
medial longitudinal fasciculus with relays in the interstitial nucleus of Cajal. Lesions in the

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interstitial nucleus of Cajal are thus associated with abolition of the oculocephalic response.

4. Posterior commissure. The posterior commissure contains crossing nerve fibers intermixed with
the nucleus of the posterior commissure (NPC). The fibers in the posterior commissure are: (a)
projections from the INC to the contralateral ocular motor nuclear complex (cranial nerves III
and IV) and the contralateral interstitial nucleus of Cajal, (b) projections from the NPC to the
contralateral INC and the RiMLF. Lesions of the posterior commissure result in impairment of
vertical gaze holding and restrict all vertical eye movements, but especially upward movements.
The impairment of vertical gaze holding is explained by involvement of axons of INC. The
restriction of vertical eye movements is attributed to involvement of the nucleus of the posterior
commissure.

Paralysis of both upward and downward gaze by both saccadic and vestibular means usually
implies involvement of the interstitial nucleus of Cajal or the posterior commissure singly or
together.

5. Nucleus of the posterior commissure. The nucleus of the posterior commissure has an important
role (not fully explored yet) in vertical eye movements as well as in lid movement.

6. The medial longitudinal fasciculus. The medial longitudinal fasciculus carries inputs from
vestibular nuclei to oculomotor nuclear complex, trochlear nuclear complex, and the interstitial
nucleus of Cajal. These fibers carry signals important for vertical vestibular eye movements and,
to a lesser extent, vertical gaze-holding commands.

CONTROL OF SACCADIC EYE MOVEMENT

Commands for saccadic eye movements are initiated from the cerebral cortex (Figure 9-22). The
frontal eye field (area 8 in the frontal lobe), the angular gyrus (area 39), and the adjacent area
19 of the parieto-occipital cortices project to the superior colliculus. The cortical areas of ocular
motility are interconnected. The superior colliculus in turn projects to the brain stem pulse generators
in the pons and midbrain. The pulse generators also receive cortical input directly from the frontal eye
fields. The pulse generator for horizontal saccades is in the PPRF. The pulse generator for vertical
saccades is in the mesencephalic RiMLF. Thus, there are two pathways concerned with saccadic
movements: (1) an anterior pathway from the frontal eye fields directly and indirectly (via the
superior colliculus) to the brain stem centers for saccadic movements (PPRF for horizontal saccades
and the mesencephalic RiMLF for vertical saccades), and (2) a posterior pathway from the parieto-
occipital cortex to the superior colliculus and then to the brain stem centers for saccadic
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movements. The anterior pathway generates intentional saccades; the posterior pathway generates
reflexive saccades. Each pathway can compensate partially for the other.

Figure 9-22. Schematic diagram showing cortical and subcortical control of saccadic eye

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movements. MLF, medial longitudinal fasciculus; PPRF, paramedian pontine reticular formation.

SMOOTH PURSUIT EYE MOVEMENTS

Each hemisphere has been shown to mediate smooth pursuit eye movements to the ipsilateral
side. The cortical areas involved in smooth pursuit are not as well delineated as are those
involved in saccadic eye movements but probably include the posterior parietal cortex or the temporo-
occipito-parietal region. The pathogenesis of the pursuit deficits and pathways involved in smooth
pursuit eye movements are not completely understood. Specific lesions in the temporo-occipito-
parietal cortex that are associated with smooth pursuit deficits in humans correspond to Brodmann
areas 19, 37, and 39. Lesions in the frontal eye field also have been associated with deficits in smooth
pursuit.

The corticofugal pathway for smooth pursuit movements remains controversial. Two pathways have
been described. The first courses from the temporo-occipito-parietal cortex through the posterior limb
of the internal capsule to the dorsolateral pontine nucleus. The second courses from the frontal eye
field to the
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dorsolateral pontine nucleus and the nucleus reticularis tegmenti pontis. Pursuit pathways in the brain
stem and cerebellum are less well defined, although the dorsolateral pontine nucleus and the
cerebellar flocculus are important in the monkey. Cerebral hemisphere lesions impair ocular pursuit
ipsilaterally or bilaterally, whereas posterior fossa lesions impair ocular pursuit contralaterally or
ipsilaterally. This variability probably reflects the involvement of a presumed pursuit pathway that
crosses from the pontine nuclei to the cerebellum and then consists of a unilateral projection from the
cerebellum to the vestibular nuclei.

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Figure 9-23. Schematic diagram showing vascular territories of the midbrain at three caudal-
rostral levels.

BLOOD SUPPLY
Compared with the vascular supply of the pons, the midbrain vasculature is complex (Figure 9-23).
The mesencephalon (midbrain) receives its blood supply from the basilar artery via paramedian as
well as superior cerebellar and posterior cerebral branches.

Inferior Colliculus Level (Figure 9-23A)

At the level of the inferior colliculus (lower midbrain), the paramedian branches supply the
medial region of the mesencephalon, including the MLF, the paramedian reticular nuclei, and the
brachium conjunctivum. The superior cerebellar artery supplies the lateral region of the midbrain,
including the inferior colliculus, the rootlets of the trochlear nerve, the spinal and medial lemniscus,
and the lateral part of the cerebral peduncle. A wedge between these two regions, which includes the
trochlear nucleus, the cerebral peduncle, and the medial part of the medial lemniscus, has a variable

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and inconstant blood supply.

Superior Colliculus Level (Figure 9-23B)

At the level of the superior colliculus (middle midbrain), the mesencephalon is divided into three
zones of blood supply. The medial zone, which includes the third cranial nerve nuclear complex,
receives blood from the tip of the basilar artery. The tectum (dorsal zone) is supplied by the superior
cerebellar artery. The rest of the midbrain is supplied by the posterior cerebral artery. This zone
includes the spinal and medial lemnisci, the substantia nigra, the cerebral peduncle, the red nucleus,
and the third cranial nerve rootlets.

Pretectal Level (Figure 9-23C)

At the level of the upper midbrain (the pretectal level), the medial zone, including the medial part of
the red nucleus, and rootlets of the oculomotor nerve receive blood from paramedian branches of the
basilar artery. The rest of the midbrain receives blood from the posterior cerebral artery.

TERMINOLOGY
Adduction (Latin adducere, “to draw toward”).
The process of drawing toward the median plane.

Adie's pupil (tonic pupil, Holmes-Adie syndrome).

A condition in which the pupil exhibits sluggish prolonged constriction to light and, when it is
constricted, takes a long time to dilate. The phenomenon results from pathology in the ciliary
ganglion. Described by James Ware in 1812, by Piltz in 1899, and by others before William John Adie,
an Australian neurologist, described it in 1931.

Akinesia (Greek a, “negative”; kinesis, “motion”).

Poverty or absence of movement.

Anisocoria (Greek anisos, “unequal, uneven”; kore, “pupil”).

Inequality in the diameters of the pupils.

Aqueduct of Sylvius (cerebral aqueduct) (Latin aqua, “water”; ductus, “canal”).

The narrow passage in the midbrain linking the third and fourth ventricles. Described by Jacques
Dubois (Sylvius) in 1555.

Argyll-Robertson pupil.
A pupil that reacts to accommodation but not to light. Described by Argyll Robertson, a Scottish
ophthalmologist, in 1869. Syphilis is the classical etiology, but diabetes and lesions in the midbrain
can cause this phenomenon.

Brachium conjunctivum (Latin, Greek brachion, “arm”; conjunctiva, “connecting”).

An armlike bundle of fibers that connects the cerebellum and midbrain.

Colliculus (Latin, a “small elevation”).

The inferior and superior colliculi are small elevations in the dorsal surface of the midbrain.

Collier's sign.
Bilateral lid retraction seen in the pretectal syndrome.

Corpora quadrigemina (Latin corpus, “body”; quadrigeminus, “fourfold”).

Four bodies in the dorsal aspect of the midbrain, consisting of two inferior colliculi and two superior
colliculi.

Darkschewitsch's nucleus.
One of the accessory oculomotor nuclei. Named after Liverij Osipovich Darkschewitsch, a Russian
anatomist.

Dentate nucleus (Latin dentatus, “toothlike”).

A nucleus in the cerebellum that is serrated like a tooth.

Diplopia (Greek diploos, “double”; ops, “eye”).

Double vision.

Dorsal longitudinal fasciculus (fasciculus of Schütz).

A periventricular ascending and descending fiber system that connects the hypothalamus with the
periaqueductal gray matter and with autonomic nuclei in the pons and medulla oblongata.

Edinger-Westphal nucleus.

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The parasympathetic component of the oculomotor nuclear complex. Described by Ludwig Edinger, a
German anatomist and neurologist, in 1885 and by Carl Friedreich Otto Westphal, a German
psychiatrist, neurologist, and anatomist, 2 years later.

Emboliform (Greek embolos, “plug”).

The emboliform nucleus in the cerebellum “plugs” the dentate nucleus.

Globose (Latin globus, “a ball, sphere-shaped”).

The globose nucleus in the cerebellum is spherical in shape.

Habenula (Latin habena, “small strap or bridle rein”).

The habenular nuclei in the caudal diencephalon near the pineal gland form part of the epithalamus.
Early anatomists considered the pineal gland the abode of the soul; it was likened to a driver who
directs the operations of the mind via the habenula, or reins.

Huntington's chorea (Greek choreia, “dance”).

A progressive neurodegenerative disorder inherited as an autosomal dominant trait. The disease was
imported to America from Suffolk in the United Kingdom by the emigrant wife of an Englishman in
1630. Her father was choreic, and the groom's father disapproved of the match because of the bride's
father's illness. The disorder is named after George Sumner Huntington, a general practitioner who
described it in 1872. Characterized by the ceaseless occurrence of a wide variety of rapid, complex,
jerky movements performed involuntarily and resembling a dance.

Intorsion (Latin in, “toward”; torsio, “twisting”).

Inward rotation of eye.

Koerber-Salus-Elschnig syndrome.
A syndrome of vertical gaze palsy, anisocoria, light-near dissociation, conversion retraction
nystagmus, lid retraction, impaired convergence, skewed eye deviation, papilledema, and lid flutter
associated most commonly
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with pineal tumors or disorders of the pretectal region. Also known as Parinaud's syndrome, the
pretectal syndrome, the sylvian aqueduct syndrome, and the syndrome of the posterior commissure.

Locus ceruleus (Latin, “place, dark blue”).

The pigmented noradrenergic nucleus in the rostral pons is dark blue in sections.

Marcus Gunn pupil.

Paradoxical dilatation of both pupils when light is shone in a symptomatic eye with an optic nerve
lesion after having been shone in the normal eye (swinging flashlight test). When light is shone in the
normal eye, both pupils constrict. When light is then swung to the symptomatic eye, less light reaches
the oculomotor nucleus because of the optic nerve lesion. The oculomotor nucleus senses the less
intense light and shuts off the parasympathetic response, resulting in paradoxical pupillary dilatation.
In 1902 Robert Marcus Gunn (1850–1909), a Scottish ophthalmologist, observed the reaction of both
eyes to stimulation of one of them, while Levatin described the swinging flashlight test and observed
the paradoxical dilatation of the pupil of the affected eye when the light was swung to it from the
normal eye.

Mollaret's triangle.
The triangular space formed by the red nucleus, inferior olive, and dentate nucleus of cerebellum.
Named after Pierre Mollaret, a French physician.

Oculomotor nerve (Latin oculus, “eye”; motor, “mover”).

The third cranial nerve affects movements of the eye.

Parinaud's syndrome.
Paralysis of upward gaze associated with pretectal lesions. Described by Henri Parinaud, a French
neuro-ophthalmologist, in 1883.

Parkinson's disease.
A chronic progressive degenerative disease characterized by tremor, rigidity, and akinesia. It was
initially described in 1817 by the English physician James Parkinson under the rubric shaking palsy.

Parvicellular nucleus (Latin parvus, “small”; cellula, “cell”).

The parvicellular nucleus is composed of small cells.

Perlia's nucleus.
A component of the autonomic oculomotor nuclear complex related to ocular conversion. Described by
Richard Perlia, a German ophthalmologist, in 1899.

Ptosis (Greek ptosis, “fall”).

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Drooping of the upper lid from oculomotor nerve palsy (levator palpebrae muscle paralysis) or
sympathetic nerve palsy (tarsal plate paralysis) as in Horner's syndrome.

Saccades (French, “jerking”).

Abrupt, rapid movements or jerks of the eyes when one is changing points of fixation.

Tectum (“rooflike structure”).

A structure that forms the roof of the midbrain.

Tegmentum (Latin tegmenta, “covering”).

A structure that covers the cerebral peduncles.

Trochlear nerve (Latin trochlearis, “resembling a pulley”).

The fourth cranial nerve supplies the superior oblique eye muscle, whose tendon angles through a
ligamentous sling like a pulley. Achillini and Vesalius included this nerve with the third pair of nerves.
It was described as a separate root by Fallopius and was named the trochlear nerve by William Molins,
an English surgeon, in 1670.

Vicq d'Azyr, Felix (1748–1794).

French physician to Queen Marie Antoinette. Described the anterior, middle, and posterior lobes of the
cerebral cortex (corresponding to the frontal, parietal, and occipital), the insula (island of Reil) well
before Reil, the substantia nigra, and the mamillothalamic tract (tract of Vicq d'Azyr).

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Fog M, Hein-Sørenson O: Mesencephalic syndromes. In Vinken PJ, Bruyn GW (eds): Handbook of

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Gale K: Role of the substantia nigra in GABA-mediated anticonvulsant actions. Adv Neurol 1986;
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Galetta SL et al: Pretectal eyelid retraction and lag. Ann Neurol 1993; 33:554–557.

Gebhart GF, Toleikis JR: An evaluation of stimulation-produced analgesia in the cat. Exp Neurol
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lesion. Neurology 1990; 40:1503–1509.

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Parkinson's disease. Ann Neurol 1991; 30:563–571.

Hommel M, Bogousslavsky J: The spectrum of vertical gaze palsy following unilateral brain stem
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Hopf HC, Gutman L: Diabetic 3rd nerve palsy: Evidence for a mesencephalic lesion. Neurology
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1991; 41:25–30.

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135.

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Editors: Afifi, Adel K.; Bergman, Ronald A.

Title: Functional Neuroanatomy: Text and Atlas, 2nd Edition

Copyright ©2005 McGraw-Hill

> Table of Contents > Part I - Text > 10 - Mesencephalon (Midbrain): Clinical Correlates

10
Mesencephalon (Midbrain): Clinical
Correlates

Mesencephalic Vascular Syndromes

Syndrome of Weber
Syndrome of Benedikt
Claude's Syndrome
Nothnagel's Syndrome
Plus-Minus Lid Syndrome
Parinaud's Syndrome
Walleyed Syndrome
Vertical One-and-a-Half Syndrome
Locked-in Syndrome
Top of the Basilar Syndrome
Peduncular Hallucinosis Syndrome
Akinetic Mutism
Decerebrate Rigidity

KEY CONCEPTS

The syndrome of Weber consists of oculomotor nerve paralysis

ipsilateral to the midbrain lesion and contralateral hemiplegia.

The syndrome of Benedikt consists of oculomotor nerve paralysis

ipsilateral to the midbrain lesion and contralateral tremor. Contralateral
hemianesthesia may occur.

Claude's syndrome consists of oculomotor nerve paralysis ipsilateral

to the midbrain lesion and contralateral ataxia and tremor.

Nothnagel's syndrome is variably described as consisting of bilateral

oculomotor nerve paralysis, ipsi- or contralateral gait ataxia, and
vertical gaze palsy.

Parinaud's syndrome consists of upgaze palsy, pupillary

abnormalities, lid retraction, and convergence retraction nystagmus on
upward gaze.

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The walleyed syndrome consists of exotropic gaze and an absence of

ocular adduction. This syndrome is also known as the walleyed bilateral
internuclear ophthalmoplegia (WEBINO) syndrome.

The vertical one-and-a-half syndrome consists of bilateral

impairment of downgaze and monocular paralysis of eye elevation. A
variant syndrome consists of bilateral impairment of upgaze and
monocular downgaze paralysis.

The locked-in syndrome consists of mute quadriplegia, preservations

of consciousness, and communication by ocular movement and blinking.

The top of the basilar syndrome consists of a variety of visual

defects, abnormalities of eye movements, pupillary abnormalities, and
behavioral disturbances. The peduncular hallucinosis syndrome consists
of hallucinations and somnolence.

Akinetic mutism characterized by complete immobility except in the

eyes occurs with lesions in the midbrain reticular formation.

Decerebrate rigidity is associated with midbrain lesions caudal to the

red nucleus, between it and the vestibular nuclei.

MESENCEPHALIC VASCULAR SYNDROMES

Midbrain infarcts have not been studied extensively. There have been only a few
reports of single cases, well described clinically and by magnetic resonance
imaging (MRI), of isolated midbrain infarcts (Table 10-1).

The most commonly affected region is the middle midbrain, and the most
frequently involved territory is the paramedian territory, followed by the posterior
cerebral artery territory and the territory intermediate between the two.
Involvement of the territory of the superior cerebellar artery is rare.

Patients with middle midbrain infarcts have a localizing clinical picture that is
linked to involvement of the third nerve or its nucleus. Paramedian infarcts are
associated with the nuclear syndrome of the oculomotor nerve, whereas more
lateral infarcts are associated with fascicular involvement of the third nerve in
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isolation or with contralateral hemiparesis (syndrome of Weber) or hemiataxia
(Claude's syndrome).

Table 10-1. Midbrain Vascular Syndromes

Syndrome Ipsilateral Contralateral Lesion site

Weber's Oculomotor Hemiparesis CN III, CP

palsy

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Benedikt Oculomotor Tremor ± hemi- CN III, RN ±

palsy anesthesia ML, ST

Claude's Oculomotor Tremor and CN III, RN, BC

palsy ataxia

Nothnagel's Oculomotor Oculomotor CN III, BC

palsy and ataxia palsy ± ataxia

Plus-minus Ptosis Lid retraction CN III fascicles

lid to the levator
syndrome palpebrae
muscle.
Nucleus of
posterior
commissure

Parinaud's Upward gaze paralysis Pretectal region

Pupillary abnormalities
Large pupil
Light-near dissociation
Covergence retraction nystagmus on
upgaze
Lid retraction (Collier's sign)

Walleyed Internuclear Internuclear MLF, bilateral

ophthalmoplegia ophthalmoplegia
(MLF syndrome) (MLF syndrome)

Vertical Downgaze palsy Downgaze palsy Efferents of

one-and-a- Monocular RiMLF, CBF
half elevation palsy

Locked-in Mute quadriplegia Ventral

mesencephalon

Peduncular Hallucinations, somnolence Tegmentum, CP

hallucinosis

NOTE: CN, cranial nerve; CP, cerebral peduncle; RN, red nucleus; BC,
brachium conjunctivum; ML, medial lemniscus; ST, spinothalamic tract;
MLF, medial longitudinal fasciculus; RiMLF, rostral interstitial nucleus of
the medial longitudinal fasciculus; CBF, corticobulbar fibers.

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Patients with rostral or caudal midbrain infarcts have a less localizing neurologic
picture except for vertical gaze impairment in those with dorsal rostral midbrain
infarcts. Ipsilateral trochlear nerve palsy, Horner's syndrome, and contralateral
ataxia point to the territory of the superior cerebellar artery. Hand-foot-mouth
hyperesthesia is due to involvement of the medial lemniscus and the ventral
ascending tract of the trigeminal nerve.

Syndrome of Weber
In the syndrome of Weber the patient presents with signs of ipsilateral
oculomotor nerve paralysis and contralateral upper motor neuron paralysis
that includes the lower face. The vascular lesion, usually an infarct, affects
rootlets of the oculomotor nerve and the underlying cerebral peduncle (Figure 10-
1). This syndrome was described by Adolph-Marie Gubler, a French physician,
about 4 years before Sir Herman David Weber, a German-English physician,
described the syndrome in 1863, and 17 years before Ernst Victor von Leyden, a
German physician, described a similar syndrome in 1875. The syndrome is
therefore referred to by some as the Gubler-Weber syndrome, Leyden paralysis,
and Leyden syndrome. Other synonyms include the cerebral peduncle syndrome,
hemiplegia alternans superior peduncularis, and syndrome of the cerebral
peduncle.

Syndrome of Benedikt
In the syndrome of Benedikt the patient presents with signs of ipsilateral
oculomotor nerve paralysis and contralateral tremor. The vascular lesion
affects rootlets of the oculomotor nerve within the tegmentum of the
mesencephalon and the underlying red nucleus (Figure 10-1). Contralateral
hemianesthesia has been described by some researchers and is attributed to
involvement of the medial lemniscus and spinotha-lamic tract. This syndrome was
first described by a Viennese physician, Moritz Benedikt, in 1889.

The tremor in this syndrome has been called rubral tremor on the basis of
damage to the red nucleus or the superior cerebellar peduncle. The tremor is
usually of low frequency and may have resting, postural, and kinetic components.
The kinetic component may be explained by the involvement of the superior
cerebellar peduncle or the red nucleus. The resting and postural components are
due to the involvement of dopaminergic nigrostriatal fibers that arise from the
pars compacta of the substantia nigra and run ventral to the red nucleus and
through field H of Forel (prerubral) on their way to the hypothalamus and
striatum. This component of the tremor responds well to treatment with
levodopa.

Claude's Syndrome
Described by the French psychiatrist and neurologist Henry Claude in 1912,
this syndrome is very rare. Claude's original case had midbrain infarction
that involved the medial half of the red nucleus, the adjacent decussating fibers
of superior cerebellar peduncle, and oculomotor nerve fascicles. Patients present
with ipsilateral oculomotor nerve palsy and contralateral tremor and ataxia.
Oculomotor nerve palsy is partial in most patients. The medial rectus is most
commonly involved, followed in order of frequency by the levator palpebrae,
superior rectus, inferior oblique, and inferior rectus. The pupil is spared in the
majority of patients. Although the tremor and ataxia are generally attributed to a
lesion in the red nucleus, it has recently been shown that the main pathology is

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in the superior cerebellar peduncle, just below and medial to the red nucleus, and
that the red nucleus contributes little to the syndrome. Infarction in the territory
of the anteromedial branches of the posterior cerebral artery is the cause of the
syndrome in the majority of patients.

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Nothnagel's Syndrome
Nothnagel's syndrome has been variably described by different authors. In
1879, Nothnagel, an Austrian physician, described a patient with bilateral
asymmetric oculomotor palsies of varying degree and gait ataxia. Subsequently,
the syndrome was variously described in patients with oculomotor nerve palsy
and ipsilateral or contralateral ataxia and patients with oculomotor nerve palsy
and vertical gaze palsy. The lesion in the original report involved the superior
and inferior colliculi. Subsequent reports described pathology in the oculomotor
nerve fascicles and the brachium conjunctivum. The syndrome may be regarded
as a variant of the dorsal midbrain (Parinaud's) syndrome or as Benedikt
syndrome with added vertical gaze palsy.

Figure 10-1. Schematic diagram showing lesions of the oculomotor nerve in

its intra- and extra-axial course and their respective clinical manifestations.

Plus-Minus Lid Syndrome

Described by Gaymard and colleagues in 1992, this syndrome consists of
unilateral ptosis and contralateral lid retraction due to a small lesion in the
rostral midbrain involving the nucleus of the posterior commissure and
oculomotor fascicles to the ipsilateral levator palpebrae muscle as they emerge
from the central caudal subnucleus. Ipsilateral ptosis is explained on interruption

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of oculomotor fascicles to the levator palpebrae. Lid retraction is explained on

overactivation of the contralateral levator palpebrae muscle due to loss of
inhibitory pathways for lid retraction from the nucleus of the posterior
commissure to the central caudal subnucleus.

Parinaud's Syndrome
Parinaud's syndrome is also known as the sylvian aqueduct syndrome, the dorsal
midbrain syndrome, Koerber-Salus-Elschnig syndrome, the pineal syndrome, and
the syndrome of the posterior commissure. The lesion is in the pretectal region.
Patients with this syndrome present with upward gaze paralysis, pupillary
abnormalities (large pupil, light-near dissociation), lid retraction (Collier's sign),
and convergence retraction nystagmus on upward gaze. This syndrome was
described in 1883 by Parinaud, who vaguely speculated about the lesion site.
Definitive localization of the lesion in the pretectal area resulted from
experimental and human observations made between 1969 and 1974 by Bender,
who coined the term pretectal syndrome.

Walleyed Syndrome
The walleyed syndrome is also known as the walleyed bilateral internuclear
ophthalmoplegia (WEBINO) syndrome. The lesion is bilateral and involves
the rostral medial longitudinal fasciculus. This syndrome is characterized by
lateral deviation of both eyes (exotropic gaze) and the absence of ocular
adduction.

Vertical One-and-a-Half Syndrome

The vertical one-and-a-half syndrome is characterized by bilateral
impairment of downgaze (the one) and monocular paralysis of elevation (the
half). The lesion usually consists of bilateral infarcts in the mesencephalic-
diencephalic region that involve efferent tracts of the rostral interstitial nucleus
of the medial longitudinal fasciculus (RiMLF) bilaterally and premotor fibers to the
contralateral superior rectus subnucleus and the ipsilateral inferior oblique
subnucleus before or after decussation in the posterior commissure. A variant of
this syndrome consists of bilateral impairment of upgaze (the one) with
monocular downgaze palsy (the half). The vertical one-and-a-half syndrome was
described by Deleu, Buisseret, and Ebinger in 1989.

Locked-in Syndrome
The locked-in syndrome is also known as the bilateral pyramidal system
syndrome. It is characterized by mute quadriplegia, preservation of
consciousness, and communication by vertical (not lateral) ocular movements and
blinking. In most patients
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the lesion is bilateral in the ventral half of the pons at or rostral to the level of
the abducens nuclei; in some patients the lesion may be bilateral in the ventral
mesencephalon or both internal capsules. The term locked-in syndrome was
proposed by Plum and Posner in 1987. This syndrome is also known as
pseudocoma, the de-efferented state, the ventral pontine or brain stem
syndrome, cerebromedullary disconnection, pontopseudocoma, the pontine
disconnection syndrome—and the Monte Cristo syndrome in reference to
Alexandre Dumas's novel The Count of Monte Cristo, in which the elderly Noirtier

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communicated only by eye blinks.

Top of the Basilar Syndrome

In the top of the basilar syndrome the lesion is not limited to the
mesencephalon but also involves other structures (the thalamus and
portions of the temporal and occipital cortices). The conglomerate signs and
symptoms of this syndrome include (1) visual defects such as hemianopia,
cortical blindness (loss of vision with intact pupillary light reflexes), and Balint's
syndrome (optic ataxia) caused by involvement of the occipital, parietal, and
temporal cortices, (2) abnormalities of eye movements, including vertical gaze
abnormalities, lid retraction (Collier's sign), and convergence disorder, (3)
pupillary abnormalities, including light-near dissociation and a small reactive or
large fixed pupil, (4) behavioral disturbances (somnolence, memory defects,
agitation, hallucination), and (5) motor and sensory deficits. The usual etiology
of this syndrome is occlusion of the rostral basilar artery.

Peduncular Hallucinosis Syndrome

The peduncular hallucinosis syndrome is characterized by nonthreatening
hallucinations, often formed nonstereotypically, colored, and vivid, that usually
occur in somnolent patients with presumed tegmental and cerebral peduncle
lesions. The symptoms probably arise from thalamic or occipitotemporal lesions
rather than from the midbrain. This condition was first described by Jean Jacques
Lhermitte, a French neurologist, in 1922 in a 75-year-old woman with midbrain
infarct whose hallucinations consisted of animals and people sharing the room
with her. The name was suggested by Ludo Van Bogaert, a Belgian neurologist, in
1924.

AKINETIC MUTISM
Various levels of unconsciousness occur in patients with lesions of the
mesencephalic reticular formation. Evidence from experimental work points
to a tonic role of the mesencephalic reticular formation in cortical excitability and
the maintenance of awareness. Bilateral limited lesions of the mesencephalic
reticular formation have been associated with akinetic mutism (Cairns syndrome),
a clinical condition characterized by absolute mutism and complete immobility
except for the eyes, which are kept open and move in all directions. The patient
appears awake and maintains a sleep-wake cycle, but no communication with the
patient through either painful or auditory stimuli can be established. The
condition was first reported by an Australian neurosurgeon, Sir Hugh Cairns, in
1941. This condition may result from injury to the mesencephalic reticular
formation caused by transtentorial brain herniation with edema, hemorrhage, or
occlusion of branches of the basilar artery. The condition is also known as
persistent vegetative state.

DECEREBRATE RIGIDITY
Decerebrate rigidity in humans results from lesions of the brain stem caudal
to the red nucleus and rostral to the vestibular nuclei. The body is forced
backward with the head bent extremely dorsally. The shoulders are internally
rotated, the elbows are extended, and the distal parts of the upper limbs are
hyperpronated with finger extension at the metacarpophalangeal joints and
flexion at the interphalangeal joints. The hips and knees are extended; the feet
and toes are plantar flexed. This syndrome is associated with severe head trauma

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and compression of the brain stem by herniation.

TERMINOLOGY
Balint's syndrome.
Also known as Balint-Holmes syndrome, ocular apraxia, optic ataxia, psychic
paralysis of visual fixation, and cortical paralysis of visual fixation. A rare
syndrome resulting from bilateral parieto-occipital disease and characterized by
an inability to direct the eyes to a certain point in the visual field despite intact
eye movements and vision. Discovered by Rudolph Balint, a Hungarian
neurologist, in 1909.

Claude's syndrome.
Described by a French psychiatrist and neurologist, Henri Claude, in 1912.

Collier's sign.
Bilateral lid retraction seen in the pretectal syndrome.

Horner's syndrome.
Drooping of the eyelid (ptosis), constriction of the pupil (miosis), retraction of
the eyeball (enophthalmos), and loss of sweating on the face (anhidrosis)
constitute a syndrome described by Johann Friedrich Horner, a Swiss
ophthalmologist, in 1869. The syndrome is caused by interruption of descending
sympathetic fibers. Also known as Bernard-Horner syndrome and
oculosympathetic palsy. The syndrome was described in animals by François du
Petit in 1727. Claude Bernard in France in 1862 and E. S. Hare in Great Britain in
1838 gave precise accounts of the syndrome before Horner did.

Koerber-Salus-Elschnig syndrome.
A syndrome of vertical gaze palsy, anisocoria (unequal pupil sizes), light-near
dissociation, conversion retraction nystagmus, lid retraction, impaired
convergence, skewed eye deviation, papilledema, and lid flutter associated most
commonly with pineal tumors or disorders of the pretectal region. Also known as
Parinaud's syndrome, the sylvian aqueduct syndrome, and the syndrome of the
posterior commissure. The best of the original descriptions was that of Salus in
1910.

Nothnagel's syndrome.
Described by Carl Wilhelm Hermann Nothnagel, an Austrian internist, neurologist,
and pathologist, in 1879.

Optic ataxia.
A rare syndrome resulting from bilateral parieto-occipital disease and
characterized by inability to direct the eyes to a certain point in the visual field
despite intact eye movements and vision. Also known as Balint's syndrome,
Balint-Holmes syndrome, and ocular apraxia.

Parinaud's syndrome.
Described by Henri Parinaud, a French neuro-ophthalmologist, in 1883.

Syndrome of Benedikt.
Described in a 4-year-old patient by Moritz Benedikt, an Austrian physician, in
1889.

Syndrome of Weber.
Named after Sir Herman David Weber, a German-English physician who described

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the syndrome in 1863.

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SUGGESTED READINGS
Balint R: Seelenlahmung des “Schauens,” optische Ataxia, raumliche storung
der Aufmerskameit. Monatsschr Psychiatr Neurol 1909; 25:51–81.

Benedikt M: Tremblement avec paralysie croisée du moteur oculaire commun.

Bull Soc Med Hop Paris 1889; 3:547–548.

Bogousslavsky J et al: Pure midbrain infarction: Clinical syndromes, MRI, and

etiologic patterns. Neurology 1994; 44:2032–2040.

Breen LA et al: Pupil-sparing oculomotor nerve palsy due to midbrain

infarction. Arch Neurol 1991; 48:105–106.

Cairns H et al: Akinetic mutism with an epidermoid cyst of the 3rd ventricle.
Brain 1941; 64:273–290.

Claude H: Syndrome pedunculaire de la region du noyau rouge. Rev Neurol

(Paris) 1912; 23:311–313.

Claude H, Loyez M: Ramollissement du noyau rouge. Rev Neurol (Paris) 1912;

24:49–51.

Deleu D et al: Vertical one-and-a-half syndrome: Supranuclear downgaze

paralysis with monocular elevation palsy. Arch Neurol 1989; 46:1361–1363.

Felice KJ et al: “Rubral” gait ataxia. Neurology 1990; 40:1004–1005.

Galetta SL et al: Unilateral ptosis and contralateral eyelid retraction from a

tha-lamic-midbrain infarction. J Clin Neuroophthalmol 1993; 13:221–224.

Gaymard B et al: Plus-minus lid syndrome. J Neurol Neurosurg Psychiatry

1992; 55:846–848.

Keane JR: The pretectal syndrome: 206 patients. Neurology 1990; 40:684–
690.

Liu GT et al: Midbrain syndromes of Benedikt, Claude, and Nothnagel: Setting

the record straight. Neurology 1992; 42:1820–1822.

Mehler MF: The neuro-ophthalmologic spectrum of the rostral basilar artery

syndrome. Arch Neurol 1988; 45:966–971.

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Nothnagel H: Topische diagnostik der Gehirnkrankheiten. Berlin, Hischwalden,

1879:220.

Parinaud H: Paralysie des mouvements associés des yeux. Arch Neurol (Paris)
1883; 5:145–172.

Plum F, Posner JB: The Diagnosis of Stupor and Coma. Philadelphia, Davis,
1987.

Pryse-Phillips W: Companion to Clinical Neurology. Boston, Little, Brown,

1995.

Ranalli PJ et al: Palsy of upward and downward saccadic, pursuit, and

vestibular movements with a unilateral midbrain lesion: Pathophysiologic
correlation. Neurology 1988; 38:114–122.

Salus R: Acquired retraction movements of the globe. Arch Augenheilk 1910;

68:61–67.

Seo SW et al: Localization of Claude's syndrome. Neurology 2001; 57:2304–

2307.

Weber HD: A contribution to the pathology of the crura cerebri. Med Chir
Trans 1863; 46:121–139.

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Editors: Afifi, Adel K.; Bergman, Ronald A.

Title: Functional Neuroanatomy: Text and Atlas, 2nd Edition

Copyright ©2005 McGraw-Hill

> Table of Conte nts > Pa rt I - Te xt > 11 - Dien ceph alon

11
Diencephalon

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Gross Topography
Divisions of Diencephalon
Epithalamus
Thalamus (Dorsal Thalamus) and Metathalamus
Internal Capsule
Subthalamus

KEY CONCEPTS

The term diencephalon includes the following structures: epithalamus, thalamus (including the metathalamus),
hypothalamus, and subthalamus.

Based on their rostrocaudal and mediolateral location, thalamic nuclei are divided into the following groups:
anterior, medial, lateral, intralaminar and reticular, midline, and posterior.

The anterior group of thalamic nuclei have reciprocal connections with the mamillary bodies and cingulate gyrus.
They belong to the modality-specific and limbic group of thalamic nuclei.

The medial group of thalamic nuclei have a reciprocal relationship with the prefrontal cortex. They belong to the
multimodal associative group of thalamic nuclei and play a role in affective behavior, memory, and the integration of
somatic visceral activities.

The pulvinar and lateral posterior nuclei form a single nuclear complex based on their anatomic connections and
functions. The pulvinar–lateral posterior complex links subcortical visual areas with the association cortical visual
areas. The pulvinar–lateral posterior complex belongs to the multimodal associative group of thalamic nuclei.

The ventral anterior nucleus links the basal ganglia and the cerebral cortex. It belongs to the modality-specific
and motor groups of thalamic nuclei.

The ventral lateral nucleus links the cerebellum with the cerebral cortex. It belongs to the modality-specific and
motor groups of thalamic nuclei.

The ventral posterior lateral nucleus links the somatosensory (medial lemniscus and spinothalamic) neural system
from the contralateral half of the body with the somatosensory cortex.

The ventral posterior medial nucleus links the somatosensory neural system from the contralateral face (tri-
geminothalamic) and taste system with the somatosensory cortex.

The intralaminar, reticular, and midline nuclei belong to the nonspecific system of thalamic nuclei. They are
concerned with arousal, motor control, and the awareness of sensory experiences.

The medial geniculate nucleus is a relay station in the auditory pathway. It belongs to the modality-specific and
sensory groups of thalamic nuclei.

The lateral geniculate nucleus is a relay station in the visual pathway. It belongs to the modality-specific and
sensory groups of nuclei.

The posterior thalamic nucleus belongs to the multimodal associative group of thalamic nuclei. It is a convergence
center for multimodal sensory modalities.

Based on their neural connectivity, thalamic nuclei are grouped into the following categories: modality-specific,
multimodal associative, nonspecific, and reticular.

Based on their function, thalamic nuclei are grouped into the following categories: motor, sensory, and limbic.

Vascular lesions in the posterior limb of the internal capsule are associated with contralateral hemiplegia and
hemisensory loss. Lesions that involve the visual and auditory radiations are in addition associated with contralateral
visual loss and hearing deficit. Lesions that involve the genu are associated with cranial nerve signs.

The thalamus receives its blood supply from four parent vessels: basilar, posterior cerebral, posterior
communicating, and internal carotid.

Vascular lesions in the thalamus are associated with a characteristic pain syndrome, the thalamic syndrome.

Lesions of the subthalamic nucleus or of the subthalamopallidal pathways are associated with contralateral
hemiballismus.

The H fields of Forel contain pallidal and cerebellar efferents to the thalamus.

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GROSS TOPOGRAPHY (Figures 11-1, 11-2, and A5-17)

The diencephalon, or “in-between brain,” is completely surrounded by the cerebral hemispheres except at its ventral surface. It
is limited posteriorly by the posterior commissure and anteriorly by the lamina terminalis and the foramen of Monro. The
posterior limb of the internal capsule limits the diencephalon laterally. Medially, the diencephalon forms the lateral wall of the
third ventricle. The dorsal surface forms the floor of the lateral ventricle and is marked medially by a band of nerve fibers, the
stria medullaris thalami. The ventral surface contains hypothalamic structures. A groove extending between the foramen of
Monro and the aqueduct of Sylvius (the hypothalamic sulcus) divides the dienceph-alon into a dorsal portion, the thalamus, and
a ventral portion, the hypothalamus. The two thalami are connected across the midline in about 70 percent of humans through
the interthalamic adhesion (massa intermedia). The diencephalon develops from the caudal vesicle of the embryologic

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prosencephalon.

DIVISIONS OF DIENCEPHALON
The diencephalon is divided into four major subdivisions. These are (1) the epithalamus, (2) the thalamus and
metathalamus, (3) the subthalamus, and (4) the hypothalamus. The first three subdivisions will be discussed in this
chapter. The fourth subdivision, the hypothalamus, will be discussed in Chapter 19.

Epithalamus
The epithalamus occupies a position dorsal to the thalamus and includes the following structures (Figure 11-1).

A. STRIA MEDULLARIS THALAMI

This band of nerve fibers courses dorsomedial to the thalamus and connects the septal (medial olfactory) area, located
underneath the rostral end of the corpus callosum in the frontal lobe, with the habenular nuclei.

B. HABENULAR NUCLEI
These nuclei are located in the caudal diencephalon; one is on each side, dorsomedial to the thalamus. They receive the stria
medullaris and project via the habenulo-interpeduncular tract (fasciculus retroflexus of Meynert) to the interpeduncular nucleus
of the midbrain. The two habenular nuclei are connected by the habenular commissure. The habenular nuclei, part of a neural
network that includes the limbic and olfactory systems, are concerned with mechanisms of emotion and behavior.

Figure 11-1. Schematic diagram showing the subdivisions of the diencephalon as seen in a midsagittal view.

Figure 11-2. Schematic diagram showing the subdivisions of the diencephalon as seen in a composite coronal view.

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C. PINEAL GLAND
This endocrine gland is located just rostral to the superior colliculi in the roof of the third ventricle. The functions of the pineal
gland are not well understood. It may have roles in gonadal function and circadian rhythm. It secretes the biogenic amines
serotonin, norepinephrine, and melatonin and contains several hypothalamic peptides including thyrotropin-releasing hormone
(TRH), leuteinizing hormone–releasing hormone (LHRH), and somatostatin–release inhibitory factor (SRIF). It synthesizes
melatonin from serotonin in a rhythmic fashion that fluctuates with the daily cycle of light. The pineal gland usually calcifies
after the age of 16 years. This fact is used in the detection of midline shifts in skull x-rays. In normal skull x-rays, pineal
calcifications are seen in the midline. Shifts of pineal calcification away from the midline suggest the presence of space-
occupying lesions displacing the pineal. Such a lesion could be blood in the subdural or epidural space, a hematoma within the
brain, or a brain tumor. Pineal gland tumors (pinealomas) depress gonadal function and delay the onset of puberty. In
contrast, lesions that destroy the pineal gland may be associated with precocious onset of puberty, suggesting that the pineal
gland exerts an inhibitory influence on gonadal function. Tumors in the region of the pineal gland usually interfere with vertical

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gaze. This loss of vertical gaze, known as Parinaud's syndrome, results from pressure of the pineal lesion on the pretectal area
and/or the posterior commissure.

Thalamus (Dorsal Thalamus) and Metathalamus

The term thalamus derives from a Greek word that means “inner chamber.” Use of the terms optic thalamus and chamber of
vision relates to the tracing, in the second century A.D., of optic nerve fibers to the thalamus by Galen. The prefix optic was
dropped when it was discovered that sensory modalities other than vision are also processed in the thalamus.

The thalamus is the largest component of the diencephalon, with a rostrocaudal dimension in humans of about 30 mm, height
of about 20 mm, width of about 20 mm, and an estimated 10 million neurons in each hemisphere. It is subdivided into the
following major nuclear groups (Figure 11-3) on the basis of their rostrocaudal and mediolateral location within the thalamus:

1. Anterior

2. Medial

3. Lateral

4. Intralaminar and reticular

5. Midline

6. Posterior

The thalamus is traversed by a band of myelinated fibers, the internal medullary lamina, which runs along the rostrocaudal
extent of the thalamus. The internal medullary lamina separates the medial from the lateral group of nuclei. Rostrally and
caudally, the internal medullary lamina splits to enclose the anterior and intralaminar nuclear groups, respectively. The
internal medullary lamina contains intrathalamic fibers connecting the different nuclei of the thalamus with each other. Another
medullated band, the external medullary lamina, forms the lateral boundary of the thalamus medial to the internal capsule.
Between the external medullary lamina and the internal capsule is the reticular nucleus of the thalamus. The external
medullary lamina contains nerve fibers leaving or entering the thalamus on their way to or from the adjacent capsule.

Literature on the thalamus in general, and on thalamic surgery in particular, is difficult to read because different
nomenclatures are in use. Most available nomenclatures are derived from studies in primates. The different nomenclatures are
based either on the cytoarchitectonic definition of nuclei or on their subcortical afferents. Human thalamic nomenclature is
based
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entirely on cytoarchitectonic subdivisions and on transfer of knowledge by analogy from monkey to human. Problems, however,
have arisen when trying to transfer the detailed knowledge from the monkey to the human brain.

Figure 11-3. Schematic diagram showing the major nuclear groups of the thalamus.

A. ANTERIOR NUCLEAR GROUP

The anterior tubercle of the thalamus (dorsal surface of the most rostral part of the thalamus) is formed by the anterior
nuclear group. In humans, the anterior nuclear group of tha-lamic nuclei consists of two nuclei: principal anterior and
anterodorsal. The principal anterior nucleus of humans corresponds to the anteromedial and anteroventral nuclei of other
species. The anterior group of thalamic nuclei has reciprocal connections (Figure 11-4) with the hypothalamus (mamillary
bodies) and the cerebral cortex (cingulate gyrus). The anterior group also receives significant input from the hippocampal
formation of the cerebral cortex (subiculum and presubiculum) via the fornix.

The reciprocal fibers between the anterior thalamic nuclear group and the mamillary bodies travel via the mamillothalamic tract
(tract of Vicq d'Azyr). The projections from the mamillary bodies to the anterior group of thalamic nuclei is topographically
organized such that the medial mamillary nucleus projects to the ipsilateral principal anterior nucleus, whereas the lateral
mamillary nucleus projects to both anterodorsal nuclei. The reciprocal connections between the anterior nuclear group and the
cingulate gyrus accompany the anterior limb of the internal capsule. The projection from the anterior thalamic group to the
cingulate gyrus is topographically organized such that the medial part of the principal anterior nucleus projects to rostral parts
of the cingulate gyrus, whereas the lateral part of the principal nucleus and the anterodorsal nucleus project to caudal parts of
the cingulate gyrus. The anterior nuclear group of the thalamus is part of the limbic system, which is concerned with emotional
behavior and memory mechanisms. Discrete damage to the mamillothalamic tract has been associated with deficits in a specific

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type of memory, episodic long-term memory, with relative sparing of short-term memory and intellectual capacities.

B. MEDIAL NUCLEAR GROUP

Of the medial nuclear group, the dorsomedial nucleus is the most highly developed in humans. In histologic sections
stained for cells, three divisions of the dorsomedial nucleus are recognized: a dorsomedial magnocellular division located
rostrally, a dorsolateral parvicellular division located caudally, and a paralaminar division adjacent to the internal medullary
lamina. The dorsomedial nucleus develops in parallel with and is reciprocally connected with the prefrontal cortex (areas 9, 10,
11, and 12), via the anterior thalamic peduncle, and the frontal eye fields (area 8) (Figure 11-5). It also receives inputs from
the temporal neocortex (via the inferior thalamic peduncle), amygdaloid nucleus and substantia nigra pars reticulata, and
adjacent thalamic nuclei, particularly the lateral and intralaminar groups. The dorsomedial nucleus belongs to a neural
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system concerned with affective behavior, decision making and judgment, memory, and the integration of somatic and visceral
activity. Bilateral lesions of the dorsomedial nucleus result in a syndrome of lost physical self-activation, manifested by
apathy, indifference, and poor motivation. The reciprocal connections between the prefrontal cortex and the dorsomedial
nucleus can be interrupted surgically to relieve severe anxiety states and other psychiatric disorders. This operation, known as
prefrontal lobotomy (ablation of prefrontal cortex) or prefrontal leukotomy (severance of the prefrontal-dorsomedial nucleus
pathway), is rarely practiced nowadays, having been replaced largely by medical treatment that achieves the same result
without undesirable side effects.

Figure 11-4. Schematic diagram showing the reciprocal connections among the anterior nucleus of the thalamus,
mamillary body, and cingulate gyrus.

C. LATERAL NUCLEAR GROUP

The lateral nuclear group of the thalamus is subdivided into two groups, dorsal and ventral.

1. Dorsal Subgroup
This subgroup includes, from rostral to caudal, the lateral dorsal, lateral posterior, and pulvinar nuclei. The lateral dorsal
nucleus, although anatomically part of the dorsal tier of the lateral group of thalamic nuclei, is functionally part of the anterior
group of thalamic nuclei, with which it collectively forms the limbic thalamus. Similar to the anterior group of thalamic nuclei,
the lateral dorsal nucleus receives inputs from the hippocampus (via the fornix) and an uncertain input from the mamillary
bodies and projects to the cingulate gyrus. In histologic sections stained for myelin, the lateral dorsal nucleus is characterized
by a distinct capsule of myelinated fibers surrounding it.

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Figure 11-5. Schematic diagram showing the major afferent and efferent connections of the dorsomedial nucleus of the
thalamus.

The borderline between the lateral posterior nucleus and the pulvinar nucleus is vague, and the term pulvinar–lateral posterior
complex has been used to refer to this nuclear complex.

The pulvinar–lateral posterior complex has reciprocal connections caudally with the lateral geniculate body and rostrally
with the association areas of the parietal, temporal, and occipital cortices (Figure 11-6). It also receives inputs from the
pretectal area and superior colliculus. The pulvinar is thus a relay station between subcortical visual centers and their
respective association cortices in the temporal, parietal, and occipital lobes. The pulvinar has a role in selective visual
attention. There is evidence that the pulvinar nucleus plays a role in speech mechanisms. Stimulation of the pulvinar nucleus
of the dominant hemisphere
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has produced anomia (nominal aphasia). The pulvinar nucleus also has been shown to play a role in pain mechanisms. Lesions
in the pulvinar nucleus have been effective in the treatment of intractable pain. Experimental studies have demonstrated
connections between the pulvinar nucleus and several cortical and subcortical areas concerned with pain mechanisms.

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Figure 11-6. Schematic diagram showing the major afferent and efferent connections of the pulvinar.

The pulvinar–lateral posterior complex and the dorsomedial nucleus are known collectively as multimodal association tha-lamic
nuclei. They all have the following in common:

1. They do not receive a direct input from the long ascending tracts.

2. Their input is mainly from other thalamic nuclei.

3. They project mainly to the association areas of the cortex.

2. Ventral Subgroup
This subgroup includes the ventral anterior, ventral lateral, and ventral posterior nuclei. The neural connectivity and functions
of this subgroup are much better understood than those of the dorsal subgroup. In contrast to the dorsal subgroup, which
belongs to the multimodal association thalamic nuclei, the ventral subgroup belongs to the modality-specific thalamic nuclei.
These nuclei share the following characteristics:

1. They receive a direct input from the long ascending tracts.

2. They have reciprocal relationships with specific cortical areas.

3. They degenerate on ablation of the specific cortical area to which they project.

a. Ventral anterior nucleus

This is the most rostrally placed of the ventral subgroup. It receives fibers from several sources (Figure 11-7).

Globus pallidus. A major input to the ventral anterior nucleus is from the internal segment of globus pallidus. Fibers
from the globus pallidus form the ansa and lenticular fasciculi and reach the nucleus via the thalamic fasciculus.
Pallidal fibers terminate in the lateral portion of the ventral anterior nucleus.

Substantia nigra pars reticulata. Nigral afferents terminate in the medial portion of the nucleus in contrast to the pallidal
afferents, which terminate in its lateral portion.

Intralaminar thalamic nuclei.

Premotor and prefrontal cortices (areas 6 and 8)

The inputs from globus pallidus and substantia nigra are GABAergic inhibitory. The inputs from the cerebral cortex are
excitatory.

The major output of the ventral anterior nucleus goes to the premotor cortices and to wide areas of the prefrontal cortex,
including the frontal eye fields. It also has reciprocal connections with the intralaminar nuclei. A projection to the primary
motor cortex has been described.

Thus the ventral anterior nucleus is a major relay station in the motor pathways from the basal ganglia to the cerebral cortex.
As such, it is involved in the regulation of movement. The medial (magnocellular) part of the ventral anterior nucleus is
concerned with control of voluntary eye, head, and neck movements. The lateral (parvicellular) part of the nucleus is
concerned with control of body and limb movements. Lesions in this nucleus and adjacent areas of the thalamus have been

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placed surgically (thalamotomy) to relieve disorders of movement, especially parkinsonism.

Figure 11-7. Schematic diagram showing the major connections of the ventral anterior nucleus of the thalamus.

b. Ventral lateral nucleus

This nucleus is located caudal to the ventral anterior nucleus and, similar to the latter, plays a major role in motor integration.
The ventral anterior and ventral lateral nuclei together comprise the motor thalamus. The afferent fibers to the ventral lateral
nucleus come from the following sources (Figure 11-8).

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Figure 11-8. Schematic diagram showing the major afferent and efferent connections of the nucleus ventralis lateralis of
the thalamus.

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Deep cerebellar nuclei. The dentatothalamic system constitutes the major input to the ventral lateral nucleus. As detailed
in Chapter 15, this fiber system originates in the deep cerebellar nuclei (mainly dentate), leaves the cerebellum via the
superior cerebellar peduncle, and decussates in the mesencephalon. Some fibers synapse in the red nucleus, while others
bypass it to reach the thalamus.

Globus pallidus (internal segment). Although the pallidotha-lamic fiber system projects primarily on ventral anterior
neurons, some fibers reach the anterior (oral) portion of the ventral lateral nucleus.

Primary motor cortex. There is a reciprocal relationship between the primary motor cortex (area 4) and the ventral lateral
nucleus.

The efferent fibers of the ventral lateral nucleus go primarily to the primary motor cortex in the precentral gyrus. Other
cortical targets include nonprimary somatosensory areas in the parietal cortex (areas 5 and 7) and the premotor and
supplementary motor cortices. The parietal cortical targets play a role in decoding sensory stimuli that provide spatial
information for targeted movements.

Thus the ventral lateral nucleus, like the ventral anterior nucleus, is a major relay station in the motor system linking the
cerebellum, the basal ganglia, and the cerebral cortex. Deep cerebellar nuclei have been shown to project exclusively to
ventral lateral thalamic nuclei, whereas the projection from the globus pallidus targets mainly the ventral anterior nucleus.
Physiologic studies have shown that the cerebellar and pallidonigral projection zones in the thalamus are separate; very few
cells have been identified that respond to both cerebellar and pallidonigral stimulation.

As in the case of the ventral anterior nucleus, lesions in the ventral lateral nucleus have been produced surgically to relieve
disorders of movement manifested by tremor. Physiologic re-cordings during surgical procedures (thalamotomy) for relief of
parkinsonian tremor have identified four types of neurons in the ventral thalamic nuclear group (Table 11-1): (1) cells with
activity related to somatosensory stimulation (sensory cells), (2) cells with activity related to active movement (voluntary
cells), (3) cells with activity related to both somatosensory stimulation and active movement (combined cells), and (4) cells
with activity related to neither somatosensory stimulation nor active movement (no-response cells). Combined voluntary and
no-response cells are located in the region of the thalamus, where a lesion will stop tremor, and anterior to the region, where
sensory cells were found. These findings suggest that thalamic cells unresponsive to somatosensory stimulation (voluntary and
no-response cells) and those responsive to somatosensory stimulation (combined cells) are involved in the mechanism of
parkinsonian tremor. Activity in sensory cells lags behind tremor, while activity of combined cells leads the tremor.

c. Ventral posterior nucleus

This nucleus is located in the caudal part of the thalamus. It receives the long ascending tracts conveying sensory
modalities (including taste) from the contralateral half of the body and face. These tracts (Figure 11-9) include the medial
lemniscus, trigeminal lemniscus (secondary trigeminal tracts), and spinothalamic tract.

Vestibular information is relayed to the cortex via the ventral posterior as well as the intralaminar and posterior group of
thalamic nuclei.

The ventral posterior nucleus is made up of two parts: the ventral posterior medial (VPM) nucleus, which receives the

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trigeminal lemniscus and taste fibers, and the ventral posterior lateral (VPL) nucleus, which receives the medial lemniscus and
spinothalamic tracts. Both nuclei also receive input from the primary somatosensory cortex. A visceral nociceptive input to the
VPL has been described. The VPL nucleus is divided into two subnuclei: pars oralis (VPL o ) and pars caudalis (VPL c ). Pars oralis
is functionally a part of the ventral lateral nucleus (motor function)
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and like VL receives input from the cerebellum and projects to the primary motor cortex.

Table 11-1. Motor Thalamus Cell Population

Activation

Cell type Active movement Somatosensory stimulation

Voluntary cells a + -

Sensory cells - +

Combined cells b + +

No-response cell - -

a Cells involved in parkinsonian tremor.

b Site of tremor-relieving lesion.

Figure 11-9. Schematic diagram showing the major afferent and efferent connections of the ventral posterior lateral and
ventral posterior medial nuclei of the thalamus.

The output from both nuclei is to the primary somatosensory cortex (SI) in the postcentral gyrus (areas 1, 2, and 3). The
projection to the cortex is somatotopically organized in such a way that fibers from the ventral posterior medial nucleus project
to the face area, while different parts of the ventral posterior lateral nucleus project to corresponding areas of body
representation in the cortex. A cortical projection from the part of the ventral posterior medial nucleus that receives taste
fibers to the parietal operculum (area 43) has been demonstrated.

A group of cells located ventrally between the ventral posterior lateral and ventral posterior medial nuclei comprises the
ventral posterior inferior (VPI) nucleus. Cells in this nucleus provide the major thalamic projection to somatosensory area II
(SII).

The ventral posterior lateral and ventral posterior medial nuclei are collectively referred to as the ventrobasal complex.

D. INTRALAMINAR, MIDLINE, AND RETICULAR NUCLEI

The intralaminar nuclei, as their name suggests, are enclosed within the internal medullary lamina in the caudal thalamus. The
reticular nuclei occupy a position between the external medullary lamina and the internal capsule (Figure 11-3).

1. Intralaminar Nuclei
The intralaminar nuclei include several nuclei, divided into caudal and rostral groups. The caudal group includes the
centromedian and parafascicular nuclei, which are the most important functionally in humans. The rostral group includes the

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paracentral, centrolateral, and centromedial nuclei. The intralaminar nuclei have the following afferent and efferent
connections.

1. Afferent connections (Figure 11-10)

Fibers projecting on the intralaminar nuclei come from the following sources.

(1) Reticular formation of the brain stem

This constitutes the major input to the intralaminar nuclei.

(2) Cerebellum
The dentatorubrothalamic system projects on the ventral lateral nucleus of the thalamus. Collaterals of this system project on
the intralaminar nuclei.

(3) Spinothalamic and trigeminal lemniscus

Afferent fibers from the ascending pain pathways project largely on the ventral posterior nucleus but also on the intralaminar
nuclei.

Figure 11-10. Schematic diagram showing the major afferent and efferent connections of the intralaminar nuclei of the
thalamus.

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(4) Globus pallidus

Pallidothalamic fibers project mainly on the ventral anterior nucleus. Collaterals of this projection reach the intralaminar
nuclei.

(5) Cerebral cortex

Cortical fibers arise primarily from the motor and premotor areas. Fibers originating in the motor cortex (area 4) terminate on
neurons in the centromedian, paracentral, and centrolateral nuclei. Those originating from the premotor cortex (area 6)
terminate on the parafascicular and centrolateral nuclei. In contrast to other tha-lamic nuclei, the connections between the

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intralaminar nuclei and cerebral cortex are not reciprocal.

(6) Other Afferent Connections

Retrograde transport studies of horseradish peroxidase have identified afferent connections to the intralaminar nuclei from the
vestibular nuclei, periaqueductal gray matter, superior colliculus, pretectum, and the locus ceruleus.

2. Efferent Connections
The intralaminar nuclei project to the following structures.

(1) Other thalamic nuclei

The intralaminar nuclei influence cortical activity through other thalamic nuclei. There are no direct cortical connections for the
intralaminar nuclei. One exception has been demonstrated, with both the horseradish peroxidase technique and
autoradiography showing a direct projection from one of the intralaminar nuclei (centrolateral) to the primary visual cortex
(area 17). The significance of this finding is twofold. First, it shows that intralaminar nuclei, contrary to previous concepts, do
project directly to cortical areas. Second, it explains the reported response of area 17 neurons to nonvisual stimuli (e.g.,
pinprick or sound); such responses would be mediated through the intralaminar nuclei.

(2) The striatum (caudate and putamen)

The striatal projection is topographically organized such that the centromedian nucleus projects to the putamen and the
parafascicular nucleus to the caudate nucleus.

2. Midline Nuclei
Consist of numerous cell groups, poorly developed in humans, located in the medial border of the thalamus along the banks of
the third ventricle. They include the paraventral, central, and reunien nuclei. Their input includes projections from the
hypothalamus, brain stem nuclei, amygdala, and parahippocampal gyrus. Their output is to the limbic cortex and ventral
striatum. They have a role in emotion, memory, and autonomic function.

The intralaminar and midline nuclei comprise the nonspecific thalamic nuclear group.

3. Reticular Nuclei
The reticular nucleus is a continuation of the reticular formation of the brain stem into the diencephalon. It receives inputs
from the cerebral cortex and other thalamic nuclei. The former are collaterals of corticothalamic projections, and the latter are
collaterals of thalamocortical projections. The reticular nucleus projects to other thalamic nuclei. The inhibitory
neurotransmitter in this projection is gamma-aminobutyric acid (GABA). The reticular nucleus is unique among thalamic nuclei
in that its axons do not leave the thalamus. Based on its connections, the reticular nucleus plays a role in integrating and
gating activities of thalamic nuclei.

Thus the intralaminar nuclei and reticular nucleus collectively receive fibers from several sources, motor and sensory, and
project diffusely to the cerebral cortex (through other thalamic nuclei). Their multisource inputs and diffuse cortical
projections enable them to play a role in the cortical arousal response. The intralaminar nuclei, by virtue of their basal ganglia
connections, are also involved in motor control mechanisms, and by virtue of the input from ascending pain-mediating
pathways, they are also involved in the awareness of painful sensory experience. The awareness of sensory experience in the
intralaminar nuclei is poorly localized and has an emotional quality, in contrast to cortical awareness, which is well localized.

E. METATHALAMUS
The term metathalamus refers to two thalamic nuclei, the medial geniculate and lateral geniculate.

1. Medial Geniculate Nucleus

This is a relay thalamic nucleus in the auditory system. It receives fibers from the lateral lemniscus directly or, more
frequently, after a synapse in the inferior colliculus. These auditory fibers reach the medial geniculate body via the
brachium of the inferior colliculus (inferior quadrigeminal brachium). The medial geniculate nucleus also receives feedback
fibers from the primary auditory cortex in the temporal lobe. The efferent outflow from the medial geniculate nucleus forms the
auditory radiation of the internal capsule (sublenticular part) to the primary auditory cortex in the temporal lobe (areas 41 and
42). Small hemorrhagic infarctions in the medial geniculate nucleus are associated with auditory illusions such as hyperacusis
and palinacusis and complete extinction of the contralateral ear input. The medial geniculate may have roles in spectral
analysis of sound, sound pattern recognition, auditory memory, and localization of sound in space, in addition to matching
auditory information with other modalities.

2. Lateral Geniculate Nucleus

This is a relay thalamic nucleus in the visual system. It receives fibers from the optic tract conveying impulses from both
retinae. The lateral geniculate nucleus is laminated, and the inflow from each retina projects on different laminae
(ipsilateral retina to laminae II, III, and V; contralateral retina to laminae I, IV, and VI). Feedback fibers also reach the
nucleus from the primary visual cortex (area 17) in the occipital lobes. The efferent outflow from the lateral geniculate nucleus
forms the optic radiation of the internal capsule (retrolenticular part) to the primary visual cortex in the occipital lobe. Some of
the efferent outflow projects to the pulvinar nucleus and to the secondary visual cortex (areas 18 and 19). Thalamic nuclei and
their cortical targets are illustrated in Figure 11-11.

F. POSTERIOR THALAMIC NUCLEAR GROUP

This group embraces the caudal pole of the ventral posterior group of thalamic nuclei medial to the pulvinar nucleus and
extends caudally to merge with the medial geniculate body and the gray matter medial to it. It receives inputs from all
somatic ascending tracts (medial lemniscus and spinothalamic), as well as from the auditory pathways and possibly the visual
pathways. Neurons in this part of the thalamus are multimodal and respond to a variety of stimuli. The outflow from the
posterior group projects to the association cortices in the parietal, temporal, and occipital lobes. The posterior nuclear group is
thus a convergence center for varied sensory modalities. It lacks the modal and spatial specificity of the classic ascending
sensory systems but allows for interaction among the divergent sensory systems that project on it. Unlike the specific sensory

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thalamic nuclei, the posterior group does not receive reciprocal feedback connections from the cerebral cortex.

G. NOMENCLATURE
There are several nomenclature systems for thalamic nuclei based on shared features of fiber connectivity and function.
Two such
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nomenclature systems are used commonly. The first nomenclature system groups thalamic nuclei into three general categories:
(1) modality-specific, (2) multimodal associative, and (3) nonspecific and reticular. The modality-specific group of nuclei
shares the following features in common: (1) they receive direct inputs from long ascending tracts concerned with
somatosensory, visual, and auditory information (ventral posterior lateral and medial, lateral geniculate, medial geniculate) or
else process information derived from the basal ganglia (ventral anterior, ventral lateral), the cerebellum (ventral lateral), or
the limbic system (anterior, lateral dorsal); (2) they have reciprocal connections with well-defined cortical areas (primary
somatosensory, auditory, and visual areas, premotor and primary motor areas, cingulate gyrus); and (3) they undergo
degeneration on ablation of the specific cortical area to which they project.

Figure 11-11. Schematic diagram of thalamic nuclei and their cortical targets. A, anterior nucleus; DM, dorsomedial
nucleus; IML, internal medullary lamina; LP, lateral posterior nucleus; Pul, pulvinar nucleus; MG, medial geniculate
nucleus; LG, lateral geniculate nucleus; VP, ventral posterior nucleus; VL, ventral lateral nucleus, VA, ventral anterior
nucleus; CC, corpus callosum.

The multimodal associative group, in contrast, receives no direct inputs from long ascending tracts and projects to association
cortical areas in the frontal, parietal, and temporal lobes. These nuclei include the dorsomedial nucleus and the pulvinar–
lateral posterior nuclear complex.

The nonspecific and reticular group of nuclei are characterized by diffuse and widespread indirect cortical projections and by
inputs from the brain stem reticular formation. These nuclei include the intralaminar, midline, and reticular nuclei.

Low-frequency stimulation of the modality-specific thalamic nuclei results in a characteristic cortical response known as the
augmenting response. This response consists of a primary excitatory postsynaptic potential (EPSP) followed by augmentation of
the amplitude and latency of the primary EPSP recorded from the specific cortical area to which the modality-specific nucleus
projects.

Stimulation of the nonspecific nuclear group, on the other hand, gives rise to the characteristic recruiting response in the
cortex. This is a bilateral generalized cortical response (in contrast to the localized augmenting response) characterized
by a predominantly surface-negative EPSP that increases in amplitude and, with continued stimulation, will wax and wane.

The other nomenclature system groups thalamic nuclei into the following categories: (1) motor, (2) sensory, (3) limbic, (4)
associative, and (5) nonspecific and reticular. The motor group receives motor inputs from the basal ganglia (ventral anterior,
ventral lateral) or the cerebellum (ventral lateral) and projects to the premotor and primary motor cortices. The sensory group
receives inputs from ascending somatosensory (ventral posterior lateral and medial), auditory (medial
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geniculate), and visual (lateral geniculate) systems. The limbic group is related to limbic structures (mamillary bodies,
hippocampus, cingulate gyrus). The associative and nonspecific and reticular groups correspond to the same groupings in the
other nomenclature system. Table 11-2 combines the two nomenclature systems.

H. NEUROTRANSMITTERS AND NEUROPEPTIDES

The following neurotransmitters have been identified in the thalamus: (1) GABA is the inhibitory neurotransmitter in terminals
from the globus pallidus, in local circuit neurons, and in projection neurons of the reticular nucleus and lateral geniculate
nucleus; and (2) glutamate and aspartate are the excitatory neurotransmitters in corticothalamic and cerebellar terminals and
in thalamocortical projection neurons. Several neuropeptides have been identified in terminals of long ascending tracts. They
include substance P, somatostatin, neuropeptide Y, en-kephalin, and cholecystokinin.

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I. NEURONAL CIRCUITRY
Thalamic nuclei contain two types of neurons. The predominant type is the principal (projection) neuron, whose axon projects
on extrathalamic targets. The other neuron is the local-circuit interneuron. Inputs to thalamic nuclei from subcortical and
cortical sites facilitate both the projection and local-circuit neurons, the neurotransmitter being glutamate or aspartate. An
exception to this is the subcortical input from the basal ganglia, which is inhibitory GABAergic. The local-circuit neuron, in
turn, inhibits the projection neuron. The neurotransmitter is GABA. Thus afferent inputs to the thalamus influence projection
(thalamocortical) neurons via two pathways: a direct excitatory pathway and an indirect (via the local-circuit neuron)
inhibitory pathway (Figure 11-12). The local-circuit neuron thus modulates activity of the projection neuron. Projection
neurons send their axons to the extrathalamic targets (cerebral cortex, striatum). Neurons in the reticular nucleus act like
local-circuit neurons. They are facilitated by collaterals of corticothalamic and thalamocortical projections, and they, in turn,
inhibit projection neurons by GABAergic transmission (Figure 11-12).

Table 11-2. Thalamus Nuclear Groups

Modality-specific Multimodal associative Nonspecific and reticular

Motor

Ventral anterior X

Ventral lateral X

Sensory

Ventral posterior X

Lateral geniculate X

Medial geniculate X

Limbic

Anterior X

Lateral dorsal X

Associative

Dorsomedial X

Pulvinar X

Posterior X

Reticular/nonspecific

Reticular X

Intralaminar X

Midline nuclei X

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Figure 11-12. Schematic diagram showing neuronal circuitry within the thalamus.

Internal Capsule (Figure 11-13)

The internal capsule is a broad, compact band of nerve fibers that are continuous rostrally with the corona radiata and caudally
with the cerebral peduncles. It contains afferent and efferent nerve fibers passing to and from the brain stem to the cerebral
cortex. In axial sections of the cerebral hemispheres, the internal capsule is bent with a lateral concavity to fit the wedge-
shaped lentiform nucleus. It is divided into an anterior limb, genu, posterior limb, retrolenticular part, and sublenticular part.

The anterior limb is sandwiched between the head of the caudate nucleus medially and the lentiform nucleus (putamen and
globus pallidus) laterally. It contains frontopontine, thalamocortical, and corticothalamic bundles; the latter two bundles
reciprocally connect the dorsomedial and anterior thalamic nuclei with the prefrontal cortex and cingulate gyrus, respectively.
Some investigators add the caudatoputamenal interconnections to components of the anterior limb.

The genu of the internal capsule contains corticobulbar and corticoreticulobulbar fibers that terminate on cranial nerve nuclei
of the brain stem. Evidence obtained from stimulation of the internal capsule during stereotaxic surgery and from vascular
lesions of the internal capsule suggests, however, that corticobulbar fibers are located in the posterior third of the posterior
limb rather than in the genu.

The posterior limb is bounded medially by the thalamus and laterally by the lentiform nucleus. It contains corticospinal and
corticorubral fibers, as well as fibers that reciprocally connect the lateral group of thalamic nuclei (ventral anterior, ventral
lateral, ventral posterior, and pulvinar) with the cerebral cortex. The corticospinal bundle is somatotopically organized in such
a way that the fibers to the upper extremity are located more anteriorly, followed by fibers to the trunk and the lower
extremity. Recent data suggest that the corticospinal fiber bundle is largely confined to the caudal half of the posterior limb.
The thalamocortical projections from the ventral anterior nucleus to premotor
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cortex (area 6), from ventral lateral nucleus to the precentral gyrus (area 4), from the ventral posterior nucleus to the
postcentral gyrus (areas 1, 2, and 3), and from the pulvinar to temporal and visual cortices are segregated in the internal
capsule, with the cortical projection from ventral anterior nucleus most rostral followed by those from ventral lateral nucleus,
ventral posterior nucleus, and pulvinar nucleus. Small focal capsular lesions may selectively involve one of these
thalamocortical projections.

The retrolenticular part of the internal capsule contains corticotectal, corticonigral, and corticotegmental fibers, as well as part
of the visual radiation. The sublenticular part of the internal capsule contains corticopontine fibers, the auditory radiation, and
part of the visual radiation.

Because of the crowding of corticothalamic and thalamocortical fibers in the internal capsule, lesions in the capsule
produce more widespread clinical signs than similar lesions elsewhere in the neuraxis. Vascular lesions in the posterior
limb of the internal capsule are associated with contralateral hemiplegia and hemisensory loss. Lesions in the most posterior
region will, in addition, be associated with contralateral visual loss (hemianopsia) and hearing deficit (hemihypacusis). Lesions
involving the genu of the internal capsule will be associated with cranial nerve signs.

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Figure 11-13. Schematic diagram showing component parts of the internal capsule and the fiber bundles within each
component.

A. BLOOD SUPPLY OF THALAMUS

Blood supply of the thalamus is derived from four parent vessels: basilar root of the posterior cerebral, posterior cerebral,
posterior communicating, and internal carotid. The basilar root of the posterior cerebral artery, via paramedian branches,
supplies the medial thalamic territory. The posterior cerebral artery, via its geniculothalamic branch, supplies the
posterolateral thalamic territory. The posterior communicating artery, via the tuberotha-lamic branch, supplies the
anterolateral thalamic territory. The internal carotid artery, via its anterior choroidal branch, supplies the lateral thalamic
territory. Because different authors use different terminology to refer to the same vessel, accounts of blood supply of the
thalamus may be confusing. Table 11-3 is a summary of blood supply of the thalamus and clinical manifestations of thalamic
infarcts.

B. BLOOD SUPPLY OF INTERNAL CAPSULE (FIGURE 11-14)

The anterior limb of the internal capsule is supplied by the striate branches of the anterior and middle cerebral arteries. The
genu is supplied by striate branches of the middle cerebral and internal carotid arteries. The bulk of the posterior limb is
supplied by striate branches of the middle cerebral artery. The anterior choroidal artery provides supply to the caudal portion
of the posterior limb.

C. FUNCTIONS
The function of the thalamus is to integrate sensory and motor activities. In addition, it has roles to play in arousal and
consciousness, as well as in affective behavior and memory. In a sense, it is the gateway to the cortex.

The thalamus plays a central role in sensory integration. All somatic and special senses, except olfaction, pass through the
thalamus before reaching the cerebral cortex. Sensory activity within the thalamus is channeled in one of three routes.

The first route is through the modality-specific sensory relay nuclei (medial geniculate, lateral geniculate, and ventral
posterior). Sensations relayed in the modality-specific sensory relay nuclei have direct access to the respective sensory cortical
areas. They are strictly organized with regard to topographic and modal specificities and are discriminative and well localized.

The second route is through the nonspecific nuclei. With its many sources of input and diffuse projections to the cortex, this
route serves the low extreme of the modality-specificity gradient.

The third route is through the posterior nuclear group. This route receives from multiple sensory sources and projects to the
association cortical areas. It plays an intermediate role between the modality-specific and nonspecific routes described above.

Table 11-3. Blood Supply of Thalamus

Thalamic Blood supply Synonyms Parent BV Structures Clinical

territory supplied manifestations
thalamic infar

(Concomitant PCA infarc

Posterolateral Geniculothalamic Posterolateral Posterior VPL, VPM, Complete: Pansensory los

Thalamogeniculate cerebral MG, pulvinar, (clinical hallma
artery (PCA) CM, ±DM, PL, (Dejerine- (Pure hemisenso
ret, Pf, LG Roussy loss)
(primary syndrome) Dysthesia
sensory Hemiparesis

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nuclei) Visual field defec

Partial: Choreiform
movements
Hemispatial negl
(with associated
infarct)
↓ Pain and touch
part of body (fac
arm, leg)
Occasional
dysarthria
Visual field defec
No hemiparesis
Visual perceptua
defect (with
associated PCA
infarct)

Anterolateral Tuberothalamic Polar Posterior VA, VL, DM, Facial paresis fo

Anterior internal communicating AV emotional
optic movements
Premamillary Hemiparesis
pedicle Visual field defec
(PCA infarct)
Sensory loss rare
Severe
neuropsycholog
impairment
(L) Speech, intel
language, memo
(R) Visuospatial

Medial Paramedian Posteromedial Basilar root of CM, Pf, DM Drowsiness

Deep PCA (bilateral or Vertical gaze par
interpeduncular unilateral), Memory, attentio
profunda CP, ±VL, AV, intellect defects
Posterior internal VPL, VPM Hemiparesis
optic occasionally
Thalamoperforating No sensory defic

Lateral Anterior — Internal IC (posterior Hemiparesis

choroidal carotid limb), GP, Sensory loss for
amygdala, and touch
optic tract, Dysarthria
lateral Visual field defec
thalamus (LG, occasionally
VPL, pul, ret), Neuropsychologi
medial defect, (L) memo
temporal lobe (R) visuospatial
Pure motor
hemiparesis

Posterior Posterior — PCA LG, pul, DL, Homonymous

choroidal ±DM, AV, quadrantaposia
±hippocampus Hemisensory
±rostral dysfunction
midbrain (hemihypesthesi
Neuropsychologi
disturbances
(memory,
transcortical
aphasia)
±Hemiparesis
±Choreoathetosi

NOTE: AV, anterior ventral; BV, blood vessel; CM, centromedian; CP, cerebral peduncle; DM, dorsomedial; GP, globus pallidus; IC,
internal capsule; LG, lateral geniculate; MG, medial geniculate; PCA, posterior cerebral artery; PL, posterior lateral; Pf, parafascicu
pul, pulvinar; ret, reticular; VA, ventral anterior; VL, ventral lateral; VPL, ventral posterior lateral; VPM, ventral posterior medial;
left; R, right.

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Figure 11-14. Schematic diagram of internal capsule showing sources of blood supply. Cd, caudate nucleus; Put, putamen
nucleus; GP, globus pallidus nucleus; Th, thalamus; MCA, middle cerebral artery; ACA, anterior cerebral artery.

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Some sensory modalities are perceived at the thalamic level and are not affected by ablation of the sensory cortex.
Following sensory cortical lesions, all sensory modalities are lost, but soon pain, thermal sense, and crude touch return.
The sense of pain that returns is the aching, burning type of pain that is carried by C-fibers. It is this type of pain that is
believed to terminate in the thalamus, whereas the pricking, well-localized pain carried by the A-fibers terminates in the
sensory cortex and is lost with its ablation. In patients with intractable pain, placement of a surgical lesion in the ventral
posterior or intralaminar nuclei (centromedian) may provide relief. Vascular lesions of the thalamus result in a characteristic
clinical syndrome known as the thalamic syndrome. Following an initial period of loss of all sensations contralateral to the
thalamic lesion, pain, thermal sense, and some crude touch return. However, the threshold of stimulation that elicits these
sensations is elevated, and the sensations are exaggerated and unpleasant when perceived. The syndrome is usually associated
with a marked affective response attributed to the intact dorsomedial nucleus, usually unaffected by the vascular lesion.

The role of the thalamus in motor control is evident from the input it receives from the cerebellum, basal ganglia, and motor
areas of the cortex. Based on striatothalamic, thalamostriate, and thalamocortical connections, it has been suggested that the
thalamus may be a place for interaction between the input and output systems of the basal ganglia. It is proposed that the
information processed by the basal ganglia and directed to the cerebral cortex through the thalamus could be reaching the
basal ganglia again via the striatum (thalamostriate connections) and thus influencing its overall organization. A tremorogenic
center has been postulated for the ventral lateral nucleus. Lesions have been placed in the ventral lateral nucleus to relieve
abnormal movement resulting from cerebellar and basal ganglia disorders.

The thalamus, as part of the ascending reticular activating system, has a central role in the conscious state and attention. The
role of the thalamus as essential for arousal and wakefulness has been challenged, in part by the recognition that the cerebral
cortex can be activated directly by cholinergic, serotonergic, noradrenergic, and histaminergic arousal systems that originate
in brain stem, basal forebrain, or hypothalamus and do not pass through the thalamus.

The connections of the medial thalamus with the prefrontal cortex reflect its role in affective behavior and executive function.
Ablation of the prefrontal cortex or its connections with the dorsomedial nucleus causes changes in personality characterized
by lack of drive, flat affect, indifference to pain, and defects in decision making and judgment.

The connections of the anterior thalamic nuclei with the hypothalamus and cingulate gyrus enable them to play a role in
memory, visceral function, and emotional behavior.

Damage to several and distinct areas of the thalamus (anterior thalamic nucleus, mamillothalamic tract, dorsomedial nucleus,
intralaminar nuclei, and midline nuclei) contribute to memory deficits (amnesia).

Discrete damage to the mamillothalamic tract has been associated with deficits in a specific type of memory, episodic long-
term memory, with relative sparing of short-term memory and intellectual capacity.

D. ROLE OF THALAMUS IN PAIN

The thalamus receives and processes all nociceptive information destined to reach the cortex. The thalamus has a role in
perception of pain and in the pathophysiology of central pain and other types of chronic pain. Nociceptive information reaches
the thalamus via the spinothalamic tracts (lateral and anterior) and the trigeminothalamic pathways. Some nociceptive input to
the thalamus is mediated via other spinal pathways and from the brain stem, but their role and importance in pain has not
been established. The regions of the thalamus involved in pain and where responses to noxious stimuli are recorded include the
VPL, VPM, VPI, centrolateral (CL), parafascicular (PF), and the dorsomedial (DM) nuclei. Most of the thalamic nuclei that
receive nociceptive input have projections to cortical areas implicated in pain. Ventral posterior lateral and medial nuclei
project to somatosensory cortex (SI), ventral posterior inferior nucleus projects to the secondary somatosensory cortex (SII),
and the dorsomedial nucleus to the anterior cingulate cortex. Most of the neurons in VPL and VPM are relay neurons for tactile
information. Ten percent of neurons are nociceptive neurons of the wide dynamic range (WDR) type that discharge maximally
to noxious mechanical and noxious heat stimuli. VPI neurons are of the wide dynamic range type as well as nociceptive-specific
(NS) type. They tend to have larger receptive fields than those of VPL and VPM. The intralaminar nuclei (CL, Pf) and the
dorsomedial nucleus (DM) mediate, in particular, the affective motivational aspect of pain as well as central pain.

Subthalamus
The subthalamus is a mass of gray and white substance in the caudal diencephalon. It is bordered medially by the

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hypothalamus, laterally by the internal capsule, dorsally by the thalamus, and ventrally by the internal capsule. The
subthalamus consists of three main structures; these are the subthalamic nucleus, the fields of Forel, and the zona incerta.

A. SUBTHALAMIC NUCLEUS (FIGURE 11-15)

The subthalamic nucleus (of Luys) is a biconvex gray mass that replaces the substantia nigra in caudal diencephalic levels. The
subthalamic nucleus receives a massive GABAergic (inhibitory) input from the external segment of globus pallidus and a
glutamatergic
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(excitatory) input from the cerebral cortex (areas 4 and 6). The input from the globus pallidus travels in the subthalamic
fasciculus, whereas the input from the cerebral cortex travels in the internal capsule. Other inputs include those from the
thalamus (primarily from the intralaminar nuclei) and the brain stem reticular formation. The two subthalamic nuclei
communicate via the supramamillary commissure. Projections to the subthalamic nucleus are arranged in distinct sensorimotor,
associative, and limbic territories similar to those reported for other basal ganglionic nuclei. The output from the subthalamic
nucleus is to both segments of the globus pallidus and to the substantia nigra pars reticulata. The neurotransmitter in both
these projections is glutamate (excitatory). It has been shown that the projections to the external and internal segments of
the globus pallidus arise from different subthalamic neurons.

Figure 11-15. Schematic diagram of the subthalamic region showing its component parts and the major afferent and
efferent connections of the subthalamic nucleus.

Interruption of the subthalamopallidal pathways or the subthalamic nucleus is responsible for the involuntary violent
hyperkinesia of the contralateral upper and lower extremities known as hemiballismus. Facial and neck muscles may be
involved.

B. FIELDS OF FOREL (FIGURE 11-16)

This term refers to fiber bundles containing pallidal and cerebellar efferents to the thalamus. Pallidothalamic fibers follow
one of two routes. Some traverse the internal capsule and gather dorsal to the subthalamic nucleus as the lenticular
fasciculus (H 2 field of Forel); others make a loop around the internal capsule as the ansa lenticularis. Both groups of fibers join
the dentatothalamic fibers in the prerubral field (H field of Forel) and then join the thalamic fasciculus (H 1 field of Forel) to
reach their respective thalamic nuclei. The fields of Forel are named after August Forel, the Swiss psychiatrist, neurologist, and
anatomist who is best remembered for his anatomic studies on the basal ganglia and subthalamic region. The H is from the
German word Haube, meaning “a cap” or “hood.”

C. ZONA INCERTA
The zona incerta (Figure 11-15) is the rostral continuation of the mesencephalic reticular formation that extends laterally into
the reticular nucleus of the thalamus. It is sandwiched between the lenticular fasciculus and the thalamic fasciculus. The zona
incerta has been implicated in a variety of functions, including locomotion, eye movements, sociosexual behavior, feeding and
drinking, arousal, and attention, and in aspects of visual, nociceptive, and somatosensory processing. The precise role of the
zona incerta in many of these functions is not certain. The diversity of functions ascribed to zona incerta reflects its
widespread connectivity. Reciprocal connections have been described in different species to almost all parts of the neuraxis,
including the neocortex, thalamus, brain stem, basal ganglia, cerebellum, hypothalamus, basal forebrain, and spinal cord.
Chronic, high-frequency, deep-brain stimulation of the zona incerta in humans and non-human primates has been shown to
suppress limb tremor. GABAergic neurons in the zona incerta have been shown to pause immediately prior to onset of and
during saccades, suggesting an inhibitory role of these neurons on saccadic eye movements. These neurons have been shown
to project to deep layers of the superior colliculus and the nucleus of Darkschewitsch, which are important in controlling
saccades. The zona incerta has also been shown to project to the pretectal area. The incertopretectal
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pathway is believed to play a role in the guidance of tectally initiated saccades by somatosensory stimuli. The zona incerta has
been shown to receive collaterals from corticothalamic fibers and to send GABAergic projections to thalamic relay neurons.

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Figure 11-16. Schematic diagram of the fields of Forel.

TERMINOLOGY
Diencephalon (Greek dia, “between”; enkephalos, “brain”).
The part of the central nervous system between the two hemispheres. It includes the epithalamus, thalamus (including the
metathalamus), subthalamus, and hypothalamus. The diencephalon is the posterior of the two brain vesicles formed from the
prosencephalon of the developing embryo.

Epithalamus (Greek epi, “upon”; thalamos, “inner chamber”).

Part of the diencephalon dorsal to the thalamus. It includes the stria medullaris thalami, habenular nucleus, and pineal gland.

Forel, August Henri (1848–1931).

Swiss neuropsychiatrist who described the fiber bundles of the subthalamus (H fields of Forel).

Galen, Claudius (A.D. 130–200).

Hellinistic physician who practiced mainly in Rome and Pergamon. He was the leading medical authority of the Christian world
for 1400 years. The great cerebral vein is named after him.

Geniculate (Latin geniculare, “to bend the knee”).

Abruptly bent, as in lateral and medial geniculate nuclei of the thalamus.

Genu (Latin “knee”).

A kneelike structure. The genu of the corpus callosum.

Habenula (Latin diminutive of habena, “a small strap or rein”).

The habenular nuclei are part of the epithalamus.

Hemiballismus (Greek hemi, “half”; ballismos, “jumping about”).

Violent flinging involuntary movements of one side of the body due to a lesion in the contralateral subthalamic nucleus.

Hypacusis (Greek hypo, “under, below”; akousis, “hearing”).

Decreased hearing.

Hyperacusis.
Abnormal perception of sound as being loud.

Hypothalamus (Greek hypo, “under, below”; thalamos, “inner chamber”).

The region of the diencephalon below the thalamus.

Luys, Jules Bernard (1828–1895).

French clinical neurologist who described the subthalamic nucleus (nucleus of Luys).

Mamillary bodies (Latin diminutive of mamma, “breast, nipple”).

A pair of small round swellings on the ventral surface of the hypothalamus mimicking the mammas.

Massa intermedia.
Bridge of gray matter that connects the thalami of the two sides across the third ventricle; also called interthalamic adhesion.

Metathalamus (Greek meta, “after”; thalamos, “inner chamber”).

The metathalamus includes the lateral and medial geniculate bodies.

Meynert, Theodor Hermann (1833–1892).

Austrian psychiatrist and neurologist. Described the habenulointerpeduncular tract in 1867.

Palinacusis. (Greek palin, “backward” or “again”; curis, “hearing, sound”).

Auditory perseveration. The pathologic continuance or recurrence of an auditory sensation after the stimulus is gone.

Parinaud, Henri (1844–1905).

French ophthalmologist. De-scribed the Parinaud syndrome in 1883. Wrote extensively about ocular movements, having had
access to the large numbers of Charcot patients at the Salpêtrière hospital in Paris. He is regarded as the father of neuro-
ophthalmology.

Pineal gland (Latin pinea, “a pine cone”).

A small midline organ shaped like a pine cone.

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Pulvinar (Latin pulvinar, “a cushioned reclining seat”).

The pulvinar nucleus is located in the posterior pole of the thalamus overhanging the superior colliculus and geniculate bodies.

Subthalamus (Latin sub, “under”; Greek thalamos, “inner chamber”).

Region of the diencephalon beneath the thalamus.

Thalamus (Greek thalamos, “inner chamber”).

Also meant “a bridal couch,” so the pulvinar nucleus is its cushion or pillow. Part of the diencephalon on each side of the third
ventricle and
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above the hypothalamic sulcus. Galen made up the word thalamus, and Willis was the first to use the term in its modern
sense.

Zona incerta (Latin zona, “zone, belt”; incerta, “in between”).

A rostral extension of the brain stem reticular formation into the subthalamus. Inserted between the lenticular and thalamic
fasciculi.

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Blum PS et al: Thalamic components of the ascending vestibular system. Exp Neurol 1979; 64:587–603.

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Hirai T, Jones EG: A new parcellation of the human thalamus on the basis of histochemical staining. Brain Res Rev 1989;
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Hirayama K et al: The representation of the pyramidal tract in the internal capsule and basis pedunculi: A study based on
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Editors: Afifi, Adel K.; Bergman, Ronald A.

Title: Functional Neuroanatomy: Text and Atlas, 2nd Edition

Copyright ©2005 McGraw-Hill

> Tab le of Conte nts > Pa rt I - Te xt > 1 2 - Dien ceph alon: Clin ica l Correlates

12
Diencephalon: Clinical Correlates

Clinical Correlates of Thalamic Anatomy

Thalamic Infarcts
Posterolateral Thalamic Territory
Anterolateral Thalamic Territory
Medial Thalamic Territory
Lateral Thalamic Territory
Posterior Thalamic Territory
Thalamic Pain Syndromes
Memory Deficits
Thalamus and Arousal
The Cheiro-Oral Syndrome
The Alien Hand Syndrome
Thalamic Acalculia
Language Deficits
Clinical Correlates of Subthalamic Anatomy
Hemiballismus

KEY CONCEPTS

Posterolateral (thalamogeniculate) thalamic territory lesions are characterized by pansensory loss associated with
thalamic pain, the Dejerine-Roussy syndrome.

Anterolateral (tuberothalamic) thalamic territory lesions are characterized by neuropsychological impairment.

Medial (paramedian) thalamic territory lesions are characterized by alteration in state of consciousness. Akinetic
mutism and the Kleine-Levin syndrome occur with lesions in this thalamic territory.

Lateral (anterior choroidal) thalamic territory lesions are characterized by hemiparesis and dysarthria.

Posterior (posterior choroidal) thalamic territory lesions are characterized by hemisensory dysfunction and visual
field defects.

Four types of thalamic pain syndromes have been described based on the presence or absence of each of tha-
lamic pain, proprioceptive and exteroceptive sensations, and abnormalities in somatosensory evoked potentials.

Encoding memory defects, severe distractibility, and verbal memory disturbances have been described in tha-
lamic lesions.

The thalamus is one (indirect) of two mechanisms for cortical activation. The other (direct) mechanism is via
cholinergic, serotonergic, noradrenergic, and histaminergic nonthalamic systems.

Language deficits occur with dominant thalamic lesions and are transient.

A violent dyskinesia (hemiballismus) occurs with lesions in the subthalamic nucleus or its connections with globus
pallidus.

CLINICAL CORRELATES OF THALAMIC ANATOMY

A multiplicity of neurologic signs and symptoms has been reported in disorders of the thalamus. These reflect (1) the anatomic
and functional heterogeneity of the thalamus, (2) simultaneous involvement of several nuclei even by discrete vascular lesions
due to the fact that arterial vascular territories in the thalamus cross nuclear boundaries, and (3) simultaneous involvement of
neighboring areas such as the midbrain in paramedian thalamic vascular lesions, the internal capsule in lateral thalamic
vascular lesions, and the subthalamus in posterior thalamic vascular lesions.

The conglomerate of signs and symptoms associated with tha-lamic lesions includes the following: sensory disturbances,
thalamic pain, hemiparesis, dyskinesias, disturbances of consciousness, memory disturbances, affective disturbances, and
disorders of language.

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Correlation of signs and symptoms with affected thalamic territory is best with vascular lesions (infarcts) of the thalamus
(Table 12-1). Clinicoanatomic correlation in patients with occlusion of thalamic arteries has been greatly facilitated by neuro-
imaging methods (computed tomography and magnetic resonance imaging). The different vascular territories of the thalamus
and associated neurologic signs and symptoms are outlined in the next sections. Most thalamic infarcts are reported in the
posterolateral and the medial thalamic territories supplied by the geniculotha-lamic and paramedian arteries, respectively.
Only a few cases are reported in the anterolateral and posterior territories supplied by the tuberothalamic and posterior

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choroidal arteries, respectively.

THALAMIC INFARCTS

Posterolateral Thalamic Territory (Figure 12-1)

Infarcts in this thalamic territory are due to occlusion of the geniculothalamic (thalamogeniculate, posterolateral) artery,
a branch of the posterior cerebral artery. Thalamic structures involved by the infarct are the primary sensory thalamic
nuclei, which include the ventral posterior lateral, ventral posterior medial, medial geniculate, pulvinar, and centromedian
nuclei. Other nuclei that are inconsistently involved include the dorsomedial, posterior lateral, reticular, parafascicular, and
lateral geniculate nuclei. The clinical hallmark of posterolateral thalamic territory infarcts is a pansensory loss contralateral to
the lesion, paresthesia, and thalamic pain. In addition, one or more of the following may occur: transient hemiparesis,
homonymous hemianopsia, hemiataxia, tremor, choreiform movements, and spatial neglect, all contralateral to the lesion in
the thalamus. An athetoid posture of the contralateral hand (thalamic hand) may appear 2 or more weeks following lesions in
this territory. The hand is flexed and pronated at the wrist and metacarpophalangeal joints and extended at the
interphalangeal joints. The fingers may be abducted. The thumb is either abducted or pushed against the palm. The
conglomerate of signs and symptoms associated with posterolateral thalamic territory infarcts comprises the thalamic
syndrome of Dejerine and Roussy. In this syndrome, severe, persistent, paroxysmal, and often intolerable pain (tha-lamic
pain) resistant to analgesic medications occurs at the time of injury or following a period of transient hemiparesis, hemiataxia,
choreiform movements, and hemisensory loss. Cutaneous stimuli trigger paroxysmal exacerbations of the pain that outlast the
stimulus. Because the perception of “epicritic” pain (from a pinprick) is reduced on the painful areas, this symptom is known as
anesthesia dolorosa, or painful anesthesia. The syndrome is named after Joseph-Jules Dejerine, a French neurologist, and his
assistant, Gustave Roussy, a Swiss-French neuropathologist, who described the “thalamic syndrome” in 1906 in six patients
with a vascular thalamic lesion who presented with a characteristic cluster of symptoms: hemihypoesthesia, intractable pain,
slight transient hemiparesis, hemiataxia, and choreoathetotic movements. The etiology of the thalamic pain syndrome is not
clear but may be the result of alterations in frequencies and patterns of inputs to the thalamus, qualities of injured neurons, or
changes in quality of output to the cortex.

Anterolateral Thalamic Territory

Infarcts in the anterolateral territory of the thalamus are usually secondary to occlusion of the tuberothalamic branch of
the posterior
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communicating artery. Synonyms for this branch include the polar, anterior internal optic, and the premamillary pedicle.
Thalamic nuclei involved in the infarct include the ventral anterior, ventral lateral, dorsomedial, and anterior. The clinical
manifestations include contralateral hemiparesis, visual field defects, facial paresis with emotional stimulation, and rarely,
hemisensory loss. Severe, usually transient neuropsychological impairments predominate in lesions in this thalamic territory.
Abulia, lack of spontaneity and initiative, and reduced quantity of speech are the predominant findings. Other impairments
consist of defects in intellect, language, and memory in left-sided lesions and visuospatial deficits in right-sided lesions.

Figure 12-1. T2-weighted axial magnetic resonance image (MRI) showing an infarct (arrow) in the posterolateral thalamic
territory.

Table 12-1. Blood Supply of Thalamus

Thalamic Blood supply Synonyms Parent BV Structures Clinical

territory supplied manifestation
thalamic infar

(Concomitant PC

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infarction)

Posterolateral Geniculothalamic Posterolateral Posterior VPL, VPM, Complete: Pansensory los

Thalamogeniculate cerebral artery MG, pulvinar, (clinical hallma
(PCA) CM, ±DM, PL, (Dejerine- (Pure hemisenso
ret, Pf, LG Roussy loss)
(primary syndrome) Dysthesia
sensory Hemiparesis
nuclei) Visual field defec
Partial: Choreiform
movements
Hemispatial negl
(with associated
infarct)
↓ Pain and touch
part of body (fac
arm, leg)
Occasional
dysarthria
Visual field defec
No hemiparesis
Visual perceptua
defect (with
associated PCA
infarct)

Anterolateral Tuberothalamic Polar Posterior VA, VL, DM, Facial paresis fo

Anterior internal communicating AV emotional
optic artery movements
Premamillary Hemiparesis
pedicle Visual field defec
(PCA infarct)
Sensory loss rar
Severe
neuropsycholog
impairment
(L) Speech, inte
language, memo
(R) Visuospatial

Medial Paramedian Posteromedial Basilar root of CM, Pf, DM Drowsiness

Deep PCA (bilateral or Vertical gaze par
interpeduncular unilateral), Memory, attentio
profunda CP, ±VL, AV, intellect defects
Posterior internal VPL, VPM Hemiparesis
optic occasionally
Thalamoperforating No sensory defic

Lateral Anterior — Internal IC (posterior Hemiparesis

choroidal carotid limb), GP, Sensory loss for
amygdala, and touch
optic tract, Dysarthria
lateral Visual field defec
thalamus (LG, occasionally
VPL, pul, ret), Neuropsychologi
medial defect, (L) memo
temporal lobe (R) visuospatial
Pure motor
hemiparesis

Posterior Posterior — PCA LG, pul, DL, Homonymous

choroidal ±DM, AV, quadrantaposia
±hippocampus Hemisensory
±rostral dysfunction
midbrain (hemihypesthesi
Neuropsychologi
disturbances
(memory,
transcortical
aphasia)
±Hemiparesis
±Choreoathetosi

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NOTE: AV, anterior ventral; BV, blood vessel; CM, centromedian; CP, cerebral peduncle; DM, dorsomedial; GP, globus pallidus; IC,
internal capsule; LG, lateral geniculate; MG, medial geniculate; PCA, posterior cerebral artery; PL, posterior lateral; Pf, parafascicu
pul, pulvinar; ret, reticular; VA, ventral anterior; VL, ventral lateral; VPL, ventral posterior lateral; VPM, ventral posterior medial;
left; R, right.

Medial Thalamic Territory (Figure 12-2)

Infarcts in the medial territory of the thalamus are associated with occlusion of the paramedian branches of the basilar
root of the posterior cerebral artery. These branches include the posteromedial, deep interpeduncular profunda, posterior
internal optic, and thalamoperforating. The thalamic nuclei involved include the intralaminar (centromedian, parafascicular)
and dorsomedial, either unilaterally or bilaterally. The paramedian territory of the midbrain is often involved by the lesion. The
following nuclei are inconsistently involved: the ventral lateral, anterior, and ventral posterior. The hallmark of the clinical
picture is drowsiness. In addition, there are abnormalities in recent memory, attention, intellect, vertical gaze, and
occasionally, mild hemiparesis or hemiataxia. No sensory deficits are as a rule associated with lesions in this territory.
Utilization behavior (instrumentally correct but highly exaggerated response to environmental cues and objects) that is
characteristic of frontal lobe damage has been reported in medial thalamic territory infarcts.

Two syndromes have also been reported in medial thalamic territory infarcts: akinetic mutism and the Kleine-Levin syndrome.
In akinetic mutism (persistent vegetative state), patients appear awake and maintain a sleep-wake cycle but are unable to
communicate in any way. In addition to thalamic infarcts, akinetic mutism has been reported to occur with lesions in the basal
ganglia, anterior cingulate gyrus, and pons. The Kleine-Levin syndrome (hypersomnia-bulimia syndrome) is characterized by
recurrent periods (lasting 1 to 2 weeks every 3 to 6 months) in adolescent males of excessive somnolence, hyperphagia
(compulsive eating), hypersexual behavior (sexual disinhibition), and impaired recent memory, and eventually ending with
recovery. A confusional state, hallucinosis, irritability, or a schizophreniform state may occur around the time of the attacks.
The syndrome was first reported by Antimoff in 1898 but more fully by Willi Kleine in 1925 in German and by Max Levin 4
years later in English.

Lateral Thalamic Territory (Figure 12-3)

Infarcts in the lateral territory of the thalamus are associated with occlusion of the anterior choroidal branch of the
internal carotid artery. Structures involved in the lesion include the posterior limb of the internal capsule, lateral thalamic
nuclei (lateral geniculate, ventral posterior lateral, pulvinar, reticular), and medial temporal lobe. The clinical hallmarks of the
infarct are contralateral hemiparesis and dysarthria. Lesions in the lateral thalamic territory may manifest with only pure
motor hemiparesis. Other clinical manifestations include hemisensory loss of pain and touch, occasional visual field defects,
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and neuropsychological defects. The latter consist of memory defects in left-sided lesions and visuospatial defects in right-
sided lesions.

Figure 12-2. T2-weighted axial MRI showing an infarct (arrow) in the medial thalamic territory.

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Figure 12-3. Proton density MRI showing an infarct (arrow) in the lateral thalamic territory.

Posterior Thalamic Territory (Figure 12-4)

Infarcts in the posterior thalamic territory are associated with occlusion of the posterior choroidal branch of the posterior
cerebral artery. Thalamic nuclei involved include the lateral geniculate, pulvinar, and dorsolateral nuclei. The following
structures are inconsistently involved in the lesion: dorsomedial and anterior thalamic nuclei, hippocampus, and rostral
midbrain. Clinical manifestations include contralateral homonymous quadrantanopsia and hemihypesthesia, as well as
neuropsychological deficits, including memory defects and transcortical aphasia. Inconsistent signs include contralateral
hemiparesis and choreoathetosis.

Thalamic Pain Syndromes

Four types of pain syndromes have been described in association with thalamic lesions (Table 12-2). The four types are
differentiated from each other on the basis of the presence or absence in each of central (thalamic) pain, proprioceptive
sensations (vibration, touch, joint), exteroceptive sensations (pain and temperature), and abnormalities in somatosensory
evoked potentials.

In type I (analgetic type), central pain is absent, both proprioceptive and exteroceptive sensations are lost, and no
somatosensory evoked potentials are elicitable. In type II, both central pain and exteroceptive sensations are present, whereas
proprioceptive sensations are lost and somatosensory evoked potentials are absent. In type III, central pain as well as
proprioceptive and exteroceptive sensations are present, whereas somatosensory evoked potentials are reduced in amplitude.
In type IV (pure algetic), central pain is present, proprioceptive and exteroceptive sensations are unimpaired, and
somatosensory evoked potentials are normal.

Memory Deficits
Discrete lesions of the thalamus can cause severe and lasting memory deficits. Although it remains uncertain which
thalamic structures are critical for memory, evidence from human and animal research suggests that one or more of the
following structures are important: anterior nuclei, midline and intralaminar nuclei, dorsomedial nucleus, and mamillothalamic
tract. There are three distinct behavioral and anatomic types of memory impairment associated with diencephalic lesions: (1)
Severe encoding defects are associated with lesions in the mamillary bodies, mamillothalamic tracts, midline thalamic nuclei,
and the dorsomedial nucleus. Performance of such patients never approximates normal memory. (2) A milder form of memory
deficit characterized by severe distractibility occurs in lesions of the intralaminar and medial thalamic nuclei. (3) Disturbances
in verbal memory (retrieval, registration, and retention) occur in lesions of the left thalamus that include the ventrolateral and
intralaminar nuclei and the mamillothalamic tract. Memory disturbances, which may be transient or permanent, are most
common with bilateral thalamic lesions but do occur with unilateral lesions of either side.

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Figure 12-4. T2-weighted MRI showing an infarct (arrow) in the posterior thalamic territory.

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Thalamus and Arousal

The essential role of the thalamus as the sole mechanism for cortical arousal has been challenged. It is now acknowledged
that cortical activation is mediated by two mechanisms: (1) an indirect mechanism, via the thalamus, comprised of the
ascending reticular activating system (ARAS), and (2) a direct mechanism (nonthalamic), via cholinergic, serotonergic,
noradrenergic, and histaminergic arousal systems that originate in the brain stem, basal forebrain, or hypothalamus and do not
pass through the thalamus.

The Cheiro-Oral Syndrome

This syndrome consists of sensory disturbances confined to one hand and to the ipsilateral mouth region. It is associated with
focal lesions in the ventral posterior thalamic nucleus. A similar syndrome has been reported with lesions in the somatosensory
cortex, border of the posterior limb of the internal capsule and corona radiata, midbrain, and pons. The involvement of the
hand and mouth areas suggests that the sensory representation of these two areas is contiguous not only in the primary
somatosensory cortex but also elsewhere in the neuraxis.

The Alien Hand Syndrome

The alien hand syndrome is defined as unwilled, uncontrollable movements of an upper limb together with failure to recognize
ownership of a limb in the absence of visual cues. The syndrome was first described by Goldstein in 1908. Most cases are
associated with lesions in the corpus callosum and mesial frontal area, alone or in combination. The condition has also been
reported in infarcts involving the posterolateral and anterolateral thalamic territories (supplied by the geniculothalamic and
tuberothalamic arteries, respectively). The lesion usually involves the ventral posterior, ventral lateral, and dorsomedial nuclei.

Thalamic Acalculia
Infarctions in the left anterolateral thalamic territory supplied by the tuberothalamic artery have been reported to produce
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acalculia. The lesion usually involves the ventral lateral and dorsomedial thalamic nuclei.

Table 12-2. Thalamic Pain Syndromes Subtypes

Type Central Vibration, touch, Pain, Somatosensory evoked

pain joint temperature potentials

I (analgetic) Absent Lost Lost Absent

II Present Lost Present Absent

III Present Present Present Reduced

IV (pure Present Present Present Normal

algetic)

Language Deficits
Dominant hemisphere thalamic lesions may cause a transient deficit in language. Three types have been described: (1)
medial, (2) anterolateral, and (3) lateral. In the medial type, involving the dorsomedial and centromedian nuclei (medial

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thalamic territory), the language deficit is characterized by anomia and attentionally induced language impairment. Lesions in
this area are associated with memory and attention deficits. In the anterolateral type, the lesion involves ventral anterior and
anterior ventral nuclei (anterolateral thalamic territory). This type is associated with an aphasic syndrome resembling
transcortical aphasia. In the third type, the lesion involves the lateral thalamic territory. The language deficit in this type is
characterized by mild anomia. Several authors have suggested that thalamic language disturbances are due to cortical
hypoperfusion and hypometabolism.

CLINICAL CORRELATES OF SUBTHALAMIC ANATOMY

Hemiballismus
Lesions in the subthalamic nucleus or in the pallidosubthalamic system are associated with violent, involuntary, flinging,
ballistic movements of the contralateral half of the body. The abnormal movement involves primarily the extremities; the
head and neck also may be involved.

TERMINOLOGY
Abulia (Greek a, “without”; boulé, “will”).
A state in which the patient manifests lack of initiative and spontaneity with preserved consciousness.

Aphasia (Greek a, “without”; phasis, “speech”).

Defect in communication by language.

Ataxia (Greek a, “without”; taxis, “order”).

Loss of muscle coordination with irregularity of movement.

Contralateral (Latin contra, “opposite”; lateris, “of a side”).

Of the other side of the body.

Dysarthria (Greek dys, “difficult”; arthroun, “to articulate”).

Difficulty in speaking.

Exteroceptor (Latin exterus, “external”; receptor, “receiver”).

Sensory receptor that serves to acquaint the individual with the external environment. Includes pain and temperature
receptors.

Hemianopsia (Greek hemi, “half”; an, “negative”; opsis, “vision”).

Defect of half the field of vision.

Hemiballismus (Greek hemi, “half”; ballismos, “jumping about”).

Violent flinging movement of one side of the body due to a lesion in the contralateral subthalamic nucleus.

Infarction (Latin infarcire, “to stuff into”).

Vascular occlusion leading to death of tissue.

Kleine, Willi.
German neuropsychiatrist who, in 1925, reported five cases of periodic somnolence and morbid hunger attributed to
hypothalamic lesion. The syndrome had been previously described in 1898 by Antimoff.

Lesion (Latin laesum, “hurt or wounded”).

The term is applied to an abnormality that may destroy tissue, as in infarction, hemorrhage, or tumor, or that may stimulate
tissue, as in epilepsy.

Levin, Max.
American neuropsychiatrist of Latvian origin. In 1929, he described a case of Kleine-Levin syndrome 4 years after Kleine
described his cases. In 1936, he summarized the features of seven cases as a new syndrome of periodic somnolence and
morbid hunger.

Paresthesia (Greek para, “beside, near, beyond”; aisthesis, “perception”).

Distorted sensation, tingling, “pins and needles.”

Proprioceptor (Latin proprius, “one's own”; receptor, “receiver”).

Sensory endings in muscles, tendons, and joints that provide information about movement and position of body parts.

Syndrome (Greek syndromos, “a running together, combining”).

A group of co-occurring symptoms and signs that characterize a disease.

SUGGESTED READINGS
Beric A: Central pain: “New” syndromes and their evaluation. Muscle Nerve 1993; 16:1017–1024.

Biller J et al: Syndrome of the paramedian thalamic arteries: Clinical and neuroimaging correlation. J Clin Neuroophthalmol
1985; 5:217–223.

Bjornstad B et al: Paroxysmal sleep as a presenting symptom of bilateral paramedian thalamic infarction. Mayo Clin Proc
2003; 78:347–349.

Bogousslavsky J et al: Thalamic infarcts: Clinical syndromes, etiology, and prognosis. Neurology 1988; 38:837–848.

Bogousslavsky J et al: Loss of psychic self-activation with bithalamic infarction: Neurobehavioral, CT, MRI, and SPECT
correlates. Acta Neurol Scand 1991; 83:309–316.

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Brandt T et al: Posterior cerebral artery territory infarcts: Clinical features, infarct topography, causes and outcome.
Cerebrovasc Dis 2000; 10:170–182.

Caplan LR: “Top of the basilar” syndrome. Neurology 1980; 30:72–79.

Castaigne P et al: Paramedian thalamic and midbrain infarcts: Clinical and neuropathological study. Ann Neurol 1981;
10:127–148.

Engelborghs S et al: Functional anatomy, vascularisation and pathology of the human thalamus. Acta Neurol Belg 1998;
98:252–265.

Eslinger PJ et al: “Frontal lobe” utilization behavior associated with paramedian thalamic infarction. Neurology 1991;
41:450–452.

Gentilini M et al: Bilateral paramedian thalamic artery infarcts: Report of eight cases. J Neurol Neurosurg Psychiatry 1987;
50:900–909.

Graff-Radford NR et al: Nonhemorrhagic thalamic infarction. Brain 1985; 108:485–516.

Guberman A, Stuss D: The syndrome of bilateral paramedian thalamic infarction. Neurology 1983; 33:540–545.

Isono O et al: Cheiro-oral topography of sensory disturbances due to lesions of thalamocortical projections. Neurology
1993; 43:51–55.

Kinney HC et al: Neuropathological findings in the brain of Karen Ann Quinlan: The role of the thalamus in the persistent
vegetative state. N Engl J Med 1994; 330:1469–1475.

Marey-Lopez J et al: Posterior alien hand syndrome after a right thalamic infarct. J Neurol Neurosurg Psychiatry 2002;
73:447–449.

Mauguiere F, Desmedt JE: Thalamic pain syndrome of Dejerine-Roussy: Differentiation of four subtypes assisted by
somatosensory evoked potentials data. Arch Neurol 1988; 45:1312–1320.

Mendez MF et al: Thalamic acalculia. J Neuropsychiatry Clin Neurosci 2003; 15:115–116.

Mennemeier M et al: Contributions of the left intralaminar and medial tha-lamic nuclei to memory. Arch Neurol 1992;
49:1050–1058.

Miwa H et al: Thalamic tremor: Case reports and implications of the tremor-generating mechanism. Neurology 1996;
46:75–79.

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Mori E et al: Left thalamic infarction and disturbances of verbal memory: A clinicoanatomical study with a new method of
computed tomographic stereotaxic lesion localization. Ann Neurol 1986; 20:671–676.

Nea JP, Bogousslavsky J: The syndrome of posterior choroidal artery territory infarction. Ann Neurol 1996; 39:779–788.

Reilly M et al: Bilateral paramedian thalamic infarction: A distinct but poorly recognized stroke syndrome. Q J Med 1992;
29:63–70.

Roitberg BZ et al: Bilateral paramedian thalamic infarct in the presence of an unpaired thalamic perforating artery. Acta
Neurochir 2002; 144:301–304.

Szczudlik A et al: Vascular thalamic syndromes—clinical and topographic analysis. Neur Neurochir Pol 1996; 30(Suppl
2):55–63.

Wallesch CW et al: Neuropsychological deficits associated with small unilateral thalamic lesions. Brain 1983; 106:141–152.

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Editors: Afifi, Adel K.; Bergman, Ronald A.

Title: Functional Neuroanatomy: Text and Atlas, 2nd Edition

Copyright ©2005 McGraw-Hill

> Table of Contents > Part I - Text > 13 - The Basal Ganglia

13
The Basal Ganglia

Definitions and Nomenclature

Neuronal Population, Synaptic Relations, and Internal Organization
Neostriatum (Striatum)
Globus Pallidus and Substantia Nigra Pars Reticulata
Neostriatal Input
Neostriatal Output
Pallidal and Nigral Inputs
Pallidal and Nigral Outputs
Subthalamic Nucleus
Ventral (Limbic) Striatum
Corticostriatothalamocortical Loops
Split Pathways
Basal Ganglia Function
Motor Function
Gating Function
Cognitive Function
Emotion and Motivation Function
Spatial Neglect
Complementarity of Basal Ganglia and Cerebellum in Motor Function
Blood Supply

KEY CONCEPTS

The terms corpus striatum, striatum, dorsal striatum, neostriatum, ventral

striatum, pallidum, paleostriatum, and lentiform nucleus refer to well-defined
components of the basal ganglia as summarized in Table 13-1.

The striatum receive inputs from the cerebral cortex (major source) and
subcortical structures (substantia nigra compacta, thalamus, raphe nuclei, locus
ceruleus, and external segment of globus pallidus).

The striatum projects to the output nuclei (globus pallidus internus and
substantia nigra reticulata) via two pathways; direct and indirect.

The striatum is the principal receptive structure and the globus pallidus is
the principal output structure of the basal ganglia.

Lesions of subthalamic nucleus result in ballism, and stimulation relieves the

symptoms of Parkinsonism.

Corticostriatothalamocortical connections are organized into five parallel and

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segregated loops and/or three split circuits.

The role of the basal ganglia in motor control includes the preparation for
and execution of cortically initiated movement.

The basal ganglia subserve roles in cognitive function, emotion, and

motivation.

Blood supply of the basal ganglia is derived from lenticulostriate branches of

the middle and anterior cerebral arteries and the anterior choroidal branch of
the internal carotid artery.

The neural control of movement is the product of interactions within and among a number
of cortical and subcortical neural structures (Figure 13-1). Among the various subcortical
structures, three are of particular significance. They are the basal ganglia, cerebellum,
and the dopaminergic mesencephalic system. Whereas lesions in the motor cortex result
in loss of movement, such as occurs in stroke, lesions in the basal ganglia or cerebellum
result in incoordinated and disorganized movement, such as occurs in Parkinsonism and
Huntington's chorea. Recent experimental studies and clinical observations have focused
on a new role for the basal ganglia in nonmotor functions, including cognition and
behavior.

Figure 13-1. Simplified schematic diagram of major cortical and subcortical neural
structures involved in movement: 1, corticospinal tract; 2, cerebrocerebellar
pathways; 3, corticostriate pathways; 4, dentatothalamic pathways; 5,
striatothalamic pathways; 6, thalamocortical pathways; and 7, dopaminergic
pathways.

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DEFINITIONS AND NOMENCLATURE

The basal ganglia are a group of interconnected nuclei involved in motor and nonmotor
functions. Anatomically, the term refers to the following nuclei: caudate, putamen, globus
pallidus, nucleus accumbens septi, and olfactory tubercle, all of which are topographically
located in the “basement” of the brain (Figure 13-2). Functionally, the substantia nigra
and subthalamic nucleus are included within the basal ganglia. The anatomic network of

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basal ganglia was not outlined with precision until the 20th century. Galen used the term
“buttocks” to refer to cellular masses (caudate nuclei) protruding into the lateral
ventricles. Prior to 1786, the basal ganglia were lumped with the thalamus in the
“striated body”. A major step in its definition was made when the thalamus was
separated from the striated body by the French anatomist Felix Vicq d'Azir in 1786. The
term basal ganglia was first introduced in the English language by Ferrier in 1876. The
distinction between striatum and pallidum was made at the beginning of the 20th
century, and the importance of the corticostriatal connections were recognized in the late
1960s. As revealed by magnetic resonance imaging (MRI), basal ganglia volume is
significantly larger on the right side, irrespective of handedness and gender.

The term corpus striatum refers to the caudate, putamen, and globus pallidus. The
terms striatum, dorsal striatum, and neostriatum refer to the caudate and putamen.
The terms pallidum and paleostriatum refer to globus pallidus. The putamen and globus
pallidus together compose the lentiform nucleus. The term ventral striatum refers to the
ventral parts of caudate and putamen, the nucleus accumbens septi, and the striatal part
of the olfactory tubercle (Table 13-1). The term extrapyramidal system, coined in 1912
by British neurologist Kinnier Wilson, refers to the basal ganglia and an array of brain
stem nuclei (red nucleus, subthalamic nucleus, substantia nigra, reticular formation) to
which they are connected. This conglomerate of neural structures plays an important role
in motor control.

NEURONAL POPULATION, SYNAPTIC RELATIONS, AND

INTERNAL ORGANIZATION

Neostriatum (Striatum)
The terms neostriatum and striatum refer to the caudate nucleus and putamen. Both
nuclei are of telencephalic origin. During ontogenesis, the caudate nucleus follows the
curvature of the telencephalic vesicle and thus becomes a C-shaped structure with an
expanded rostral extremity, the head, which tapers down in size to form a body and a
tail. The head of the caudate nucleus bears a characteristic relationship to the anterior
horn of the lateral ventricle (Figure 13-2). This part of the caudate characteristically
bulges into the lateral ventricle. In degenerative central nervous diseases involving the
caudate nucleus, such as Huntington's chorea, described by the American general
practitioner George Huntington in 1872, the characteristic bulge of the caudate nucleus
into the lateral ventricle is lost. While the head and body of the caudate nucleus maintain
a relationship to the lateral wall of the anterior horn and body of the lateral ventricle,
respectively, the tail of the caudate occupies a position in the roof of the inferior horn of
the lateral ventricle (Figure 13-3). The tail of the caudate is very small in humans.

The putamen is located lateral to the globus pallidus and medial to the external capsule
(Figure 13-2). It is separated from the caudate nucleus by the internal capsule, except
rostrally, where the head of the caudate and the putamen are continuous around the
anterior limb of the internal capsule (Figure 13-4).

Neostriatal neurons are of two types: aspiny and spiny. Aspiny neurons (4 percent) are
intrinsic neurons (interneurons). They are divided into four types: large cholinergic, small
GABAergic and parvalbumin-containing (largest population), somatostatin and
neuropeptide Y–containing, and calretinin immunoreactive
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neurons. In addition, immunocytochemical studies demonstrate the presence of intrinsic
dopaminergic interneurons in the striatum. They are few in number in the normal
striatum but increase in number when the dopaminergic input to the striatum is
interrupted, as in Parkinson's disease.

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Figure 13-2. Parasagittal A and coronal B sections of the brain showing the
anatomic components of the basal ganglia.

Spiny neurons, the neostriatal projection (principal) neurons, constitute the great
majority (96 percent) of neostriatal neurons. They contain GABA, taurine, and a number
of neuropeptides, including substance P, enkephalin, neurotensin, dynorphin, and
cholecystokinin. Spiny neurons are silent at rest
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and discharge when stimulated by cortical or other inputs. Spiny projection neurons and
the large cholinergic aspiny interneurons are lost in Huntington's chorea.

Table 13-1. Basal Ganglia Nomenclature

Corpus Striatum, Ventral Pallidum, Lentiform

striatum dorsal striatum paleostriatum nucleus

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striatum,
neostriatum

Caudate + + + – –

Putamen + + + – +

Globus + – – + +
pallidus

Nucleus – – + – –
accumbens

Olfactory – – + – –
tubercle

Molecular biology techniques have identified at least six dopamine receptor isoforms
grouped into two subfamilies (D 1 -like and D 2 -like). D 1 and D 2 receptors are found in the
striatum. D 2 receptors mediate the antipsychotic effects of neuroleptic drugs and exert
feedback control on dopaminergic transmission. In Parkinson's disease, D 1 receptors are
reduced, while D 2 receptors are significantly increased. Colocalization of D 1 and D 2
receptors has been reported in virtually all striatal neurons.

Axons from the cerebral cortex terminate on distal spines of projection neurons. Axons
from substantia nigra, thalamus, and intrastriatal sites (interneurons and other spiny
neurons) terminate
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on dendritic shafts and cell bodies of projection neurons (Figure 13-5). This pattern of
termination allows cortical input to be modulated or inhibited by the other inputs to the
projection neurons.

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Figure 13-3. Axial section of the brain showing the head and tail of the caudate
nucleus, and their relationships to the anterior and inferior (temporal) horns of the
lateral ventricle.

Figure 13-4. Coronal section of the brain showing continuity of the putamen with
the head of the caudate around the anterior limb of the internal capsule.

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The adult neostriatum is made up of two compartments: The patches (striosomes)

compartment contains cells that stain weakly for acetylcholine esterase and is
interspersed between strongly staining areas, the matrix compartment. Besides
differences in acetylcholine esterase reactivity, the two compartments differ in their
input, output, neurotransmitters, neuromodulators, sources of dopaminergic input, and
distribution of dopaminergic receptor subtypes (Table 13-2).

Figure 13-5. Schematic diagram of striatal medium spiny projection neuron showing
the different patterns of termination of cortical, nigral, thalamic, and intrastriatal
neurons on dendrites and soma. S, soma; D, dendrite; Sp, dendritic spine. (Modified
from Trends in Neurosci-ence 13:259–265, 1990, figure 3, with permission from
Elsevier Science Ltd.)

Table 13-2. Characteristics of Striosome and Matrix Compartments

Striosomes Matrix

Acetylcholinesterase Light Heavy

staining

Cell development Early Late

Input Medial frontal cortex, Sensorimotor cortex,

limbic cortex, supplementary motor cortex,
substantia nigra pars association cortex, limbic
compacta, ventral cortex, intralaminar thalamic

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substantia nigra pars nuclei, ventral tegmental

reticulata area, dorsal substantia nigra
pars compacta

Output Substantia nigra pars Substantia nigra pars

compacta reticulata, globus pallidus

Neurotransmitter GABA GABA

Neuromodulators Neurotensin, Somatostatin, enkephalin,

dynorphin, substance substance P
P

Dopamine receptor D1 D2

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Globus Pallidus and Substantia Nigra Pars Reticulata

The globus pallidus is a wedge-shaped nuclear mass located between the putamen and
internal capsule. A lamina of fibers (external pallidal lamina) separates the globus
pallidus from the putamen. Another lamina (internal pallidal lamina) divides the globus
pallidus into a larger lateral (outer) and a smaller medial (inner) segment (Figure 13-2A).
The entopeduncular nucleus of nonprimate mammals is part of the medial pallidal
segment in primate mammals.

The substantia nigra pars reticulata occupies the ventral zone of the substantia nigra and
contains iron compounds.

Morphologically and chemically, the globus pallidus and the substantia nigra pars
reticulata are similar. The latter is considered the part of the globus pallidus containing
head and neck representation, whereas the internal segment of globus pallidus has arm
and leg representation.

Most neurons in the globus pallidus and substantia nigra pars reticulata are large
multipolar projection neurons. Interneurons are infrequent. All pallidal and nigral neurons
use GABA as the inhibitory neurotransmitter. Pallidal and nigral neurons are about 100
times less numerous than spiny striatal neurons, thus providing convergence of input
from the striatum to the pallidum. About 90 percent of the input to pallidal and nigral
neurons originates from the striatum.

Subthalamic Nucleus
Subthalamic nucleus neurons are cytologically homogenous, use glutamate as their
neurotransmitter, have only few spines, and are intermediate in their dendritic
arborization between those of striatal and pallidal neurons.

Neostriatal Input
A. CORTICOSTRIATE PROJECTIONS
Projections from the cerebral cortex to the striatum are both direct and indirect. Direct
corticostriate projections reach the neostriatum via the internal and external capsules
and via the subcallosal fasciculus. The indirect pathways include the corticothalamostriate
pathway, collaterals of the cortico-olivary pathway, and collaterals of the corticopontine

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pathway (Figure 13-6).

The corticostriate projection comprises the most massive striatal afferents. Almost
all cortical areas contribute to this projection. Cortical areas interconnected via
corticocortical fibers tend to share common zones of termination in the neostriatum.
Corticostriatal fibers are topographically organized into three distinct striatal territories:
(1) sensorimotor (post-commissural putamen), (2) associative (caudate and pre-
commissured putamen), and (3) limbic (nucleus accumbens). The sensorimotor territory
receives its inputs from sensory and motor cortical areas. The associative territory
receives fibers from the association cortices. The limbic territory receives input from
limbic and paralimbic cortical areas. The cingulate cortex projects to both the
sensorimotor and limbic striatum. It thus serves to modulate motor responses based on
limbic information.

Corticostriate pathways are also somatotopically organized such that cortical association
areas project to the caudate nucleus, whereas sensorimotor cortical areas preferentially
project to the putamen. Corticoputamenal projections are further organized in that the
cortical arm, leg, and face areas project to corresponding areas within the putamen. The
somatotopic organization of corticostriate projection is replicated throughout the basal
ganglia. The excitatory neurotransmitter of corticostriate projections is glutamate.

B. MESENCEPHALOSTRIATE PROJECTIONS
The principal mesencephalostriate projection originates from dopamine-containing cells of
the substantia nigra pars compacta. Dopamine has a net excitatory effect on D 1 striatal
neurons that project to the internal segment of globus pallidus and substantia nigra pars
reticulata and a net inhibitory effect on D 2 striatal neurons that project to the external
segment of globus pallidus (Figure 13-7). Collaterals from nigrostriate projections have
recently been traced to globus pallidus and subthalamic
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nucleus. These collaterals provide the anatomic basis for nigral dopaminergic neurons to
directly affect the pallidum and subthalamic nucleus.

Figure 13-6. Schematic diagram of the direct (1) and indirect (2, 3, 4)
corticostriate projections.

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Figure 13-7. Schematic diagram of nigrostriatal pathway showing the facilitatory

action (+) of dopamine on striatal neurons that project to substantia nigra pars
reticulata and internal segment of globus pallidus, and the inhibitory action (–) of
dopamine on striatal neurons that project to the external segment of globus pallidus.
D 1 , dopamine 1 class receptor neuron; D 2 , dopamine 2 class receptor neuron; DA,
dopamine; GABA, gamma-aminobutyric acid; GPe, external segment of globus
pallidus; GPi, internal segment of globus pallidus; SNr, substantia nigra pars
reticulata. (Modified from J Child Neurol 9:249–260, 1994, figure 1, with permission
from Decker Periodicals.)

In addition to the substantia nigra, the following mesencephalic dopaminergic nuclear

groups project to the striatum: the ventral tegmental area of Tasi (area A-10) and the
retrorubral nucleus (substantia nigra pars dorsalis, area A-8).

C. THALAMOSTRIATE PROJECTIONS
Thalamostriate projections are the second most prominent afferents to the striatum. The
centromedian nucleus projects mainly to the sensorimotor striatal territory, while the
parafascicular nucleus projects to the associative and limbic striatal territories. Other
thalamic sources of input to the striatum include ventral anterior, ventral lateral, and
posterior thalamic nuclei. Thalamostriate projections from ventral anterior and ventral
lateral nuclei overlap extensively with corticostriate projections from frontal motor
cortical areas. Thalamostriate fibers are believed to be excitatory. The neurotransmitter
is glutamate.

D. OTHER PROJECTIONS
Other projections to the neostriatum include those from the raphe nuclei (serotonergic),
the locus ceruleus (noradrenergic), and external segment of globus pallidus. Figure 13-8
is a schema of the major inputs to the neostriatum. The main target of striatal afferents
is the GABAergic medium-size spiny projection neuron. Although less massively
innervated, the aspiny interneurons also receive direct cortical, thalamic, and nigral
inputs.

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Figure 13-8. Schematic diagram of major sources of input to the sensorimotor,

association, and limbic zones of the neostriatum. Glu, glutamine; DA, dopamine.

Neostriatal Output
The neostriatum projects to the substantia nigra pars reticulata, both segments of the
globus pallidus, and the ventral pallidum. There is also a small projection from the
neostriatum to the substantia nigra pars compacta.

The neostriatal projections to the different target areas, although containing one
neurotransmitter (GABA), have different neuropeptides (Table 13-3).

The striatal output to the globus pallidus and the substantia nigra pars reticulata is
organized into direct and indirect projections (Figure 13-9). The direct projection is
from the neostriatum to the internal segment of the globus pallidus and the substantia
nigra pars reticulata (output nuclei). The indirect projection is from the neostriatum to
the external segment of the globus pallidus and via the subthalamic nucleus to the
internal segment of the globus pallidus and the substantia nigra pars reticulata. The two
pathways have opposing effects on the output nuclei and their thalamic targets.
Activation of the direct pathway leads to a net disinhibitory (facilitatory) effect on the
thalamus and an increase in motor behavior. Activation of the indirect pathway leads to
increased inhibition of the thalamus and decreased motor activity. Enhanced activity of
the indirect pathway may be responsible for the poverty of movement (hypokinesia) of
some basal ganglia disorders (Parkinson's disease), whereas reduced activity in the direct
pathway may result in excessive activity (hyperkinesia) of some basal ganglia disorders
(Huntington's chorea).

The concept of separate direct and indirect pathways has been challenged by the
following recent findings: (1) direct projections from the external pallidal segment to the
output nuclei and to the striatum, (2) subthalamic nucleus projections to the striatum,
external pallidal segment, and substantia nigra pars compacta, (3) abundant
collateralization of striatal axons terminating in several target nuclei, and (4)
interconnection of striatal neurons giving rise to the direct and indirect pathways and the
convergence of both pathways at single output neurons. The indirect pathway is
functionally immature in childhood, whereas the direct pathway is functionally mature in
childhood.

Table 13-3. Neurotransmitters and Neuromodulators Involved in Striatal

Output

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To GPi To Gpe To SNr To SNc

GABA + + + +

Substance P + – + –

Enkephalin – + – –

Dynorphin + – + +

Neurotensin – + – +

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Pallidal and Nigral Inputs

A. STRIATOPALLIDAL AND STRIATONIGRAL PROJECTIONS
The input to both segments of the globus pallidus is primarily from the putamen and the
subthalamic nucleus, whereas the input to the substantia nigra pars reticulata is primarily
from the caudate and the subthalamic nucleus. The input from the neostriatum is
GABAergic (inhibitory). The input from the subtha-lamic nucleus is glutamatergic
(excitatory).

B. OTHER PROJECTIONS
Other, less significant pallidal afferents include those from dopaminergic and serotonergic
neurons of the brain stem.

Pallidal and Nigral Outputs (Figure 13-10)

A. MAJOR OUTPUT
The major output from the internal segment of the globus pallidus and the
substantia nigra pars reticulata (output nuclei) is to the thalamus. Pallidothalamic
fibers follow one of two routes. Some traverse the internal capsule and gather dorsal to
the subthalamic nucleus as the lenticular fasciculus (H 2 field of Forel, after the Swiss
neuropsychiatrist August Henri Forel, who described these bundles); others pass around
the internal capsule (ansa lenticularis). Both groups of fibers gather together to form the
prerubral field (H field of Forel) and then join the thalamic fasciculus (H 1 field of Forel) to
reach the target thalamic nuclei. The target thalamic nuclei are the ventral anterior,
ventral lateral, dorsomedial, and intralaminar nuclei. The neurotransmitter is GABA.
Pallidal output thus inhibits the excitatory thalamocortical loop. The pallidothalamic and
nigrothalamic projections constitute the link between the neostriatum and the cerebral
cortex.

The intralaminar nuclei (centromedian and parafascicular) are crucial elements in the
striatothalamocortical circuitry. The centromedian nucleus forms a nodal point in
sensorimotor, and the parafascicular nucleus an important relay in the associative-limbic
components of the circuit.

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Figure 13-9. Schematic diagram of the direct and indirect striatopallidal pathways.
GABA, gamma-aminobutyric acid; GPe, external segment of globus pallidus; GPi,
internal segment of globus pallidus; SNr, substantia nigra pars reticulata; +,
facilitatory pathway; -, inhibitory pathway.

B. MINOR OUTPUT
Minor outputs from the internal segment of the globus pallidus and the substantia nigra
pars reticulata go to the following areas.

1. Nucleus Tegmenti Pedunculopontis.

This projection serves to link the basal ganglia with the spinal cord via the reticulospinal
tract. The projection to the nucleus tegmenti pedunculopontis assumes particular
significance because of the multiple connections and functions of this nucleus, the best
known being
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motor function (mesencephalic locomotor center), arousal, and sleep. Others include
motivation, attention, and learning.

Figure 13-10. Schematic diagram of the efferent connections of internal segment of

globus pallidus and substantia nigra pars reticulata. GPe, external segment of globus
pallidus; GPi, internal segment of globus pallidus; SNr, substantia nigra pars

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reticulata. (From J Child Neurol 9:249–260, 1994, figure 2, with permission from
Decker Periodicals.)

2. Habenular Nucleus
Via this connection, the basal ganglia are linked with the limbic system.

3. Superior Colliculus.
Through this pathway, the basal ganglia are linked (via the tectospinal tract) to the
spinal cord and (via the tectoreticular tract) to brain stem nuclei related to head and eye
movements.

C. SIDE TRACK OUTPUT

This output reciprocally relates the external segment of the globus pallidus with the
subthalamic nucleus. The neurotransmitter is GABA.

The inputs and outputs of the basal ganglia are schematically summarized in Figure 13-
11.

The basal ganglia and its related neural systems may be viewed as composed of (1) a
core and (2) regulators of the core. The core is composed of the striatum and its pallidal
and nigral targets. The regulators of the core fall into two categories: (1) regulators of
the striatum and (2) pallidonigral regulators (Figure 13-12).

Subthalamic Nucleus (Figure 13-13)

Like the striatum, the subthalamic nucleus is divided into sensorimotor, associative, and
limbic territories. It receives inputs from the following sources:

Corticosubthalamic Projection. Although the striatum is the main site of cortical

input, the subthalamic nucleus receives excitatory glutamatergic projections
primarily from the primary motor area, with minor contributions from prefrontal,
premotor, and supplementary motor cortices. They are somatotopically and
topographically organized, similar to the corticostriate projections.

Pallidosubthalamic Projection. A massive GABAergic projection from the external

segment of globus pallidus to the subthalamic nucleus plays an important role in the
indirect pathway that links input and output nuclei of the basal ganglia.

Thalamosubthalamic Projection. Centromedian and parafascicular nuclei comprise

the major sources of this projection.

Nigrosubthalamic Projection. This dopaminergic pathway originates from the

substantia nigra pars compacta and the ventral tegmental area as collateral
branches from the nigrostriatal pathway.

Reticulosubthalamic Projection. The dorsal nucleus of the raphe is the main

source of this serotonergic projection.

The major outflow from the subthalamic nucleus is to both segments of globus
pallidus and to the substantia nigra pars reticulata. Subthalamic nucleus lesions or
lesions interrupting the subthalamic–pallidal connection are responsible for the violent
hyperkinesia of ballism. The subthalamic nucleus has been a favorable site for deep brain
stimulation in treatment of Parkinson's disease. Information flow through the striatum
and the subthalamic nucleus is different. Cortical input to the subthalamic nucleus is from
the frontal lobe, whereas the striatum receives from virtually all cortical areas. The

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output from the striatum is GABAergic (inhibitory) and slow, whereas subthalamic nucleus
output is glutamatergic (excitatory) and fast. Subthalamic projection to the output nuclei
interacts with many output neurons, whereas striatal projection is focused on a single
neuron. The pathway through the subthalamic nucleus thus provides a fast, divergent
excitation, whereas the pathway through the striatum provides focused inhibition of the
output nuclei. These two pathways provide the anatomic basis for the model of focused
inhibition and surround excitation of output nuclei.

Ventral (Limbic) Striatum

Currently, the term ventral striatum refers to the following nuclei: nucleus accumbens
septi, striate-like deep portions of the olfactory tubercle and ventral parts of the caudate
nucleus, and the putamen (Table 13-1). The ventral striatum receives fibers from the
following sources: hippocampus, amygdala, entorhinal and perirhinal cortices (areas 28
and 35), anterior cingulate cortex (area 24), medial orbitofrontal cortex, and widespread
sources within the temporal lobe. Dopaminergic input to the ventral striatum is
substantial. The output from the ventral striatum is to the ventral pallidum. As is evident
from its connections, the ventral striatum is related to the limbic system. The
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ventral striatum has been the focus of various studies suggesting that the nucleus
accumbens septi plays a prominent role in mediating reward and motivation, with
potential involvement in drug addiction and mental disorders such as schizophrenia and
Tourette syndrome.

Figure 13-11. Simplified schematic summary diagram of afferent and efferent

connections of the basal ganglia showing that the striatum is the major receiving
area, whereas the internal segment of globus pallidus and substantia nigra pars
reticulata constitute the major output nuclei. +, facilitation; -, inhibition; DA,
dopamine; Ser, serotonin; NA, noradrenaline; GPe, external segment of globus
pallidus; GPi, internal segment of globus pallidus; SNr, substantia nigra pars
reticulata; VA, ventral anterior nucleus; VL, ventrolateral nucleus; CM, centromedian
nucleus; DM, dorsomedial nucleus. (Modified from J Child Neurol 9:249–260, 1994,
figure 3, with permission from Decker Periodicals.)

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Figure 13-12. Schematic diagram showing the organization of the basal ganglia–
associated neural system into a core made up of the striatum and its pallidonigral
targets, and regulators acting either on the striatum or pallidonigral components of
the core.

Corticostriatothalamocortical Loops
Corticostriatothalamocortical connections are organized in five parallel and largely
segregated loops (circuits): motor, oculomotor, dorsolateral prefrontal, lateral
orbitofrontal, and limbic (Figure 13-14). Their names reflect the major cortical area(s) of
origin and/or function of each. Information flow in each circuit passes from its cortical
area of origin to the striatum (caudate, putamen, or ventral striatum), pallidum (dorsal
or ventral), and thalamus before returning to the major cortical area(s) from which each
circuit originated. According to this model, cortical areas that are targets of output from
a channel are the cortical areas from which the major input to the channel originated.
Injury to a circuit results in selective disturbance in motor, cognitive, or emotional
behavior.

A. MOTOR LOOP PATHWAY

The motor loop pathway is centered on the putamen and its connections (Figure 13-14A).
The putamen of primates receives somatotopically organized (arm, leg, face) inputs from
the primary motor, primary sensory, somatosensory association, premotor, and
supplementary motor cortices. Within each of these anatomic subchannels, further levels
of functional organization
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exist pertaining to such behavioral variables as target location, limb kinematics, and
muscle pattern. The putamen projects to both segments of the globus pallidus and to the
substantia nigra pars reticulata. The internal pallidal segment projects to ventral lateral,
ventral anterior, and centromedian nuclei of the thalamus, whereas the substantia nigra
pars reticulata projects to the ventral anterior thalamic nucleus. The motor loop is
completed by thalamocortical projections to the supplementary motor, premotor, and
primary motor cortices.

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Figure 13-13. Schematic diagram of the input and output of the subthalamic
nucleus. Glu, glutamatergic pathway; DA, dopaminergic pathway; Ser, serotonergic
pathway; GABA, GABAergic pathway.

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Figure 13-14. Schematic diagrams showing the anatomic substrates of the motor
loop A, oculomotor loop B, dorsolateral prefrontal loop C, lateral orbitofrontal loop
D, and the limbic loop E. MC, primary motor cortex (area 4); SC, primary sensory
cortex (areas 3, 1, and 2); SSA, somatosensory association cortex (area 5); PM,
premotor cortex; SMA, supplementary motor area; GPi, internal segment of globus
pallidus; SNr, substantia nigra pars reticulata; STh, subthalamic nucleus; GPe,
external segment of globus pallidus; VLo, ventrolateral nucleus of thalamus, pars
oralis; VApc, ventral anterior nucleus of thalamus, pars parvicellularis; VAmc,
ventral anterior nucleus of thalamus, pars magnocellularis; CM, centromedian
nucleus of thalamus; FEF, frontal eye field (area 8); SEF, supplementary eye field;
DLPC, dorsolateral prefrontal cortex (areas 9 and 10); PPC, posterior parietal cortex;
DMpm, dorsomedial nucleus of thalamus, pars multiformis; SC, superior colliculus;
LOFC, lateral orbitofrontal cortex; DMmc, dorsomedial nucleus of thalamus, pars
magnocellularis; ACC, anterior cingulate cortex; MOFC, medial orbitofrontal cortex.
(From J Child Neurology 9:352–361, 1994, figures 2, 3, 4, 5, to 6, with permission
from Decker Periodicals.)

An offshoot from the pallidothalamic component of the motor loop is a projection from
the internal segment of the globus pallidus to the pedunculopontine nucleus.

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A side loop in this motor pathway passes from the putamen to the external segment of
the globus pallidus and from there to
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the subthalamic nucleus and back to the internal segment of the globus pallidus.

B. OCULOMOTOR LOOP PATHWAY

The oculomotor loop pathway (Figure 13-14B) is centered on the caudate nucleus.
Cortical sources of input to the caudate nucleus include the frontal eye field,
supplementary eye field, dorsolateral prefrontal cortex, and posterior parietal cortex. The
caudate, in turn, projects to the internal segment of the globus pallidus and the
substantia nigra pars reticulata. The thalamic targets of the oculomotor loop include the
ventral anterior and dorsomedial nuclei. The oculomotor loop is completed by tha-
lamocortical projections to frontal eye field and supplementary eye field.

C. DORSOLATERAL PREFRONTAL LOOP PATHWAY

The dorsolateral prefrontal loop pathway (Figure 13-14C) is also centered on the caudate
nucleus. Corticostriate input to this pathway originates from the dorsolateral prefrontal
cortex and posterior parietal cortex. The caudate nucleus projects to the internal segment
of the globus pallidus and the substantia nigra pars reticulata. The thalamic targets of
this pathway are the ventral anterior and dorsomedial nuclei. The loop is completed by
thalamic projections to the dorsolateral prefrontal cortex.

D. LATERAL ORBITOFRONTAL PREFRONTAL LOOP PATHWAY

The lateral orbitofrontal prefrontal loop pathway (Figure 13-14D) is similarly centered on
the caudate nucleus. The cortico-striate projection originates from the lateral
orbitofrontal cortex. The caudate nucleus projects to the internal segment of the globus
pallidus and the substantia nigra pars reticulata. The tha-lamic targets of this pathway
are the dorsomedial and ventral anterior nuclei. The loop is completed by thalamic
projections to the lateral orbitofrontal cortex.

E. LIMBIC LOOP PATHWAY

The limbic loop pathway (Figure 13-14E) is centered on the ventral striatum.
Corticostriate projections originate from the anterior cingulate cortex, medial
orbitofrontal cortex, and widespread areas in the temporal lobe. The ventral striatum
projects to ventral pallidum. The thalamic target of this pathway is the dorsomedial
nucleus. The loop is completed by thalamic projections to anterior cingulate and medial
orbitofrontal cortices. A role for the limbic circuit in the genesis of schizophrenia has
been proposed.

Each of the five circuits has a direct and an indirect pathway from the striatum to the
output nuclei (internal segment of the globus pallidus and substantia nigra pars
reticulata). The direct pathway contains GABA and substance P and directly connects the
striatum with the output nuclei (Figure 13-15). The indirect pathway (Figure 13-16)
connects the striatum with the output nuclei via relays in the external segment of globus
pallidus and the subthalamic nucleus. Activation of the direct pathway tends to disinhibit
thalamocortical target neurons. Activation of the indirect system has a net effect of
increasing the inhibition of thalamocortical target neurons.

Split Pathways
The preceding five circuits (loops) are characterized by parallel, segregated, and closed
connections, in which little, if any, intercommunication takes place. An alternate model
has been proposed that allows for cross-communication between circuits. In this model,
three circuits are proposed: motor, associative, and limbic. Within each of these circuits,
there are both closed and open loops (Figures 13-17). The novel feature of the open and
closed loops (split circuitry) model is that in each split circuit the engaged striatal area
can influence, via its open loop, a cortical field that does not project to it. Thus, it allows

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for the coexistence of different symptoms and signs (motor, cognitive, and emotional) as
a result of a lesion in only one of the circuits. Interaction between split circuits can occur
at two levels, the cerebral cortex and the substantia nigra.

Figure 13-15. Schematic diagram showing the anatomic substrates of the direct
striatopallidal pathway. Gl, glutamate; GABA, gamma-aminobutyric acid; GPi,
internal segment of globus pallidus; SNR, substantia nigra pars reticulata; +,
facilitation; -, inhibition. (Modified from J Child Neurol 9:352–361, 1994, figure 7,
with permission from Decker Periodicals.)

BASAL GANGLIA FUNCTION

The basal ganglia have long been considered central in the control of movement. It is
now widely accepted that they also play a role in nonmotor behavior, including cognition
and emotion.

Motor Function
The basal ganglia play a role in the automatic execution of learned motor plan and in
the preparation for movement. Studies that
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time neuronal discharge in relation to onset of stimulus-triggered movement suggest that
activity within the basal ganglia is initiated at cortical levels. In the cortically initiated
movement, information flow from the cortex to the basal ganglia (Figure 13-18) begins
with a command from the cortex to the striatum that initiates action of striatal neurons.
The nigral input to the striatum provides a continuous damping effect so that cortical
commands will be focused. The input from the thalamus and other sites informs and
updates the striatum of the activity in other systems concerned with movement. The
striatum integrates and feeds information to the globus pallidus and the substantia nigra
pars reticulata. These in turn influence activity of the thalamus and other targets (i.e.,
superior colliculus, reticular formation). According to Marsden, the basal ganglia are
responsible for the automatic execution of a learned motor plan. As a motor skill is
learned, the basal ganglia take over the role of automatically executing the learned
strategy. When basal ganglia are damaged, the individual must revert to a slower, less
automatic, and less accurate cortical mechanism for motor behavior.

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Figure 13-16. Schematic diagram showing the anatomic substrates of the direct
striatopallidal pathway. Gl, glutamate; GABA, gamma-aminobutyric acid; ENK,
enkephalin; GPe, external segment of globus pallidus; GPi, internal segment of
globus pallidus; SNr, substantia nigra pars reticulata; STh, subthalamic nucleus; +,
facilitation; -, inhibition. (Modified from J Child Neurol 9:352–361, 1994, figure 8,
with permission from Decker Periodicals.)

Figure 13-17. Schematic diagram of split motor circuit showing the closed loop and
the open loop of the circuit. (Modified from Neuroscience 63:363–379, 1994, figure
3, with permission from Elsevier Science Ltd.)

Other roles for the basal ganglia in motor control include the preparation for movement.
During both the preparation and execution of movement, separate populations of neurons
within the motor loop discharge selectively in relation to either target location in space,
direction of limb movement, or muscle pattern. Similarly, in the oculomotor loop,
populations of neurons have been described that discharge in relation to visual fixation,
saccadic eye movement, or passive visual stimuli. A subset of caudate neurons has been
shown to participate in the reward-based control of visual attention.

The recognition that basal ganglia neurons respond to stimuli colored by memory or
significance indicates that this region of the brain is concerned with higher-order motor
control. A role for the basal ganglia in Tourette syndrome, a chronic tic disorder
described by the French neuropsychiatrist George Gilles de la Tourette in 1885, has been

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proposed. A hypothetical model for basal ganglia reorganization in tic disorders and
Tourette syndrome has also been proposed.

Gating Function
Several lines of evidence support a role of the basal ganglia in gating of sensory
information for motor control. The benefit of external sensory cues in Parkinson's disease
and the sensory trick in dystonia support such a role. According to the gating hy-
pothesis, in normal subjects, dopamine (inhibitory) and cortical sensorimotor (excitatory)
inputs to the striatum are in physiologic balance. The inhibitory output of the pallidum
thus regulates sensorimotor access. In Parkinson's disease, the loss of dopamine
(inhibitory) will allow cortical facilitation a free hand to stimulate the inhibitory basal
ganglia output. This limits access of sensory information to the motor system and
decreases motor activity (hypokinesia). In Huntington's chorea, loss of basal ganglia
neurons results in a decrease in inhibitory output of the basal ganglia, with a resulting
increase in access of sensory information to the motor system and increased activity.

Figure 13-18. Schematic diagram of information flow in the basal ganglia (1)
Command from cortex initiates action in striatum. (2) Nigral input from SNc to
striatum provides continuous damping of static so that cortical command will be
focused. (3) Input from the thalamus and other sites updates and informs striatum
of activity in other systems. (4) Striatum has an integrator role and feeds its results
to GP and SNr. (5) GP and SNr influence (facilitate or inhibit) activity of thalamus
and other targets (superior colliculus, reticular formation, etc). SNc, substantia nigra
pars compacta; GP, globus pallidus; SNr substantia nigra pars reticulata. (Modified
from J Child Neurol 9:352–361, 1994, figure 9 with permission from Decker
Periodicals.)

Cognitive Function
In addition to their role in motor control, the basal ganglia subserve cognitive
function. Lesions of the dorsolateral prefrontal circuit (loop) result in cognitive
deficits and deficits on tasks that require spatial memory. The basal ganglia play a role in
retrieval of episodic and semantic information for explicit memory and in implicit tasks
that require the initiation or modification of central motor programs.

Lesions in the dorsolateral prefrontal circuit in humans have been linked to cognitive
disturbances in schizophrenia, Huntington's chorea, and Parkinson's disease. Lesions in
the lateral orbitofrontal circuit have been linked to obsessive-compulsive behavior.

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Emotion and Motivation Function

The limbic loop plays a role in emotional and motivational processes. A role for the limbic
loop in schizophrenia and depression
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has also been proposed. Decrease in size of the basal ganglia has been reported in
bipolar disorders.

Figure 13-19. Simplified schematic diagram showing varied types of information

received by the cerebral cortex, and the complementarity of basal ganglia and
cerebellar roles in motor function.

Spatial Neglect
Various studies have implicated the putamen (and to a lesser extent, the caudate) in
spatial neglect with right-sided basal ganglia lesions. Both nuclei are directly connected
with the superior temporal gyrus, which plays a central role in spatial neglect.

COMPLEMENTARITY OF BASAL GANGLIA AND

CEREBELLUM IN MOTOR FUNCTION
Review of basal ganglia and cerebellar structure, connectivity, and organization reveals
many features in common. Both are components of the motor system, both influence
cerebral cortical activity via the thalamus, both are linked with the cerebral cortex via
recurrent loops, both have internal (local) circuitry that modulates loop activity, and both
receive modulating inputs that influence their activities (climbing fibers in the cerebellum
and dopaminergic input in the basal ganglia).

The emerging concept (Figure 13-19) of the complementarity of basal ganglia and
cerebellum in motor function suggests that the basal ganglia function as context
encoders, providing to the cerebral cortex information that could be useful in planning
and gating of action. The cerebellum, in contrast, functions as pattern generator and
executor. According to this concept, the cerebral cortex, which receives diverse sensory
information from the periphery via the different ascending tracts, as well as complex
information already processed within the basal ganglia and cerebellum, serves two
functions: a repository function to receive this diverse information, compute it, and share
it with the basal ganglia and cerebellum and an executive function to implement the
action emanating from its collective computation process.

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Table 13-4. Blood Supply of Basal Ganglia

Middle cerebral, Anterior cerebral, Internal carotid,

lateral striate medial striate anterior choroidal
branch branch

Caudate
nucleus

Head × ×

Body ×

Tail ×

Putamen

Rostral ×

Caudal ×

Globus
pallidus

Lateral × ×

Medial ×

BLOOD SUPPLY (Table 13-4)

The basal ganglia receive their blood supply from perforating (lenticulostriate)
branches of the middle and anterior cerebral arteries and the anterior choroidal
branch of the internal carotid artery. The caudate and putamen nuclei (the striatum) are
supplied mainly by the lateral striate branches of the middle cerebral artery.
Rostromedial parts of the head of the caudate nucleus receive blood supply from the
medial striate artery (of Huebner), a branch of the anterior cerebral artery. The tail of
the caudate nucleus and caudal part of the putamen receive branches of the anterior
choroidal artery. Most of the globus pallidus is supplied by the anterior choroidal branch
of the internal carotid artery. The lateral (outer) segment of the globus pallidus receives
blood supply also from the lateral striate branch of the middle cerebral artery.

TERMINOLOGY
Ballism (Greek ballismos, “jumping”).
Violent involuntary movement due to a lesion in the subthalamic nucleus.

Caudate nucleus (Latin, “having a tail”).

The caudate nucleus is so named because it has a long extension or tail.

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Chorea (Latin from Greek choros, “a dance”).

Disorder of the neostriatum causing irregular, involuntary movements of the limbs or
face. Formerly called St. Vitus dance.

Corpus striatum (Latin corpus, “body” striatu, “striped”).

Gray matter comprising caudate, putamen, and globus pallidus with striped appearance
produced by myelinated fibers traversing the gray matter.

Extrapyramidal system.
Vague term introduced but not defined by the British neurologist Kinnier Wilson.
Currently used to refer to the basal ganglia and their connections.
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Ferrier, Sir David (1843–1928).

Scottish neurophysiologist and neurologist who made many significant contributions to
cerebral localization, including localization of auditory function to the superior temporal
gyrus among other sensory and motor areas.

Galen, Claudius (A.D. 130–200).

Founder of the galenic system of medicine. Described the great cerebral vein (of Galen)
and the choroid vein among many other brain structures, including seven pairs of cranial
nerves. He localized mental functions in the cerebrum rather than in the ventricles.

Globus pallidus (Latin globus, “a ball or round mass,” pallidus, “pale”).

The paler inner part of the lentiform nucleus.

Lentiform nucleus (Latin lens, “lentil” forma, “shape”).

Lentiform nucleus (putamen and globus pallidus) so named because it is shaped like a
lentil.

Neostriatum (Greek neos, “new”; Latin striatus, “striped”).

The phylogenetically newer part of the corpus striatum comprises the caudate and
putamen nuclei.

Paleostriatum (Greek palaios, “ancient”; Latin striatus, “striped”).

The phylogenetically older part of the corpus striatum comprises the globus pallidus.

Pallidum (Latin pallidus, “pale”).

The paler part of the basal ganglia comprises the globus pallidus.

Putamen (Latin, “shell”).

Lateral part of the lentiform nucleus.

Striatum (Latin striatus, “striped”).

The caudate and putamen, so named because of their striped appearance in sections.

Substantia nigra (Latin, “black substance”).

Group of neurons between the cerebral peduncle and midbrain tegmentum. So named
because of their melanin-containing neurons.

Vicq d'Azir, Felix (1748–1794).

French physician to queen Marie Antoinette. Among his many contributions are his
descriptions of the insula (before Reil), the substantia nigra, and the mamillothalamic
tract (tract of Vicq d' Azir).

SUGGESTED READINGS
Afifi AK: Basal ganglia: Functional anatomy and physiology. Part I. J Child Neurol
1994; 9:249–260.

Afifi AK: Basal ganglia: Functional anatomy and physiology. Part II. J Child Neurol

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1994; 9:352–361.

Afifi AK, Uc EY: Cortical–subcortical circuitry for movement, cognition and behavior.
In CE Coffey, RA Brumback (eds): Textbook of Pediatric Neuropsychiatry.
Washington, American Psychiatric Press, 1998:65–100.

Albin RL et al: The functional anatomy of basal ganglia disorders. Trends Neurosci
1989; 12:366–375.

Alexander GE et al: Basal ganglia–thalamocortical circuits: Parallel substrates for

motor, oculomotor, “prefrontal” and “limbic” functions. Prog Brain Res 1990; 85:119–
146.

Butters N et al: Specificity of the memory deficits associated with basal ganglia
dysfunction. Rev Neurol 1994; 150:580–587.

Carpenter MB et al: Connections of the subthalamic nucleus in the monkey. Brain Res
1981; 224:1–29.

Cossette M, Levesque M, Parent A: Extrastriatal dopaminergic innervation of human

basal ganglia. Neurosci Res 1999; 34(Suppl):51–54.

Flaherty AW, Graybiel AM: Anatomy of basal ganglia. In Marsden CD, Fahn S (eds):
Movement Disorders. Boston, Butterworth-Heinemann, 1994:3–27.

Goldman-Rakic PS: Cytoarchitectonic heterogeneity of the primate neostriatum:

Subdivision into island and matrix cellular compartments. J Comp Neurol 1982;
205:398–413.

Graybiel AM: Neurotransmitters and neuromodulators in the basal ganglia. Trends

Neurosci 1990; 13:244–254.

Graybiel AM: The basal ganglia. Curr Biol 2000; 10:R509–511.

Haber S, McFarland NR: The place of the thalamus in frontal cortical–basal ganglia
circuits. Neuroscientist 2001; 7:315–324.

Houk JC, Wise SP: Distributed modular architectures linking basal ganglia,
cerebellum, and cerebral cortex: Their role in planning and controlling action.
Cerebral Cortex 1995; 2:95–110.

Joel D, Weiner I: The organization of the basal ganglia–thalamocortical circuits: Open

interconnected rather than closed segregated. Neuroscience 1994; 63:363–379.

Kampe KK et al: Reward value of attractiveness and gaze. Nature 2001; 413:589.

Lynd-Balta E, Haber SN: The organization of midbrain projections to the striatum in

the primate: Sensorimotor-related striatum versus ventral striatum. Neuroscience
1994; 59:625–640.

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Marsden CD: Movement disorders and the basal ganglia. Trends Neurosci 1986;
9:512–515.

McGeer EG et al: Neurotransmitters in the basal ganglia. Can J Neurol Sci 1984;
11:89–99.

Nauta HJW, Cole M: Efferent projections of the subthalamic nucleus: An

autoradiographic study in monkey and cat. J Comp Neurol 1978; 180:1–16.

O'Connor WT: Functional neuroanatomy of basal ganglia as studied by dual-probe

microdialysis. Nucl Med Biol 1998; 25:743–746.

Parent A: Extrinsic connections of the basal ganglia. Trends Neurosci 1990; 13:254–
258.

Penney JB, Young AB: GABA as the pallidothalamic neurotransmitter: Implications for
basal ganglia function. Brain Res 1981; 207:195–199.

Prensa L et al: Dopaminergic innervation of human basal ganglia. J Chem Neuroanat

2000; 20:207–213.

Rolls E: Neurophysiology and cognitive functions of the striatum. Rev Neurol 1994;
150:648–660.

Sadikot AF et al: The center median and parafascicular thalamic nuclei project
respectively to the sensorimotor and associative-limbic striatal territories in the
squirrel monkey. Brain Res 1990; 510:161–165.

Schneider JS et al: Deficits in orofacial sensorimotor function in Parkinson's disease.

Ann Neurol 1986; 19:275–282.

Segawa M: Development of the nigrostriatal dopamine neuron and the pathways in

the basal ganglia. Brain Dev 2000; 22(Suppl):S1–S4.

Selemon LD, Goldman-Rakic PS: Common cortical and subcortical targets of the
dorsolateral prefrontal and posterior parietal cortices in the rhesus monkey: Evidence
for a distributed neural network subserving spatially guided behavior. J Neurosci
1988; 8:4049–4068.

Selemon LD, Goldman-Rakic PS: Longitudinal topography and interdigitations of

corticostriatal projections in the rhesus monkey. J Neurosci 1985; 5:776–794.

Smith AD, Bolam JP: The neural network of the basal ganglia as revealed by the
study of synaptic connections of identified neurones. Trends Neurosci 1990; 13:259–
265.

Staines WA et al: Neurotransmitters contained in the efferents of the striatum. Brain

Res 1980; 194:391–402.

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Steckler T et al: The pedunculopontine tegmental nucleus: A role in cognitive

processes? Brain Res Rev 1994; 19:298–318.

Stoetter B et al: Functional neuroanatomy of Tourette syndrome: Limbic-motor

interactions studied with FDG PET. Adv Neurol 1992; 58:213–226.

Yelnik J: Functional anatomy of the basal ganglia. Movement Dis 2002; 17 Suppl
3:S15–S21.

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Editors: Afifi, Adel K.; Bergman, Ronald A.

Title: Functional Neuroanatomy: Text and Atlas, 2nd Edition

Copyright ©2005 McGraw-Hill

> Table of Contents > Part I - Text > 14 - Basal Ganglia: Clinical Correlates

14
Basal Ganglia: Clinical Correlates

Hyperkinetic Disorders
Chorea
Athetosis
Ballism
Dystonia
Tic Disorder
Tourette Syndrome
Hypokinetic Disorders
@CC2:Parkinsonism

KEY CONCEPTS

Movement disorders associated with basal ganglia lesions

are of two categories: hyper- and hypokinetic or akinetic.

There are two varieties of chorea: benign reversible

Sydenham's chorea and malignant progressive Huntington's
chorea.

Athetosis frequently accompanies chorea

(choreoathetosis) and involves predominantly distal parts of
extremities.

Ballism, a violent flinging movement of extremities

contralateral to a lesion in the subthalamic nucleus.

Dystonia may be focal (writer's cramp), regional

(torticollis), or generalized.

Tourette syndrome is a conglomerate of signs and

symptoms that includes motor and vocal tics and behavioral

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abnormalities (attention, compulsiveness, etc.).

Parkinson's disease is characterized by tremor, rigidity,

and akinesia or hypokinesia.

Depletion of dopaminergic neurons in the substantia nigra

and, secondarily, dopamine stores in the striatum are the
pathologic landmarks of Parkinson's disease.

Diseases of the basal ganglia are associated with abnormal involuntary

movements that typically occur at rest and disappear in sleep. They are
generally divided into two categories: hyperkinetic, characterized by
excessive involuntary movement and hypokinetic, characterized by slow
movement (bradykinesia) or absence or difficulty in initiating
movement (akinesia).

The hyperkinetic variety is seen in such disorders as chorea,

athetosis, ballism, dystonia, tremor, and tics. The hypokinetic
variety is seen largely in Parkinson's disease. Despite voluminous
literature on basal ganglia, clinicoanatomic correlations are not
available for all basal ganglia disorders. However, the following
anatomic loci for pathology are agreed on: substantia nigra in
Parkinson's disease, caudate nucleus in chorea, and subthalamic
nucleus in ballism. Discrete lesions in the caudate nucleus are more
likely to cause behavioral and cognitive manifestations, whereas similar
lesions in the putamen are more likely to be associated with motor
manifestations. These observations are consistent with known anatomic
connections of these nuclei. Abulia (a syndrome of apathy and loss of
initiative, spontaneous thought, and emotional response) has been
described in association with discrete lesions in the caudate nucleus.

The genetic basis of many movement disorders is being increasingly

recognized. Familiarity with such disorders is important in making
accurate diagnoses and in family counseling.

HYPERKINETIC DISORDERS

Chorea
Chorea is a disorder of movement characterized by sudden, frequent,
involuntary, purposeless, and quick jerks of the trunk, extremities, and
head associated with facial grimaces. The term chorea is derived from

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the Greek word choreia, for “dance.” The lesion producing chorea is
believed to be in the caudate nucleus (Figure 14-1), although the
pathology is often diffuse and multiple involving other neural
structures.

At the cellular level, reduced levels of the following neurotransmitters

and neuropeptides have been reported: gamma-aminobutyric
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acid (GABA), acetylcholine, enkephalin, substance P, dynorphin, and
cholecystokinin. Loss of noradrenergic neurons in the locus ceruleus
also has been reported. Two varieties of chorea are known to occur.

Figure 14-1. Coronal brain section from a patient with

Huntington's chorea showing atrophy of the caudate nucleus.

These are a benign, reversible variety (Sydenham's chorea)

occurring in children as a complication of rheumatic fever and a
malignant variety (Huntington's chorea) that is a hereditary (autosomal
dominant) disorder linked to a single gene defect on chromosome 4
and associated with progressive mental and cognitive deterioration.

Appendicular musculature is predominantly involved in the Sydenham's

variety, whereas truncal musculature is predominantly involved in the
Huntington's variety. Choreic patients are often unable to sustain a
tight hand grip (milkmaid's grip) and cannot maintain a protruded
tongue, which tends to dart in and out irregularly (trombone tongue).
Figure 14-2 is a diagram showing how the striatal lesion in
Huntington's chorea results in random expression of unwanted
movement. A variety of chorea associated with pregnancy (chorea
gravidarum) usually occurs during the second trimester of pregnancy in

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patients with a previous history of Sydenham's chorea.

Athetosis
Athetosis is a disorder of movement characterized by slow, writhing,
continuous, wormlike movements of the distal parts of the extremities,
chiefly the fingers, which show bizarre posturing.

The term athetosis is derived from the Greek word athetos,

meaning “without position.” The lesion producing athetosis is
probably in the putamen. Differentiation of athetosis from chorea may
at times be difficult because it is common to see patients with mixed
choreoathetosis.

Ballism
Ballism is a disorder of movement usually caused by a vascular lesion
in the subthalamic nucleus.

The term ballism is derived from the Greek word ballismos,

meaning “jump or throw.” The movements of the limbs in this
disorder are sudden, quick, continuous, unusually violent, and flinging
in nature. The hyperkinesia is usually confined to one side of the body
(hemiballismus) contralateral to the lesion in the subthalamic nucleus.

Figure 14-2. Schematic diagram showing how the striatal lesion

in Huntington's chorea affects the indirect striatopallidal pathway
and results in random expression of movement. (1) Loss of matrix
neurons projecting to external segment of globus pallidus (GPe).
(2) Disinhibition of GPe. (3) Excess inhibition of subthalamic

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nucleus (STh). (4) Decreased excitation of internal segment of

globus pallidus (GPi) and substantia nigra pars reticulata (SNr).
(5) Less inhibition of thalamus. (6) Random expression of
unwanted movement. (Modified from Adel K. Afifi: Basal ganglia:
Functional anatomy and physiology. Part II. J Child Neurol 9:352–
361, 1994, figure 12, with permission from Decker Periodicals.)

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Dystonia
Dystonia is characterized by a twisting, slow, contorting, involuntary
movement that is somewhat sustained and often repetitive.

The term dystonia is derived from the Greek words dys and tonos,
for “bad tone.” The affected body part may, with time, develop a
fixed abnormal posture. Dystonia may be focal (involving a single body
part such as the hand), segmental (involving two or more adjacent
body parts such as the neck and arm), or generalized. Writer's cramp,
an involuntary contraction of hand or finger muscles while writing, is
an example of focal dystonia. Torticollis (involuntary turning or tilting
of head) combined with facial dystonia constitutes segmental dystonia.
Idiopathic torsion dystonia, a hereditary (autosomal dominant)
disorder that begins in childhood, is an example of generalized
dystonia.

No obvious specific pathology has been defined in the basal ganglia in

hereditary idiopathic dystonia. However, discrete lesions in the
striatum (Figure 14-3) caused by stroke, tumor, or trauma have been
associated with the development of dystonia.

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Figure 14-3. Computed tomography scan of brain showing a

lesion in the caudate nucleus and putamen in a patient with
dystonia.

Tic Disorder
Tics are brief, sudden, rapid, and intermittent movements (motor tics)
or sounds (vocal tics). Tics may be simple or complex. Simple tics are
caused by contractions of only one group of muscles (e.g., eye
blinking) or a single meaningless sound (e.g., “ah”). Complex tics
consist of coordinated sequenced movement of more than one group of
muscles (e.g., eye blinking and shoulder shrug) or meaningful
verbalizations. Tics may be transient (days to weeks) or chronic
(months to years), and they may be a prelude to Tourette syndrome.

Tourette Syndrome
Tourette syndrome is characterized by motor and vocal tics. Motor tics
are sudden, brief involuntary movements involving muscles in different
body parts such as eye blinking and shoulder shrugging.

Vocal tics consist of gutteral sounds, grunts, or verbalization of

words and phrases. The motor manifestations are often associated
with behavioral abnormalities such as attention deficits and compulsive
ritualistic behaviors.

Previously considered a psychiatric or emotional disorder, Tourette

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syndrome is currently believed to have organic etiology.

Morphometric magnetic resonance imaging (MRI) studies in Tourette

syndrome reveal volume reduction in the caudate nucleus and the
lenticular nucleus.

Postmortem studies in Tourette syndrome brains, although limited in

number, report a decrease in overall volume of the striatum coupled
with an increase in the number of small neurons and decreased
dynorphin in striatopallidal axons. Based on the motor manifestations
of Tourette syndrome (tics), the motor circuit of the basal ganglia or
some subunits of it have been proposed as the primary site of
pathology. The associated behavioral manifestations lend credence to
involvement of the limbic basal ganglia circuit. An inhibitory limbic
system drive acting on the motor cortex and motor striatum (Figure
14-4) has been proposed as instrumental in the genesis of tics.

Tourette syndrome is named after Gilles de la Tourette, a French

physician who described the syndrome in 1885. The first afflicted
sufferer was reportedly the French prince of Condé, who had to stuff
clothes into his mouth to stop himself from barking (vocal tics) at King
Louis XIV.

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Figure 14-4. Schematic diagram depicting the roles of the limbic

system drive, cerebral cortex, and subcortical motor centers in the
genesis of tics. In early stages of tics A, the cerebral cortex plays
the major role in tic generation (thick arrow), while subcortical
motor centers play a minor role (thin arrow). In late stages of tics
B, both the cortex and subcortical centers are equally capable of
generating tics. (From A. E. Lang, et al: “Signing tics”: Insights
into the pathophysiology of symptoms in Tourette's syndrome. Ann
Neurol 33:212–215, 1993, figures A and B, with permission.)

Figure 14-5. Schematic diagram showing how dopamine depletion

in Parkinson's disease affects the direct and indirect striatopallidal

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pathways and movement. A: Slowness and poverty of movement.

(1) Loss of excitatory dopamine (DA) input to striatal neurons
projecting to internal segment of globus pallidus (GPi) and
substantia nigra pars reticulata (SNr). (2) Decreased inhibition of
GPi and SNr neurons. (3) Decreased disinhibition of thalamic
neurons. (4) Slowness and poverty of movement. B: Inhibition of
unwanted movement; difficulty switching to new behavior. (1)
Loss of inhibitory DA input to striatal neurons projecting to
external segment of globus pallidus (GPe). (2) Increased inhibition
of GPe neurons. (3) Disinhibition of subtha-lamic nucleus (STh)
input to GPi and SNr. (4) Reinforcing inhibition of unwanted
movement. (Modified from Adel K. Afifi: Basal ganglia: Functional
anatomy and physiology. Part II. J Child Neurol 9:352–361, 1994,
figure 11, with permission from Decker Periodicals.)

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HYPOKINETIC DISORDERS

Parkinsonism
Parkinson's disease is characterized by tremor, rigidity, and
hypokinesia or akinesia. The tremor of Parkinson's disease is rhythmic
fine tremor recurring at the rate of 3 to 6 cycles per second and is best
seen when the extremity is in a fixed posture rather than in motion (in
contradistinction to cerebellar tremor, which is seen during movement
of an extremity).

The rigidity is characterized by resistance to passive movement of

a joint throughout the range of motion (cogwheel rigidity),
resulting from an increase in tone of muscles with opposing action
(agonists and antagonists).

Hypokinesia or akinesia is manifested by a diminution or loss of

associated movements (e.g, swinging of upper extremities when
walking), difficulty in initiating movement, and slow movement. The
hypokinesia often causes difficulties for patients in getting dressed,
feeding, and maintaining personal hygiene.

The coexistence of rigidity and hypokinesia in facial muscles accounts

for decreased blinking rate and the expressionless mask facies.

The lesion producing Parkinson's disease is widespread in the central

nervous system but affects the dopaminergic neurons in the substantia
nigra pars compacta most consistently.

The lesion thus affects the dopaminergic nigrostriatal fiber system

and depletes the striatal dopamine stores. The disease thus can

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be ameliorated by administration of L-dopa. Figure 14-5 is a diagram

showing how dopamine depletion contributes to the poverty of
movement and the difficulty in switching to new behaviors. In addition
to the depletion of dopamine, reduction in concentration of the
following neuropeptides occurs: enkephalin, somatostatin, neurotensin,
substance P, and bombesin. Decrease in angiotensin II binding sites
and loss of adrenergic neurons in the locus ceruleus also have been
reported.

Prior to the discovery of the significance of L-dopa in parkinsonism, the

tremor and rigidity of parkinsonism were treated by surgical lesions in
the globus pallidus or thalamus. The former was more effective in the
relief of rigidity and the latter in the relief of tremor.

Surgical approaches to treatment became less popular following the

introduction of L-dopa therapy. Based on recent physiologic and
anatomic data, it is now recognized that hyperactivity of the
subthalamic nucleus is an important feature of Parkinson's disease.
Hyperactivity of the subthalamic nucleus increases the excitatory drive
onto the internal segment of globus pallidus and substantia nigra pars
reticulata, which, in turn, overinhibits the motor projections to the
thalamus. Thus, the subthalamic nucleus and internal segment of
globus pallidus have become the preferred surgical targets to treat
selected drug-refractory patients. Lesions in these sites (pallidotomy
and subthalamic nucleotomy) or functional blockade (by deep brain
stimulation) have been increasingly used.

TERMINOLOGY
Abulia (Greek, “without will”).
A state in which the patient manifests lack of initiative and spontaneity
with preserved consciousness.

Akinesia (Greek a, “negative, without” kinesis, “movement”).

Lack of spontaneous movement as seen in Parkinson's disease.

Athetosis (Greek athetos, “without position or place”).

Involuntary movement disorder characterized by irregular, slow,
writhing movements of distal parts of extremities. The condition was
described by William Hammond in 1871.

Ballism (Greek ballismos, “jumping, throwing”).

Violent flinging movements usually of one side of the body due to a
lesion in the contralateral subthalamic nucleus.

Bradykinesia (Greek brady, “slow”; kinesis, “movement”).

Abnormal slowness of movement as seen in Parkinson's disease.

Chorea (Latin choros, “a dance”).

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Irregular involuntary movements of the limbs or face secondary to

striatal lesion. The names of four saints (Vitus, Valentine, Modesti, and
John) have been associated with chorea over the ages. The most used
is St. Vitus's dance.

Cogwheel rigidity.
The arrhythmic, repetitive alteration of resistance to passive stretch
occurring during passive movement of a joint; palpable tremor. A sign
of basal ganglia disorder.

Dystonia.
Sustained and patterned muscle contractions of agonists and
antagonist muscles leading to twisting involuntary movements. The
clinical condition was first described by German physician Marcus
Walter Schwalbe in 1908.

Huntington's chorea.
Progressive neurodegenerative disorder inherited as an autosomal
dominant trait. The disease was imported to America from Suffolk in
the United Kingdom by the emigrant wife of an Englishman in 1630.
Her father was choreic,
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and his father disapproved of the match because of the bride's father's
illness. The disorder is named after George Sumner Huntington, a
general practitioner who described the disease.

Hypokinesia.
Poverty of willed movement.

Milkmaid's grip.
Variability in the isometric force exerted by the wrist and by individual
fingers during attempts to grasp an object. The sign is present in
chorea.

Parkinsonism.
A chronic progressive degenerative disease characterized by tremor,
rigidity, and akinesia. It was described initially by English physician
James Parkinson under the rubric “shaking palsy” published in 1817.
Earlier descriptions were made by Galen, Boetius, and others.

Sydenham's chorea.
An acute, benign, and self-limited chorea, a manifestation of rheumatic
fever. Named after Thomas Sydenham, the English physician who first
described the disorder in 1686.

Tics.
Sudden, brief, repetitive involuntary movements that may be
suppressed for a period by effort or will.

Torticollis (Latin tortere, “to twist” collis, “neck”).

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A focal dystonia causing intermittent or persistent rotation of the neck.

Tourette syndrome.
A dominantly inherited syndrome characterized by motor and vocal tics
and a variety of behavioral symptoms and signs that include attention
deficits and obsessive-compulsive behaviors. The syndrome is named
after George-Edmond-Albert-Brutus Gilles de la Tourette, the French
neuropsychiatrist who described the condition in 1885. The first
recorded sufferer was the French prince of Condé, who stuffed clothes
into his mouth to stop himself from barking at King Louis XIV.

Trombone tongue.
Repetitive protrusion and replacement of the tongue seen
characteristically in Huntington's disease.

Writer's cramp.
A focal (hand) occupational dystonia precipitated by writing or typing.
When first described by Bell in 1830, it was considered a psychiatric
disorder.

SUGGESTED READINGS
Bhatia KP, Marsden CD: The behavioral and motor consequences of
focal lesions of the basal ganglia in man. Brain 1994; 117:859–876.

Ceballos-Baumann AO et al: Restoration of thalamocortical activity

after posteroventral pallidotomy in Parkinson's disease. Lancet
1994; 344:814.

Dogali M et al: Stereotactic ventral pallidotomy for Parkinson's

disease. Neurology 1995; 45:753–761.

Koller WC: Chorea, hemichorea, hemiballismus, choreoathetosis

and related disorders of movement. Curr Opin Neurol Neurosurg
1991; 4:350–353.

Lavoie B et al: Immunohistochemical study of the basal ganglia in

normal and parkinsonian monkeys. Adv Neurol 1992; 58:115–121.

Lozano AM et al: Effect of GPi pallidotomy on motor function in

Parkinson's disease. Lancet 1995; 346:1387–1388.

Munro-Davis LE et al: The role of the pedunculopontine region in

basal-ganglia mechanism of akinesia. Exp Brain Res 1999;

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129:511–517.

Obeso JA et al: Pathophysiologic basis of surgery for Parkinson's

disease. Neurology 2000; 55(Suppl 6):S7–S12.

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Editors: Afifi, Adel K.; Bergman, Ronald A.

Title: Functional Neuroanatomy: Text and Atlas, 2nd Edition

Copyright ©2005 McGraw-Hill

> Table of Contents > Part I - Text > 15 - Cerebellum

15
Cerebellum

Gross Features
Lobes and Subdivisions
Somatotopic Representation
Microscopic Structure
Cerebellar Cortex
Principal (Purkinje) Neuron
Intrinsic Neurons
Cerebellar Glomerulus
Cerebellar Input
Inferior Cerebellar Peduncle
Middle Cerebellar Peduncle
Superior Cerebellar Peduncle
Internal Cerebellar Circuitry
Mossy Fiber Input
Climbing Fiber Input
Cerebellar Output
Deep Cerebellar Nuclei
Dentate Nucleus
Interposed Nuclei
Fastigial Nucleus
Cerebrocerebellar and Cerebellocerebral Circuitries
Neurotransmitters
Cerebellar Physiology
Cerebellar Cortex
Deep Cerebellar Nuclei
Cerebellar Function
Historical Perspective
Motor Functions of the Cerebellum
Neocerebellar Signs
Archicerebellar and Paleocerebellar Signs
Ocular Motor Signs
Cerebellum and Epilepsy
Complementarity of Basal Ganglia and Cerebellum in Motor Function
Nonmotor Functions of the Cerebellum
The Cerebellum and Autism
Sensory Systems and Cerebellum
Arterial Supply
Venous Drainage

KEY CONCEPTS

The cerebellum is divided into three imperfectly delineated lobes or zones based on
morphology, connectivity, function, or phylogeny.

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The cerebellar cortex has three layers and contains five cell types (one principal
and four intrinsic).

The major inputs to the cerebellum are from three sources: spinal cord, vestibular
system, and cerebral cortex.

Within the cerebellum, various inputs are segregated into one of three fiber
systems.

Cerebellar inputs excite Purkinje cells directly via climbing fibers and indirectly via
granule cell axons. Intrinsic cerebellar neurons are excited by cerebellar inputs and in
turn inhibit Purkinje cells.

Deep cerebellar nuclei provide cerebellar output to extracerebellar targets.

Extracerebellar targets include the vestibular and reticular nuclei, red nucleus, and
thalamus.

Signs of cerebellar disorders include asynergia (dyssynergia), dysarthria,

adiadochokinesis, dysmetria, tremor, muscular hypotonia, ataxia, and nystagmus.

Nonmotor roles for the cerebellum in autonomic regulation, behavior, cognition,

and learning are being increasingly documented.

Blood supply of the cerebellum is provided by three arteries from the vertebral–
basilar arterial system. They are the posterior inferior cerebellar, anterior inferior
cerebellar, and superior cerebellar.

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GROSS FEATURES
The cerebellum, or “small brain,” develops from the embryologic rhombic lip, a zone of cells
between the alar and roof plates at the level of the pontine flexure. Although it develops from a
“sensory” region (the rhombic lip), the cerebellum is concerned primarily (but not exclusively)
with motor function.

The cerebellum is located in the posterior fossa of the skull, separated from the occipital lobes
by a dural fold, the tentorium cerebelli. It overlies the dorsal surfaces of the pons and medulla
oblongata and contributes to the formation of the roof of the fourth ventricle.

The cerebellum consists of a midline vermis and two laterally placed hemispheres. The parts of
the hemispheres adjacent to the vermis are known as the paravermal or intermediate zones
(Figure 15-1).

The dorsal cerebellar surface is rather flat; the demarcation of vermis and hemispheres is not
evident on this surface (Figure 15-2). The ventral surface is convex with a deep groove
(vallecula) in the midline through which the vermis is apparent (Figure 15-3).

The adult human cerebellum weighs approximately 150 g (10 percent of brain weight) and has a
surface area of approximately 1000 cm 2 (40 percent of the cerebral cortex).

The cerebellum is connected to the midbrain, pons, and medulla oblongata by three pairs of
peduncles (Figure 15-4).

1. The superior cerebellar peduncle (brachium conjunctivum) connects the cerebellum with the
midbrain.

2. The middle cerebellar peduncle (brachium pontis) connects the pons with the cerebellum.

3. The inferior cerebellar peduncle (restiform and juxtarestiform bodies) connects the medulla
with the cerebellum.

The contents of each of these peduncles are discussed in the chapters on the mesencephalon

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(Chapter 9), pons (Chapter 7), and medulla oblongata (Chapter 5).

The cerebellum consists of a highly convoluted layer of gray matter, the cerebellar cortex,
surrounding a core of white matter that contains the afferent and efferent tracts. The branching
pattern of the white matter was referred to by early anatomists as the arbor vitae (tree of life)
(Figure 15-4). Hence the cortical convolutions in the cerebellum are referred to as folia (leaves)
instead of gyri (term used to describe cortical convolutions in the cerebral cortex). Embedded in
the white matter core are four pairs of deep cerebellar nuclei arranged from lateral to medial
(Figure 15-5).

Figure 15-1. Schematic diagram of ventral surface of the cerebellum showing its
subdivision into vermis, paravermis, and hemisphere.

1. Dentate nucleus

2. Emboliform nucleus

3. Globose nucleus

4. Fastigial nucleus

The globose and emboliform nuclei are referred to collectively as the interposed nucleus. A
commonly used mnemonic to recall the deep cerebellar nuclei is “Don't Eat Greasy Food.”

Lobes and Subdivisions (Table 15-1)

The cerebellum is divided anatomically by two transverse fissures (anterior and
posterolateral or prenodular) into three lobes: anterior, posterior, and flocculonodular. The
demarcation of the three lobes is best seen in midsagittal sections (Figure 15-6). The posterior
lobe contains, on its inferior
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surface, the cerebellar tonsils (Figure 15-3). In cases of increased intracranial pressure such as
occurs in brain tumors, intracranial hemorrhage, or severe head trauma, the cerebellar tonsils
may herniate through the foramen magnum. This tonsillar herniation is a life-threatening
neurologic emergency due to compromise of vital centers in the brain stem.

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Figure 15-2. Photograph of dorsal surface of the cerebellum. (From Gluhbegovic and
Williams: The Human Brain, A Photographic Guide. Harper and Row Publishers, 1980,
courtesy of the authors.)

Figure 15-3. Photograph of ventral surface of the cerebellum. (From Gluhbegovic and
Williams: The Human Brain, A Photographic Guide. Harper and Row Publishers, 1980,
courtesy of the authors.)

The cerebellum is also subdivided into three longitudinal zones, based on the arrangement of
projections from the cerebellar cortex to deep cerebellar nuclei (Figure 15-1). These are the
midline (vermis) zone, the intermediate (paravermal) zone, and the lateral (hemisphere) zone.
The cortex of the vermis projects to the fastigial deep cerebellar nucleus, that of the paravermis
to
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the interposed deep nuclei (emboliform and globose), and that of the cerebellar hemisphere to
the dentate nucleus. The borders that separate each of the transverse and longitudinal lobes
and zones are far from precise. Clear functional subdivisions are thus scarcely possible with
reference to either the transversely oriented lobes or the longitudinally oriented zones.

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Figure 15-4. Section through the cerebral hemisphere and cerebellum showing the three
cerebellar peduncles (superior, middle, inferior). Shown also are the arbor vitae and folia of
the cerebellum.

Figure 15-5. Schematic diagram of unfolded cerebellum showing the four cerebellar nuclei.

Based on fiber connectivity, however, three functional subdivisions of the cerebellum have been
delineated:

1. The vestibulocerebellum (corresponds best with the flocculonodular lobe) has reciprocal
connections with vestibular and reticular nuclei and plays a role in control of body
equilibrium and eye movement.

2. The spinocerebellum (corresponds best to the anterior lobe) has reciprocal connections
with the spinal cord and plays a role in control of muscle tone as well as axial and limb
movements, such as those used in walking and swimming.

3. The cerebrocerebellum or pontocerebellum (corresponds best to the posterior lobe) has

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reciprocal connections with the cerebral cortex and plays a role in planning and initiation of
movements, as well as the regulation of discrete limb movements.

Phylogenetically, the cerebellum is divided into three zones: The archicerebellum, the oldest
zone, corresponds to the flocculonodular lobe. The paleocerebellum, of more recent phylogenetic
development than the archicerebellum, corresponds to the anterior lobe and a small part of the
posterior lobe. The neocerebellum, the most recent phylogenetically, corresponds to the
posterior lobe.

Somatotopic Representation (Figure 15-7)

Somatotopic representation of body parts in the cerebellum was first described in 1943 by
Adrian and later confirmed by others. In the anterior lobe, the body appears inverted, with
hindlimbs represented rostral to the forelimbs and face. In the posterior lobe, the body appears
noninverted and dually represented on each side of the midline, with face anteriorly and legs
posteriorly represented. In general, the trunk is represented in the midline, and the extremities
are represented more laterally in the hemispheres. Thus, in disorders predominantly affecting
the midline cerebellum, disturbances of movement will be manifest primarily in trunk
musculature and would affect body equilibrium. In contrast, in disorders primarily affecting the
cerebellar hemispheres, disturbances of movement will manifest primarily in extremity
movement.

MICROSCOPIC STRUCTURE

Cerebellar Cortex
The cerebellar cortex is made up of the following three layers.

1. Outer molecular layer (about 300 µm in thickness)

2. Middle Purkinje cell layer (about 100 µm in thickness)

3. Innermost granule cell layer (about 200 µm in thickness)

Five cell types (Table 15-2) are distributed in the different cortical layers. Basket and stellate
cells are in the molecular layer, Purkinje cells are in the Purkinje cell layer, and granule and
Golgi cells are in the granule cell layer.

Of these five cell types, the Purkinje cell constitutes the principal neuron of the cerebellum,
since it is the only cerebellar neuron that sends its axons outside the cerebellum (projection
neuron). All the other cells are intrinsic neurons and establish connections within the
cerebellum.

Table 15-1. Cerebellar Lobes and Subdivisions

A Anatomic
subdivisions
Transverse
plane Flocculonodular
Longitudinal Anterior lobe Posterior lobe lobe
plane Vermis Paravermis Hemisphere

B Functional Spinocerebellum Cerebrocerebellum Vestibulocerebellum

subdivisions

C Phylogenetic Paleocerebellum Neocerebellum Archicerebellum

subdivisions

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Figure 15-6. Schematic diagram of midsagittal view of the cerebellum and brain stem
showing the three anatomic lobes of the cerebellum.

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Principal (Purkinje) Neuron (Table 15-2)

Described in 1837 by the Bohemian priest and physiologist Johannes Purkinje, cell bodies of
Purkinje cells are arranged in a single row at the border zone between the molecular and
granule cell layers. The cell is flask-shaped when viewed in the transverse plane and is narrow
and vertical when viewed in longitudinal sections. The Purkinje cell measures approximately 30
to 35 µm in transverse diameter. Adjacent Purkinje cells are separated by 50 µm in the
transverse plane and by 50 to 100 µm in the longitudinal plane. Each Purkinje cell has an
elaborate dendritic tree that stretches throughout the extent of the molecular layer and is
arranged at right angles to the long axis of the folium. The dendritic tree is made up of a
sequence of primary, secondary, and tertiary branches, with the smaller dendritic branches
profusely covered with dendritic spines or gemmules. It is estimated that each Purkinje cell has
over 150,000 spines on its dendritic tree.

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Figure 15-7. Schematic diagram of unfolded cerebellum showing somatotopic

representation of body parts in the cerebellum. H, head; UE, upper extremity; LE, lower
extremity; T, trunk.

Each Purkinje cell has a single axon that courses through the granule cell layer and deep white
matter to project on deep cerebellar nuclei. Some Purkinje cell axons (from the vermis) bypass
the deep cerebellar nuclei to reach the lateral vestibular nucleus. Recurrent collateral axonal
branches arise from Purkinje cell axons and project on adjacent Purkinje cells as well as on
basket, stellate, and Golgi cells in neighboring or even distant folia. It is estimated that there
are about 15 million Purkinje cells in the human cerebellum.

Intrinsic Neurons (Table 15-2)

A. BASKET CELL
Basket cells are situated in deeper parts of the molecular layer in close proximity to Purkinje
cells. Dendritic arborizations of basket cells are disposed in the transverse plane of the folium in
a manner similar to but less elaborate than the Purkinje cells. The axon courses in the molecular
layer in the transverse plane of the folium just above the cell bodies of Purkinje cells. Each axon
gives rise to several descending branches that surround Purkinje cell perikarya and initial
segments of their axons in the form of a basket, hence their name. Each basket cell axon covers
the territory of about 10 Purkinje cells. Basket formation, however, skips the Purkinje cell
immediately adjacent to the basket cell and descends on the second Purkinje cell and onward in
the row. In addition, axonal branches extend in the longitudinal plane of the folium to reach an
additional three to six rows of Purkinje cells on both sides of the main axons. As a result of this,
a single basket cell may reach as many as 200 Purkinje cells. More than one basket cell may
contribute to a single basket formation around one Purkinje cell. While the descending branches
of basket cell axons establish contact with Purkinje cell perikarya and initial
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segments of their axons, ascending branches of basket cell axons ascend in the molecular layer
to reach the proximal dendrites of Purkinje cells. It is estimated that there are about 7 million
basket cells in the human cerebellum.

Table 15-2. Cerebellar Cortex Neurons

Neuron Type Layer Projection Synaptic

action

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Purkinje Principal Purkinje Deep cerebellar Inhibitory

(projection) nuclei
Lateral vestibular
nucleus
Other Purkinje cells
Intrinsic neurons

Basket Interneuron Molecular Purkinje cell Inhibitory

Stellate Interneuron Molecular Purkinje cell Inhibitory

Granule Interneuron Granule Purkinje cell Excitatory

Basket cell
Stellate cell
Golgi cell

Golgi Interneuron Granule Granule cell Inhibitory

B. STELLATE CELL
Stellate cells are located in the superficial and deeper parts of the molecular layer. Axons of
stellate cells are also disposed transversely in the folium and terminate on Purkinje cell
dendrites. It is estimated that there are 12 million stellate cells in the human cerebellum.

The basket and stellate cells can be considered as belonging to the same class. Both receive the
same input, and both act on Purkinje cells. The difference lies in the fact that stellate cells
establish contact with the dendrites of Purkinje cells, whereas basket cells establish contact with
dendrites, perikarya, and axons of Purkinje cells.

C. GRANULE CELL
Granule cells are among the smallest cells in the brain (6 to 9 µm) and fill the granule cell
layer. Each cell gives rise to about three to five dendrites that establish synaptic contacts with
axons in a synaptic zone (the glomerulus) within the granule cell layer. Axons of granule cells
ascend in the granule cell layer, Purkinje layer, and molecular layer, where they bifurcate in a T
fashion and run parallel to the surface to form the parallel fiber system. Parallel fibers run
horizontally in the molecular layer perpendicular to the plane of the Purkinje dendrites. Each
parallel fiber branch is 1 to 1.5 mm in length; thus the axon of a single granule cell spans an
area of approximately 3 mm. The parallel fibers establish contact with dendrites of Purkinje
cells, Golgi cells, stellate cells, and basket cells. Generally, a parallel fiber comes in contact
with a Purkinje cell only once or, rarely, twice. The individual parallel fibers are thus not a
strong drive to the Purkinje neuron.

A single Purkinje cell, however, can receive up to 100,000 parallel fibers. Although a single
parallel fiber is not a strong drive to the Purkinje neuron, contact by 100,000 parallel fibers can
provide a powerful drive to this neuron.

The total number of granule cells is estimated to be on the order of 2.2 billion.

D. GOLGI TYPE II CELL

Golgi neurons occupy the superficial part of the granule cell layer adjacent to the Purkinje cells.
They are large neurons, about the same size as the Purkinje cell bodies. Dendrites of Golgi
neurons arborize in either the molecular or the granule cell layer. Those which remain in the
granule cell layer contribute to the glomeruli of that layer. Those which reach the molecular
layer arborize widely and overlap the territories of three Purkinje cells in both the transverse
and longitudinal planes. The Golgi neuron dendritic arborization is thus three times that of the
Purkinje cell.

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Axons of Golgi cells take part in the formation of the glomer-ulus. They are characterized by a
dense arborization of short axonal branches that span the entire granule cell layer. The field of
axonal arborization approaches that of dendritic arborization. The axonal arborization of the
Golgi neurons is among the most unique in the brain. The Golgi neuron forms the central point
of a functional hexagon that includes about 10 Purkinje cells. It is estimated that there are 4
million Golgi cells.

Cerebellar Glomerulus
In histologic sections of the cerebellar cortex there are islands between granule cells that stain
lighter than the rest of the granule cell layer. These are the cerebellar glomeruli (Figure 15-8).
They are the sites of synaptic contact between the incoming cerebellar fibers (mossy fiber
system) and processes of neurons within the granule cell layer. The elements that form a
cerebellar glomerulus are

1. Cerebellar input via the mossy fiber system (origins of this system will be discussed later)

2. Dendrites of granule cells

3. Axon terminals of Golgi neurons

4. Proximal parts of Golgi dendrites

Electron micrographs have shown that the mossy fiber axonal terminal is the central element in
the glomerulus (terminal rosettes), around which are clustered dendrites of granule cells and
axons of Golgi neurons. Both mossy fiber axons and Golgi axons act on the dendrites of granule
cells. In addition, mossy fiber axons project on dendrites of Golgi neurons. The whole complex
is surrounded by a glial envelope. It is estimated that a glomerulus contains about 100 to 300
dendritic terminals from some 20 granule cells.

CEREBELLAR INPUT
Containing more than half the neurons in the brain, the cerebellum is one of the busiest
neuronal intersections in the brain, receiving input from and sending signals back to every
major part of the central nervous system. Input to the cerebellum originates
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from a variety of sources. The three major sources of afferents, however, are the spinal cord,
vestibular system, and cerebral cortex.

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Figure 15-8. Schematic diagram of a cerebellar glomerulus showing the different sources
of converging fibers.

Inputs from the spinal cord are transmitted to the cerebellum (Figure 15-9) via the dorsal and
ventral spinocerebellar tracts and the rostral extension of the dorsal spinocerebellar tract, the
cuneocerebellar tract. These tracts provide the cerebellum with information related to the
position and condition of muscles, tendons, and joints.

Inputs from the vestibular system (Figure 15-10) arise from the primary vestibular end organ in
the vestibular labyrinth, as well as from vestibular nuclei (inferior and medial) in the brain
stem. Vestibulocerebellar inputs provide information related to body equilibrium.

Cortical inputs to the cerebellum originate in neocortical as well as paleocortical and

archicortical areas. These include primary motor and sensory cortices as well as association and
limbic cortices. Inputs from neocortical areas (Figure 15-11) reach the cerebellum after relays
in the pontine nuclei (the vast majority) and inferior olive. Inputs from paleocortical and
archicortical areas establish relays in the reticular nuclei and hypothalamus prior to reaching
the cerebellum. Corticocerebellar inputs provide information related to the planning and
initiation of movement.

Other fiber inputs to the cerebellum include a noradrenergic projection from the locus ceruleus
(A-6 cell group of primates), a dopaminergic projection from the ventral tegmental area of Tsai
in the midbrain (A-10 cell group of primates), and a serotonergic projection from the raphe
nuclei (B-5 and B-6 cell groups of primates) in the brain stem. The input from the locus ceruleus
projects on Purkinje cell dendrites and exerts an inhibitory effect on Purkinje cell activity. It has
been postulated that the input from the locus ceruleus plays a role in the development of
Purkinje cells. The terminals from the locus ceruleus develop prior to Purkinje cell maturation.
Destruction of the locus ceruleus results in immature development of Purkinje cells.

In the past few years, a series of investigations has revealed the existence of a complex
network of direct and indirect pathways between the hypothalamus and the cerebellum. The
projections are bilateral with ipsilateral preponderance. They originate from various
hypothalamic nuclei and areas but principally from the lateral, dorsal, and posterior

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hypothalamic areas and the dorsomedial, ventromedial, supramamillary, lateral mamillary, and
tuberomamillary nuclei. The indirect pathway reaches the cerebellum after relays in a number of
brain stem nuclei. Hypothalamocerebellar fibers terminate in relation to neurons in all layers of
the cerebellar cortex. The hypothalamocerebellar network may provide the neuroanatomic
substrate for the autonomic responses elicited from cerebellar stimulation.

Fiber inputs to the cerebellum from the preceding various sources arrive via three cerebellar
peduncles: the inferior (restiform body), the middle (brachium pontis), and the superior
(brachium conjunctivum). Figure 15-12 is a composite schematic diagram of inputs to the
cerebellum.

Inferior Cerebellar Peduncle

The fiber systems reaching the cerebellum via this peduncle are the following:

1. Dorsal spinocerebellar tract from the dorsal nucleus of Clarke

2. Cuneocerebellar tract from the accessory cuneate nuclei

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3. Olivocerebellar tract from the inferior olivary nuclei (major component)

4. Reticulocerebellar tract from the reticular nuclei of the brain stem

5. Vestibulocerebellar tract (both primary afferents from the vestibular end organ and
secondary afferents from the vestibular nuclei)

6. Arcuatocerebellar tract from the arcuate nuclei of the medulla

7. Trigeminocerebellar tract from the spinal and main sensory nuclei of the trigeminal nerve

Middle Cerebellar Peduncle

The fiber systems reaching the cerebellum via this route are the following:

1. Pontocerebellar (corticopontocerebellar) tract from the pontine nuclei (major component)

2. Serotonergic fibers from the raphe nuclei

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Figure 15-9. Schematic diagram of spinocerebellar input. DSCT, dorsal spinocerebellar

tracts; VSCT, ventral spinocerebellar tract; ACN, accessory cuneate nucleus; CCT,
cuneocerebellar tract.

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Figure 15-10. Schematic diagram of vestibular input to the cerebellum.

Superior Cerebellar Peduncle

The fiber input to the cerebellum via this route includes the following:

1. Ventral spinocerebellar tract

2. Trigeminocerebellar tract from the mesencephalic trigeminal nucleus

3. Cerulocerebellar tract from the nucleus ceruleus

4. Tectocerebellar tract from the superior and inferior colliculi

The various inputs to the cerebellum are segregated within the cerebellum into one of three
fiber systems: climbing, mossy, and a recently described multilayered.

A. CLIMBING FIBER SYSTEM (Figure 15-13)

It is generally believed that the olivocerebellar tract is the major component of this system.
Climbing fibers establish synapses on dendrites of the principal neuron of the cerebellum (the
Purkinje cell), as well as on dendrites of intrinsic neurons (Golgi, basket, and stellate) (Table
15-3). The climbing fiber input is known to exert a powerful excitatory effect on a single
Purkinje cell and a much less powerful effect on intrinsic neurons. The relationship of climbing
fibers to principal neurons is so intimate that one
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climbing fiber is restricted to one Purkinje cell and follows the branches of the Purkinje cell

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dendrites like a grapevine. The climbing fiber effect on a Purkinje cell is thus one-to-one, all-or-
none excitation. It is estimated that one climbing fiber establishes 1000 to 2000 synaptic
contacts with its Purkinje cell. Stimulation of the climbing fiber system elicits a prolonged burst
of high-frequency action potentials (complex spike) from the Purkinje cell capable of overriding
any ongoing activity in that cell. Several lines of evidence suggest that olivocerebellar input via
the climbing fiber pathway is powerfully modulated during active movements. Available data
suggest that access of sensory signals from the spinal cord to the cerebellum via the inferior
olive (spino-olivo-cerebellar pathway) and the climbing fiber system is powerfully gated and is
subject to central control. The importance of the climbing fiber system is evident by the fact
that ablation of the inferior olive (source of climbing fiber pathway) results in movement
disorder similar to the motor deficits that follow direct damage to the cerebellum. One notable
aspect of the olivocerebellar projection is its highly ordered topography.

Figure 15-11. Schematic diagram showing neocortical input to the cerebellum with relay in
the pontine nuclei and inferior olive. MCP, middle cerebellar peduncle (brachium pontis);
ICP, inferior cerebellar peduncle (restiform body).

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Figure 15-12. Composite schematic diagram showing major sources of input to the
cerebellum.

B. MOSSY FIBER SYSTEM

The mossy fiber system includes all afferents to the cerebellum except those which contribute to
the climbing fibers and the multilayered fiber system. Like the climbing fibers, mossy fibers
enter the cerebellum via the core of deep white matter. They then diverge into the folia of the
cerebellum, where they branch out into the granule cell layer. Within the granule cell layer,
mossy fibers divide into several subbranches of terminal rosettes that occupy the center of each
glomerulus, where they come in contact with dendrites of granule and Golgi neurons (Figure 15-
13 and Table 15-3). It is estimated that each mossy fiber establishes contact with
approximately 400 granule cell dendrites within a single folium and that each terminal mossy
rosette contacts approximately 20 different granule cells. On the other hand, each granule cell
receives synaptic contacts from four to five different mossy fiber terminals. The mossy fiber is
believed to stimulate the largest number of cells to be activated by a single afferent fiber. Thus,
in contrast to the climbing fiber input, which is highly specific and sharply focused on the
Purkinje cell, the mossy fiber input is diffuse and complex (Figure 15-13). In addition to their
contribution to the Purkinje and granule cells of the cerebellar cortex, both climbing and mossy
fibers send collaterals to the deep cerebellar nuclei (Figure 15-13). These collaterals are
excitatory in nature and help maintain a constant background discharge of these deep nuclei.

C. MULTILAYERED FIBER SYSTEM

This recently described fiber system includes afferents to the cerebellum from the
hypothalamus, as well as the serotonergic input
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from the raphe nuclei, the noradrenergic input from the nucleus locus ceruleus, and the
dopaminergic input from the mesencephalic dopaminergic neurons. Similar to the climbing and
mossy fiber systems, the multilayered fiber system projects on neurons in the cerebellar cortex
and the deep cerebellar nuclei.

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Figure 15-13. Schematic diagram comparing the climbing and mossy fiber systems within
the cerebellum.

INTERNAL CEREBELLAR CIRCUITRY (Figures 15-14 and 15-

15)

Mossy Fiber Input

A mossy fiber input excites dendrites of a group of granule cells. The discharge from these
granule cells will be transmitted through their axons (parallel fibers), which bifurcate in a T
configuration in the molecular layer, coming in contact with dendrites of Purkinje, stellate,
basket, and Golgi neurons. If the excited parallel fiber bundle is wide enough to cover the
Purkinje cell dendritic field, activation will result in a firing of a single row of Purkinje cells and
in the related basket and stellate cells. The activation of the basket and stellate cells will inhibit
a wide zone of Purkinje cells on each side of the row of activated Purkinje cells. Thus the mossy
fiber input will produce a row of activated Purkinje cells flanked on each side by a strip of
inhibited Purkinje cells. The inhibited rows of Purkinje cells, by silencing surrounding activity,
help the process of neural sharpening within the activated row of Purkinje cells.

If the activated bundle of parallel fibers becomes wide enough to span the dendritic field of a
Golgi neuron, the Golgi cell is then excited and, through its axon in the glomerulus, will inhibit
the granule cell. Thus, a mossy fiber excitatory input to the granule cell will be transferred into
inhibition via one of two mechanisms (Figure 15-14):

1. Mossy fiber to granule cell dendrite to granule cell axon (parallel fibers) to basket and
stellate cells dendrites to basket and stellate cells axons to Purkinje cell body (basket cells
axons) and dendrites (stellate cells axons)

2. Mossy fibers to granule cell dendrite to granule cell axon (parallel fibers) to Golgi cell
dendrites, to Golgi cell axon, to granule cell dendrites.

A third inhibitory mechanism of the mossy fiber system (Figure 15-15) is via mossy fiber input
to Golgi cell dendrites to Golgi cell axon and back to granule cell dendrites.

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Table 15-3. Climbing and Mossy Fibers

Projection targets
Fiber type
Deep nuclei Purkinje Basket Stellate Granule Golgi

Climbing X X X X X

Mossy X X X

Figure 15-14. Schematic diagram showing how an excitatory mossy fiber input can be
transformed into inhibition via granule cell axon. MF, mossy fiber; G, granule cell; GO,
Golgi cell; B, basket cell; S, stellate cell; PC, Purkinje cell; ML, molecular layer; PCL,
Purkinje cell layer; GCL, granule cell layer; PF, parallel fibers; A, axon; D, dendrite; +,
facilitation; -, inhibition.

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Figure 15-15. Schematic diagram showing how an excitatory mossy fiber input can be
transformed into inhibition via Golgi cell axon. MF, mossy fiber; G, granule cell; GO, Golgi
cell; ML, molecular layer; PCL, Purkinje cell layer; GCL, granule cell layer; PF, parallel
fibers; A, axon; D, dendrite; +, facilitation; -, inhibition.

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The mossy fiber input has both high divergence and convergence ratios. A single mossy fiber
has 40 rosettes, each rosette connects with the dendritic terminals of 20 granule cells, and a
single granule cell connects through the parallel fibers with 100 to 300 Purkinje cells. This gives
a divergence ratio of about 1:100,000 to 1:300,000 from one mossy fiber to Purkinje cells. On
the other hand, each Purkinje cell has about 100,000 dendritic spines in synaptic contact with
parallel fibers (granule cells) and hence a large ratio of convergence.

Climbing Fiber Input

Similarly, a climbing fiber input will excite Purkinje cells as well as stellate, basket, and Golgi
neurons. The effect on these different cells is similar to that described for the mossy fiber input
and helps to focus on the activation of the Purkinje cell amid a zone of inhibition induced by
basket, stellate, and Golgi neurons. In contrast to the mossy fiber system, the convergence and
divergence factors for the climbing fiber input are small (1:1).

Incoming fibers (climbing and mossy) to the cerebellum thus excite Purkinje and granule cells of
the cerebellar cortex, as well as the deep cerebellar nuclei. Purkinje cells are excited directly by
climbing fibers and indirectly (via the granule cell) by mossy fibers. The excitation of Purkinje
cells is modulated by several feedback circuits (via basket and stellate inhibitory interneurons)
that inhibit Purkinje cell activity and suppress transmission of impulses from Purkinje cells to
deep cerebellar nuclei. The output of Purkinje cells to the deep cerebellar nuclei is thus a finely
modulated inhibitory signal. The output of the deep cerebellar nuclei to extracerebellar targets
is thus the product of excitatory input from climbing and mossy fibers and inhibitory projections
from Purkinje cells (Figure 15-16).

The mossy fiber pathways conduct faster than the climbing fiber pathways. However, the
ultimate inhibitory potentials produced by the mossy fiber system develop slowly so that by the

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time the climbing fiber input arrives in the cerebellum, the full effect of the mossy fiber
inhibitory potentials has not yet developed. This allows the climbing fiber system to act on the
background activity of excitation and inhibition initiated by the mossy fiber input.

Thus, of all the cells of the cerebellar cortex, only the granule cell is excitatory; all others,
including the Purkinje cells, are inhibitory. Recent studies on the cerebellum have given the
Golgi neuron a central role in cerebellar organization. Through its contact with both the mossy
fibers in the glomerulus and the climbing fiber collaterals, the Golgi neuron is able to select
what input will reach the Purkinje cell at any one time.

CEREBELLAR OUTPUT
The cerebellar output system has two components: intracerebellar and extracerebellar. The
intracerebellar component comprises the inhibitory projections of Purkinje cells to deep
cerebellar nuclei. These projections are somatotopically organized (Figure 15-17). Purkinje cells
in the vermis project to the nucleus fastigii, while those in the paravermal and cerebellar
hemisphere zones project, respectively, to the interposed nucleus (emboliform and globose) and
the dentate nucleus. The vast majority of the extracerebellar component comprises the
projections of deep cerebellar nuclei to extracerebellar targets. A smaller part of it originates
from a group of Purkinje cells in the vestibulocerebellum whose axons bypass the deep
cerebellar nuclei and project on the lateral vestibular nucleus in the brain stem. Extracere-bellar
targets of deep cerebellar nuclei (Figures 15-18,15-19,15-20) include the vestibular and
reticular nuclei of the brain stem (from the nucleus fastigii), the red nucleus in the midbrain and
the inferior olivary nucleus in the medulla (from the interposed nucleus), the thalamus (from
the dentate and interposed nuclei), and the hypothalamus (from all deep cerebellar nuclei).

Efferents from the cerebellum leave via the inferior and superior cerebellar peduncles (Figure
15-21). Cerebellovestibular and cerebelloreticular fibers travel via the inferior cerebellar
peduncle, whereas the cerebellothalamic, cerebellorubral, and cerebello-olivary fibers travel via
the superior cerebellar peduncle. The superior cerebellar peduncle crosses in the midbrain
tegmentum (at the inferior colliculus level) and projects on the contralateral red nucleus and
ventrolateral nucleus of the thalamus. A small fascicle from this crossed system descends to the
inferior olivary nucleus. The cerebellum exerts its most important influence on the motor and
premotor cortices via the ventrolateral nucleus of the thalamus. Electrophysiologic studies show
that pyramidal tract neurons in the motor and premotor cortices receive di-synaptic or
trisynaptic excitatory inputs from the dentate and interposed nuclei after relays in the
ventrolateral thalamic nucleus. Other corticofugal neurons in the motor and premotor cortices,
such as those which project to the red nucleus, pontine nuclei,
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and spinal cord, also receive cerebellar fibers. In addition to the motor and premotor cortices,
the cerebellum projects to the parietal and temporal association cortices.

Figure 15-16. Schematic diagram of the intrinsic cerebellar circuitry. +, excitation; -,

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inhibition.

Figure 15-17. Schematic diagram showing topographic projections of Purkinje cells of

different cerebellar zones into the respective deep cerebellar nuclei.

DEEP CEREBELLAR NUCLEI

The deep cerebellar nuclei are embedded in the white matter core of the cerebellum. There are
four pairs of nuclei arranged from lateral to medial as follows: dentate, emboliform, globose,
and fastigi (Figure 15-5). A mnemonic used frequently to remember the lateral to medial order
of deep cerebellar nuclei is “Lucky Dude Engages Girl From Montana” where L is for lateral, D
for dentate, E for emboliform, G for globose, F for fastigii, and M for medial.

Dentate Nucleus
The dentate nucleus is composed of multipolar neurons and resembles the inferior olive in
configuration. It receives the axons of Purkinje cells located in the lateral part of the cerebellar
hemispheres and collaterals of climbing and mossy fibers. The Purkinje
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cell input is inhibitory, whereas the inputs from climbing and mossy fibers are excitatory to the
dentate nucleus (Figure 15-18).

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Figure 15-18. Schematic diagram showing the afferent and efferent connections of the
dentate nucleus. +, facilitation; -, inhibition; CF, Climbing fiber; MF, mossy fiber; BC,
brachium conjunctivum.

Figure 15-19. Schematic diagram showing the afferent and efferent connections of the
interposed nuclei. +, facilitation; -, inhibition; CF, climbing fiber; MF, mossy fiber; BC,
brachium conjunctivum.

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Figure 15-20. Schematic diagram showing the afferent and efferent connections of the
nucleus fastigii. +, facilitation; -, inhibition.

The bulk of axons of the dentate nucleus project via the superior cerebellar peduncle (brachium
conjunctivum) to the contralateral ventrolateral nucleus of the thalamus. A relatively small
number of axons project to the intralaminar nuclei of the thalamus (mainly the central lateral
nucleus), to the rostral third of the red nucleus (origin of rubroolivary tract), and, via the
descending limb of the brachium conjunctivum, to the reticulotegmental nucleus and inferior
olive.

The expansion of the dentate nucleus and the lateral cerebellar hemisphere in the course of
hominid evolution provided the neural basis for novel cerebellar trajectories and new functions.
The phylogenetically older part of the dentate nucleus (the dorsomedial part) maintains
connections with the motor cortex via the motor thalamus (ventrolateral nucleus) and with the
spinal cord via the red nucleus, in line with the traditionally established role of the cerebellum
in motor control. The phylogenetically newer part of the dentate nucleus (the ventrolateral
part), in contrast, has connections, in addition to the motor cortex, with the prefrontal cortex,
which has expanded in parallel with the dentate nucleus in the course of hominid evolution.
Evidence is accumulating in favor of a nonmotor function of the neodentate nucleus.

Interposed Nuclei
These nuclei include the emboliform nucleus, located medial to the hilum of the dentate nucleus,
and the globose nucleus, located medial to the emboliform nucleus (Figure 15-5).

The interposed nuclei receive afferent fibers from the following sources (Figure 15-19):

1. Axons of Purkinje cells in the paravermal (intermediate) zone of the cerebellum that are
inhibitory in function

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2. Collaterals from climbing and mossy fiber systems that are excitatory in function

Axons of interposed nuclei leave the cerebellum via the superior cerebellar peduncle (brachium
conjunctivum). The bulk projects on neurons in the caudal two-thirds of the red nucleus (the
part that gives rise to the rubrospinal tract). A smaller number of axons project on the
ventrolateral nucleus of the thalamus and, via the descending limb of the brachium
conjunctivum, to the inferior olive.

Fastigial Nucleus
This nucleus is located in the roof of the fourth ventricle medial to the globose nucleus; hence it
is called the roof nucleus. It receives afferent fibers from the following sources (Figure 15-20):

1. Axons of Purkinje cells in the vermis of the cerebellum that are inhibitory in function

2. Collaterals of mossy and climbing fiber systems that are excitatory

In contrast to efferents from the dentate and the interposed nuclei, efferents of the fastigial
nucleus do not travel via the brachium conjunctivum. A large number of fastigial efferents cross
within the cerebellum and form the uncinate fasciculus. Uncrossed
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fastigial fibers join the juxtarestiform body. The bulk of fastigial efferents project on the
vestibular nuclei (lateral and inferior) and several reticular nuclei of the brain stem. Fastigial
projections to vestibular nuclei are bilateral. Fastigioreticular fibers are mainly crossed. A small
number of fastigial efferents course rostrally in the brain stem to project on the superior
colliculus, nuclei of the posterior commissure, and the ventrolateral thalamic nucleus.

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Figure 15-21. Schematic summary diagram showing the cerebellar output via the superior
cerebellar peduncle (SCP) and inferior cerebellar peduncle (ICP). CBL, cerebellum.

In addition to the efferent projections of the deep cerebellar nuclei described above, all deep
cerebellar nuclei have been shown to send axon collaterals to the areas of the cerebellar cortex
from which they receive fibers; thus the nucleus fastigii sends axon collaterals to the cerebellar
vermis, the interposed nuclei to the paravermal region, and the dentate nucleus to lateral parts
of the cerebellar hemispheres. Although deep cerebellar nuclei receive axons of Purkinje cells,
their axon collaterals do not project directly on Purkinje cells but on neuronal elements in the
granule cell layer via the mossy fiber system. The exact cell type in the granule cell layer that
receives these axon collaterals has not been identified with certainty.

Thus all the deep cerebellar nuclei receive a dual input; these are an excitatory input from
extracerebellar sources (mossy and climbing fibers) and an inhibitory input from the cerebellar
cortex (axons of Purkinje cells). In contrast, the output of the deep cerebellar nuclei is
excitatory.

CEREBROCEREBELLAR AND CEREBELLOCEREBRAL

CIRCUITRIES
The cerebral cortex communicates with the cerebellum via a multitude of pathways, of which the
following are well recognized (Figure 15-22):

1. Corticoolivocerebellar via the red nucleus and inferior olivary nucleus

2. Corticopontocerebellar via the pontine nuclei

3. Corticoreticulocerebellar via the reticular nuclei of the brain stem

The first two pathways convey to the cerebellum precisely localized and somatotopically
organized information. Of these two, the pathway via the pontine nuclei is quantitatively more
impressive. The pathway via the reticular nuclei is part of a system with diffuse input and
output (reticular formation), in which information of cortical origin is integrated with
information from other sources before transmission to the cerebellum.

The cerebellum influences the cerebrum mainly via the dentatothalamic system. The
cerebellocerebral pathways are modest in number when compared with the cerebrocerebellar
pathways (approximately 1:3). This is a reflection of the efficiency of the cerebellar machinery
that makes it possible for the cerebellum to regulate cortically originating signals for movement.
Corticocerebellar fibers originate from motor and nonmotor (associative and limbic) areas of the
cerebral cortex. Similarly, cerebellar output fibers target both motor and nonmotor cerebral
cortical areas.

NEUROTRANSMITTERS
The following neurotransmitters have been identified in the cerebellum: gamma-aminobutyric
acid (GABA), taurine, glutamate, aspartate, acetylcholine, norepinephrine, serotonin, and
dopamine.

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Figure 15-22. Schematic diagram of cerebrocerebellar and cerebellocerebral connections.

Heavy arrows denote quantitatively significant pathway.

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GABA is liberated from axons of Purkinje, basket, and Golgi neurons and exerts an inhibitory
effect on target neurons. Taurine is believed to be the inhibitory neurotransmitter of the
superficial stellate cells; taurine levels are high in the molecular layer and drop substantially
when stellate cell development is blocked by x-irradiation. Glutamate is believed to be the
excitatory neurotransmitter of granule cells; glutamate levels in the granule cell layer drop
substantially in the agranular cerebellum of virus-infected and mutant mice. Glutamate has also
been reported to be the excitatory neurotransmitter in climbing and mossy fibers. Acetylcholine
has been reported in granule cells, Golgi cells, and mossy fibers. Glycine, enkephalin, and
somatostatin have been reported in Golgi cells. Norepinephrine is the inhibitory
neurotransmitter of the locus ceruleus projection on Purkinje cell dendrites. In addition to its
presumed role in maturation of Purkinje neurons, norepinephrine seems to modulate Purkinje
cell response to other cerebellar neurotransmitters. Stimulation of the locus ceruleus enhances
sensitivity of Purkinje neurons to both glutamate and GABA. Serotonin and dopamine are
released in terminals of projections from the raphe nuclei and midbrain dopamine neurons,
respectively.

CEREBELLAR PHYSIOLOGY

Cerebellar Cortex
Cerebellar neurons are characterized by high rates of resting impulse discharge. Purkinje cells
discharge at the rate of approximately 20 to 40 Hz, granule cells at 50 to 70 Hz, and inhibitory
interneurons (basket, stellate, and Golgi) at 7 to 30 Hz. This high discharge rate of cerebellar
neurons is derived from the nature of their synaptic drive.

Stimulation of the mossy fiber system or of the parallel fibers (axons of granule cells) elicits in
the Purkinje cell a brief excitatory postsynaptic potential (EPSP) (simple spike) lasting 5 to 10
ms, followed by a prolonged inhibitory postsynaptic potential (IPSP). The short EPSP is
attributed to the activation of Purkinje cell dendrites by the parallel fibers. The IPSP, on the
other hand, is attributed to the feedforward inhibition of Purkinje cells by stellate and basket
cells that are activated simultaneously by the beam of parallel fibers (Figure 15-23).

Stimulation of the climbing fiber system elicits in the Purkinje cell an intense and prolonged
reaction characterized by an initial large spike followed by several small ones. This pattern is
referred to as a complex spike. This complex EPSP is followed by a prolonged IPSP. The complex
spike is explained on the basis of more than one mechanism. One mechanism for this complex
spike in the Purkinje cell is the repetitive discharge emanating from inferior olive neurons
because of axonal collaterals within the inferior olive. Another mechanism for the complex
response of Purkinje cells lies in the intrinsic property of their membranes. The IPSP that

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follows the complex EPSP is attributed to simultaneous activation of stellate and basket cells by
the climbing fibers, which in turn inhibit the Purkinje cell by a feedforward pathway. Both mossy
and climbing fibers facilitate the Golgi cell, which in turn inhibits the granule cell and can thus
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contribute to Purkinje cell inhibition. After their initial activation by the mossy and climbing
fiber input, intrinsic neurons (basket, stellate, and Golgi) ultimately are inhibited by Purkinje
axon collaterals. The action of the recurrent Purkinje axon collaterals is thus to disinhibit the
Purkinje cell.

Figure 15-23. Schematic diagram showing the mechanism of generation of excitatory

(EPSP) and inhibitory (IPSP) postsynaptic action potentials in the Purkinje cell. MF, mossy
fiber; CF, climbing fiber; PF, parallel fibers; SS, simple spike; CS, complex spike.

It becomes evident from the preceding that the mossy and climbing input fibers are excitatory
to the granule and Purkinje cells, whereas the action of all other cells within the cerebellum
(except the granule cell) is inhibitory. It is thus not possible for cerebellar activity in response
to an afferent input to be sustained.

Several investigators have studied the effects of cerebellar stimulation in humans. The results
of such stimulation are similar to those described above.

Deep Cerebellar Nuclei

Like the Purkinje cells, deep nuclei have high rates of impulse discharge at rest. Also like the
Purkinje cells, the deep cerebellar nuclei receive both excitatory and inhibitory inputs, the
former arriving via the climbing and mossy fibers and the latter by axons of Purkinje cells
(Figure 15-16). Thus a mossy fiber input, for example, will cause first a high-frequency burst in
the deep cerebellar nuclei followed by a lowering of the frequency as a result of inhibition
arriving through the slower Purkinje cell loop. Purkinje cell inhibition is mediated by gamma-

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aminobutyric acid (GABA).

CEREBELLAR FUNCTION

Historical Perspective
The cerebellum has puzzled and fascinated anatomists, physiologists, and clinicians since its
early description by Aristotle and Galen. Early observers attributed to it roles as controller of
motor nerves, seat of memory, director of automatic and involuntary visceral movements, and
the seat of sexual activity. Fluorens' experiments from 1822 to 1824 showed that the
cerebellum was concerned with coordination of movement. Fraser in 1880 considered it the seat
of sexual appetite.

A. PHRENOLOGIC ERA
In phrenologic maps of the brain, the cerebellum was the primary anatomic locus of amative
(sexual) love. The overlying occipital pole was the locus of maternal/paternal love. Analysis of
cerebellar morphology was an important prenuptial check. Cagey lovers were reported to
perform a discrete examination of the crania of prospective partners to check on the degree of
prominence of their occipital ridge. Circulated reports at the time described a well-known
society physician with a markedly prominent occipital ridge who outlived three wives and
required the attention of four mistresses. Another described a Viennese fortune teller, famous
for his libidinous desires, whose autopsy revealed a marked degree of cerebellar hypertrophy. It
was also believed at the time that the cerebellum and external genitalia were lateralized and
reciprocally activating such that an injury to the left testicle was expected to result in atrophy
of the contralateral cerebellar hemisphere.

B. EXPERIMENTAL ERA (19TH CENTURY)

The experimental era of cerebellar function was ushered in by the studies of Magendie, Cuvier,
and Rolando. The experimentalists described the phrenologist perspective as a collection of
absurdities, incoherence, and gross ignorance. Surgical lesions in cerebella of experimental
animals resulted in various degrees of ipsilateral weakness, disequilibrium, and loss of motor
coordination.

C. HUMAN BRAIN INJURIES

Gordon Holmes, in the first quarter of the 20th century, conceptualized about cerebellar
function from observations made on patients who received bullet wound injuries to the
cerebellum during the first world war. Thus was coined the Holmes triad of asthenia, ataxia, and
atonia.

D. THE ERA OF IMAGING

The use of imaging (computerized axial tomography and magnetic resonance imaging) in the
mid-1970s and 1980s permitted a better correlation of lesions and disturbance of function.

Motor Functions of the Cerebellum

The cerebellum traditionally has been relegated a motor function. As early as 1822, Flourens
showed that the cerebellum was concerned with coordination of movement, and in 1891, Italian
physiologist Luigi Luciani described the triad of cerebellar signs: atonia, asthenia (weakness),
and astasia (motor incoordination). Later he added a fourth sign, dysmetria.

Based on studies conducted by Gordon Holmes in the first quarter of the 20th century on
patients with wound injuries to the cerebellum, the Holmes motor triad of asthenia (easy
fatigability), ataxia, and atonia became synonymous with cerebellar disease. Subsequent clinical
and experimental studies confirmed a role for the cerebellum in control and integration of motor
activity.

Neocerebellar Signs
The cerebellum is generally thought to integrate motor commands and sensory information
to help coordinate movement. The incoordination of movement noted in diseases of the
neocerebellum is the result of disturbances in speed, range, force, or timing of movement.
These are manifested clinically in the following neocerebellar signs: dyssynergia or asynergia,

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dysarthria, adiadochokinesis, dysmetria, tremor, muscular hypotonia, ataxia, and nystagmus.

The lack of uniform velocity is responsible for the irregular and jerky movements of extremities
(dyssynergia or asynergia) of cerebellar disease. Asynergy of muscles of articulation is
responsible for the slow, slurred speech (dysarthria) of cerebellar disorders.

Proper timing in initiation and termination of movement is also essential in the execution of
smooth movement. A delay in the initiation of each successive movement will lead to the
adiadochokinesis (disturbance in performance of rapid movement using antagonistic muscle
groups) of cerebellar disease. A delay in the termination of movement results in dysmetria.
Dysmetria can manifest as overshooting intended target (hypermetria), or undershooting
intended target (hypometria). Thus, adiadochokinesis and dysmetria are the result of an error in
timing.

Intention (volitional) tremor is due to defective feedback control from the cerebellum on
cortically initiated movement. Normally, cerebellar feedback mechanisms control the force and
timing of cortically initiated movement. Failure of these mechanisms in cerebellar disease
results in tremor. The cerebellum is able to exert its corrective influence on cortically
originating movement by virtue of the input it receives from the cerebral cortex and periphery.
The cerebral cortex informs the cerebellum of intended movement via the cerebrocerebellar
pathways described previously. During movement, the cerebellum receives also a constant flow
of information, both proprioceptive and exteroceptive, from peripheral receptors (e.g., muscle
spindle, Golgi tendon organ) concerning movement in progress. The
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cerebellum correlates peripheral information on movement in progress with central information
on intended movement and corrects errors of movement accordingly. The cerebellum thus
serves to optimize cortically originating movement using sensory information. Based on the
cerebellar role in sensory-motor integration, it has been suggested that the cerebellum might be
involved in generating the prediction of the sensory consequences of movement. Such a role
may explain why we cannot tickle ourselves.

In addition, the cerebellum may be involved in motor learning and the initiation of movement.
Long-lasting changes in synaptic efficacy may take place in the cerebellar cortex during motor
learning, suggesting that the cerebellum may be capable of remembering what was done and
thereby adapting its influence on motor neurons in accordance with the outcome of movement.
Experimental evidence suggests that deep cerebellar nuclei fire simultaneously with pyramidal
cortical neurons prior to movement.

The cerebellum also influences movement via its effects on the gamma system. The cerebellum
normally increases the sensitivity of muscle spindles to stretch. Cerebellar lesions are
associated with a depression of gamma motor neuron activity that leads to erroneous
information in the gamma system about the degree of muscle stretch. The erroneous
information conveyed by the muscle spindle to the alpha motor neuron results in disturbances in
discharge of the alpha motor neuron and is manifested by a disturbance in force and timing of
movement.

The depression of tonic activity of gamma motor neurons in cerebellar disease is also the basis
of the hypotonia associated with neocerebellar syndromes. The ataxia of neocerebellar lesions
are usually appendicular (unsteady limb movement). The nystagmus (rhythmic oscillation of eye
movements) seen in neocerebellar lesions is apparent with horizontal ocular movement and
reflects dysmetria of eye tracking.

Archicerebellar and Paleocerebellar Signs

The archicerebellum and paleocerebellum influence spinal activity via the vestibulospinal and
reticulospinal tracts. Archicerebellar signs are usually associated with lesions in the
flocculonodular lobe and are manifested by truncal ataxia (staggering gait and unsteady posture
while standing) and nystagmus (rhythmic oscillation of the eyes at rest and/or with ocular
movements). Paleocerebellar lesions are rare in humans and usually affect the anterior lobe.
The increase in myotatic and postural reflexes associated with the anterior lobe syndrome is due
to an increase in motor signals to the alpha motor neurons and a simultaneous decrease in
signals to the gamma system. Thus, the rigidity of cerebellar disease is an alpha type of
rigidity. In humans, unsteadiness of gait (gait ataxia) may be the only manifestation of
paleocerebellar lesions.

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Ocular Motor Signs

The cerebellum is necessary for the production of both accurate saccadic and smooth pursuit
movements. Evidence is accumulating for a role of the cerebellum in vergence eye movements.

Saccades are the voluntary rapid eye movements that move our eyes from one visual target to
another. The objective of smooth pursuit eye movements is to reduce the slip of a visual image
over the fovea to velocities slow enough to allow clear vision. Vergence is simultaneous
movement of both eyes in different directions. Convergence is movement of both eyes nasally;
divergence is movement of both eyes temporally. Convergence and divergence occur in response
to changes in position of a visual target along the far–near axis.

The posterior lobe vermis (oculomotor vermis) and the caudal nucleus fastigii to which it
projects are necessary for horizontal saccades and make them fast, accurate, and consistent. In
lesions of the caudal fastigial nucleus, saccades are inaccurate, slow, and abnormally variable in
size and speed. The caudal fastigial nucleus influences saccadic machinery via its projections to
saccade-related neurons in the brain stem (excitatory burst neurons, inhibitory burst neurons,
omnipause neurons). The interpositus nucleus is related to vertical saccades. Both the caudal
fastigial nucleus and the floccculus/paraflocculus are necessary for normal smooth pursuit eye
movements. The caudal fastigial nucleus is believed to be important in pursuit initiation and the
flocculus in pursuit maintenance. In addition to playing a role in saccades and smooth pursuit,
the caudal fastigial nucleus and interpositus nucleus also influence vergence eye movements.

Cerebellum and Epilepsy

Cerebellar stimulation has been shown to have beneficial effects on both experimentally induced
epilepsy and human epilepsy. The results are variable, and more study is needed before the role
of the cerebellum in the control of epilepsy can be defined clearly.

Complementarity of Basal Ganglia and Cerebellum in Motor

Function
Review of basal ganglia and cerebellar structure, connectivity, and organization reveals many
features in common. Both are components of the motor system, influence cerebral cortical
activity via the thalamus, are linked with the cerebral cortex via recurrent loops, have internal
(local) circuitry that modulates loop activity, receive modulating inputs that influence their
activities (climbing fibers in the cerebellum and dopaminergic input in the basal ganglia), have a
high convergence ratio of inputs on their principal neurons (spiny neuron in the basal ganglia
and Purkinje cell in the cerebellum), and play a role in pattern recognition.

The emerging concept (Figure 15-24) of the complementarity of basal ganglia and cerebellar
roles in motor function suggests that the basal ganglia function as detectors of specific
contexts, providing to the cerebral cortex information that could be useful in planning and
gating of action. The cerebellum, in contrast, functions in programming, execution, and
termination of actions. According to this concept, the cerebral cortex, which receives diverse
sensory information from the periphery via the different ascending tracts as well as complex
information already processed within the basal ganglia and cerebellum, serves two functions: a
repository function to receive this diverse information, compute it, and share it with the basal
ganglia and cerebellum and an executive function to implement the action emanating from its
collective computation process.

Another complementarity model (Figure 15-25), based on the roles of the cerebellum and basal
ganglia in both motor and cognitive functions, suggests that cerebellum, basal ganglia, and
cerebral cortex are specialized for different types of learning. According to this model, the
cerebellum is specialized for supervised (error-based) learning, guided by the error signal
encoded in the climbing fiber input from the inferior olive. The basal ganglia are specialized for
reinforcement (reward-based) learning, guided by the reward signals encoded in the
dopaminergic input from the substantia nigra. The cerebral cortex is specialized
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for unsupervised learning guided by the statistical properties of the input signal regulated by
ascending neuromodulatory inputs.

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Figure 15-24. Schematic diagram showing the complementarity of the cerebellum and
basal ganglia in motor function.

Nonmotor Functions of the Cerebellum

A growing body of data suggest a nontraditional role for the cerebellum in the regulation of
autonomic function, behavior, and cognition. Following cerebellar ablation or stimulation, a
multitude of visceral and affective responses has been reported, including cardiovascular and
endocrine changes; altered respiration, intestinal motility, and bladder tone; reduced
aggressiveness; mood changes; and alerting reactions. These visceral and affective responses
were believed to be mediated through cerebellar connections with brain stem reticular nuclei.
Evidence for a complex network of pathways between the hypothalamus and cerebellum
suggests an alternate mechanism for these responses.

Figure 15-25. Schematic diagram showing error-based cerebellar and reward-based basal
ganglia feedback inputs to the cerebral cortex.

The possibility that the cerebellum may be involved in nonmotor function was first suggested by
phrenologists in the eighteenth and nineteenth centuries and by later studies dating back almost
half a century. The founder of phrenology, Franz Gall, considered the primary function of the
cerebellum to be a locus of the emotion of love.

Reports of neuropsychological dysfunction in patients with developmental and acquired

cerebellar pathology and neuroimaging studies in normal adults have given credence to the

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proposed involvement of the cerebellum in “higher-order” nonmotor processes. Psychiatric

disorders (schizophrenia, manic depression, and dementia) have been reported in association
with cerebellar agenesis or hypoplasia by some authors but not by others. Damage to the
cerebellum has been shown to impair rapid and accurate mental shifts of attention between and
within sensory modalities. Increased planning and word-retrieval time have been described in
patients with cortical cerebellar atrophy; profound deficits in practice-related nonmotoric
learning have been reported in association with right-sided cerebellar infarcts; and transient
mutism has been reported following posterior fossa craniectomy for cerebellar tumors and
following bilateral stereotactic lesions of the dentate nucleus. Mutism and agrammatic, Broca's
aphasia-like speech have also been described with right cerebellar infarcts. Data from positron-
emission tomography (PET), functional magnetic resonance imaging (fMRI), and single
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photon emission computed tomography (SPECT) seem to confirm a role for the cerebellum in
nonmotor function. Neocerebellar areas are metabolically active during language and cognitive
processes such as the association of verbs to nouns, mental imagery, mental arithmetic, motor
ideation, and learning to recognize complicated figures, whereas vermal and paravermal
structures are metabolically active during panic and anxiety states. Developmental dyslexia and
autism have been reported in developmental cerebellar disorders.

Table 15-4. Functions of Cerebellum

Region Motor function Nonmotor function (proposed)

(established)

Archicerebellum Equilibrium and Primitive autonomic responses, emotion,

posture affect, sexuality, affectively important
memory (“limbic” cerebellum)

Neocerebellum Coordination of Modulation of thought, planning, strategy

extremity formation, spatial and temporal
movement parameters, learning, memory, language

Stimulation of the fastigial nucleus in animals has been reported to produce an alerting
reaction, grooming response, savage predatory attack, and outbursts of sham rage, suggesting
that the fastigial nucleus may serve a modulatory role for emotional reactions. Following lesions
in the cerebellar vermis, aggressive monkeys are reported to have become docile, and chronic
cerebellar stimulation in humans has been reported to reduce anxiety, tension, and aggression.

The reported association between cerebellar disorders and cognition and behavior does not
necessarily imply causality, however. Whether the cognitive and behavioral manifestations
reported in cerebellar disorders are due to the cerebellar lesion itself or are secondary to
associated cerebral hemisphere dysfunction remains unsettled. The cerebellum and cerebral
cortex are closely related anatomically and functionally.

Based on the available behavioral and cognitive data, a new concept of cerebellar function has
evolved that assigns to each cerebellar lobe a role in behavior and cognition (Table 15-4). Thus
the archicerebellum may be concerned not only with control of equilibrium and posture but also
with primitive defense mechanism such as the “fight or flight” response, emotion, affect, and
sexuality, whereas the neocerebellum may be concerned, in addition to coordination of rapid
movement of the extremities, with modulation of thought, planning, strategy formation, spatial
and temporal parameters, learning, memory, and language.

The Cerebellum and Autism

In 1987, Courchesne and colleagues were the first to report hypoplasia of cerebellar vermis and
hemispheres in MRI scans of autistic patients and to suggest that the abnormality may be
responsible for the deficits in attention, sensory modulation, and motor and behavioral initiation
seen in this disorder. In subsequent imaging studies, vermal hypoplasia and hyperplasia as well
as normal cerebellar morphology have been reported. Neuropathologic studies of autistic

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patients describe loss of Purkinje and granule cells in the vermis and hemispheres as well as
neurons in nucleus fastigii of possible prenatal onset. The cerebellum, however, is not the only
site in the central nervous system to be impaired in autistic disorders. Other studies have shown
reduction in the size of the brain stem, posterior portion of corpus callosum, parietal lobes,
amygdala, and hippocampus.

Figure 15-26. Photograph of the ventral surfaces of the cerebellum showing the territories
of arterial supply.

Figure 15-27. Photograph of the dorsal surfaces of the cerebellum showing the territories
of arterial supply.

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SENSORY SYSTEMS AND CEREBELLUM

Although the cerebellum is generally regarded as a motor center, studies suggest that it has a
role in sensory mechanisms. The cerebellum has been shown to receive tactile, visual, and
auditory impulses. Furthermore, reciprocal connections have been demonstrated between the
cerebral and cerebellar tactile, visual, and auditory areas.

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ARTERIAL SUPPLY
The cerebellum is supplied by three long circumferential arteries arising from the vertebral
basilar system: (1) the posterior inferior cerebellar artery (PICA), (2) the anterior inferior
cerebellar artery (AICA), and (3) the superior cerebellar artery (SCA).

The posterior inferior cerebellar artery (PICA) arises from the rostral end of the vertebral artery
and supplies most of the inferior surface of the cerebellum (Figure 15-26), including the
cerebellar hemispheres, inferior vermis, and the tonsils. It also supplies the choroid plexus of
the fourth ventricle and gives collaterals from its medial branch to supply the dorsolateral
medulla.

The anterior inferior cerebellar artery (AICA) arises from the caudal third of the basilar artery.
Because of its usual small size, it supplies a small area of the anterolateral part of the inferior
surface of the cerebellum (Figure 15-26). Proximal branches of the artery usually supply the
lateral portion of the pons, including the facial, trigeminal, vestibular, and cochlear nuclei, the
roots of the facial and cochleovestibular cranial nerves, and the spinotha-lamic tract. When
there is a large AICA, the ipsilateral PICA is usually hypoplastic, and the AICA territory then
encompasses the whole anteroinferior aspect of the cerebellum.

The superior cerebellar artery (SCA) is the most constant in caliber and territory of supply. It
arises from the rostral basilar artery. The SCA supplies most of the superior surface of the
cerebellar hemisphere and vermis (Figure 15-27) as well as the deep cerebellar nuclei. Along its
course, branches of the SCA supply the lateral tegmentum of the rostral pons, including the
superior cerebellar peduncle, spinothalamic tract, lateral lemniscus, descending sympathetics,
and more dorsally, the root of the trochlear nerve.

The three circumferential arteries and their branches are connected by numerous free cortical
anastomoses that help limit the size of the infarct with cerebellar, vertebral, or basilar artery
occlusions.

VENOUS DRAINAGE
The cerebellum is drained by three veins: superior, posterior, and anterior. The superior vein
drains the entire superior surface of the cerebellum and empties into the great cerebral vein of
Galen. The posterior vein drains the posterior part of the inferior surface and empties into the
straight or transverse sinus. The anterior vein, known to neurosurgeons as the petrosal vein, is
a constant vein that drains the inferoanterior surface of the cerebellum and empties into the
superior or inferior petrosal sinus.

TERMINOLOGY
Archicerebellum (Greek arche, “beginning”).
Phylogenetically old part of the cerebellum concerned with equilibrium and posture.

Astasia (Greek a, “without” stasis, stand).

Motor incoordination.

Asthenia. (Greek a, “without” sthenos, “strength”).

The asthenic habitus is a thin, frail person.

Asynergia (Greek synergia, “cooperation”).

Lack of coordination among parts. Disturbance of proper association in the contraction of
muscles that ensures that the different components of an act follow in proper sequence and at
the proper moment so that the act is executed accurately.

Ataxia (Greek taxis, “order”).

Want of order; lack of coordination, resulting in unsteadiness of movement. The term was used
by Hippocrates and Galen for any morbid state, especially one with disordered or irregular
action of any part, such as irregularity of the pulse.

Brachium (Latin “arm”).

Denotes a discrete bundle of interconnecting fibers.

Cerebellum (Latin “little brain”).

The hind brain, located in the posterior fossa.

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Cuvier, Baron de la (1769–1832).

French anatomist and naturalist. He is best known for classification of the animal world in his La
Régne Animal published in 1817.

Dentate nucleus (Latin dentatus, “toothed”).

Like a tooth.
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Dysmetria (Greek dys, “difficult” metron, “a measure”).

Difficulty in accurately controlling (measuring) the range of movement. Occurrence of errors in
judgment of distance when a limb is made to perform a precise movement.

Emboliform nucleus (Greek embolos, “plug” Latin forma, “form”).

Plug-shaped. The emboliform nucleus plugs the opening of the dentate nucleus.

Fastigial nucleus (Latin fastigium, “apex of a gabled, pointed roof”).

The roof nucleus. The nucleus fastigii is located in the pointed roof of the fourth ventricle.

Fluorens, Marie-Jean-Pierre (1794–1867).

French comparative anatomist who suggested that functions were precisely located in many
parts of the cerebral cortex. He identified the cerebellum as concerned with motor coordination,
although he wrongly supposed that this control is exerted contralaterally. He correctly ascribed
to the vestibular system a role in vertigo and nystagmus.

Gall, Franz (1758–1829).

Viennese physician and anatomist. Founder of the discipline of phrenology, and father of
cerebral localization. Described the cervical and lumbar enlargements of the spinal cord,
differentiated gray from white matter, and described the origins of the optic, oculomotor,
trochlear, and abducens cranial nerves. He is best known, however, for cerebral localization of
function. He isolated 26 brain areas and related them to intellect, sentiments, and mental
attribute—most of which turned out to be ill-founded. After decades of success, the discipline of
phrenology fell into disrepute when it was claimed as a method for selecting members of
parliament among others.

Globose nucleus (Latin globus, “a ball”).

Rounded. The globose nucleus is rounded (spherical) in shape.

Glomerulus (Latin glomero, “to wind into a ball”).

Small, rounded synaptic configuration around mossy fiber rosettes.

Golgi, Camillo (1844–1926).

Italian anatomist whose staining method (developed in his kitchen) allowed the full description
of neuronal morphology. Described two types of cortical cells in 1880. The Golgi neuron of the
cerebellum is the type II Golgi neuron. Type I neurons have long axons that terminate at a
distance. He was the first to describe dendrites and shared the Nobel prize for 1906 with Ramon
y Cajal, with whom his relationship was poor.

Holmes, Sir Gordon (1876–1965).

Irish neurologist. Had interest in spinal cord tracts and their connections. As consultant
neurologist to the British army during World War One, he and Sir Percy Sargent, his
neurosurgical colleague, treated hundreds of soldiers with head injuries. This experience
provided him an opportunity to study the effects of lesions in specific brain regions on balance,
vision, and bladder function.

Luciani, Luigi (1840–1919).

Italian physiologist. Pioneer in cerebellar physiology. He made many important contributions to
the physiology of the nervous system, including the cerebellar triad of atonia, asthenia, and
astasia as well as cortical pathogenesis of epilepsy. He is best known for two monographs: the
physi-ology of starvation in man and the physiology and pathology of the cerebellum.

Magendie, Francois (1783–1855).

French physiologist. Credited with introducing the methods of experimental physiology into
pharmacology and pathology. With Sir Charles Bell, he developed the Bell-Magendie law
(anterior spinal roots being motor and posterior spinal roots sensory). He described the CSF in
1827, and the foramen of Magendie in the roof of the fourth ventricle in 1842.

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Neocerebellum (Greek neos, “new” Latin cerebellum, “small brain”).

Phylogenetically new part of the cerebellum.

Nystagmus (Greek nystagmos, “nodding in sleep”).

Rhythmic involuntary oscillatory movements of the eyes. The term is said to have been first
used by Plenck. The association of these eye movements with vertigo was first noted by
Purkinje and further investigated by Flourens.

Paleocerebellum (Greek palaios, “ancient” Latin cerebellum, “little brain”).

Phylogenetically old part of the cerebellum.

Peduncle (Latin pedunculus, “little foot”).

Stemlike or stalklike process by which an anatomic part is joined to the main organ. The
cerebellar peduncles connect the brain stem with the cerebellum.

Purkinje, Johannes Evangelista von (1787–1869).

Bohemian priest and professor of physiology at Breslau and Prague. Described the Purkinje cells
in the cerebellum in 1837. Besides his professional duties, he served as newspaper editor and
member of the Czech parliament. His interest in experimentation led him to induce seizures in
himself by taking camphor. Because of his ethnicity and his eclectic research, he was known as
the “gypsy physiologist.”

Restiform body (Latin restis, “cord or rope” forma, “form or shape”).

The inferior cerebellar peduncle has a cordlike appearance on the dorsolateral surface of the
medulla. The restiform body was described and named by Humphrey Ridley (1653–1708), an
English anatomist, in Anatomy of the Brain (London, 1695, p. 78).

Rolando, Luigi (1773–1831).

Italian anatomist. Best known for describing the central sulcus in 1825 (named after him by
Leurat in 1839). Leurat was unaware of the earlier description by Vicq d'Azir. He also is
accredited for describing the substantia gelatinosa of the spinal cord and ipsilateral motor
function of the cerebellum.

Tentorium cerebelli (Latin tentorium, “a tent”).

Horizontal dural fold between the cerebellum and cerebral hemisphere. The term was adopted
near the end of the 18th century.

Vermis (Latin “a worm”).

The midline portion of the cerebellum. The appearance of its folia bears a resemblance to the
segmented body of a worm.

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Brown-Gould B: The organization of afferents to the cerebellar cortex in the cat: Projections

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from the deep cerebellar nuclei. J Comp Neurol 1979; 184:27–42.

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Editors: Afifi, Adel K.; Bergman, Ronald A.

Title: Functional Neuroanatomy: Text and Atlas, 2nd Edition

Copyright ©2005 McGraw-Hill

> Table of Contents > Part I - Text > 16 - Cerebellum: Clinical Correlates

16
Cerebellum: Clinical Correlates

Clinical Manifestations
Cerebellar Syndromes
Experimental Animals
Humans
Vascular Syndromes
Superior Cerebellar Artery (SCA) Syndrome
Anterior Inferior Cerebellar Artery (AICA) Syndrome
Posterior Inferior Cerebellar Artery (PICA) Syndrome
Developmental Syndromes
Chiari Malformation
Dandy-Walker Malformation
Cerebellar Hypoplasia

KEY CONCEPTS

Signs of cerebellar disease are ipsilateral to the side of the

cerebellar lesion.

Lesions of the vermis are manifest by abnormalities in trunk

movements, whereas lesions of the cerebellar hemispheres are
manifested by abnormalities of movement in the extremities.

Midline cerebellar syndrome is manifested by unsteadiness of gait

and nystagmus.

Lateral (hemispheral, neocerebellar) syndrome is manifested by

ataxia, dysmetria, dyssynergia, dysdiadochokinesia, intention tremor,
muscular hypotonia, dysarthria, and nystagmus.

Three vascular cerebellar syndromes are well defined: superior

cerebellar artery (SCA) syndrome, anterior inferior cerebellar artery
(AICA) syndrome, and posterior inferior cerebellar artery syndrome
(PICA). The SCA and PICA syndromes are more frequently encountered
than the AICA syndrome.

Early descriptions of cerebellar clinical symptoms and signs came from studies of

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patients with heredofamilial (e.g., Friedreich's ataxia) and demyelinating (e.g.,

multiple sclerosis) disorders, both of which involve, in addition to the cerebellum,
many extracerebellar areas in the brain stem and spinal cord. In the first quarter
of the 20th century, Gordon Holmes established the triad of cerebellar signs of
asthenia (fatigability), ataxia (incoordination, unsteadiness), and atonia
(decreased muscle tone). He derived his triad from observation of patients with
cerebellar injuries during World War I. Attempts at anatomicoclinical correlations
of cerebellar signs utilizing patients with cerebellar strokes were not rewarding.
Localizing signs could not be elicited in unconscious stroke patients and were
present in less than half the conscious patients. The introduction in the mid-
1970s of computed tomography (CT) scans and in the 1980s of magnetic
resonance imaging (MRI) and magnetic resonance arteriography (MRA), coupled
with better definition of cerebellar vascular territories, permitted a more accurate
anatomicoclinical correlation in cerebellar disorders.

CLINICAL MANIFESTATIONS
Clinical cerebellar disorders are associated with a variety of etiologies: congenital
malformations, hereditary, metabolic, infectious, toxic, vascular, demyelinating,
and neoplastic. Cerebellar disorders share the following clinical characteristics:

1. Ipsilateral signs

2. Abnormalities in limb movements (appendicular ataxia) associated with

lateral cerebellar hemisphere lesions

3. Abnormalities in trunk movements (truncal ataxia) associated with

midline vermis lesions

4. Lesions in deep cerebellar nuclei or the superior cerebellar peduncle

producing more severe signs than lesions in the cerebellar cortex

5. Signs of cerebellar disease tending to improve with time, especially when

the lesion occurs in childhood and the underlying disease is nonprogressive

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CEREBELLAR SYNDROMES
The classically described archicerebellar, paleocerebellar, and neocerebellar
syndromes in experimental animals following ablation of the respective lobes of
the cerebellum are not ordinarily observed in humans. Instead, in humans, two
cerebellar syndromes are clearly delineated: midline (archicerebellar and
paleocerebellar) and lateral cerebellar hemisphere (neocerebellar).

Experimental Animals
A. ARCHICEREBELLAR SYNDROME
The archicerebellum (flocculonodular lobe) is related to the vestibular system. It
receives fibers from the vestibular nuclei and nerve and projects to the vestibular
and reticular nuclei, which in turn project to the spinal cord (via the
vestibulospinal and reticulospinal tracts) and ocular motor system (via the medial
longitudinal fasciculus). The function of this system is the control of body
equilibrium and eye movements. Ablation of the flocculonodular lobe in
experimental animals produces nystagmus and disturbances in body equilibrium

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(truncal ataxia).

B. PALEOCEREBELLAR SYNDROME
The paleocerebellum is functionally related to the spinal cord and is concerned
with posture, muscle tone, and gait. Ablation of the paleocerebellum in animals
produces decerebrate rigidity and an increase in myotatic and postural reflexes.

C. NEOCEREBELLAR SYNDROME
The neocerebellum is functionally related to the cerebral cortex and plays a role
in planning and initiation of movement as well as the regulation of discrete limb
movements.

Humans
A. MIDLINE SYNDROME
A picture corresponding to the archicerebellar (flocculonodular lobe)
syndrome is often seen in children with a special type of tumor, the
medulloblastoma. This tumor almost always arises in the most posterior part of
the vermis and is manifested by unsteadiness of gait and nystagmus.

The paleocerebellar syndrome as described in experimental animals is usually not

encountered in humans. However, some patients with atrophy of the cerebellum
demonstrate unsteadiness of gait and increased myotatic reflexes in the lower
limbs. It is believed that in such patients the anterior lobe is affected primarily
by the atrophy.

B. CEREBELLAR HEMISPHERE SYNDROME

Lesions of the cerebellar hemispheres (neocerebellum) produce the following
manifestations:

Ataxia: A drunken, unsteady gait.

Dysmetria: Inability to estimate the range of voluntary movement. In

attempting to touch the tip of the finger to the tip of the nose, a patient will
overshoot the finger past the nose to the cheek or ear.

Decomposition of movement (dyssynergia): Jerky and tremulous

voluntary movements. In attempting to touch the nose with the finger or to
move the heel over the shin, the patient's movements are uneven and jerky
throughout the range of motion.

Adiadochokinesia (dysdiadochokinesia): Inability to perform rapid successive

movements such as tapping one hand on the other in an alternating
supination and pronation sequence.

Intention tremor: Terminal tremor as the moving limb approaches its

target.

Muscular hypotonia: Decrease in muscular tone and in the resistance to

passive stretching of muscles.

Dysarthria: Slurred, hesitating type of speech.

Nystagmus: Nystagmus is frequently observed in cerebellar hemisphere

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lesions with the fast component to the side of the cerebellar lesion.

C. PANCEREBELLAR SYNDROME
This syndrome is a combination of the preceding two syndromes and is
characterized by bilateral signs of cerebellar dysfunction involving the trunk,
limbs, and eyes.

The cerebellum is well known for its ability to compensate for its deficits. The
compensation is especially marked in children. The mechanisms underlying this
ability to compensate are not known. The assumption of lost cerebellar functions
by other noncerebellar structures or by remaining parts of the cerebellum are two
explanations for this compensation.

VASCULAR SYNDROMES

Superior Cerebellar Artery (SCA) Syndrome (Figure

16-1)
This is the most frequently encountered vascular syndrome of the
cerebellum. Clinical signs include ipsilateral dysmetria, limb ataxia, and
Horner's syndrome, contralateral pain and thermal sensory loss, and contralateral
trochlear nerve palsy. Horner's syndrome, the pain and thermal sensory deficits,
and trochlear nerve palsy are due to involvement of the brain stem tegmentum.
Dysarthria is common and is characteristic of rostral cerebellar lesions, whereas
vertigo is not as common in SCA infarcts
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and is more characteristic of the posterior inferior cerebellar artery (PICA)
syndrome. Isolated dysarthria (without other cerebellar signs) has been reported
in occlusion of the medial branch of the superior cerebellar artery with an infarct
limited to the paravermal area. Prognosis for recovery in SCA syndrome is usually
good.

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Figure 16-1. T1-weighted parasagittal MR image showing a cerebellar

infarct (arrow) in the distribution of the superior cerebellar artery (SCA).

Anterior Inferior Cerebellar Artery (AICA)

Syndrome
Occlusion of the anterior inferior cerebellar artery (AICA) is uncommon, and often
is misdiagnosed as the lateral medullary syndrome (PICA syndrome). It is
characterized by ipsilateral dysmetria, vestibular signs, Horner's syndrome, facial
sensory impairment, contralateral pain and thermal sensory loss in the limbs, and
at times, dysphagia. Other signs seen in this syndrome and unusual in the lateral
medullary syndrome include ipsilateral severe facial motor palsy, deafness,
lateral gaze palsy, and multimodal sensory impairment over the face due to
involvement of facial, cochleovestibular, abducens, and trigeminal nerves and/or
nuclei, respectively. AICA occlusion also can be manifest by purely cerebellar
signs.

Posterior Inferior Cerebellar Artery (PICA)

Syndrome (Figure 16-2)
This syndrome is as frequent as the superior cerebellar artery (SCA) syndrome.
Clinical features of the syndrome are described in the chapter on clinical
correlates of the medulla oblongata (Chapter 6).

Occlusion of the medial branch of the PICA may be clinically silent or may present
with one of the following three patterns: (1) isolated vertigo often misdiagnosed
as inner ear disease (labyrinthitis), (2) vertigo, ipsilateral axial lateropulsion
(involuntary tendency to go to one side while in motion), and dysmetria or
unsteadiness, or (3) classic lateral medullary syndrome when the medulla is also
involved in the lesion.

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Figure 16-2. T1-weighted parasagittal MR image showing a cerebellar

infarct (arrow) in the distribution of the posterior inferior cerebellar artery
(PICA).

Clinical manifestations of occlusion of the lateral branch of the PICA are

unknown, since reported cases have been chance autopsy findings with no
available clinical information.

DEVELOPMENTAL SYNDROMES

Chiari Malformation (Figure 16-3)

The Chiari malformation was first described by Cleland in 1883. Chiari provided
detailed neuropathologic descriptions in 1891 and 1896, and he proposed a
classification system that is still used. Three types of Chiari malformation are
recognized.

Type I. In this type, the inferior pole of the cerebellar hemispheres

protrude through the foramen magnum. Most patients are asymptomatic,
and the malformation is often found incidentally on MRI. Occasionally,
patients present with headache, usually associated with occipital and neck
pain and exacerbated by coughing and straining. Hydromyelia or
syringomyelia may be associated with Chiari malformation.

Type II. In this type, in addition to the protrusion of the cerebellum, the
medulla oblongata protrudes through the foramen magnum, resulting in
kinking of the cervical medullary junction. Part of the fourth ventricle is also
displaced caudally. The foramina of Magendie and Luschka are occluded. The
malformation is frequently associated with hydromyelia or syringomyelia,
hydrocephalus, and meningomyelocele. Type II Chiari malformation is
frequently referred to as the Arnold-Chiari malformation. The term was
coined in 1907 by two students of Arnold based on Arnold's description of
the malformation in 1895. Patients with type II malformation are
symptomatic. They present with dysphonia, respiratory stridor, swallowing

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difficulties, and other symptoms.

Type III. This malformation has features of types I and II as well as

herniation of the entire cerebellum into a high cervical meningocele.
Hydrocephalus is a constant finding.

Dandy-Walker Malformation (Figure 16-4)

This malformation is characterized by a triad of (1) complete or partial agenesis
of the cerebellar vermis, (2) cystic dilation of the fourth ventricle, and (3) an
enlarged posterior fossa with upward displacement of the tentorium, torcula, and
transverse sinus. Hydrocephalus is frequently present. Mental retardation is also
common. The malformation was first described by Dandy and Blackfan in 1914
and reviewed by Taggart and Walker in 1942. The term Dandy-Walker
malformation was coined by Benda in 1954. The malformation had been described
in 1887 by Sutton and possibly by Virchow in 1863. Patients present with
hydrocephalus. Mental retardation is frequent.

Cerebellar Hypoplasia
Cerebellar hypoplasia refers to incomplete development of the cerebellum. On
imaging, the cerebellum appears small, the cerebellar sulci and fissures are
prominent, and the subarachnoid cerebellar cistern (cisterna magna) and fourth
ventricle are markedly enlarged. Cerebellar hypoplasia may occur alone or
associated with malformations elsewhere in the brain. The malformation may be
sporadic, familial, or associated with chromosomal anomalies or metabolic
disorders. Patients may be asymptomatic or may present with hypotonia and
other cerebellar signs.

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Figure 16-3. Midsagittal MRI of brain showing cerebellar herniation through

the foramen magnum (Chiari malformation) and associated spinal cord
syrinx.

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TERMINOLOGY
Arnold, Julius (1835–1915).
German physician who described type II Chiari malformation in 1895. He also
described superior laryngeal neuralgia. His father, Friedrich Arnold (1803–1890)
described the frontopontine tract and made precise differentiation between the
frontal, parietal, occipital, and temporosphenoidal lobes.

Ataxia (Greek taxis, “order”).

Want of order, lack of coordination, resulting in unsteadiness of movement. The
term was used by Hippocrates and Galen for any morbid state, especially one

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with disordered or irregular action of any part, such as irregularity of the pulse.

Chiari, Hans (1851–1916).

Austrian pathologist. Described type I Chiari malformation in 1891 and 1896.
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Dandy, Walter Edward (1886–1946).

American neurosurgeon and student of Cushing, with whom he did not get along.
Described the Dandy-Walker malformation in 1914.

Figure 16-4. Axial MRI of the brain showing Dandy-Walker malformation.

Dysarthria (Greek dys, “difficult” arthroun, “to articulate”).

The indistinct pronunciation of words usually resulting from disturbances in the
muscular control of the speech mechanism.

Dysdiadochokinesia (Greek dys, “difficult” diadochos, “succeeding”

kinesis, “motion”).
Impairment of the ability to perform rapid alternating movements, such as
sequential pronation and supination of the arm.

Dysmetria (Greek dys, “difficult” metron, “a measure”).

Difficulty in accurately controlling (measuring) the range of movement.
Occurrence of errors in judgment of distance when a limb is made to perform a
precise movement.

Dyssynergia (Greek dys, “difficult” synergia, “cooperation”).

Disturbance of muscular coordination between contraction and relaxation of
muscles that normally act together in a group to produce smooth movement.

Friedreich's ataxia.

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Progressive hereditary degenerative central nervous system disorder

characterized by combination of posterior column, lateral corticospinal, and
spinocerebellar tract signs. Described in 1863 by Nikolaus Friedreich, the German
pathologist.

Nystagmus (Greek nystagmos, “nodding in sleep”).

Rhythmic involuntary oscillatory movements of the eyes. The term is said to have
been first used by Planck. The association of these eye movements with vertigo
was first noted by Purkinje and further investigated by Flourens.

SUGGESTED READINGS
Amarenco P: The spectrum of cerebellar infarctions. Neurology 1991; 41:973–
979.

Amarenco P et al: Infarction in the anterior rostral cerebellum (the territory

of the lateral branch of the superior cerebellar artery). Neurology 1991;
41:253–258.

Amarenco P et al: Paravermal infarct and isolated cerebellar dysarthria. Ann

Neurol 1991; 30:211–213.

Amarenco P et al: Anterior inferior cerebellar artery territory infarcts:

Mechanisms and clinical features. Arch Neurol 1993; 50:154–161.

Barth A et al: The clinical and topographic spectrum of cerebellar infarcts: A

clinical–magnetic resonance imaging correlation study. Ann Neurol 1993;
33:451–456.

Chaves CJ et al: Cerebellar infarcts. Curr Neurol 1994; 14:143–177.

Niesen CE: Malformations of the posterior fossa. Current perspective. Sem

Pediatr Neurol 2002; 9:320–334.

Shuman RM: The Chiari malformation: A constellation of anomalies. Sem

Pediatr Neurol 1995; 2:220–226.

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Editors: Afifi, Adel K.; Bergman, Ronald A.

Title: Functional Neuroanatomy: Text and Atlas, 2nd Edition

Copyright ©2005 McGraw-Hill

> Table of Contents > Part I - Text > 17 - Cerebral Cortex

17
Cerebral Cortex

Types of Cortex
Isocortex (Neocortex or Homogenetic Cortex)
Allocortex (Paleocortex, Archicortex, or Heterogenetic Cortex)
Mesocortex (Periallocortex, Periarchicortex)
Microscopic Structure
Cell Types
Principal (Projection) Neurons
Interneurons
Layers
Input to Cerebral Cortex
Thalamocortical Input
Extrathalamic Modulatory Input
Association Fiber System
Commissural Fiber System
Output of Cerebral Cortex
Corticospinal Pathway
Aberrant Pyramidal Tract
Corticoreticular Pathway
Corticobulbar Pathway
Corticopontine Pathway
Corticothalamic Pathway
Corticohypothalamic Pathway
Corticostriate Pathway
Other Corticofugal Pathways
Intracortical Circuitry
Cortical Cytoarchitectonic Areas
Cortical Sensory Areas
Primary Somesthetic (General Sensory, Somatosensory) Area (SI)
Secondary Somesthetic Area (SII)
Supplementary Sensory Area (SSA)
Primary (Unimodal)Somatosensory (Somesthetic) Association Areas
Primary Visual Cortex (V 1 )
Primary (Unimodal) Visual Association Areas
Primary Auditory Cortex
Primary (Unimodal) Auditory Association Cortex
Primary Gustatory Cortex
Primary Olfactory Cortex

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Primary Vestibular Cortex

Cortical Motor Areas
Primary Motor Area (MI)
Supplementary Motor Area (MII)
Premotor Area
Cortical Eye Fields
Cortical Language Areas
Wernicke's Area
Broca's Area
The Arcuate Fasciculus
Sequence of Cortical Activities during Language Processing
The Right Hemisphere and Language
Cortical Localization of Music
Other Cortical Areas
Prefrontal Cortex
Major Association Cortex
The Insula (Island of Reil)
Cortical Electrophysiology
Evoked Potentials
Somatosensory, Visual, and Auditory Evoked Responses
Electroencephalography
Blood Supply
Arterial Supply
Venous Drainage

KEY CONCEPTS

The cerebral cortex receives fibers from internal and external

sources. Internal sources include the cortex of the same hemisphere via
association fiber bundles and the contralateral hemisphere via
commissural fibers. External sources of input include the thalamus and
nonthalamic subcortical sources.

Corticofugal fiber system includes the corticospinal, corticoreticular,

corticobulbar, corticopontine, corticothalamic, corticohypothalamic,
corticostriate, and others.

Based on thickness of cortex, width of the different cortical layers,

cell types within each layer, and nerve fiber lamination patterns, the
cerebral cortex has been divided into between 20 and 200
cytoarchitectonic areas. The most widely used classification is that of
Brodmann, which contains 52 areas numbered in the order in which they
were studied.

There are six primary sensory cortical areas: somesthetic, visual,

auditory, gustatory, olfactory, and vestibular.

The primary (unimodal) somatosensory association areas are

concerned with the perception of shape, size, and texture and the

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identification of objects by contact (stereognosis).

Three motor areas have been defined: primary motor,

supplementary motor, and premotor.

The cerebral areas most important for saccadic control are the
posterior parietal cortex, frontal eye field, supplementary eye field, and
the dorsolateral prefrontal cortex.

Cortical areas for smooth pursuit movement include the posterior

parietal cortex or the temporooccipitoparietal region.

Two cortical areas traditionally have been associated with language

function: Wernicke's and Broca's areas in the left hemisphere.

The prefrontal cortex plays a role in executive function, emotion,

and social behavior.

The major association cortex is interconnected with all the sensory

cortical areas and thus functions in higher-order, complex, multisensory
perception.

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The cerebral cortex is the layer of gray matter capping the white matter core of
the cerebral hemispheres. Its thickness varies from 1.5 to 4.5 mm, with an
average thickness of 2.5 mm. The cerebral cortex is thickest in the primary motor
area (4.5 mm thick) and thinnest in the primary visual cortex (1.5 mm thick). The
cortex is irregularly convoluted, forming gyri separated by sulci or fissures. The
outer layer of the human cerebral cortex is around 0.2 m 2 , but only one-third of
this area is exposed to the surface, the rest being buried in sulci or incorporated
in the insula. The number of neurons in the cerebral cortex is estimated at
between 10 and 20 billion. Morphometric studies of the cerebral cortex in males
and females demonstrate no gender-based differences in cortical thickness. On
the other hand they show neuronal density to be higher in the male with a
reciprocal increase in neuropil and neuronal processes in the female. A relatively
small area of the cerebral cortex in humans is specialized for receiving sensory
input from the eyes, ears, and skin and for projecting motor output down the
pyramidal tract to bring about movement. More than 80 percent of the cortex in
humans serves an association function specially related to integrative and
cognitive activities such as language, calculation, planning, and abstract
reasoning.

TYPES OF CORTEX
On the basis of phylogenetic development and microscopic structure, the
following three types of cortices are recognized.

Isocortex (Neocortex or Homogenetic Cortex)

This cortex is six layered and of recent phylogenetic development. It is
characteristic of mammalian species, increases in size in higher mammals, and

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comprises 90% of the cerebral cortex in humans.

Isocortex in which the six layers are clearly evident (such as the primary sensory
cortex) is termed homotypical cortex. Isocortex in which some of the six layers
are obscured (such as the motor cortex and visual cortex) is termed heterotypical
cortex. The visual cortex is also known as granular cortex or koniocortex (from
the Greek konis, meaning “dust”). The motor cortex, in contrast, is known as
agranular cortex because of the predominance of large pyramidal neurons.

Allocortex (Paleocortex, Archicortex, or

Heterogenetic Cortex)
The allocortex is three layered and phylogenetically older. It is subdivided into
paleocortex (rostral insular cortex, piriform cortex, and primary olfactory cortex)
and archicortex (hippocampal formation).

Mesocortex (Periallocortex, Periarchicortex)

This type of cortex is found in much of the cingulate gyrus, entorhinal,
parahippocampal, and orbital cortices and is intermediate in histology between
the isocortex and allocortex. The terms periallocortex and periarchicortex are
used to refer to this cortex to denote its transitional nature between neocortex
and allocortex.

MICROSCOPIC STRUCTURE

Cell Types (Figure 17-1)

Attempts to make a comprehensive inventory of types of cortical neurons started
with Ramon y Cajal in 1911 and have continued
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until today. The neurons of the cerebral cortex are of two functional categories:
(1) principal (projection) neurons and (2) interneurons. The principal neurons
provide corticocortical and corticosubcortical outputs. Interneurons are concerned
with local information processing. Recent evidence suggests that the two
neuronal types are generated in distinct proliferative zones. Principal neurons are
derived from neuroepithelium in the ventricular zone. Interneurons, in contrast,
arise from the ganglionic eminence of the ventral telencephalon, which gives rise
also to the basal ganglia. The cerebral cortex has its full complement of neurons
(10 to 20 billion) by the 18th week of intrauterine life.

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Figure 17-1. Schematic diagram of the various types of cortical neurons.

Principal (Projection) Neurons

Two types of cortical neurons belong to the principal category. They are the
pyramidal neurons and the fusiform neurons. The excitatory neurotransmitter in
both is glutamate or aspartate. Principal neurons constitute more than half of all
cortical neurons.

A. PYRAMIDAL NEURONS (FIGURE 17-1A)

These neurons derive their name from their shape. The apex of the pyramid is
directed toward the cortical surface. Each pyramidal neuron has an apical
dendrite directed toward the surface of the cortex and several horizontally
oriented basal dendrites that arise from the base of the pyramid. Branches of all
dendrites contain numerous spines that increase the size of the synaptic area. A
slender axon leaves the base of the pyramidal neuron and projects on other
neurons in the same or contralateral hemisphere or else leaves the cortex to
project on subcortical regions. The axon gives rise within the cortex to two types
of axon collaterals. These are the recurrent axon collaterals (RACs), which
project back on neurons in more superficial layers, and the horizontal axon
collaterals (HACs), which extend horizontally to synapse on neurons in the
vicinity.

Pyramidal neurons are found in all cortical layers except layer I. They vary in
size; most are between 10 and 50 µm in height. The largest are the giant
pyramidal cells of Betz, which measure about 100 µm in height and are found in

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layer V of the motor cortex.

B. FUSIFORM, SPINDLE NEURONS (Figure 17-1C)

These are small neurons with elongated perikarya in which the long axis is
oriented perpendicular to the cortical surface. A short dendrite arises from the
lower pole of the perikaryon and arborizes in the vicinity. A longer dendrite arises
from the upper pole of the perikaryon and extends to more superficial layers. The
axon enters the deep white matter. Fusiform neurons are found in the deepest
cortical laminae.

Interneurons
Several types of cortical interneurons are recognized on the basis of dendritic
architecture. They include the stellate neurons, the horizontal cells of Cajal, and
the cells of Martinotti.

A. STELLATE OR GRANULE NEURONS (Figure 17-1B)

These are small (4 to 8 µm) star-shaped neurons with short, extensively
branched, spiny dendrites and short axons. They are most numerous in lamina
IV. Stellate cells are the only type of excitatory interneurons in the cortex. The
neurotransmitter is
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glutamate. All other interneurons exert inhibitory influence by gamma-
aminobutyric acid (GABA).

B. HORIZONTAL CELLS OF CAJAL (Figure 17-1D)

These are small fusiform neurons with their long axes directed parallel to the
cortical surface. A branching dendrite arises from each pole of the perikaryon,
and an axon arises from one pole. The dendrites and axon are oriented parallel to
the cortical surface. The horizontal cells of Cajal are found only in lamina I and
disappear or are rare after the neonatal period.

C. CELLS OF MARTINOTTI (Figure 17-1E)

Giovanni Martinotti in 1890 first described cells whose axons ascend toward the
surface of the cortex. Martinotti neurons are multipolar with short branching
dendrites and an axon that projects to more superficial layers, giving out
horizontal axon collaterals en route. The Martinotti neurons are found in deeper
cortical laminae.

Layers
The division of the neocortex into layers has been the outcome of extensive
cytoarchitectonic (organization based on studies of stained cells) and
myeloarchitectonic (organization based on studies of myelinated fiber
preparations) studies. Although several such studies are available, the most
widely used are the cytoarchitectonic classification of Brodmann and the
myeloarchitectonic classification of the Vogts (Césile and Oskar, wife and
husband). According to these two classifications, the neocortex is divided into six
layers (Table 17-1).

The six layers of the neocortex are recognizable by about the seventh month of
intrauterine life. The neurons in the six cortical layers develop in waves from the

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periventricular germinal matrix. Successive waves of migrating neuroblasts

become situated progressively farther away from the germinal matrix (inside-out
gradient of cortical histogenesis) (Table 17-2). Interruption of the normal process
of migration or its arrest is associated with cortical gyral malformations such as
agyria, pachygyria, micropolygyria, and heterotopia. Many of these are
associated with mental retardation, seizures, and other neurologic deficits.

A. LAYER I (MOLECULAR, PLEXIFORM)

Layer I consists primarily of a dense network of nerve cell processes among
which are scattered sparse interneurons (horizontal cells of Cajal) and neuroglia.
The nerve cell processes in this layer comprise projection axons from
extracortical sites as well as axons and dendrites of neurons in other cortical
areas. This layer of the cortex is primarily a synaptic area.

Table 17-1. Cortical Layers

Layer Cytoarchitectonic Myeloarchitectonic name

name

I Molecular Tangential

II External granular Dysfibrous

III External pyramidal Suprastriatal

IV Internal granular External Baillarger

V Internal pyramidal Internal of Baillarger and

interstriatal

VI Multiform Infrastriatal

Table 17-2. Chronologic Age of Cortical Layers

Layer Order of neuroblast migration

I Oldest (acellular)

II Fifth wave

III Fourth wave

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IV Third wave

V Second wave

VI First wave

B. LAYER II (EXTERNAL GRANULAR)

Layer II consists of a dense packing of small and medium-sized pyramidal
neurons and interneurons intermingled with axons from other cortical layers of
the same and opposite hemispheres (association and commissural fibers), as well
as axons and dendrites passing through this layer from deeper layers. The
dendrites of pyramidal neurons in this layer project to layer I, while their axons
project to deeper layers. This layer of the cortex contributes to the complexity of
intracortical circuitry.

C. LAYER III (EXTERNAL PYRAMIDAL)

Layer III consists of pyramidal neurons that increase in size in deeper parts of
the layer. The dendrites of neurons in this layer extend to layer I, while the
axons project to other layers within the same and contralateral hemisphere
(association and commissural fibers) or leave the hemisphere as projection fibers
to more distant extracortical sites. This layer receives primarily axons of neurons
in other cortical areas (association and commissural fibers), as well as axons of
neurons in extracortical regions such as the thalamus. This layer contains the
distinctive stripes of Kaes-Bekhterev.

D. LAYER IV (INTERNAL GRANULAR)

Layer IV consists of pyramidal cells and densely packed small stellate cells with
processes that terminate within the same layer, either on axons of other stellate
cells or on axons of cortical or subcortical origin passing through this layer. The
cell packing density in layer IV is the greatest of all cortical layers. Few of the
larger stellate cells in this layer project their axons to deeper cortical layers.
Layer IV is especially well developed in primary sensory cortical areas. In the
primary visual (striate) cortex, this layer is traversed by a dense band of
horizontally oriented tha-lamocortical nerve fibers known as the external band of
Baillarger or the stripe of Gennari. The band of Baillarger was described by the
nineteenth-century French neurologist and psychiatrist Jean-Gabriel-Francois
Baillarger. The stripe of Gennari was first described in 1782 by Francesco
Gennari, an eighteenth-century Italian medical student, and independently by Vic
d'Azyr in 1786. Because of the presence of this stripe, the primary visual cortex
is known as the striate cortex. The internal granular layer is the major recipient
of thalamocortical fibers from modality-specific sensory relay nuclei (visual

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radiation, auditory radiation, and primary sensory radiation).

E. LAYER V (INTERNAL PYRAMIDAL)

Layer V consists of large and medium-sized pyramidal cells, stellate cells, and
cells of Martinotti. The cell packing density in this layer is the lowest of all
cortical layers. The largest pyramidal cells in the cerebral cortex (cells of Betz)
are found in this layer (hence the name ganglionic layer). Dendrites of neurons in
this layer project to the more superficial layers. Axons project on neurons
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in other cortical areas but mainly to subcortical sites (projection fibers) except
the thalamus, which receives fibers from layer VI. This layer receives axons and
dendrites arising in other cortical sites or in subcortical sites. It is also traversed
by a dense band of horizontally oriented fibers; this is the internal band of
Baillarger. Fibers originating in thalamic sensory nuclei contribute heavily to the
formation of the lines of Baillarger, especially the outer one in lamina IV. The
lines of Baillarger are thus prominent in primary cortical sensory areas.

F. LAYER VI (MULTIFORM)
Layer VI consists of cells of varying shapes and sizes, including fusiform cells and
the cells of Martinotti, which are prominent in this layer. Dendrites of smaller
cells arborize locally or in adjacent layers, while those of large neurons reach the
molecular layer. Axons of neurons in this layer project to other cortical laminae
or to subcortical regions.

Layers I, V, and VI are present in all types of cortex (neocortex, paleocortex, and
archicortex). Layers II, III, and IV, however, are present only in neocortex and
thus are considered of more recent phylogenetic development. In general, layers
I to IV are considered receptive. The somata of the majority of cells that
establish intracortical connections (ipsilaterally and contralaterally) lie in layers
II and III. Layers V and VI are efferent. Neurons in lamina V give rise to
corticofugal fibers that target subcortical areas (brain stem and spinal cord).
Neurons in lamina VI give rise to corticofugal fibers to the thalamus.

In contrast to the horizontal anatomic lamination, the vertical lamination

described by Mountcastle seems to be the more functionally appropriate. The
studies of Lorente de Nó, Mountcastle, Szentágothai, and others have shown that
the functional unit of cortical activity is a column of neurons oriented vertically to
the surface of the cortex. Each such column or module is 300 to 500 µm in
diameter, with its height the thickness of the cortex, and contains 4000 neurons,
2000 of which are pyramidal neurons. All neurons in a column are activated
selectively by the same peripheral stimulus. There are approximately 3 million
such modules in the human neocortex. Each module sends pyramidal cell axons
to other modules within the same hemisphere or to modules in the other
hemisphere. Of interest is the fact that activation of a module tends to inhibit
neuronal activity in adjacent modules. The columnar organization of the
neocortex is established in fetal life, but the synaptic connections increase in
number in the postnatal period in response to stimulation from the external
environment. Lack of external stimuli during a critical period of cortical
maturation, usually in the first year of life, will adversely affect normal cortical
development.

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Figure 17-2. Schematic diagram showing sources of fiber input to the

cerebral cortex.

INPUT TO CEREBRAL CORTEX

The input to the cerebral cortex originates in four sites (Figure 17-2):

1. Thalamus

2. Extrathalamic modulatory

3. Cortex of the same hemisphere (association fibers)

4. Cortex of the contralateral hemisphere (commissural fibers)

Thalamocortical Input
The input from the thalamus travels via two systems. (1) The modality-specific
thalamocortical system originates in modality-specific thalamic nuclei (e.g.,
ventral anterior, ventral lateral, ventral posterior) and projects on specific
cortical areas (primary motor, premotor, and somesthetic cortex). This fiber
system reaches the cortex as an ascending component of the internal capsule.
The majority of fibers in this system project on neurons in lamina IV (Figure 17-
3A), with some projecting on neurons in lamina III and lamina VI. (2) The
nonspecific thalamocortical system is related to the reticular system and
originates in nonspecific thalamic nuclei (intralaminar, midline, and reticular
nuclei). In the cortex, fibers of this system project diffusely on all laminae
(Figure 17-3B) and establish mostly axodendritic types of synapses. This fiber
system is intimately involved in the arousal response and wakefulness.

Extrathalamic Modulatory Input

Until recently, it was commonly assumed that essentially all afferents to the
cortex arose from the thalamus. With the development of methods to visualize
monoaminergic and cholinergic processes, it is now clear that there are at least
four substantial extrathalamic projections to the cortex.

Monoaminergic and cholinergic pathways reach the cerebral cortex directly

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without passing through the thalamus.

A. MONOAMINERGIC INPUT

1. Serotonergic Input.
The serotonergic input to the cerebral cortex originates from the raphe nuclei in
the mesencephalon and rostral pons and runs in the medial forebrain bundle. It
terminates in the same cortical layers that receive the thalamocortical input
(layers III, IV, and VI). Serotonergic fibers project widely in the cerebral cortex
with the visual cortex receiving an especially rich serotonergic innervation. The
function of the serotonergic pathway to the cortex is not well understood.
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Serotonergic pathways elsewhere have been related to a variety of functions,
including pain control, emotion, and sleep. The serotonergic input to the cortex is
believed to alter cortical neuronal responses to afferent input in response to
change in state. They include inhibition of spontaneous activity, excitation, and
voltage dependent facilitation.

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Figure 17-3. Schematic diagram of the termination pattern of the various

inputs to cortical laminae.

2. Dopaminergic Input.
The dopaminergic input to the cerebral cortex originates from dopaminergic
neurons in the mesencephalon (ventral tegmental area of Tsai and substantia
nigra pars compacta). It terminates in all areas of the cortex, but especially in
the motor, prefrontal, and temporal association areas. The dopaminergic input to
the cortex is believed to play a role in orienting behavior. The laminar and
regional pattern of termination of this system suggests that it influences
activities of corticocortical rather than thalamocortical circuits and higher-order
integrative processes than the more analytic aspects of sensory processing. In
addition, it may influence cortical regulation of motor control. Dysfunction in this
system may be responsible for psychiatric symptoms noted in Parkinson's

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disease.

3. Noradrenergic Input.
The noradrenergic input to the cerebral cortex originates from cells in the locus
ceruleus in the rostral pons. It projects widely to the cerebral cortex and
terminates in cortical layers that give rise to corticofugal fibers. The
noradrenergic input is implicated in higher-order information processing and the
state of arousal. It is believed to enhance the selectivity and vigor of cortical
responses to sensory stimuli or other synaptic inputs to the target neurons in the
cortex.

4. Histaminergic Input.
The histaminergic input to the cerebral cortex originates from the
tuberomamillary nucleus in the posterolateral hypothalamus. The function of this
system is not known.

5. Cholinergic Input.
The cholinergic input to the cerebral cortex originates from the nucleus basalis of
Meynert. This input terminates in all areas of the cortex. It is the most important
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system for cortical arousal and motivation. It has been implicated in the genesis
of memory deficit in Alzheimer's disease.

B. GABAERGIC INPUT
The GABAergic input to the cerebral cortex originates from cells in the septum
and the diagonal band of Broca. It terminates primarily in the hippocampus.

Association Fiber System (Figure 17-2)

The association fibers arise from nearby (short association u-fibers) and distant
(long association fibers) regions of the same hemisphere. They too project
diffusely in all laminae but mostly in laminae I to III (Figure 17-3).

The long association fiber system (Figure 17-4) includes such bundles as the
cingulum, superior longitudinal fasciculus, arcuate fasciculus, inferior longitudinal
fasciculus, occipitofrontal fasciculus, and the uncinate fasciculus. The cingulum
(Figure 17-4B and C) is the white matter core of the cingulate gyrus. It connects
the anterior perforated substance and the parahippocampal gyrus. The superior
longitudinal fasciculus (Figure 17-4A and C), located in the lateral part of the
hemisphere above the insula, connects portions of the frontal lobe with parietal,
occipital, and temporal lobes. The arcuate fasciculus (Figure 17-4A) is the part of
the superior longitudinal fasciculus that sweeps around the insula (island of Reil)
to connect the speech areas in the inferior frontal gyrus (Broca's area) and
superior temporal gyrus (Wernicke's area). The inferior longitudinal fasciculus
(Figure 17-4A and C) is a thin sheet of fibers that runs superficially beneath the
lateral and ventral surfaces of the temporal and occipital lobes. This fiber bundle
is difficult to demonstrate by dissection and to separate from other fiber systems
running in its vicinity. The existence of the inferior longitudinal fasciculus in
humans has been questioned. The only long fiber bundle common to both the
occipital and temporal lobes in humans is the optic radiation (geniculostriate
pathway). In addition, the two lobes are interconnected by a series of u-fibers
(short association fibers) that connect adjacent regions of occipital and temporal

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cortices. Based on this, it has been proposed that the term inferior longitudinal
fasciculus be replaced by the term occipitotemporal
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projection system. The occipitofrontal fasciculus (Figure 17-4A and C) extends
backwards from the frontal lobe, radiating into the temporal and occipital lobes.
Two subdivisions of the occipitofrontal fasciculus are recognized. The superior
(subcallosal) bundle (Figure 17-4C) is located deep in the hemisphere,
dorsolateral to the lateral ventricle, sandwiched between the corpus callosum,
internal capsule, and caudate nucleus. The inferior bundle (Figure 17-4C) is
located lateral to the temporal horn of the lateral ventricle and below the insular
cortex and lentiform nucleus. The uncinate fasciculus (Figure 17-4A) is the
component of the inferior occipitofrontal fasciculus that courses at the bottom of
the sylvian fissure to connect the inferior frontal gyrus with the anterior temporal
lobe.

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Figure 17-4. Schematic diagram showing the long association fiber bundles.

Commissural Fiber System

The commissural fibers arise from corresponding and noncorresponding regions in
the contralateral hemisphere, travel via the corpus callosum and project on
neurons in all laminae but mostly laminae I, II, and III (Figure 17-3).

Studies on the topographic distribution of interhemispheric projections in the

corpus callosum have shown that the genu interconnects the prefrontal cortex,
the rostral part of the body interconnects the premotor and supplementary motor
cortices, the middle part of the body interconnects the primary motor and
primary and secondary somatic sensory areas, the caudal part of the body
interconnects the posterior parietal cortex, and the splenium interconnects
temporal and occipital cortices. Other interhemispheric commissural systems
include the anterior commissure, which interconnects the two temporal lobes, and
the hippocampal commissure (commissure of the fornix), which interconnects the
two hippocampi.

OUTPUT OF CEREBRAL CORTEX

Efferent outflow from the cerebral cortex is grouped into three categories (Figure
17-5). These are (1) the association fiber system, (2) the commissural fiber
system, and (3) the corticofugal fiber system. The laminar origin of axons of
most cortical projections are unique. The short association fibers arise from
lamina II, the long association fibers from laminae III and V, interhemispheric
commissural fibers from lamina III, corticothalamic fibers from lamina VI,
corticospinal and corticobulbar fibers from laminae III and V, and corticostriate
and corticopontine fibers from lamina V.

Figure 17-5. Schematic diagram of the major groups of cortical output.

The association and commissural fiber systems have been described in the

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section on input to the cortex. Essentially, they represent intrahemispheric and

interhemispheric connections.

The corticofugal fiber system includes all fiber tracts that leave the cerebral
cortex to project on various subcortical structures. They include the
following pathways.

Corticospinal Pathway (Figure 17-6)

This corticofugal fiber tract connects the cerebral cortex directly with motor
neurons in the spinal cord and is concerned with highly skilled volitional
movement. It arises from pyramidal neurons in layer V from wide areas of the
cerebral cortex but principally from the somatic motor, premotor, and
somatosensory cortices. It contains, on each side, roughly 1 million fibers of
various sizes (9 to 22 µm), about 3% of which are large in size and arise from
the giant cells of Betz in layer V of the motor cortex. The fibers of this system
descend in the internal capsule, the middle part of the cerebral peduncle, the
basis pontis, and the pyramids before gathering in the spinal cord as the lateral
and anterior corticospinal tracts. The former (lateral corticospinal) constitutes
the majority of the descending corticospinal fibers and decussates in the
pyramids (motor decussation); the latter (anterior corticospinal) is smaller and
crosses at segmental levels in the spinal cord. The classic notion that the
corticospinal tract is of particular importance for skilled and delicate voluntary
movement is in essence correct, but it is obvious that a number of other indirect
tracts passing through the brain stem nuclei, reticular formation, and cerebellum
are also involved. The direct corticospinal tract most likely superimposes speed
and agility on the motor mechanisms subserved by other descending indirect
pathways. The component of the corticospinal pathway from the somatosensory
cortex terminates on sensory neurons in the dorsal horn of the spinal cord and is
concerned with somatosensory function possibly related to ongoing movement. A
fairly large proportion of the sensory component of the corticospinal pathway
originates from area 3a, which adjoins the primary motor cortex and receives
sensory input from proprioceptors.

Aberrant Pyramidal Tract

This fiber tract separates from the corticospinal fiber system in the cerebral
peduncle and joins the medial lemniscus in the caudal midbrain extending
through the pons to the middle medulla oblongata, where it becomes
undetectable. It is presumed to constitute a part of the corticobulbar tract that
supplies cranial nerve nuclei. It is thus responsible for the reported supranuclear
cranial nerve palsies in lesions of medial lemniscus. Some fibers of the tract have
been traced to the spinal cord. The aberrant pyramidal tract has been described
in the literature under the following synonyms: accessory fillet fibers (Barnes,
1901), fibre aberrantes protuberantielles (Dejerine, 1901), fasciculi pontini
lateralis (Marburg, 1927), aberrant pyramidal system (Crosby, 1962), and fibrae
corticotegmentalis (Voogd and Van Hujizen, 1963).

Corticoreticular Pathway
This fiber tract arises from most if not all parts of the cerebral cortex but
primarily from motor, premotor, and somatosensory
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cortices and accompanies the corticospinal fiber system, leaving it at different
levels of the neuraxis to project on reticular neurons in the brain stem. The

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corticoreticular fibers arising from one cerebral hemisphere project roughly

equally to both sides of the brain stem reticular formation. Many of these fibers
ultimately project on cranial nerve nuclei in the brain stem, thus forming the
corticoreticulobulbar pathway.

Figure 17-6. Schematic diagram of the corticospinal pathway.

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Corticobulbar Pathway
Corticobulbar fibers originate from the face area of the motor cortex. They
project on motor nuclei of the trigeminal, facial, glossopharyngeal, vagus,
accessory, and hypoglossal nerves.

Direct corticobulbar fibers (without intermediate synapses on reticular neurons)

are known to project from the cerebral cortex to nuclei of trigeminal (CN V),
facial (CN VII), and hypoglossal (CN XII) cranial nerves. Corticobulbar fibers
descend in the genu of the internal capsule and occupy a dorsolateral corner of
the corticospinal segment of the cerebral peduncle, as well as a small area in the
medial part of the base of the cerebral peduncle. In the pons, corticobulbar fibers
are intermixed with the corticospinal fibers within the basis pontis. Bilateral
interruption of the corticobulbar or corticoreticulobulbar fiber system results in
paresis(weakness) but not paralysis of the muscles supplied by the corresponding
cranial nerve nucleus. This condition is known as pseudobulbar palsy to
distinguish it from bulbar palsy, which is a condition characterized by complete
paralysis of muscles supplied by a cranial nerve nucleus as a result of a lesion of
the nucleus. The corticobulbar input to nuclei of trigeminal and hypoglossal
cranial nerves is bilateral. As a result, pseudobulbar palsy results only when
corticobulbar inputs to these nuclei from both hemispheres are interrupted. The
corticobulbar input to the facial nucleus is bilateral to the facial subnucleus that
supplies upper facial muscles and is only contralateral to the facial subnucleus
that supplies lower facial muscles. As a result, infarcts in one hemisphere (as in
middle cerebral artery occlusion) are manifested by contralateral lower facial
paralysis and sparing of upper facial muscles. The relationship between the
cerebral cortex and the facial nerve nucleus has been the subject of several
investigations. The classical narrative that dominated knowledge during the past
century stated that the primary motor cortex (M-1) is the source of corticobulbar
inputs to facial nucleus, and that the facial subnucleus that supplies upper facial
muscles receives inputs from both primary motor cortices, whereas the facial
subnucleus that supplies lower facial muscles receives input only from the
contralateral primary motor cortex. While this narrative was adequate to explain
contralateral lower facial palsy in hemispheric lesions, it did not account for the
reported dissociation between voluntary and emotional facial movements,
emotional facial paralysis (amimia), or the uncontrollable excessive emotionally
affiliated facial movements.

Several lines of research have now revealed that there are five cortical areas for
face representation in human and in non-human primates. In addition to the well-
established primary motor cortex (M-1), the following areas have face
representation: supplementary motor cortex (M-2), rostral cingulate gyrus (M-3),
caudal cingulate gyrus (M-4), and the ventral lateral premotor cortex (LPMC V ). Of
these, the primary motor cortex (M-1) and the ventral lateral premotor cortex
(LPMC V ) give rise to the heaviest projections to the facial nucleus, followed by
the supplementary motor cortex (M-2), which sends a moderate projection, and
by the cingulate gyrus (M-3 and M-4), which sends a light projection. It has been
shown that the primary motor cortex (M-1), the caudal cingulate gyrus (M-4),
and the ventral lateral premotor cortex (LPMC V ) innervate primarily the
contralateral lower facial subnucleus (Figure 17-7A), whereas the supplementary
motor cortex (M-2) and the rostral cingulate gyrus (M-3) provide innervation to

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both upper facial subnuclei (Figure 17-7B). It has been suggested that the
different cortical face representations mediate different elements of facial
expression and that separate neural systems may mediate voluntary and
emotional facial movements. Thus, volitional facial paresis is associated
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with lesions in the primary motor cortex (M-2) and the underlying subcortical
white matter. The cingulate gyrus (M-3 and M-4) projections, in contrast,
subserve emotional expressions of facial movements. Damage in the anterior
cingulate gyrus (M-3) is associated with blunted emotional expression in upper
facial muscles, suggesting that it controls emotionally related movements of the
face. Functional neuroimaging studies have shown that the orbitofrontal cortex
plays a role in emotional processing of pleasant facial expressions. Enhanced
responses in the orbitofrontal cortex are associated with recognition of happy
faces.

Figure 17-7. Schematic diagram showing origins of corticobulbar fibers to

the contralateral lower facial subnucleus A, and to both upper facial
subnuclei B.

Corticopontine Pathway (Figure 17-8)

Fibers comprising this pathway arise from all parts of the cerebral cortex but
primarily from the frontal, parietal, and occipital lobes. Most fibers, however,
arise from the primary motor (precentral gyrus) and primary sensory (postcentral
gyrus) cortices, with relatively substantial contribution from the premotor,
supplementary motor, and posterior parietal cortices and few from the temporal
and prefrontal cortices. These fibers descend in the internal capsule and occupy
the most medial and lateral parts of the cerebral peduncle before reaching the
basis pontis, where they project on pontine nuclei. The corticopontine fibers
constitute by far the largest component of the corticofugal fiber system. It is
estimated that each corticopontine pathway contains approximately 19 million
fibers. With approximately the same number of pontine neurons on each side of
the basis pontis, the ratio of corticopontine fibers to pontine neurons becomes
1:1. Corticopontine fibers terminate in sharply delineated lamellae extending
rostrocaudally. Various cortical regions project to separate parts of the pontine

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nuclei, although considerable overlap takes place between some projection areas.
Pontine neurons that receive corticopontine fibers give rise to the pontocerebellar
pathway discussed in the chapter on the pons (Chapter 7). The corticopontine
pathway is thus one of several pathways that link the cerebral cortex with the
cerebellum for the coordination and regulation of movement. Lesions of the
corticopontine pathway at its sites of origin in the cortex or along its course will
result in incoordinated movement (ataxia) contralateral to the lesion. The
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ataxia observed in some patients with frontal or temporal lobe pathology is thus
explained as an interruption of the corticopontine pathway.

Figure 17-8. Schematic diagram of the corticopontine and pontocerebellar

pathways.

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Corticothalamic Pathway
The corticothalamic pathway arises from cortical areas that receive thalamic
projections and thus constitutes a feedback mechanism by which the cerebral
cortex influences thalamic activity. The thalamocortical relationship is such that a
thalamic nucleus that projects to a cortical area receives in turn a projection
from that area. Examples of such reciprocal connections (Figure 17-9) include the
dorsomedial thalamic nucleus and prefrontal cortex, anterior thalamic nucleus
and cingulate cortex, ventrolateral tha-lamic nucleus and motor cortex,
posteroventral thalamic nucleus and postcentral gyrus, medial geniculate nucleus
and auditory cortex, and lateral geniculate nucleus and visual cortex. The
corticothalamic input to the reticular thalamic nucleus, however, is not reciprocal.
The reticular nucleus receives afferents from almost all cortical areas but does
not project back to the cerebral cortex. The reticular nucleus receives collaterals
from all tha-lamocortical and all corticothalamic projections. Thus the reticular
nucleus is informed of activities passing in both directions between the thalamus
and cerebral cortex.

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Figure 17-9. Schematic diagram of thalamocortical relationships.

Corticothalamic fibers descend in various parts of the internal capsule and enter
the thalamus in one bundle known as the thalamic radiation, which also includes
the reciprocal thalamocortical fibers.

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Corticohypothalamic Pathway
The corticohypothalamic fibers arise from prefrontal cortex, cingulate gyrus,
amygdala, olfactory cortex, hippocampus, and septal area.

Corticostriate Pathway
Projections from the cerebral cortex to the striatum are both direct and indirect.
Direct corticostriate projections reach the neostriatum via the internal and
external capsules and via the subcallosal fasciculus. The indirect pathways
include the corticothalamostriate pathway, collaterals of the corticoolivary
pathway, and collaterals of the corticopontine pathway.

The corticostriate projection comprises the most massive striatal afferents.

Almost all cortical areas contribute to this projection. Cortical areas
interconnected via corticocortical fibers tend to share common zones of
termination in the neostriatum. Corticostriatal fibers are organized
topographically into three distinct striatal territories: (1) sensorimotor, (2)
associative, and (3) limbic. The sensorimotor territory receives its inputs from
sensory and motor cortical areas. The associative territory receives fibers from
the association cortices. The limbic territory receives input from limbic and
paralimbic cortical areas.

Corticostriate pathways are also organized somatotopically such that cortical

association areas project to the caudate nucleus, whereas sensorimotor cortical
areas preferentially project to the putamen. Corticoputamenal projections are
further organized in that the cortical arm, leg, and face areas project to
corresponding areas within the putamen.

Other Corticofugal Pathways

These include cortical projections to several sensory brain stem nuclei, such as
the nuclei gracilis and cuneatus, trigeminal nuclei, and others. Most of these
fibers serve a feedback purpose. Corticosubthalamic projections originate from
the primary motor and premotor cortical areas. A corticotectal projection has
been described arising from the frontal eyefields (area 8 of the frontal cortex) in
addition to that from the occipital cortex. Corticorubral fibers originate from the
same cortical areas as the corticospinal tract and terminate on the red nucleus in
the midbrain.

INTRACORTICAL CIRCUITRY
Cortical neurons may have descending, ascending, horizontal, or short axons
(Figure 17-1). The descending axons contribute to
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the association and the corticofugal fiber systems outlined above. The ascending,
horizontal, and short axons play important roles in intracortical circuitry. Neurons
with ascending axons are the cells of Martinotti. The horizontal cells of Cajal have
horizontal axons. Short axons arborizing in the vicinity of the cell body are seen
in stellate neurons. Pyramidal neurons have horizontal and recurrent axon
collaterals that terminate at all levels of the cortex and contribute significantly to
intracortical connections. The axon collaterals of pyramidal neurons may project
on a stellate cell or a Martinotti cell that in turn may influence other cortical
neurons and thus provide for rapid dispersion of activity throughout a population
of neurons. This fact was recognized by Cajal, who referred to it as avalanche

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conduction. A simplified account of intracortical circuitry is illustrated

diagrammatically in Figure 17-10. A thalamocortical input will excite pyramidal
(projection) neurons in layer VI and interneurons (excitatory and inhibitory) in
layer IV (point 1 in Figure 17-10). Inhibitory interneurons in layer IV inhibit other
interneurons in the same layer (point 2 in Figure 17-10). Excitatory interneurons
in layer IV excite pyramidal neurons and inhibitory interneurons in layers II and
III (point 3 in Figure 17-10). Inhibitory interneurons in layers II and III inhibit
pyramidal neurons in the same layers (point 4 in Figure 17-10). Pyramidal
neurons in layers II and III excite projection neurons in layers IV and V (point 5
in Figure 17-10). Axon collaterals of projection neurons in layer V excite
corticothalamic projection neurons in layer VI (point 6 in Figure 17-10). Axon
collaterals of corticothalamic projection neurons in layer VI project back to the
excitatory interneurons in layer IV (point 7 in Figure 17-10), thus closing the
loop. Interneurons in deep cortical layers (cells of Martinotti) and in superficial
cortical layers (horizontal cells of Cajal) contribute to intracortical circuitry by
vertical and horizontal spread of impulses. Martinotti cells, excited by axon
collaterals of pyramidal neurons, in turn excite either a pyramidal neuron or
another interneuron. Similarly, the horizontally oriented axons of the horizontal
cells of Cajal influence the vertically oriented processes of pyramidal neurons or
interneurons. Because of their paucity or absence in the post-neonatal period,
the horizontal cells of Cajal play a minimal role in intracortical circuitry in the
adult.

From the preceding it can be seen that an input to the cortex is spread both
horizontally and vertically via the various intracortical connections. The
complexity of these interconnections is far from clear definition, and is the basis
of the complexity of human brain function.

CORTICAL CYTOARCHITECTONIC AREAS

Different parts of the cortex vary in relation to the following parameters:

1. Thickness of the cortex

2. Width of the different layers of the cortex

3. Cell types in each layer

4. Cell density in each layer

5. Nerve fiber lamination

Based on the preceding variations, different investigators have parceled the

cortex into from 20 to 200 areas
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depending on the criteria used. The classification of the German histologist
Korbinian Brodmann, published in 1909, remains the most widely used. It
contains 52 cytoarchitectonic areas numbered in the order in which he studied
them (Table 17-3).

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Figure 17-10. Schematic diagram showing intrinsic cortical circuitry.

Careful counting of the numbers of Brodmann areas in textbook illustrations

indicates that numbers 13 through 16 are missing. Review of Brodmann's 1909
monograph revealed that the missing numbers are in the insula (island of Reil).
Areas 13 and 14 refer to the anteriorly placed two insulae breves, and areas 15
and 16 refer to the posteriorly placed two insulae longes. More important than
the cytoarchitectonic classification is the functional classification of the cortex
into several motor and sensory areas. The account that follows will focus on
functional areas of the cortex. Brodmann's terminology will be used because it is
the most frequently cited. The commonly used classification of cortical areas into
purely sensory and motor is somewhat misleading and inaccurate. There is ample
evidence to suggest that motor responses can be elicited from so-called sensory
areas. This has prompted the use of the term sensory motor cortex to refer to
previously designated sensory and motor areas.

Table 17-3. Brodmann Areas

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Brodmann Neuroanatomic, functional designation

Area

1, 2, 3 Postcentral gyrus, primary sensory cortex [intermediate

(1), caudal (2), and rostral (3) parts]

4 Precentral gyrus, primary motor cortex

5 Superior parietal lobule caudal to postcentral sulcus

6 Precentral gyrus (including supplementary motor area)

7 Superior parietal lobule caudal to area 5

8 Middle frontal gyrus, rostral to area 6

9, 10 Prefrontal cortex (dorsolateral and mesial)

11, 12 Orbital gyri

13, 14 Anterior part of the insula (island of Reil)

15, 16 Posterior part of the insula (island of Reil)

17 Calcarine gyrus, primary visual (striate) cortex

18 Surrounds area 17, secondary visual association cortex

19 Surrounds area 18, tertiary visual association cortex

20 Inferior temporal gyrus, visual association cortex

21 Middle temporal gyrus, visual association cortex

22 Superior temporal gyrus, auditory association cortex,

Wernicke's area

23 Ventral posterior cingulate gyrus, limbic cortex

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24 Ventral anterior cingulate gyrus, limbic cortex

25 Subcallosal area, subgenu area

26 Retrosplenial area, limbic cortex

27 Presubicular area, limbic cortex

28 Entorhinal cortex

29, 30 Retrosplenial cortex, limbic cortex

31 Dorsal posterior cingulate gyrus, limbic cortex

32 Dorsal anterior cingulate gyrus and adjacent frontal area

33 Rostral cingulate gyrus (pregenu area), limbic cortex

34 Dorsal entorhinal area

35 Perirhinal area, parahippocampal gyrus

36 Ectorhinal area, lateral to the rhinal sulcus, para-

hippocampal gyrus

37 Occipitotemporal area, inferolateral part of the temporal

lobe, decoding of visual information

38 Temporal pole, retrieval of proper nouns

39 Angular gyrus

40 Supramarginal gyrus

41, 42 Heschl's gyrus, primary auditory cortex

43 Frontoparietal (rolandic) operculum, gustatory cortex

44 Pars opercularis of inferior frontal gyrus, Broca's area of

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speech

45 Pars triangularis of inferior frontal gyrus, Broca's area of

speech

46 Middle frontal gyrus, dorsolateral prefrontal area,

association cortex

47 Pars orbitalis of inferior frontal gyrus

48 Retrosubicular area

49 Parasubiculum

51 Prepiriform area

52 Parainsular area, superior bank of superior temporal

gyrus along the posterior margin of the insula

However, for didactic purposes, the motor and sensory areas of the cortex will be
discussed separately.

CORTICAL SENSORY AREAS

Sensory function in the cortex is localized mainly in three lobes: parietal,
occipital, and temporal. There are six primary sensory areas in the cortex:

1. Primary somesthetic (general sensory, somatosensory) area in the

postcentral gyrus of the parietal lobe

2. Primary visual area in the calcarine gyrus of the occipital lobe

3. Primary auditory area in the transverse gyri of Heschl of the temporal lobe

4. Primary gustatory (taste) area in the most ventral part of the postcentral
gyrus of the parietal lobe

5. Primary olfactory (smell) area in the piriform and periamygdaloid regions of

the temporal lobe

6. Primary vestibular area in the temporal lobe

Each of these areas receives a specific sensory modality (i.e., pain, touch,
vibration, vision, audition, taste, smell). Sensory modalities reaching each of
these areas (except olfaction) pass through the thalamus (modality-specific
thalamic nucleus) prior to reaching the cortex. Each of the preceding sensory
areas is designated as a primary sensory area. Primary sensory cortices have

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restricted receptive fields. Adjacent to the primary somesthetic, visual, and

auditory areas are secondary sensory areas. The secondary sensory areas are
found by recording evoked potentials in the respective areas following an
appropriate peripheral stimulus (sound, light, etc.). In general, the secondary
sensory areas are smaller in size than the primary areas, and their ablation is
without effect on the specific sensory modality.

Primary Somesthetic (General Sensory,

Somatosensory) Area (SI)
This area (Figure 17-11) corresponds to the postcentral gyrus of the parietal lobe
(areas 1, 2, and 3 of Brodmann) and the posterior part of the paracentral lobule.
Area 3 is divided into two parts: 3b on the posterior wall of the central sulcus
and 3a in the depth of the sulcus. In 1916, Dusser de Barenne applied
strychnine, a central stimulant drug, to the postcentral gyrus of monkeys and
noted that the animals scratched their skin. Subsequent work by Head on World
War I soldiers with head injuries and by the neurosurgeons Cushing and Penfield
has added tremendously to knowledge about the function of this area.

Although the primary somesthetic area is concerned basically with sensory

modalities, it is possible to elicit motor responses
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following its stimulation. The primary somesthetic area receives nerve fibers from
the ventral posterolateral and ventral posteromedial nuclei of the thalamus.
These fibers convey general sensory (touch, pain, and temperature) as well as
proprioceptive sensory modalities (position, vibration, and two-point
discrimination).

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Figure 17-11. Schematic diagram of the primary somesthetic cortex.

In addition to thalamic afferents, the primary somesthetic cortex receives

commissural fibers through the corpus callosum from the contralateral primary
somesthetic cortex and short association fibers from the adjacent primary motor
cortex. Efferents from the primary somesthetic cortex project to the motor
cortex, the opposite primary somesthetic cortex, and the association
somatosensory cortex (areas 5 and 7) in the posterior parietal cortex. The
primary and secondary somesthetic areas are reciprocally interconnected. In
addition, projection fibers descend within the internal capsule to the ventral
posterior nuclei of the thalamus, posterior column nuclei of the medulla
oblongata, and dorsal horn of the spinal cord. The contralateral half of the body
is represented in a precise but disproportionate manner (sensory homunculus) in
each of the three areas (1, 2, and 3) of the som-esthetic cortex (Figure 17-12).
The pharynx, tongue, and jaw are represented in the most ventral portion of the
lateral surface of the somesthetic area, followed in ascending order by the face,
hand, arm, trunk, and thigh. The leg and foot are represented on the medial

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surface of this area. The anal and genital regions are represented in the most
ventral portion of the medial surface just above the cingulate gyrus. The
representation of the face, lips, hand, thumb, and index finger is
disproportionately large in comparison with their relative size in the body. This is
a reflection of the functional importance of these parts in sensory function.

Stimulation of the primary somesthetic cortex in conscious patients elicits

sensations of numbness and tingling, a feeling of electricity, and a feeling of
movement without actual movement. These sensations are referred to the
contralateral half of the body, except when the face area is stimulated. The face
and tongue are represented bilaterally.

Ablation of the postcentral gyrus will result, in the immediate postoperative

period, in loss of all modalities of sensation (touch, pressure, pain, and
temperature). Soon, however, pain and temperature sensations will return. It is
believed that pain and temperature sensations are determined at the thalamic
level, whereas the source, severity, and quality of such sensations are perceived
in the postcentral gyrus. Thus the effects of postcentral gyrus lesions would be
(1) complete loss of discriminative touch and proprioception and (2) crude
awareness of pain, temperature, and light touch.

Neurophysiologic studies of the somesthetic cortex have revealed the following

information: (1) The functional cortical unit appears to be associated with a
vertical column of cells that is modality specific. Neurons within a cortical unit
are activated by the same peripheral stimulus and are related to the same
peripheral receptive field. (2) Area 3b is activated by cutaneous stimuli and areas
2 and 3a by proprioceptive impulses, whereas area 1 is activated by either
cutaneous or proprioceptive impulses. (3) Somatosensory neurons responding to
joint movement show a marked degree of specificity in that they respond to
displacement in one direction. (4) Fast- and slow-adapting neuronal pools have
been identified in response to hair displacement or cutaneous deformation. (5)
Fibers mediating cutaneous sensations terminate rostrally, while those mediating
proprioceptive sensations terminate more caudally in the somesthetic area.

Secondary Somesthetic Area (SII)

A secondary somesthetic area has been described in humans and primates. It is
located on the most inferior aspect of the postcentral
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gyrus and in the superior bank and depth of the lateral sulcus (parietal
operculum). Body representation in this area is bilateral, with contralateral
predominance, and is the reverse of that in the primary area so that the two face
areas are adjacent to each other.

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Figure 17-12. Schematic diagram of the sensory homunculus.

The secondary sensory area contains neurons with receptive fields that are large,
poorly demarcated, overlap extensively, and often have bilateral representation.
Lesions of the secondary somesthetic area and the insula produce asymbolia for
pain, suggesting that the secondary somesthetic area is an important cortical
locus for the conscious perception of noxious stimuli. Positron-emission
tomographic (PET) studies in human volunteers subjected to noxious stimuli have
demonstrated increased metabolic activity in the secondary somesthetic area as
well as in the postcentral and cingulate gyri. Damage to SII or possibly to the
posterior insula leads to the inability of the patient to identify objects by touch
(tactile agnosia, agraphesthesia). The primary and secondary somesthetic areas
are reciprocally interconnected. The secondary somesthetic area contains no cells
sensitive to joint movement or joint position. The secondary somesthetic area has
been shown to have reciprocal connections with ventral posteromedial and
centrolateral nuclei of the thalamus. It also receives inputs from the ipsilateral
and contralateral primary somesthetic cortices. Efferent connections project to
the primary somesthetic and primary motor areas within the same hemisphere.
Lesions interrupting connections between the secondary somesthetic area,
posterior parietal cortex, and ventral posteromedial and centrolateral thalamic
nuclei have been associated with pseudothalamic pain syndrome. The pain is
spontaneous and characterized as burning or icelike and is associated with
impairment of pain and temperature appreciation.

Supplementary Sensory Area (SSA)

This area was defined originally by Penfield and Jasper with intraoperative
stimulation studies in humans. The supplementary sensory area lacks Brodmann's
numeric designation, but it encompasses medial area 5 of Brodmann and probably
the anterior part of medial area 7. Neurons in the supplementary sensory area
have large receptive fields, and some neurons are sensitive to pain.

Primary (Unimodal) Somatosensory (Somesthetic)

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Association Areas
The primary somatosensory association areas encompass areas 5 and 7 in
the superior parietal lobe. They receive their inputs mainly from the primary
somatosensory areas but also have recip-rocal connections with the pulvinar
nucleus of the thalamus. Neuronal responses in the primary somatosensory
association areas are complex and involve the integration of a number of cortical
and thalamic inputs. The processing of multisensory somatosensory inputs in
these areas allows for the perception of shape, size, and texture and the
identification of objects by contact (stereognosis). The primary somatosensory
association areas project to multimodal nonprimary association areas (areas 39
and 40) in the inferior parietal lobule that receive inputs from more than one
sensory modality and serve intermodal integration and multisensory perceptions.

Single-cell recordings in area 5 in monkeys suggest that this area is essential for
the proper use of somatosensory information, for goal-directed voluntary
movements, and for the manipulation of objects.

Single-cell recordings in area 7 indicate that this area plays an important role in
the integration of visual and somatosensory stimuli, which is essential for
coordination of eyes and hands in visually guided movements.

Bilateral lesions in the primary somatosensory association areas in humans are

associated with inability to move the hand toward an object that is clearly seen
(optic ataxia). Such patients are unable to pour water from a bottle into a glass
and repeatedly pour the water outside the glass. Unilateral lesions in the primary
somatosensory association areas in the nondominant hemisphere produce neglect
of the contralateral half of the body and visual space.

Primary Visual Cortex (V 1 )

This area (Figure 17-13) corresponds to the calcarine gyrus on the medial surface
of the occipital lobe on each side of the calcarine sulcus (area 17 of Brodmann),
encompassing parts of the lingual gyrus ventrally and cuneus gyrus dorsally. In
sections of fresh cortex, this area is characterized by the appearance of a
prominent band of white matter that can be identified by the naked eye and is
named the band of Gennari, after the Italian medical student who described it in
1782. The band of Gennari represents a thickened external band of Baillarger in
layer IV of the cortex. In myelin preparations, the band of Gennari appears as a
prominent dark band in the visual cortex, also known as the striate cortex. The
term striate refers to the presence in unstained preparations of the thick white
band of Gennari.

The primary visual area receives fibers from the lateral geniculate nucleus. These
fibers originate in the retina, synapse in the lateral geniculate nucleus, and reach
the visual cortex via the optic (geniculocalcarine) radiation. Each visual cortex
receives fibers from the ipsilateral half of each retina (Figure 17-14) that convey
information about the contralateral half of the visual field. Thus lesions of one
visual cortex are manifested by loss of vision in the contralateral half of the
visual field (homonymous hemianopsia). The projections from the retina into the
visual cortex are organized spatially in such a way that macular fibers occupy the
posterior part of the visual cortex, while peripheral retinal fibers occupy the
anterior part (Figure 17-15). Fibers originating from the superior half of the
retina terminate in the superior part of the visual cortex; those from the inferior
half of the retina
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terminate in the inferior part (Figure 17-16). Thus lesions involving portions of
the visual cortex, such as the inferior calcarcine cortex, produce an upper
contralateral quadrantanopsia in which blindness is limited to the contralateral
upper quadrant of the visual field. Similarly, lesions limited to the upper
calcarine cortex produce a lower contralateral quadrantanopsia in which blindness
is limited to the contralateral lower quadrant of the visual field. The
representation of the macula in the visual cortex is disproportionately large in
comparison with its relative size in the retina. This is a reflection of its important
function as the retinal area of keenest vision.

Figure 17-13. Schematic diagram of the primary and secondary visual

cortices.

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Figure 17-14. Schematic diagram of retinal representation in the primary

visual cortex.

Figure 17-15. Schematic diagram of retinal representation in the primary

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visual cortex.

Figure 17-16. Schematic diagram of retinal representation in the primary

visual cortex.

Stimulation of the visual cortex elicits a crude sensation of bright flashes of light;
patients with irritative lesions (such as tumors) of the visual cortex experience
visual hallucinations that consist of bright light. Conversely, lesions that destroy
the visual cortex of one hemisphere result in loss of vision in the contralateral
half of the visual field. If the destructive lesion is of vascular origin, such as
occurs in occlusions of the posterior cerebral artery, central (macular) vision in
the affected visual field is spared. This phenomenon is known clinically as
macular sparing and is attributed to the collateral arterial supply of the posterior
visual cortex (macular area) from the patent middle cerebral artery.

Functional magnetic resonance imaging (fMRI) studies in blind persons have

found increased responsiveness in their primary visual cortex during a verbal
memory task without any sensory input. This suggests that, while sighted people
devote much of their cortex to visual processing, the visual cortex in the blind
are recruited for other senses. Elegant neurophysiologic studies of single neurons
in the visual cortex have revealed the following information:

1. The visual cortex is organized into units that correspond to specific areas in
the retina.

2. These units respond to linear stripe (straight-line) configurations.

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3. For each unit, a particular orientation of the stimulus is most effective.

Some units respond only to vertically oriented stripes, while others respond
only to horizontally oriented stripes. Some units respond at onset of
illumination, while others respond at cessation of illumination.

4. Units are of two varieties, simple and complex. Simple units react only to
stimuli in corresponding fixed retinal receptive fields. Complex units are
connected to several simple cortical
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units. It is presumed that the complex units represent an advanced stage in
cortical integration.

5. Units that respond to the same stimulus pattern and orientation are grouped
together in repeating units referred to as columns, similar to those
described for the somesthetic cortex. Two general varieties of functional
columns have been described: ocular dominance and orientation columns.
Ocular dominance columns are parallel columns arranged perpendicular to
the cortical surface and reflect eye preference (right versus left) of cortical
neurons. Alternating ocular dominance columns are dominated by inputs
from the left and right eyes. Orientation columns comprise a sequence of
cells that have the same receptive field axis orientation.

6. Visual columns respond poorly, if at all, to diffuse retinal illumination.

7. Visual units respond optimally to moving stimuli.

8. Most cortical units receive fibers from corresponding receptive fields in both
retinas, thus allowing for single-image vision of corresponding points in the
two retinas.

9. The striate cortex is organized into vertical and horizontal systems. The
vertical (columnar) system is concerned with retinal position, line
orientation, and ocular dominance. The horizontal system segregates cells of
different orders of complexity. Simple cells located in layer IV are driven
monocularly, while complex and hypercomplex cells, located in other layers,
are driven by impulses from both eyes.

The output from the primary visual cortex follows two pathways or streams: a
dorsal stream to the occipitoparietal cortex (the “where” pathway) and a ventral
stream to the occipitotemporal cortex (the “what” pathway). Bilateral lesions in
the “where” pathway result in the inability to direct the eyes to a certain point in
the visual field despite intact eye movements (Balint-Holmes syndrome). Bilateral
lesions in the “what” pathway result in the inability of patients, with normal
visual perception, to comprehend the meaning of nonverbal visual stimuli (visual
agnosia).

Primary (Unimodal) Visual Association Areas

Adjacent to the primary visual area are the primary association visual areas
(extrastriate, prestriate). They include areas 18 and 19 of Brodmann (Figure 17-
13) on the lateral and medial aspects of the hemisphere. Areas 20, 21, and 37 in
the inferior temporal cortex are also dedicated to visual information processing.
The visual association cortices are concerned with higher-order aspects of visual
processing, as detailed later. Area 18 corresponds to the second (V 2 ) and area 19
to the third (V 3 ) visual areas. V 4 , in humans, is probably located in the inferior
occipitotemporal area, in the region of the lingual or fusiform gyrus. V 5 in

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humans is probably located in area 19 of Brodmann. V 2 , like V 1 , is retinotopically

organized. Visual areas beyond V 2 are associated with varying visual functions. V 3
is associated with form, V 4 with color, and V 5 with motion. Units in the primary
visual association areas are of the complex or hypercomplex types.

Afferents to areas 18 and 19 are mainly from the primary visual area (area 17)
but include some direct thalamic projections from the lateral geniculate nucleus
and pulvinar nucleus. The primary visual area projects bilaterally and reciprocally
to areas 18 and 19. The projections from the pulvinar nucleus constitute
important extrageniculate links to the visual cortex.

Outputs from areas 18 and 19 project to the posterior parietal cortex (area 7)
and to the inferotemporal cortex (areas 20 and 21). The projection to area 7 is
concerned with stereopsis (depth perception) and movement. The inferotemporal
projection is concerned with analysis of form and color. The inferotemporal cortex
represents highest visual function. Electrical stimulation of area 21 evokes lifelike
visual hallucinations. Area 37, behind area 21, at the occipitotemporal junction
contains modules devoted to recognition of faces. Bilateral lesions in this area
result in failure to recognize familiar faces (prosopagnosia). Color vision is
localized inferiorly in the inferior occipitotemporal cortex (V 4 ). No color
representation is found in the superior association visual cortex. Thus in
unilateral inferior association visual cortex lesions the patient loses color vision
in the contralateral half field (central hemiachromatopsia). Loss of color vision
and face recognition usually coexist because of the proximity of the areas
responsible for them. Connections of the association visual cortex to the angular
gyrus (area 39) play a role in recognition of visual stimuli. Lesions interrupting
this connection result in visual agnosia, inability to recognize objects in the
visual field. Bilateral lesions of the fifth visual area (V 5 ) are associated with a
defect in visual motion perception (akinetopsia).

Projections from areas 18 and 19 also reach the frontal eye fields (area 8 of
Brodmann) in the frontal lobe, as well as the superior colliculus and motor nuclei
of extraocular muscles. These projections play a key role in conjugate eye
movement induced by visual stimuli (visual pursuit).

Primary Auditory Cortex

David Ferrier, a British physician, is credited with localizing the primary auditory
cortex of monkeys to the superior temporal gyrus during the latter half of the
nineteenth century. This localization was not accepted by his contemporaries.
Subsequent studies in animals and humans, however, have confirmed his early
observations.

The primary auditory cortex (Figure 17-17) corresponds to the transverse

temporal gyri of Heschl (areas 41 and 42 of Brodmann) located in the temporal
lobe within the lateral fissure. Recording of primary evoked responses to auditory
stimuli during surgery for epilepsy provides evidence for a restricted portion of
Heschl's gyrus (its posteromedial part) as the primary auditory area.

The primary auditory cortex receives fibers (auditory radiation) from the medial
geniculate nucleus. These fibers reach the auditory cortex via the sublenticular
part of the internal capsule.
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Auditory fibers originate in the peripheral organ of Corti and establish several
synapses in the neuraxis, both homolateral and contralateral to their side of
origin, before reaching the medial geniculate nucleus of the thalamus. The

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primary auditory cortex, therefore, receives fibers originating from both organs
of Corti, predominantly from the contralateral side. Stimulation of the primary
auditory cortex produces crude auditory sensations such as buzzing, humming, or
knocking. Such sensations are referred to clinically as tinnitus. Lesions of the
auditory cortex result in (1) impairment in sound localization in space and (2)
diminution of hearing bilaterally but mostly contralaterally. The functional
organization of the auditory cortex is similar to that of the somesthetic and visual
cortices. Column cells in the auditory cortex share the same functional
properties. Columnar organization is thus based on isofrequency stripes, each
stripe responding to a particular tonal frequency.

Figure 17-17. Schematic diagram of the primary auditory cortex.

The primary auditory cortex is connected with the primary (unimodal) association
auditory cortex. Other important connections include the auditory cortex of the
contralateral hemisphere, the primary somesthetic cortex, frontal eye fields,
Broca's area of speech in the frontal lobe, and the medial geniculate nucleus. Via
its projection to the medial geniculate body in the thalamus, the primary auditory
cortex controls its own input by changing the excitability of medial geniculate
neurons. Responses of some auditory cortex neurons to sound stimuli depend on
whether the type of these sounds was anticipated. A similar anticipatory response
to sound stimuli exists in some medial geniculate neurons, suggesting that
transmission of information through the auditory thalamus (medial geniculate
nucleus) and on to the auditory cortex is controlled by behavioral contingencies.

Physiologic studies of the primary auditory cortex have revealed that it does not
play a major role in sound frequency discrimination but rather in the temporal
pattern of acoustic stimuli. Frequency discrimination of sound is a function of
subcortical acoustic structures. The optimal stimulus that fires auditory cortical
units seems to be a changing frequency of sound stimuli rather than a steady-
frequency stimulus.

Primary (Unimodal) Auditory Association Cortex

Adjacent to the primary auditory cortex is the primary (unimodal) auditory
association cortex (area 22 of Brodmann). It comprises the area adjacent to

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Heschl's gyri in the superior temporal gyrus, including the posterior portion of
the floor of the sylvian fissure (the planum temporale). This area is concerned
with the comprehension of spoken sound. Area 22 in the dominant hemisphere is
known as Wernicke's area. Lesions of this area are associated with a receptive
type of aphasia, a disorder of communication characterized by the inability of the
patient to comprehend spoken words. The primary auditory association cortex in
the nondominant (right) hemisphere is specialized for nonspeech auditory
information, such as environmental sounds, musical melodies, and tonal qualities
of sound (prosody). Bilateral lesions in the primary auditory association cortices
result in the inability to recognize sounds (auditory agnosia) in the presence of
normal hearing, alertness, and intelligence. Disconnection of the primary auditory
association cortex (area 22) from the primary auditory cortex (areas 41 and 42)
results in a condition known as pure word deafness, characterized by poor
comprehension of spoken language and poor repetition with intact comprehension
of written language. The auditory association cortex is connected via the anterior
commissure with the prefrontal cortex and via the corpus callosum with the
prefrontal, premotor, parietal, and cingulate cortices.

Primary Gustatory Cortex

The cortical receptive area for taste is located in the parietal operculum, ventral
to the primary somesthetic area and in close proximity to the cortical areas
receiving sensory afferents from the tongue and pharynx. It corresponds to area
43 of Brodmann. Irritative lesions in this area in humans have been shown to
give rise to hallucinations of taste, usually preceding the onset of an epileptic
attack. Such a prodromal symptom preceding an epileptic fit focuses attention on
the site of the irritative lesion. Conversely, ablation of this area produces
impairment of taste contralateral to the site of the lesion. The gustatory cortex
receives fibers from the posteroventral medial nucleus of the thalamus, upon
which converge sensory fibers from the face and mouth, including taste fibers.
Although crude taste sensations can be perceived at the thalamic level,
discrimination among different taste sensations is a cortical function.

Primary Olfactory Cortex

The primary olfactory cortex is located in the tip of the temporal lobe and
consists of the piriform cortex and the periamygdaloid area. The primary
olfactory cortex receives fibers from the lateral olfactory stria and has an
intimate relationship with adjacent cortical regions comprising part of the limbic
system. Such relationships, as well as the role of olfaction in emotion and
behavior, are discussed in the chapter on the limbic system (Chapter 21).
Adjacent to the primary olfactory cortex is the entorhinal cortex (area 28), which
is considered the association or secondary olfactory cortical area.

Irritative lesions in the region of the olfactory cortex give rise to olfactory
hallucinations that are usually disagreeable. As in the case of taste, such
hallucinations frequently precede an epileptic fit. Since olfactory hallucinations
frequently occur in association with lesions in the uncus of the temporal lobe
(including the olfactory cortex), they are referred to clinically as uncinate fits.

The olfactory system is the only sensory system in which fibers reach the cortex
without passing through the thalamus. Basic olfactory functions needed for reflex
action reside in subcortical structures. The discrimination of different odors,
however, is a function of the olfactory cortex.

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Primary Vestibular Cortex

Data are scant about the anatomic location as well as the physiologic properties
of the primary vestibular cortex. Many cortical areas have been identified in
humans as possibly involved in vestibular processing. However, the various
methods used provide variable degrees of accuracy and do not provide precise
localization. Recent studies using cortical stimulation in patients undergoing brain
surgery for treatment of epilepsy have identified a lateral cortical
temporoparietal area (the temporoperisylvian vestibular cortex) from which
vestibular symptoms, including rotatory sensations, were easily elicited. The area
extended above and below the sylvian fissure, mainly inside Brodmann areas 40
(supramarginal gyrus), 21 (middle temporal gyrus), and 22 (primary auditory
association area in the superior temporal gyrus). It included the parietal
operculum. Lesions in this area in humans impair perceptual judgments about
body orientation and movement. Such lesions, however, do not impair brain stem
vestibular reflexes such as the vestibuloocular reflex.

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CORTICAL MOTOR AREAS

There are three major cerebral cortical areas involved in motor control:

1. Primary motor area (MI)

2. Supplementary motor area (MII)

3. Premotor area

The primary motor area is coextensive with area 4 of Brodmann, and the
supplementary motor and premotor areas are coextensive with area 6 of
Brodmann. The supplementary motor and premotor areas together represent the
nonprimary motor cortex. The three motor areas differ in their electrical
excitability, functional neuronal properties, and connectivity. They receive inputs
from different thalamic nuclei and have different corticocortical connections and
different output projections.

Primary Motor Area (MI)

The primary motor area (Figure 17-18) corresponds to the precentral gyrus (area
4 of Brodmann). On the medial surface of the hemisphere, the primary motor
area comprises the anterior part of the paracentral lobule. The contralateral half
of the body is represented in the primary motor area in a precise but
disproportionate manner, giving rise to the motor homunculus in the same way as
that described for the primary somesthetic cortex. Stimulation of the motor
cortex in conscious humans gives rise to discrete and isolated contralateral
movement limited to a single joint or a single muscle. Bilateral responses are
seen in extraocular muscles and muscles of the face, tongue, jaw, larynx, and
pharynx. The primary motor cortex thus functions in the initiation of highly
skilled fine movements, such as buttoning one's shirt or sewing.

The representation of bodily regions in the contralateral motor cortex does not
seem to be rigidly fixed. Thus repetitive stimulation of the thumb area will
produce movement of the thumb, followed after a while by immobility of the
thumb and movement at the index finger or even the wrist. This has been
interpreted to mean that in the thumb area of the cortex the motor units

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controlling the index finger and wrist have a higher thresh-old for stimulation
than those controlling the thumb.

Figure 17-18. Schematic diagram of the primary motor area (area 4),
premotor area (area 6), and the frontal eye field (area 8).

The motor area receives fibers from the ventrolateral nucleus of the thalamus,
the main projection area of the cerebellum. The motor area also receives fibers
from the somesthetic cortex (areas 1, 2, and 5) and the supplementary motor
cortex. The connections between the primary motor and somesthetic cortices are
reciprocal. The output contributes to the association, commissural, and
corticofugal fiber systems discussed earlier. The primary motor cortex is the site
of origin of about 30% to 40% of the fibers in the pyramidal tract. Furthermore,
all the large-diameter axons (approximately 3% of the pyramidal fibers) originate
from the giant motor neurons (of Betz) in the primary motor cortex. Most of the
neurons contributing fibers to the corticospinal tract have glutamate or aspartate
as their excitatory neurotransmitter. Ablation of the primary motor cortex results
in flaccid (hypotonic) paralysis in the contralateral half of the body associated
with loss of all reflexes. With time, there is recovery of stereotyped movement at
proximal joints, but the function of distal muscles concerned with skilled
movement remains impaired. Exaggerated myotatic reflexes and a Babinski sign
also appear.

Although the primary motor cortex is not the sole area from which movement can
be elicited, it is nevertheless characterized by initiating highly skilled movement
at a lower threshold of stimulation than the other motor areas. Epileptic patients
with a lesion in the primary motor cortex frequently manifest a seizure (epileptic)
pattern that consists of progression of the epileptic movement from one part of
the body to another in a characteristic sequence corresponding to body
representation in the motor cortex. Such a phenomenon is known clinically as a
Jacksonian march, after the English neurologist John Hughlings-Jackson.
Neurophysiologic studies of motor cortex neurons reveal that action potentials
can be recorded from motor neurons in the cortex about 60 to 80 ms before
muscle movement. Furthermore, two types of neurons in the motor cortex have

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been identified. These are a larger neuron with a phasic pattern of firing and a
smaller neuron that fires in a tonic pattern. From experiments on conscious
animals performing specific tasks, it has been shown that the frequency of firing
is highly correlated with the force exerted to perform a specific movement. Motor
neurons supplying a given muscle are usually grouped together in a columnar
fashion. Although some motor neurons can be stimulated from a wide area, each
has a so-called best point from which it can be stimulated most easily. Such best
points usually are confined to a cylindric area of cortex about 1 mm in diameter.

Supplementary Motor Area (MII)

The supplementary motor area is located on the medial surface of the frontal
lobe, anterior to the medial extension of the primary motor cortex (area 4). It
corresponds roughly to the medial extensions of area 6 of Brodmann. Although
the existence of a motor area in the medial aspect of the frontal cortex rostral to
the precentral leg area of primates has long been known, Penfield and Welch
were the first to call this portion of the cortex the supplementary motor area in
1949 and 1951. A homunculus has been defined for the supplementary motor
area in which face and upper limbs are represented rostral to the lower limbs and
trunk. Stimulation in humans gives rise to complex movement in preparation for
the assumption of characteristic postures.

Although simple motor tasks are elicited from stimulation of the supplementary
motor area, the role of this area in simple motor tasks is much less significant
and is likely to be subsidiary to that of the primary motor area. On the other
hand, the supplementary motor area assumes more significance in executing
simple motor tasks as a compensatory mechanism when the
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primary motor area is destroyed. The supplementary motor area seems crucial in
the temporal organization of movement, especially in sequential performance of
multiple movements, and in motor tasks that demand retrieval of motor memory.
Cells were identified in the supplementary motor area in response to movements
of both proximal and distal extremity muscles, ipsilateral and contralateral.
Supplementary motor area neurons differ from primary motor area neurons in
that only a small percentage (5%) of supplementary motor area neurons
contribute axons to the pyramidal tract and these neurons have insignificant
input from the periphery and are activated bilaterally.

The supplementary motor cortex is connected reciprocally with the ipsilateral

primary motor (area 4), premotor (area 6), and somatosensory (areas 5, 7)
cortices and the contralateral supplementary motor cortex. Subcortical
projections to the supplementary motor area are predominantly from the basal
ganglia via the thalamus. An input from the cerebellum via the basal ganglia also
has been shown to exist. Subcortical projections of the supplementary motor
cortex are profuse to parts of the caudate nucleus and putamen and to the
ventral anterior, ventral lateral, and dorsomedial thalamic nuclei. Approximately
5% of neurons in the supplementary motor cortex contribute fibers to the
corticospinal tract. Available anatomic and physiologic data suggest that the
supplementary motor area could be the site where external inputs and commands
are matched with internal needs and drives to facilitate formulation
(programming) of a strategy of voluntary movement. The threshold of stimulation
of the supplementary motor area is higher than that of the primary motor cortex
and the responses elicited are ipsilateral or bilateral.

In contrast to the evidence from physiologic studies, few clinical case reports

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have described persistent effects on motor behavior of damage to the

supplementary motor area. In the acute phase, patients have global reduction in
movement (akinesia) that is particularly pronounced on the side contralateral to
the lesion and a grasp reflex. Lesions in the supplementary motor area of the
dominant hemisphere are associated with severe impairment of spontaneous
speech with preserved repetition. These manifestations are mostly transient and
resolve within a few weeks. The lasting disorder of motor behavior reported to
occur in humans after supplementary motor area lesions has been a disturbance
of alternating movements of the two hands. Other clinical manifestations, of
uncertain etiology, associated with lesions in the supplementary motor area
include hypertonia, increase in myotatic reflexes, clonus, and the Babinski sign.

The traditionally defined supplementary motor area includes two separate

regions: a caudal region (supplementary motor area proper) that has reciprocal
connections with the primary motor area and projects to the spinal cord and a
rostral region (presupplementary motor area) that receives projections from the
prefrontal and cingulate cortices. Basal ganglia input reaches the caudal region,
whereas cerebellar input reaches the rostral region. Neuronal responses to visual
stimuli prevail in the rostral region, whereas somatosensory responses prevail in
the caudal region. The urge to initiate movement in humans is elicited only from
the rostral region.

Premotor Area
The concept of a premotor cortex was first proposed in 1905 by Campbell, who
called it the intermediate precentral cortex. The term premotor cortex was first
used by Hines in 1929. The premotor cortex has undergone a strong phylogenetic
development. Whereas in monkeys the premotor area is equally large as the
primary motor area, in humans the premotor area is about six times larger than
the primary motor area.

The premotor area (Figure 17-18) is located in the frontal lobe just anterior to
the primary motor area. It corresponds to area 6 of Brodmann. The premotor
area is concerned with voluntary motor function dependent on sensory inputs
(visual, auditory, somatosensory). Stimulation of the premotor area elicits a
stereotyped gross movement that requires coordination among many muscles,
such as turning movements of the head, eyes, and trunk toward the opposite
side, elevation of the arm, elbow flexion, and pronation of the hand. The
threshold of stimuli that elicit responses from this area is higher than that
required for the primary motor cortex.

In normal subjects, the premotor area shows increased activity when motor
routines are run in response to visual, auditory, or somatosensory cues such as
reaching for an object in space, obeying a spoken command, or identifying an
object by manipulation. The premotor area exerts influence on movement via the
primary motor area or directly through its projections to the pyramidal and
extrapyramidal systems. Approximately 30% of pyramidal fibers originate from
the premotor area. The premotor area is activated when a new motor program is
established or when the motor program is changed on the basis of sensory
information received, for example, when the subject is exploring the environment
or objects. Ablation of the premotor cortex in humans may produce a deficit in
the execution of skilled, sequential, and complex movement such as walking.
Such a deficit is known clinically as idiomotor apraxia. In such a syndrome, the
patient has difficulty in walking, although there is no voluntary motor paralysis.
The grasp reflex attributed to lesions of the premotor area in the older literature

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is now believed to be due to involvement of the supplementary motor cortex.

Some neuroscientists consider the separation of the motor cortex into primary
motor and nonprimary motor areas somewhat artificial. However, closer
consideration of this issue justifies this separation on the basis of the threshold
of stimuli that elicit motor responses (much lower in the primary motor area) as
well as the type of movement elicited from stimulation (simple from the primary
motor area versus coordinated, complex movement from the nonprimary areas).

Although neural activity in relation to each of many aspects of motor control

seems to be distributed in multiple cortical areas, an individual motor area
(primary motor, premotor, supplementary motor) is used preferentially under
specific circumstances requiring a certain variety of motor behavior.

In clinical situations, however, all areas are more often than not involved
together in disease processes, be it vascular occlusion or hemorrhage leading to
stroke or a tumor invading this region of the cortex. In such situations, the
clinical manifestations can be classified into those seen immediately after the
onset of the pathology and those which follow after a few days or weeks. The
former consist of loss of all reflexes and hypotonia of affected muscles. Within
hours or days, however, stereotyped movement, particularly in proximal muscles,
returns, hypotonia changes to hypertonia and areflexia to hyperactive myotatic
reflexes, and a Babinski sign appears. The discrete movements in distal muscles,
however, remain impaired. Such a clinical picture is seen often following a stroke
involving this region of the cortex.

Cortical Eye Fields

A. SACCADIC EYE MOVEMENTS
Saccadic movements are fast eye movements with rapid refixation of vision
from point to point with no interest in the points in between. Positron
emission tomography
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(PET) scans and lesion studies indicate that the cerebral areas most important for
saccadic control are: (1) posterior parietal cortex and (2) frontal premotor
cortex. The posterior parietal cortex (cortex in the posterior region of the
intraparietal sulcus and the adjacent superior parietal lobule) is activated by the
primary visual cortex during saccades for which there is a visual goal.

Three areas in the frontal lobe participate in saccadic processing: (1) the frontal
eye field (area 8 of Brodmann), (2) the dorsolateral prefrontal cortex (area 46 of
Brodmann), and (3) the supplementary eye field (anterior part of the
supplementary motor area). The frontal and supplementary eye fields are
activated during all types of saccadic movements. The dorsolateral prefrontal
cortex is activated during fixation.

1. Frontal Eye Field.

The frontal eye field (Figure 17-18) is located in the middle frontal gyrus anterior
to or in the anterior portion of the motor strip. It corresponds to area 8 of
Brodmann and the immediately adjacent cortex. The frontal eye field triggers
intentional (voluntary) saccades to visible targets in the visual environment, to
remembered target locations, or to the location where it is predicted that the
target will appear. These movements subserve intentional exploration of the
visual environment. The frontal eye field receives multiple cortical inputs, in

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particular from the parietooccipital cortex, supplementary eye field, and the
prefrontal cortex (area 46 of Brodmann). The frontal eye field elicits intentional
(voluntary) saccades through connections to nuclei of extraocular muscles in the
brain stem. The pathway from the frontal eye field to the nuclei of extraocular
movement is not direct but involves multiple brain stem reticular nuclei, including
the superior colliculus, the interstitial nucleus of the medial longitudinal
fasciculus (RiMLF), and the paramedian pontine reticular formation (PPRF).
Irritating lesions in the frontal eye field, as in an epileptic focus, will deviate both
eyes in a direction contralateral to the irritative lesion (Figure 17-19).
Conversely, ablation of the frontal eye field will result in deviation of the eyes to
the side of ablation (Figure 17-19) as a result of the unopposed action of the
intact frontal eye field. Such a condition is encountered in patients with occlusion
of the middle cerebral artery, which supplies the bulk of the lateral surface of the
hemisphere, including the frontal eye field. As a result of the arterial occlusion,
infarction (death) of cortical tissue will ensue. Such patients manifest paralysis of
face and limbs (upper limbs more than lower) contralateral to the side of arterial
occlusion and conjugate deviation of the eyes toward the cortical lesion.

Figure 17-19. Schematic diagram of the effects of stimulation and lesions in

the frontal eye fields on conjugate eye movements.

In humans, conjugate eye deviations occur more frequently after lesions in the
right hemisphere than after lesions in the left hemisphere. There is no
explanation for this other than that it may be related to the neglect syndrome
associated more frequently with right hemisphere lesions. Conjugate eye
deviations also have been observed with lesions that spare the frontal eye field
but that interrupt the connections between the posterior parietal and frontal eye
fields or their subcortical projections.

2. Supplementary Eye Field.

An oculomotor area in the frontal cortex, separate from the frontal eye field, was
first defined by Schlag in 1985. It is located rostral to the supplementary motor
area (MII) on the medial surface of the hemisphere. The supplementary eye field
receives multiple cortical inputs, in particular from the prefrontal cortex and the

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posterior part of the cerebral hemisphere. The supplementary eye field projects
to the frontal eye field and to subcortical nuclei involved in eye movements
(superior colliculus and reticular formation). The supplementary eye field plays a
role in triggering sequences of saccades and in the control of saccades concerned
with complex motor programming such as those made during head or body
movements (spatiotopic saccades).

3. Posterior Parietal Eye Field.

The posterior parietal eye field corresponds to areas 39, 40, and 19 of Brodmann.
This area triggers reflexive, visually guided saccades. It exerts its influence on
saccadic eye movements via its connections to the frontal eye field or directly to
the superior colliculus. Patients with lesions in the posterior parietal eye field
lose reflexive visually guided saccades but are able to move their eyes in
response to command (intentional saccades).

B. CORTICAL AREAS PREPARING SACCADES

Three cortical areas not involved directly in triggering of saccades play important
roles in planning, integration, and chronologic ordering of saccades. The
prefrontal cortex (area 46 of Brodmann) plays a role in planning saccades to
remembered target locations. The inferior parietal lobule is involved in
visuospatial integration. Bilateral lesions in this area result in Balint syndrome,
named after the Hungarian neurologist Rudolph Balint (optic ataxia, ocular
apraxia, psychic paralysis of visual fixation), a rare syndrome characterized by
the inability to direct the eyes to a certain point in the visual field despite
retention of intact vision and eye movements. The hippocampus appears to
control the temporal working memory required for chronologic order of saccade
sequences.

C. SMOOTH-PURSUIT EYE MOVEMENTS

Smooth-pursuit movements are slow eye movements initiated by a moving
object. The goal of the pursuit system is to produce eye velocity that
matches the velocity of the moving object. Unlike saccades, smooth-pursuit
movements cannot occur in darkness. They require a visual stimulus to occur.
Cortical areas involved in smooth pursuit include the temporooccipital region and
the frontal eye field. Each of these areas has direct projections to brain stem
neurons that drive pursuit. The temporooccipital region is driven by input from
the primary visual cortex. Two other cortical areas (the posterior parietal and the
superior temporal cortices) may contribute to smooth pursuit indirectly through
visual attention. Specific lesions in the temporooccipitoparietal cortex in humans
associated with smooth-pursuit deficits correspond to Brodmann areas 19, 37,
and 39. Lesions in the frontal eye field also have been associated with
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deficits in smooth pursuit. The corticofugal pathways for smooth-pursuit
movements follow two routes. The first courses from the temporooccipitoparietal
cortex through the posterior limb of the internal capsule to the dorsolateral
pontine nucleus in the midpons. The second courses from the frontal eye field to
the dorsolateral pontine nucleus and nucleus reticularis tegmenti pontis. Cortical
areas for smooth pursuit also project to the flocculus of the cerebellum after
relays in the dorsolateral pontine nucleus. The flocculus, in turn, projects on the
vestibular nuclei, which project to cranial nerve nuclei of extraocular movement
(CN III, IV, VI).

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Cerebral hemisphere lesions impair ocular pursuit ipsilaterally or bilaterally,

whereas posterior fossa lesions impair ocular pursuit either contralaterally or
ipsilaterally. This variability probably reflects involvement of a presumed pursuit
pathway that crosses from the pontine nuclei to the cerebellum and then consists
of a unilateral projection from the cerebellum to vestibular nuclei.

CORTICAL LANGUAGE AREAS

Language is an arbitrary and abstract way to represent thought processes by
means of sentences and to present concepts or ideas by means of words.
The neural system for language is made up of many components in several areas
of the brain. Most components of the language system are located in the left
hemisphere. The left hemisphere is the dominant hemisphere for language in
approximately 95% of humans as determined by functional imaging and cortical
stimulation studies. Nearly all right-handers and about two-thirds of left-handers
have such dominance. A disorder in language function (aphasia or dysphasia)
includes disturbances in the ability to comprehend (decoding) and/or program
(coding) the symbols necessary for communication. The cortical area of the left
hemisphere invariably involved in aphasia is a central core surrounding the
sylvian fissure, which includes Wernicke's area, the arcuate fasciculus, the
angular gyrus, and Broca's area. This perisylvian core area is surrounded by a
larger region in which aphasia occurs less frequently.

Traditionally, a distinction has been made between two major cortical language
areas: (1) Wernicke's area and (2) Broca's area. The two areas are connected via
a long association fiber bundle, the arcuate fasciculus.

Wernicke's Area
Wernicke's area, named after the German neurologist Karl Wernicke, comprises
an extensive region that includes the posterior part of the superior temporal
gyrus (Brodmann area 22) including the planum temporale in the floor of the
sylvian fissure, and the parietooccipitotemporal junction area including the
angular gyrus (Brodmann area 39). The latter component is a recent addition to
Wernicke's area not included in the area originally described by Wernicke. The
upper surface of area 22, the planum temporale, is distinctly longer on the left
side (dominant hemisphere for language) in most people. Wernicke's area is
concerned with the comprehension of language. The superior temporal gyrus
component of Wernicke's area (area 22) is concerned with comprehension of
spoken language, whereas the angular gyrus (area 39) and adjacent regions are
concerned with comprehension of written language. Spoken language is perceived
in the primary auditory area (Heschl's gyrus, areas 41 and 42) in the superior
temporal gyrus and transmitted to the adjacently located Wernicke's area where
it is comprehended (Figure 17-20). Lesions in Wernicke's area are associated with
a type of aphasia (sensory, receptive, posterior, fluent) in which patients have
difficulty comprehending spoken language.

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Figure 17-20. Schematic diagram showing transmission of auditory symbols

from the primary auditory cortex to Wernicke's area for comprehension, and
via the arcuate fasciculus, to Broca's area of speech.

Broca's Area
Broca's area, named after the French pathologist Pierre Paul Broca who defined
this area in 1861, comprises the posterior part of the triangular gyrus (Brodmann
area 45) and the adjacent opercular gyrus (Brodmann area 44) in the inferior
frontal gyrus of the dominant hemisphere (Figure 17-21). Broca's area receives
inputs from Wernicke's area via the arcuate fasciculus (Figure 17-20). Within
Broca's area, a coordination program for vocalization is formulated. The elements
of the program are transmitted
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to the face, tongue, vocal cords, and pharynx areas of the motor cortex for
execution of speech. Broca's area is also connected to the supplementary motor
area, which is concerned with the initiation of speech. Lesions in Broca's area are
associated with a type of aphasia (motor, anterior, expressive, nonfluent)
characterized by inability of the patient to express himself or herself by speech.
Such patients are able to comprehend language (intact Wernicke's area).

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Figure 17-21. Schematic diagram of Broca's area of speech.

Electrophysiologic studies and cerebral blood flow studies have confirmed the role
of Broca's area in speech expression. Records made from scalp electrodes placed
over Broca's area have revealed a slow negative potential of several seconds in
duration appearing over Broca's area 1 to 2 s prior to uttering of words.
Stimulation of Broca's area in conscious patients may inhibit speech or may result
in utterance of vowel sounds. Studies on cerebral blood flow have shown a
marked increase in flow in Broca's area during speech.

Recent data from functional imaging studies of the human brain reveal that, in
addition to a role in language, Broca's area is also activated during nonlinguistic
tasks, such as observation of finger movement and recognition of manual
gestures.

The Arcuate Fasciculus

The arcuate fasciculus (Figure 17-20) is a long association fiber bundle that links
Wernicke's and Broca's areas of speech. Damage to the arcuate fasciculus is
associated with impairment of repetition of spoken language.

Sequence of Cortical Activities during Language

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Processing
The sequence of the complex cortical activities during the production of language
may be summarized as follows: When a word is heard, the output from the
primary auditory area (Heschl's gyrus) is conveyed to the adjacent Wernicke's
area, where the word is comprehended (Figure 17-20). If the word is to be
spoken, the comprehended pattern is transmitted via the arcuate fasciculus from
Wernicke's area to Broca's area in the inferior frontal gyrus (Figure 17-20). If the
word is to be read, representations visualized as words or images are conveyed
from the visual cortex (areas 17, 18, and 19) to the angular gyrus (area 39),
which in turn arouses the corresponding auditory form of the word in Wernicke's
area (Figure 17-22). From Wernicke's area, the information is relayed via the
arcuate fasciculus to Broca's area.

Figure 17-22. Schematic diagram showing transmission of output from the

primary visual area to the angular gyrus where the auditory form of the word
is elicited from Wernicke's area.

The Right Hemisphere and Language

Although several areas in the left hemisphere are dominant in the reception,
programming, and production of language function, corresponding areas in the
right hemisphere are metabolically active during speech. These areas are
believed to be concerned with melodic function of speech (prosody). Lesions in
such areas of the right hemisphere render speech amelodic (aprosodic). Lesions
in area 44 on the right side, for example, result in a dull monotonic speech.

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Lesions in area 22 on the right side, on the other hand, may lead to inability of
the patient to detect inflection of speech. Such patients may be unable to
differentiate whether a particular remark is intended as a statement of fact or as
a question.

CORTICAL LOCALIZATION OF MUSIC

With the allocation of specific functions to each hemisphere, the question has
arisen as to which hemisphere is specialized for music. In this context, one
should separate musical perception from musical execution by the naive, casual
listener and the music professional. Whereas a naive listener perceives music in
its overall melodic contour, the professional perceives music as a relation
between musical elements and symbols (language). With this type of analysis, it
is conceivable that the naive listener perceives music in the right hemisphere,
whereas the professional perceives music in the left hemisphere. Musical
execution (singing), on the other hand, seems to be a function of the right
hemisphere irrespective of musical knowledge and training.

OTHER CORTICAL AREAS

In addition to the previously discussed cortical areas, the cerebral cortex
contains other functionally important areas. These include the multimodal
(heteromodal) prefrontal cortex and the posterolateral parietal (major
association) cortex. Multimodal cortices are related to more than one
sensorimotor modality. They have undergone major expansion in humans relative
to animals.

Prefrontal Cortex
The prefrontal cortex (Figure 17-23) comprises the bulk of the frontal lobe
rostral to the premotor cortex (area 6). It includes Brodmann areas 9, 10,
11, 12, and 46, located on the medial, lateral and orbital surfaces of the frontal
lobe. Motor responses are as a rule not elicited by stimulation of this area of the
frontal lobe. The prefrontal cortex is well developed only in primates and
especially so in humans. It is believed to play a role in affective behavior and
judgment. Clues about the functions of the prefrontal cortex have been gained by
studying patients with frontal lobe damage, such as Phineas Gage, the New
England railroad worker who was struck by a thick iron bar that penetrated his
prefrontal cortex. Miraculously, he survived but with a striking change in his
personality. Whereas prior to the injury he was an efficient and capable
supervisor, following the accident he was unfit to perform such work. He became
fitful and engaged in profanity. Lesions in the prefrontal cortex lead to
impairment in executive functions such as decision making, prioritization, and
planning. These usually occur in association
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with alterations in emotion and of social behavior. Such patients usually neglect
their appearance, laugh or cry inappropriately, and have no appreciation of norms
of social behavior and conduct. They are uninhibited and highly distractible. The
prefrontal cortex can be thought of in terms of three divisions: (1) dorsolateral
prefrontal (areas 9, 10, 46), (2) ventromedial (areas 11 and 12), and (3)
superior mesial (mesial 6 and parts of 9 and 32 areas). Damage to the
dorsolateral prefrontal area results in impairment of working (short-term)
memory, allocation of attention, and speed of processing. Damage to the
ventromedial area results in severe impairment of decision making and emotion.

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Damage to the superior mesial area impacts emotion, motivation, and initiation
of behavior. Bilateral damage tends to produce greater impairments than does
unilateral damage. Patients with prefrontal cortex lesion thus exhibit one or more
of the following signs: impaired decision making, distractibility, emotional
lability, social disinhibition, impulsiveness, hyperphagia, lack of planning,
restricted emotion, deficient empathy, failure to complete tasks, and lack of
awareness or concern. A characteristic symptom in humans with prefrontal lobe
lesions is perseveration, the inappropriate repetition of behavior (speech or
motor behavior). Surgical ablation of the prefrontal cortex (prefrontal lobotomy)
was resorted to in the past to treat patients with mental disorders such as
schizophrenia and intractable pain. In the latter group, the effect of the operation
was not to relieve the sensation of pain but rather to alter the affective reaction
(suffering) of the patient to pain. Such patients continue to feel pain but become
indifferent to it. The ablation of the prefrontal area in patients with mental illness
has been replaced largely by administration of psychopharmacologic drugs.
Through its interconnections with association cortices of other lobes and with the
hypothalamus, medial thalamus, and amygdala, the prefrontal cortex receives
information about all sensory modalities as well as about motivational and
emotional states.

Figure 17-23. Schematic diagram of the prefrontal cortex.

Major Association Cortex

The major association cortex (Figure 17-24) refers to the supramarginal and
angular gyri in the inferior parietal lobule. It corresponds to areas 39 and 40

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of Brodmann. The major association cortex in Einstein's brain was found to be

15% wider than in controls, suggesting a role in mathematical and visual
reasoning. The major association cortex is connected with all the sensory cortical
areas and thus functions in higher-order and complex multisensory perception.
Its relation to the speech areas in the temporal and frontal lobes gives it an
important role in communication skills. Patients with lesions in the major
association cortex of the dominant hemisphere present a conglomerate of
manifestations that include receptive and expressive aphasia, inability to write
(agraphia), inability to synthesize, correlate, and recognize multisensory
perceptions (agnosia), left-right confusion, difficulty in recognizing the different
fingers (finger agnosia), and inability to calculate (acalculia). These symptoms
and signs are grouped together under the term Gerstmann's syndrome.

Involvement of the major association cortex in the nondominant hemisphere is

usually manifested by disturbances in drawing (constructional apraxia) and in the
awareness of body image. Such patients have difficulty in drawing a square or
circle or copying a complex figure. They often are unaware of a body part and
thus neglect to shave half the face or dress half the body.

Figure 17-24. Schematic diagram of the major association cortex.

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THE INSULA (ISLAND OF REIL)

Vicq d'Azyr was the first, in 1786, to express interest in the insula. He referred to
it as the “convolutions situated between the sylvian fissure and the corpus
callosum.” In 1809, Reil was the first to describe the insula. In humans, the
insula is a highly developed structure in the depth of the sylvian fissure, covered
by the frontal, parietal, and temporal opercula. The sulcus separating the insula
from the operculae is referred to by different authors as the periinsular sulcus,
limiting sulcus, circuminsular sulcus, or insular sulcus. It is one of the paralimbic
structures comprised of mesocortex, interposed anatomically and functionally
between allocortex and neocortex. A variety of functions have been attributed to

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the insula, including olfaction, taste, visceral control, memory, affect, and drive.
The insula is shaped like a pyramid. The summit of the pyramid is the insular
apex (referred to by some as insular pole or limen insula). The insula is traversed
by an obliquely directed central insular sulcus which divides the insula into two
zones. The anterior zone is larger and exhibits more gyri than the posterior zone.
The anterior zone exhibits transverse and accessory insular gyri and three short
insular gyri (anterior, middle, and posterior). The transverse and accessory
insular gyri form the insular pole located at the most anterior inferior aspect of
the insula. The posterior zone, located caudal to the central insular sulcus, is
composed of the anterior and posterior long gyri, separated by the postcentral
insular sulcus. The anterior insular zone connects with the frontal lobe. The
posterior zone connects with the parietal and temporal lobes. Lesion-based
analysis has shown that destruction of the left anterior zone impairs coordination
of articulation and speech production. The insula is surrounded by the superior
longitudinal (arcuate) fasciculus, a long association bundle that interconnects the
temporal, parietal, and frontal lobes. The uncinate fasciculus interconnects the
insula with other para-limbic structures (temporal pole, orbital gyri). The
occipitofrontal fasciculus, another long association bundle, passes beneath the
inferior portion of the insular cortex to connect the frontal, insular, temporal, and
occipital regions.

CORTICAL ELECTROPHYSIOLOGY

Evoked Potentials
Evoked potentials represent the electrical responses recorded from a population
of neurons in a particular cortical area following stimulation of the input to that
area. The most studied of the evoked potentials is the primary response recorded
from the cortical surface and elicited by a single shock to a major thalamocortical
pathway. This response is characterized by a diphasic, positive-negative wave
and is generated primarily by synaptic currents in cortical neurons.

Evoked potentials elicited by a volley of impulses in thalamocortical pathways are

of two varieties, recruiting responses and augmenting responses.

Recruiting responses are recorded following 6- to 12-cps (cycles per second)

stimulation of a nonspecific thalamocortical pathway (e.g., from intralaminar
nuclei). They are characterized by a long latency (multisynaptic pathway), a
predominantly surface negative response that increases in amplitude to a
maximum by the fourth to the sixth stimulus of a repetitive train. This is followed
by a decrease in amplitude (waxing and waning). Such a response has a diffuse
cortical distribution. This pattern of response is generally attributed to an
oscillator network at cortical as well as thalamic levels in which cortical and
thalamic elements provide both positive and negative feedback.

Augmenting responses are recorded following low-frequency (6–12 cps)

stimulation of a specific thalamocortical pathway (e.g., from ventrolateral
thalamic nucleus). They are characterized by a short latency (monosynaptic
pathway), a diphasic, positive-negative configuration that increases in amplitude
and latency during the initial four to six stimuli of the train. The response to
subsequent stimuli remains augmented but waxes and wanes in amplitude. This
type of response is localized in the primary
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cortical area to which the stimulated specific thalamocortical pathway projects.

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Figure 17-25. Electroencephalograms showing the normal alpha pattern A,

slow delta pattern B, and spike potentials C.

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Somatosensory, Visual, and Auditory Evoked

Responses
Recording of cortical evoked potentials following somatosensory (skin), visual
(flashes or patterns of light), and auditory (sound) stimuli has been used to
study pathology along each of these pathways in humans. The determination of
latency and amplitude of the evoked potential frequently can aid in localizing the
site of pathology in the respective pathway.

ELECTROENCEPHALOGRAPHY
Electroencephalography (Figure 17-25) is the recording of spontaneous cortical
activity from the surface of the scalp. This procedure is used very commonly in
the investigation of diseases of the brain. Its usefulness is mainly in the
diagnoses of epilepsy and localized (focal) brain pathology (e.g., brain tumors).
In recent years and with the advent of the concept of brain death, the
electroencephalogram (EEG) has been used to confirm a state of electrical brain
silence (brain death). In such a condition, electroencephalographic tracings will
show no evidence of cortical potentials (flat EEG).

The spontaneous rhythmic activity of the cortex is classified into four types:

1. Alpha rhythm with a range of frequency from 8 to 13 cps. This type is most
developed over the posterior part of the hemisphere.

2. Beta rhythm with a range of frequency faster than 13 cps (17 to 30 cps).
This activity can be seen over wide regions of the cortex and is especially
apparent in records from patients receiving sedative drugs.

3. Theta rhythm with a range of frequency from 3 to 7 cps.

4. Delta rhythm with a range of frequency from 0.5 to 3 cps.

The EEG pattern varies in different age groups. The EEG is dominated by slow
activity (theta and delta) in childhood. The alpha rhythm increases in amount
with the advent of puberty. In the adult, delta activity and excessive theta
activity usually denote cerebral abnormality.

The EEG of unconscious patients is dominated by generalized slow frequencies.

The EEG in epileptic patients is characterized by the presence of spike potentials.
Two EEG patterns have been associated with sleep. The first is a slow pattern
(delta and theta) associated with the early phase of sleep. The second is a fast
pattern (beta) associated with a later and deeper stage of sleep. This second
pattern is associated with rapid eye movements (REM) and dreaming; hence this
stage of sleep has been called REM sleep or D-sleep (dreaming).

BLOOD SUPPLY

Arterial Supply
The blood supply to the cerebral cortex is provided by the anterior and middle
cerebral arteries (branches of the internal carotid artery) and the posterior
cerebral artery (branch of the basilar artery). The anterior cerebral artery runs
through the interhemispheric fissure, giving off five major branches:
orbitofrontal, frontopolar, pericallosal, callosomarginal, and paracentral. These
branches supply the medial surface of the frontal and parietal lobes as far back

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as the parietooccipital fissure (Figure 17-26). All branches cross the convexity of
the frontal and parietal lobes to supply a strip of marginal cortex on the lateral
surface of the hemisphere. Occlusion of the anterior cerebral artery results in
paralysis and sensory deficits in the contralateral lower limb due to interruption
of blood supply to the lower limb area in the medial surface of the motor and
sensory cortices.

The middle cerebral artery is a continuation of the main branch of the internal
carotid artery. It courses within the lateral (sylvian) fissure and divides into a
number of branches (frontal, rolandic, temporal, parietal) that supply most of the
lateral surface of the hemisphere (Figure 17-27).

The posterior cerebral artery constitutes the terminal branch of the basilar
artery. Several branches (temporal, occipital, parietooccipital) supply the medial
surfaces of the occipital lobe, temporal lobe, and caudal parietal lobe (Figure 17-
26).

Venous Drainage
Three groups of cerebral veins drain the lateral and inferior surfaces of the
cerebral hemisphere: superior, middle, and inferior
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(Figure 17-28). The superior cerebral group drains the dorsolateral and
dorsomedial surfaces of the hemisphere and opens into the superior sagittal
sinus. Conventionally, the most prominent of these veins in the central sulcus is
called the superior anastomotic vein of Trolard, which connects the superior and
middle groups of veins.

Figure 17-26. Schematic diagram of the major branches of the anterior

cerebral and posterior cerebral arteries and the areas they supply.

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Figure 17-27. Schematic diagram of the major branches of the middle

cerebral artery and the areas they supply.

The middle cerebral group runs along the sylvian fissure, drains the inferolateral
surface of the hemisphere, and opens into the cavernous sinus. The inferior
cerebral group drains the inferior surface of the hemisphere and opens into the
cavernous and transverse sinuses. The anastomic vein of Labbé interconnects the
middle and inferior groups of cerebral veins.

The medial surface of the hemisphere is drained by a number of veins that open
into the superior and inferior sagittal sinuses, as well as into the basal vein and
the great cerebral vein of Galen.

Figure 17-28. Schematic diagram of the superficial system of venous

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drainage of the brain.

TERMINOLOGY
Acalculia (Greek a, “negative”; Latin calculare, “to reckon”).
Difficulty in calculating. Usually associated with inability to copy (acopia). The
condition was described and named by Henschen in 1919.

Agnosia (Greek a, “negative” gnosis, “knowledge”).

Inability to recognize and interpret sensory information.

Agraphia (Greek a, “negative” graphein, “to write”).

Inability to express thoughts in writing. The first modern descriptions were those
of Albert Pitres in 1884 and Dejerine in 1891.

Agyria (Greek a, “negative”; gyros, “ring”).

A malformation in which the convolutions of the cerebral cortex are not normally
developed. Also called lissencephaly (smooth brain).

Akinesia (Greek a, “negative”; kinesis, “motion”).

Absence or poverty of movement.

Akinetopsia.
Cerebral motion blindness, a syndrome in which a patient loses specifically the
ability to perceive visual motion as a result of cortical lesions outside the striate
cortex.

Allocortex (Greek allos, “other” Latin cortex, “bark”).

Phylogenetically old, three-layered cerebral cortex, divided into paleocortex and
archicortex.

Aphasia (Greek a, “negative”; phasis, “speech”).

Impairment of language function; inability either to speak (motor aphasia) or to
comprehend (sensory aphasia).

Apraxia (Greek a, “negative”; pratto, “to do”).

Inability to perform complex purposeful movements, although muscles are not
paralyzed.

Aprosodia (Greek a, “negative”; prosodos, “a solemn procession”).

The variation in stress, pitch, and rhythm of speech by which different shades of
meaning are conveyed; the affective component of language.

Archicortex (Greek arche, “beginning” Latin cortex, “bark”).

Phylogenetically old, three-layered cortex seen in the hippocampal formation. A
variety of paleocortex or allocortex.

Arcuate (Latin arcuatus, “bow-shaped”).

Shaped like an arc. The arcuate fasciculus arches around the sylvian fissure to
connect Wernicke's area in the temporal lobe with Broca's area in the frontal
lobe.

Asymbolia (Greek a, “negative”; symbolon, “symbol”).

Loss of power to comprehend symbols as words, figures, gestures, and signs.

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Asymbolia of pain is the absence of psychic reaction to painful sensations. The

term asymbolia for pain was first described by Schilder and Stengel in 1938.

Badal, Jules (1840–1929).

French neuroophthalmologist who, in 1888, published the case of a posteclamptic
woman (Valerie) who developed Gerstmann syndrome.

Baillarger, Jules-Gabriel-Franéois (1809–1890).

French psychiatrist who described the lines of Baillarger in the cerebral cortex.

Balint syndrome.
Also known as Balint-Holmes syndrome, ocular apraxia, optic ataxia. A rare
syndrome resulting from bilateral parietooccipital disease and characterized by
inability to direct the eyes to a certain point in the visual field despite intact eye
movements. Named after Rudolph Balint (1874–1929), a Hungarian neurologist.

Betz, Vladimir A. (1834–1894).

Russian anatomist who described the giant pyramidal cells in the motor area of
the cerebral cortex in 1874.

Bravais, Louis.
French physician who described spread of epileptic seizure (Jacksonian march) in
his graduation thesis in 1827.
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Broca, Pierre Paul (1824–1880).

French pathologist and anthropologist. Broca localized the cortical motor speech
area in the inferior frontal gyrus. He also described the diagonal band of Broca in
the anterior perforated substance. He is also credited with description of
muscular dystrophy before Duchenne.

Brodmann, Korbinian (1868–1918).

German physicist who divided the cerebral cortex into 52 areas on the basis of
disposition of the cellular (cytoarchitectonics) between 1903 and 1908.

Campbell, Alfred Walter (1868–1937).

Australian neurologist and psychiatrist. Known for his elegant work on the
architectonics of the cerebral cortex. He and Brodmann are considered the
fathers of cerebral architectonics.

Cingulum (Latin “a girdle”).

A bundle of association fibers within the cingulate gyrus.

Cortex (Latin “bark”).

External gray layer of the cerebrum.

Cushing, Harvey Williams (1869–1939).

American neurosurgeon, regarded as the father of modern neurosurgery. He
trained with William Osler who taught him about neurology and whose life
became the basis for Cushing's writings and subsequent Pulitzer Prize.

Cytoarchitectonic.
The design of the cellular characteristics of the cortex, which varies in different
regions of the brain and allows mapping of the brain.

Dejerine, Joseph-Jules (1849–1917).

French neurologist who contributed significantly to knowledge about the anatomy
of the nervous system, cerebral localization, agraphia, and alexia.

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Dysphasia (Greek dys, “difficult” phasis, “speech”).

Difficulty in the understanding or expression of language.

Ferrier, David (1843–1928).

Scottish neurophysiologist and neurologist who is credited with localization of the
primary auditory cortex in the superior temporal gyrus.

Fusiform (Latin fusus, “spindle”; forma, “shape”).

A cell that is widest in the middle and tapering at both ends.

Gennari, Francesco.
Italian physician who, as a medical student, described the lines of Gennari (outer
band of Baillarger) that characterize lamina IV of the visual cortex. He referred
to it as lineola albidor.

Gerstmann, Josef (1887–1969).

Austrian neuropsychiatrist who described finger agnosia in 1924 and the full
Gerstmann syndrome in 1930. Badal's earlier description of the syndrome, in
1888, was less complete and was attributed to psychic blindness.

Gerstmann syndrome.
A clinical syndrome characterized by right–left disorientation, acalculia, agraphia,
and finger agnosia due to a lesion in the left angular gyrus. Josef Gerstmann,
Austrian neuropsychiatrist, developed the concept of a body image with visual,
tactile, and somesthetic components in 1924 and considered cortical
representation for these in the angular gyrus. The syndrome is also known as
angular gyrus syndrome and the Badal-Gerstmann syndrome.
Jules Badal's description of the syndrome in 1888 was less complete.

Gustatory (Latin gustatorius, “pertaining to the sense of taste”).

Head, Sir Henry (1861–1940).

English neurologist and neurophysiologist. Among his many contributions is the
mapping of dermatomes (Head's zones), which was the subject of his graduation
thesis at Cambridge. He sectioned his own nerves in order to delineate the
resulting sensory loss. He described the anatomy and variations of major
peripheral nerves and the brachial plexus, and he localized the site of herpes
zoster inflammation to the dorsal root ganglia. He also wrote on aphasia and
published a book of poetry. He was afflicted with Parkinson's disease.

Hemiachromatopsia.
Loss of color vision in one-half the visual field.

Henschen, Solomon Eberhard (1847–1930).

Swedish internist and neurologist who is credited with describing the striate and
extrastriate cortex in addition to the acalculia. He was one of the physicians who
attended Lenin when stricken with aphasia.

Heschl, Richard (1824–1881).

Austrian anatomist and pathologist who described the anterior transverse
temporal gyri (Heschl's convolutions), which serve as the primary auditory area.

Heterotopia (Greek heteros, “other, different”; topos, “place”).

The presence of cortical tissue in an abnormal location during development.

Heterotypical cortex (Greek heteros, “different”; typos, “pattern”).

The isocortex (neocortex) in which some of the six layers are obscured, as in

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motor cortex and visual cortex.

Holmes, Sir Gordon Morgan (1876–1965).

Irish neurologist and father of British neurology (along with John Hughlings-
Jackson). Made significant contributions to sensation (with Head), spinal cord
injury, cerebellar disease, neuroophthalmology, and neurological localization.
Many of his contributions emanated from observations he made in army field
hospitals in northern France.

Homotypical cortex (Greek homos, “same”; typos, “pattern”).

Association areas of the neocortex all have a similar (same) pattern six-layered
structure. They are thus examples of homotypical cortex.

Hughlings-Jackson, John (1835–1911).

British neurologist and one of the greatest figures in neurology's history. Made
major contributions, including hierarchical organization of the nervous system,
organization of movement, mind–brain relationship, speech, and epilepsy. He
introduced the term uncinate fits in 1899 and the routine use of the
ophthalmoscope.

Isocortex (Greek isos, “equal”; Latin cortex, “bark”).

Six-layered cerebral cortex.

Jacksonian march (Jacksonian epilepsy, Bravais-Jackson epilepsy).

The spread of tonic-clonic epileptic activity through contiguous body parts on one
side of the body due to spread of epileptic activity in the corresponding motor
areas of the cortex. Named after John Hughlings-Jackson (1835–1911), one of
the greatest figures in the history of neurology. Bravais described the same
pattern of epileptic spread in his graduation thesis in 1827 but did not elaborate
on the etiology.

Koniocortex (Greek konis, “dust” Latin cortex, “bark”).

Areas of cerebral cortex with large number of small neurons.

Lamina (Latin “a thin plate or layer”).

Lorente de Nó, Rafael.

American neurobiologist who described columnar organization within the cerebral
cortex. In addition, he is credited with description of the CA1–4 regions of the
hippocampus.

Martinotti, Giovanni.
Italian physician who described the Martinotti neuron in the cerebral cortex.

Mesocortex.
Intermediate cortex (in histology) between the isocortex and allocortex. Also
known as periallocortex and periarchicortex.

Micropolygyria (polymicrogyria) (Greek mikros, “small”; gyros,

“convolutions”).
A malformation of the brain characterized by the development of numerous small
convolutions.

Myeloarchitectonics.
The arrangement of nerve fibers in the cerebral and cerebellar cortex that varies
in different regions and allows mapping of the brain.
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Neocortex (Greek neos, “new” Latin cortex, “bark”).

The most recent phylogenetic development of the cerebral cortex.

Operculum (Latin opertum, “covered”).

The frontal, temporal, and parietal opercula cover the insular cortex.

Optic ataxia.
The inability to reach for objects under visual guidance. Isolated optic ataxia
results from bilateral lesions in the posterior parietal cortex (Brodmann area 7).
When combined with bilateral lesions in unimodal (primary) visual association
area (Brodmann area 19), it constitutes Balint syndrome. Optic ataxia was first
described by Balint in 1909.

Pachygyria (Greek pachys, “thick”; gyros, “convolutions”).

A developmental disorder of neuronal migration in which there are few,
thickened, and wide cerebral gyri.

Paleocortex (Greek palaios, “ancient” Latin cortex, “bark”).

Phylogenetically old, three-layered cortex found in rostral insular cortex, piriform
cortex, and primary olfactory cortex.

Penfield, Wilder (1891–1973).

American-Canadian neurosurgeon who directed the Montreal Neurological
Institute. Contributed significantly to neuroscience and especially to treatment of
epilepsy and cortical localization.

Piriform (Latin pyrum, “pear”; forma, “form”).

Pear-shaped. The piriform cortex is a region of the olfactory cortex.

Pitres, Albert (1848–1928).

French neurologist who contributed to cerebral localization and aphasia. His
description of agraphia is considered the first modern narrative on the subject.

Prosody (Greek prosodos, “a solemn procession”).

Variation in stress, pitch, and rhythm of speech by which different shades of
meaning are conveyed.

Prosopagnosia (Greek prosopon, “face”; gnosis, “to know”).

Inability to recognize familiar faces. Prosopagnosia patients have no problem in
recognizing that a face is a face, in discriminating faces according to sex or race,
or in decoding their emotional expression. Errors occur only in identifying whose
face it is. The severity of the disorder ranges from patients who fail to recognize
their own faces in the mirror to those who fail only to recognize faces of other
persons they have known.

Quadrantanopsia.
Loss of vision in one-quarter of the visual field. This occurs with parietal (inferior
quadrant loss) or temporal (superior quadrant loss) lobe lesions.

Reil, Johann Christian (1759–1813).

Danish physiologist, anatomist, and psychiatrist who was the first to describe the
insula or island of Reil in 1796. He is also credited with the use of the term
“vegetative nervous system” to refer to the autonomic nervous system.

Rolando, Luigi.
Italian anatomist. The central sulcus of the cerebral hemisphere is named after
him and so is the substantia gelatinosa of the spinal cord.

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Saccadic (French saccader, “to jerk”).

Quick movements of the eyes.

Somesthetic (Greek soma, “body”; aisthesis, “perception”).

Somesthetic sensations are those of pain, temperature, touch, pressure, position,
movement, and vibration.

Stellate (Latin stella, “star”).

Stellate neurons have many short dendrites that radiate in all directions like a
star.

Stereopsis (Greek stereos, “solid, having three dimensions”; opsis,

“vision”).
The ability to discriminate depth; stereoscopic vision.

Sylvius, Franéois de la Boe (1614–1672).

French anatomist who gave the first description of the lateral sulcus of the
cerebral hemisphere.

Uncinate (Latin “hook-shaped”) fasciculus.

Connects the cortex of the ventral surface of the frontal lobe with that of the
temporal pole.

Uncinate fits.
Complex partial seizures in which olfactory hallucinations occur as part of the
seizure. The term was introduced by Hughlings-Jackson in 1899.

Vogt, Césile (1875–1931).

French neuroanatomist who, with her Danish-German neuroanatomist husband,
Oskar Vogt (1870–1959), developed the myeloarchitectonic organization of the
cerebral cortex. The Vogts also assisted Brodmann in developing the
cytoarchitectonic organization of the cerebral cortex.

Wernicke, Karl (1848–1905).

German neuropsychiatrist who, in 1874, conceived that sensory aphasia was due
to damage to the left temporal lobe. He also conceived that motor aphasia was
due to lesion in Broca's area, conduction aphasia to lesion of the pathway
between Wernicke's and Broca's areas, and global aphasia to lesion in both
speech areas.

SUGGESTED READINGS
Baizer JS: Serotonergic innervation of the primate claustrum. Brain Res Bull
2001; 55:431–434.

Bechara A et al: The somatic marker hypothesis and decision making. In

Grafman J (ed): Handbook of Neuropsychology 1, vol 7, 2d ed. Amsterdam,
Elsevier, 2002;117-143.

Brandt TH et al: Vestibular cortex lesions affect the perception of verticality.

Ann Neurol 1994; 35:403–412.

Brinkman C, Porter R: Supplementary motor area in the monkey: Activity of

neurons during performance of a learned motor task. J Neurophysiol 1979;

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42:681–709.

Brodal P: The corticopontine projection in the rhesus monkey: Origin and

principles of organization. Brain 1978; 101:251–283.

Brouwer B, Ashby P: Altered corticospinal projections to lower limb

motoneurons in subjects with cerebral palsy. Brain 1991; 114:1395–1407.

Buchel C: Cortical hierarchy turned on its head. Nature Neuroscience 2003;

6:657–658.

Caselli RJ: Ventrolateral and dorsomedial somatosensory association cortex

damage produces distinct somesthetic syndromes in humans. Neurology
1993; 43:762–771.

Cherubini E et al: Caudate neuronal responses evoked by cortical stimulation:

Contribution of an indirect corticothalamic pathway. Brain Res 1979;
173:331–336.

Damasio A et al: Central achromatosia: Behavioral, anatomic and physiologic

aspects. Neurology 1980; 30:1064–1071.

Damasio H et al: The return of Phineas Gage: Clues about the brain from the
skull of a famous patient. Science 1994; 264:1102–1105.

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Editors: Afifi, Adel K.; Bergman, Ronald A.

Title: Functional Neuroanatomy: Text and Atlas, 2nd Edition

Copyright ©2005 McGraw-Hill

> Table of Contents > Part I - Text > 18 - Cerebral Cortex: Clinical Correlates

18
Cerebral Cortex: Clinical Correlates

Epileptic Seizures
Hemisphere Specialization
Aphasia
Apraxia
Ideomotor Apraxia
Ideational Apraxia
Visuoconstructive Apraxia
Alexia (Dyslexia)
Agnosia
Callosal Syndrome
Visual Effects
Hemialexia
Unilateral (Left) Ideomotor Apraxia
Unilateral (Left) Agraphia
Unilateral (Left) Tactile Anomia
Left Ear Extinction
Prefrontal Lobe Syndrome
The Grasp Reflex
Forced Collectionism
Alzheimer's Disease
Balint's Syndrome
Gerstmann's Syndrome
Anosognosia (Denial Syndrome, Anton-Babinski Syndrome)
Anton's Syndrome
Kluver-Bucy Syndrome
Simultanagnosia
The Alien Hand (Limb) Syndrome

KEY CONCEPTS

Epileptic seizures are manifestations of synchronized discharges of

groups of neurons.

The left hemisphere is specialized or dominant for comprehension

and expression of language, arithmetic, and analytic functions. The right

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hemisphere is specialized or dominant for complex nonverbal perceptual

tasks, emotion, and some aspects of visual and spatial perception.

Aphasias are classified into two major categories based on whether

repetition is intact or not.

Apraxia is the inability to perform skilled, learned, purposeful motor

acts correctly.

Alexia pertains to the inability to comprehend written language

(reading disability). It can be developmental or acquired. Two forms of
acquired alexia are recognized: pure alexia (without agraphia) and
alexia with agraphia.

Agnosia pertains to the inability to recognize stimuli that were

recognized formerly. Agnosia is modality specific: visual, auditory, and
tactile.

Callosal syndromes include hemialexia, unilateral (left) ideomotor

apraxia, unilateral (left) agraphia, unilateral (left) tactile anomia, and
left ear extinction.

Prefrontal lobe syndrome pertains to a conglomerate set of signs and

symptoms that includes impairments in decision making, ability to plan,
social judgment, conduct, modulation of affect and of emotional
response, and creativity.

Alzheimer's disease is the example par excellence of cortical

dementia.

EPILEPTIC SEIZURES
Epilepsy is a common clinical condition characterized by recurrent
paroxysmal attacks of motor, sensory, autonomic, or psychic symptoms and
signs depending on the area of the brain involved. Epileptic seizures are triggered
by synchronized discharges of a group of neurons in the cerebral cortex as a
result of developmental abnormality, infection, trauma, tumor, metabolic
derangement, or stroke. Epileptic seizures may be focal or generalized. When
generalized, they are usually associated
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with loss of consciousness. The most common generalized seizure type is the
tonic-clonic seizure type known as grand mal seizure. Focal seizures are
manifestations of the function of the cortical area from which epileptic discharges
emanate. Epileptic discharges in the region of the central sulcus may give rise to
motor and sensory symptoms. Spreading of the epileptic discharge along the
motor or sensory homunculus produces the so-called Jacksonian seizures or
Jacksonian march. In such a patient, a focal motor seizure may start by shaking
of the side of the face contralateral to the cortical lesion in the precentral gyrus
and spread to involve the thumb, hand, arm, and leg in this order in a pattern
consistent with the location of these body parts in the motor homunculus.

A similar pattern of sensory march is associated with lesions in the

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postcentral gyrus. An epileptic discharge in the frontal eye field produces attacks
consisting of contralateral turning of eyes and head (adversive seizures).
Occipital discharges are associated with visual hallucinations. Discharges in the
primary visual cortex produce contralateral flashes of light, whereas discharges in
the association visual cortex produce well-formed images. Epileptic discharges
from the uncus and adjacent regions of the temporal lobe (uncinate fits) produce
a combination of complex motor and autonomic symptoms (psychomotor
seizures). The epileptic attack in such patients consists of a dreamy state,
olfactory hallucinations (usually of “bad” odors), gustatory hallucinations, oral
movements of chewing, swallowing, or smacking of lips, visual hallucinations
(déjá vu experiences), and possibly aggressive behavior. Complex acts and
movements such as walking and fastening or unfastening buttons may occur.

HEMISPHERE SPECIALIZATION
The concept of cerebral dominance has undergone significant modification in
recent years, primarily because of studies on patients with unilateral brain
damage. The older concept, introduced by Gustav Dax and Paul Broca in 1865,
which assigned to the left hemisphere a dominant role in higher cerebral
function, with the right hemisphere being subordinate to the dominant
hemisphere, has been replaced by a new concept of hemisphere specialization
that implies that each hemisphere is in some way dominant for the execution of
specific tasks. According to this concept, the left hemisphere is dominant or
specialized for comprehension and expression of language, arithmetic, and
analytic functions, whereas the right hemisphere is specialized for complex
nonverbal perceptual tasks and for some aspects of visual (e.g., face) and spatial
perception. The right side of the brain is also dedicated to mapping feelings,
bodily sensations linked to emotions of happiness, anger, and fear. Language is
localized to the left hemisphere in more than 90% of right-handed people and
two-thirds of left-handers. Thus lesions of the left hemisphere are associated
with disorders of language (aphasia or dysphasia), whereas lesions of the right
hemisphere are associated with impairment of visuospatial and visuoconstructive
skills. Patients with right hemisphere lesions are more likely to show such
manifestations as constructional apraxia (inability to construct or to draw figures
and shapes), dressing apraxia, denial of the left side of the body (denial that
their left side is part of their body), and hemineglect (visual and spatial neglect
of the left side of their space, including their own body parts). Idiographic
(pictographic) language (Japanese Kanji) may be processed by the right
hemisphere because of its pictorial features.

APHASIA
The term aphasia refers to an acquired disturbance in comprehension,
formulation of verbal messages (language), or both. It can affect the grammatical
structure of sentences (syntax), the dictionary of words (contained in language)
that denote meanings (lexicon), or the combination of phonemes that results in
word structure (word morphology).

Aphasia, as a specific impairment of language, should not be confused with

mutism, dysarthria, aphemia, and speech apraxia. Mutism is a nonvolitional state
in which the patient does not attempt to initiate speech. Dysarthria is a speech
articulation due to disturbance in the muscular control of the speech mechanism
associated with damage to the central or peripheral nervous system. Aphemia is
a condition in which no articulation occurs due to a central motor deficit. Speech

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apraxia is an imprecisely defined condition of impaired articulation of speech in

which speech is phonetically and prosodically awkward compared to dysarthric
speech. Aphasia is encountered most frequently in cortical lesions in the left
hemisphere, although it may occur in subcortical lesions. The cortical area of the
left hemisphere invariably involved in aphasia is a central core surrounding the
sylvian fissure. The perisylvian core area is surrounded by a larger region in
which aphasia occurs less frequently.

The sequence of complex cortical activities during the production of language

may be simplified as follows: When a word is heard, the output from the primary
auditory area (Heschl's gyrus) is conveyed to an adjacent cortical area
(Wernicke's area), where the speech sounds are processed into word form and
the word is comprehended (see Figure 17-20). If the word is to be spoken, the
comprehended pattern is transmitted via the arcuate fasciculus from Wernicke's
area to Broca's area of speech in the inferior frontal gyrus (see Figure 17-20). If
the word is to be read, the output from the primary visual area in the occipital
cortex is transmitted to the angular gyrus, which in turn arouses the
corresponding auditory form of the word in Wernicke's area (see Figure 17-22).

For didactic purposes, aphasia is classified into Broca's, Wernicke's, conduction,

transcortical, anomic, and global.

The different varieties of aphasia can be classified into those with impaired
repetition (Broca's, Wernicke's, conduction, and global aphasias) and those
in which repetition is preserved (transcortical and anomic aphasias) (Table 18-1).

Broca's aphasia is also known as nonfluent, anterior, motor, or expressive

aphasia. This type of aphasia is characterized by a difficulty in initiating speech
and a decreased and labored language output of 10 words or less per minute,
during which the patient utilizes facial grimaces, body posturing, deep breaths,
and hand gestures to aid output; characteristically, small grammatical words and
the endings of nouns and verbs are omitted, resulting in telegraphic speech. The
speech output is thus unmelodic and dysrhythmic (dysprosody). Despite the
preceding limitations in verbal output, the speech often conveys considerable
information. These patients are unable to repeat what has been said to them.
Paraphasias are common and usually involve omission of phonemes or
substitution of incorrect phonemes (“ha” for “hall,” “pem” for “pen”). Writing and
confrontation naming are impaired. Although Broca's aphasia is usually attributed
to a lesion in Broca's area of the frontal lobe, recent correlations of aphasic
speech with lesions seen on imaging studies have shown that the lesion is
frequently larger than Broca's area and involves the anterior insula, frontal
operculum and the underlying white matter. Pure damage to Broca's area
(Brodmann areas 44 and 45) produces mild transient speech deficit. Since the
temporal lobe is
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intact in these patients, comprehension of language in aural and written forms is
usually intact. Most patients with Broca's aphasia can sing.

Table 18-1. Aphasias

Type Repetition Fluency Auditory Localization

Comprehension

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Broca's X Broca's
area,
anterior
insula,
frontal
operculum,
underlying
white
matter

Wernicke's X Posterior
and
superior
temporal
gyrus,
planum
temporale,
lower
parietal
cortex

Conduction X X Posterior
perisylvian
region

Global Massive
perisylvian
or separate
Broca's and
Wernicke's
areas

Transcortical X X Anterior or
motor superior to
Broca's
area; may
involve part
of Broca's
area

Sensory X X Surrounding
Wernicke's
area

Mixed X Border
zone,

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watershed
area of
middle and
anterior
cerebral
arteries

Anomic X X X Inferior or
anterior
temporal

Broca's aphasia occurs often as a result of stroke (infarcts) most commonly

affecting the middle cerebral artery territory. Such infarcts often involve the
motor cortex; thus patients with Broca's aphasia are often hemiplegic with the
arm (middle cerebral artery territory) more affected than the leg (anterior
cerebral artery territory). Broca's aphasia is named after Paul Broca, the French
anthropologist-physician who studied the patient Leborgne (nicknamed “Tan”
because the only word he could utter was tan) with aphasia and localized the
lesion to the posterior part of the left inferior frontal convolutions. Pierre Marie,
in 1906, examined Leborgne's brain and found that the lesion was more
extensive.

Wernicke's aphasia is also known as fluent, posterior, sensory, or receptive

aphasia. In contrast to Broca's aphasia, the quantity of output in this type ranges
from low normal to supernormal, with an output in most patients of 100 to 150
words per minute. Speech is produced with little or no effort, articulation and
phrase length are normal, and the output is melodic. Pauses to search for a
meaningful word are frequent, and substitution without language (paraphasia) is
common; this may be substitution of a syllable (literal paraphasia) (wellow for
yellow), phonemic substitution of a word (kench for wrench) (verbal paraphasia),
semantic substitution (knife for fork), or substitution of a meaningless nonsense
word (neologism). If a word is not readily available, the patient may attempt to
describe it, and the description may necessitate yet another description, resulting
in a meaningless output (circumlocution). Very highly paraphasic fluent speech is
termed jargon aphasia. Paraphasias also may occur in Broca's aphasia, but these
are articulatory errors, in contrast to those in Wernicke's aphasia, which are true
substitutions. Despite the fluent nature of speech output in Wernicke's aphasia,
little information is conveyed (empty speech). As in Broca's aphasia, patients
with Wernicke's aphasia are unable to repeat what is said to them. In contrast to
Broca's aphasia, comprehension of both aural and written forms of language is
severely impaired in Wernicke's aphasia. As in Broca's aphasia, naming is
impaired. Wernicke's aphasia is attributed to a lesion in Wernicke's area in the
posterior part of the superior temporal gyrus and adjacent areas in posterior
temporal (including the planum temporale) and lower parietal cortex of the left
hemisphere.

Wernicke's aphasia is named after Karl Wernicke, a German neurologist who in

1874 designated the posterior part of the superior temporal gyrus (area 22) of
the left hemisphere as an area concerned with the understanding of the spoken
word. Wernicke's aphasia is also known as Bastian aphasia, after Henry Charlton

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Bastian, the English neurologist who described it in 1869, five years before
Wernicke.

Conduction aphasia is characterized by fluent paraphasic speech, intact

comprehension, poor naming, and repetition. Classically, patients with conduction
aphasia cannot read out loud because of paraphasic intervention. Patients with
conduction aphasia cannot write to dictation, but write better when copying text
and in spontaneous composition. Pathology in these patients is usually located in
the posterior perisylvian region and interrupts the output from Wernicke's area to
Broca's area via the arcuate fasciculus.

Global aphasia is a severe form of aphasia in which all the major functions of
language (verbal output, comprehension, repetition, naming, reading, and
writing) are severely impaired. Global aphasics retain limited capacity for singing.
Global aphasics are differentiated from patients with mutism in that the former
make an attempt to speak and communicate with other means, whereas the latter
do not make such an attempt. Pathol-ogy is invariably extensive, involving most
of the left perisylvian area including Broca's area, Wernicke's area, the inferior
parietal cortex, and underlying white matter. In rare cases, two separate lesions
in Broca's and Wernicke's area are found.

Transcortical aphasia has been subdivided into motor, sensory, and mixed types.
All are characterized by preserved repetition. In transcortical motor aphasia,
verbal output is nonfluent and comprehension is intact, but writing and reading
are invariably abnormal. Pathology in this type of aphasia is located in the
dominant frontal lobe in the neighborhood of Broca's area. It involves the
premotor region or a limited part of the inferior frontal gyrus in the left
hemisphere. This type of aphasia has been also reported with a lesion in the left
basal ganglia. In transcortical sensory aphasia, speech output is fluent and
paraphasic, comprehension is poor, and there are associated difficulties in
reading, naming, and writing. Pathology in such cases is usually in the border
zone between the temporal and parietal lobes in the neighborhood of Wernicke's
area. Mixed transcortical aphasia, also known as isolation of the speech area, is
characterized by
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nonfluent speech output, poor comprehension, and inability to name, read, or
write. Pathology in these patients usually spares the perisylvian core region but
involves the surrounding border zone or watershed area, which is supplied by the
most distal tributaries of the middle cerebral artery.

Anomic aphasia, also known as amnestic or nominal aphasia, is characterized

primarily by word-finding difficulty. Although naming defects are common in
almost all aphasic syndromes, anomic aphasia refers to an isolated severe
impairment of confrontation naming without concomitant other speech
impairments. This type of aphasia is most commonly encountered with lesions in
the left inferior or anterior temporal cortex. Different types of naming
impairments have been associated with damage to different cortical areas.
Selective noun retrieval deficits have been associated with damage to the left
inferior and left anterolateral temporal cortex. Disproportionate difficulty in verb
retrieval, on the other hand, has been associated with damage to the left
premotor-prefrontal cortex. Within the temporal lobe, lesions in the ventral
inferotemporal cortex have been associated with disproportionate difficulty in
naming natural entities (like animals), whereas damage in the left temporal pole
has been associated with disproportionate difficulty in naming specific persons.

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Crossed aphasia refers to the rare development of aphasia in right-handed

persons, with right (instead of left) hemisphere lesion. The aphasic syndrome in
crossed aphasia may follow the classical pattern (Broca, Wernicke, etc) with
lesions in the corresponding area in the right hemisphere, or be anomalous. In
the latter, Broca's area lesion may present with Wernicke's aphasia and
Wernicke's area lesion with Broca's aphasia.

Subcortical aphasia. Aphasia has been reported in left basal ganglia and thalamic
lesions. Within the basal ganglia, the left caudate nucleus is especially involved.
Within the thalamus, the left ventrolateral and anteroventral thalamic nuclei are
invariably involved. Aphasia associated with left basal ganglia lesions is
characterized by relatively fluent, paraphasic, and dysarthric speech.
Comprehension and repetition are often impaired. Thalamic aphasia has the
profile of Broca's or transcortical motor aphasia.

Pure word deafness, also known as verbal auditory agnosia, is characterized by

poor comprehension of spoken language and by poor repetition with intact
comprehension of written language, naming, writing, and spontaneous speech.
The lesion in this type of disorder either affects the primary auditory area or
disconnects this area from Wernicke's area. This syndrome is “pure” in the sense
that it is not associated with other aphasic symptoms.

APRAXIA
Apraxia is the inability to perform skilled, learned, purposeful motor acts
correctly despite intact relevant motor and sensory neural structures,
attention, and comprehension. The concept of apraxia and the first classification
of apraxia are credited to Hugo Karl Liepmann, the German neurologist. There are
several types of apraxia: ideomotor, ideational, and visuoconstructive.

Ideomotor Apraxia
Ideomotor apraxia is the inability to carry out, on verbal command, an activity
that can be performed perfectly well spontaneously. It is implied that this
“inability” is not due to compre hension, motor, or sensory defects. Thus a
patient with ideomotor apraxia will not be able to carry out a verbal command to
walk, stop, salute, open a door, stick out the tongue, etc.

To appreciate the pathophysiology of ideomotor apraxia, it should be understood

that for a skilled task to be performed, several events must take place. For
example, the command to walk, if oral, reaches the primary auditory area and is
relayed to the left auditory association cortex (Wernicke's area) for
comprehension. Wernicke's area is connected to the ipsilateral premotor area
(motor association cortex, area 6) via the arcuate fasciculus. The motor
association area on the left side is connected to the primary motor cortex (area
4) on the left side. When the person is asked to carry out a command with the
left hand, the information is relayed from the left premotor area to the right
premotor area (via the anterior part of the corpus callosum) and from there to
the right primary motor area, which controls movements of the left side of the
body (Figure 18-1). Based on the preceding anatomic connections, three clinical
varieties of ideomotor apraxia have been recognized: parietal, in which the lesion
is in the anteroinferior parietal lobe of the dominant hemisphere; sympathetic, in
which the lesion is in the left premotor area; and callosal, in which the lesion is
in the anterior part of the corpus callosum.

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Ideational Apraxia
Ideational apraxia is an abnormality in the conception of movement so that the
patient may have difficulty sequencing the different components of a complex
motor act. To mail a letter, for example, one must seal it, stamp it, and place it
in the mailbox. The lesion in ideational apraxia is in the dominant
temporoparietooccipital area.

Visuoconstructive Apraxia
Visuoconstructive apraxia, also known as constructional apraxia, is the inability
of the individual to put together or articulate component parts to form a single
shape or figure, such as assembling blocks to form a design or drawing four lines
to form a shape. It implies a defect in perceiving spatial relationships among the
component parts. Visuoconstructive apraxia was described originally in lesions of
the left (dominant) posterior parietal area. Subsequently, it was shown that this
type of apraxia is more prevalent and severe in right hemisphere parietal lesions.

Figure 18-1. Schematic diagram showing the pathways in-volved in carrying

out a motor skill in response to an oral command.

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The term constructional apraxia was suggested by Kleist in 1923 and fully
described by Mayer-Gross in 1935. Lord Brain proposed the term apractagnosia.

ALEXIA (DYSLEXIA)
Alexia (dyslexia) is the inability to comprehend written language (reading
disability). It may be acquired (acquired alexia or dyslexia), as in stroke
patients who lose the ability to read, or developmental (developmental dyslexia),
in which there is an inability to learn to read normally from childhood. Acquired
alexia is of two types: pure alexia (alexia without agraphia, pure word blindness)
and alexia with agraphia (parietal alexia).

In pure alexia, the defect in comprehension may manifest as an inability to read

letters (literal alexia) or words (verbal alexia) or may be global with a total
inability to read either letters or words (global alexia). The anatomic substrate of

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pure alexia is usually a lesion in the left primary visual area coupled with an
other lesion in the splenium of the corpus callosum (Figure 18-2). The lesion in
the left visual area prevents visual stimuli entering the left hemisphere from
reaching the left (dominant) angular gyrus, which is necessary for comprehension
of written language. The lesion in the splenium of the corpus callosum prevents
visual stimuli entering the intact right visual area from reaching the left angular
gyrus. Writing is normal in this type of alexia, but the patient cannot read what
he or she writes. Cases have been described of pure alexia without a splenial
lesion. In such cases, one deep lesion in the left occipitotemporal region isolates
both occipital cortices from the left speech area in the angular gyrus.

Most commonly, alexia without agraphia occurs as a result of infarction in the

territory of the left posterior cerebral artery that supplies neural structures
involved. Usually, a right homonymous visual field defect is present.

In alexia with agraphia, there is a defect in both reading comprehension and

writing. The reading disorder is usually verbal (inability to read words). The
writing difficulty is usually severe. The anatomic substrate of this type of alexia
is a lesion in the dominant angular gyrus, hence the name parietal alexia.

The concept of alexia as separate from other language disorders was developed in
1885 by the German neurologist Ludwig Lichtheim. The two types of acquired
alexia (without and with agraphia) were introduced by Dejerine in 1891 and
1892.

AGNOSIA
Agnosia is the inability of the individual to recognize perceived sensory
information. Implied in this definition is an intact sensory processing of the
input, clear mental state, and intact naming ability.

Agnosia is often modality specific: visual, auditory, and tactile. Visual agnosias
include visual object agnosia (inability to recognize objects presented visually),
visual color agnosia (inability to recognize colors), prosopagnosia (i.e., inability
to recognize faces, including one's own face, cars, types of trees), picture
agnosia, and simultanagnosia (inability to recognize the whole, although parts of
the whole are appreciated correctly).

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Figure 18-2. Schematic diagram showing the neural substrate of the

syndrome of pure alexia without agraphia A and of hemialexiaB.

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Auditory agnosia is the inability to recognize sounds in the presence of otherwise
adequate hearing. It includes auditory verbal agnosia (inability to recognize
spoken language or pure word deafness), auditory sound agnosia (i.e., inability
to recognize nonverbal sounds such as animal sounds, sound of running water,
sound of a bell), and sensory amusia (inability to recognize music).

Tactile agnosia is the inability to recognize objects by touch. It is usually

associated with parietal lobe lesions of the contralateral hemisphere.
Astereognosis is the loss of ability to judge the form of an object by touch. It
includes amorphognosia (impaired recognition of size and shape of objects),
ahylognosia (impaired discrimination of quality of objects, such as weight,
texture, density), and asymbolia (impaired recognition of the identity of an
object in the absence of amorphognosia and ahylognosia). Asymbolia is used by
some authors to refer to tactile agnosia.

CALLOSAL SYNDROME
The disconnection of the right from the left hemisphere by lesions in the corpus
callosum results in the isolation of each hemisphere in such a way that each has
its own learning processes and memories that are inaccessible to the other
hemisphere. The following are some of the effects of callosal disconnection. The
effects of callosal transection are considerably less in younger children compared
with adults because of the continued reliance in this age group on ipsilateral
pathways.

Visual Effects

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Each hemisphere retains its own visual images and memories, but only the left
hemisphere is able to communicate, because of the callosal disconnection, what it
sees through speech or writing.

Hemialexia
Patients are unable to read material presented in the left hemifield. This occurs
when the splenium of the corpus callosum is involved in the lesion. Such visually
presented material reaches the right occipital cortex but cannot be comprehended
because the splenial lesion interferes with transmission of the visual image to the
left (dominant) angular gyrus (Figure 18-2).

Unilateral (Left) Ideomotor Apraxia

In response to verbal commands, patients are unable to carry out with the left
hand some behavior that is readily carried out with the right hand. The verbal
command is adequately received by the left (dominant) hemisphere but, because
of the callosal disconnection, cannot reach the right hemisphere, which controls
left hand movement (Figure 18-3).

Unilateral (Left) Agraphia

Patients with callosal lesions are unable to write using their left hand (Figure 18-
3).

Unilateral (Left) Tactile Anomia

Patients with callosal disconnection are unable, with eyes closed, to name or
describe an object placed in the left hand, although they readily name the same
object in the right hand. The object placed in the left hand is perceived correctly
in the right somatosensory cortex but cannot be identified because of the callosal
lesion that disconnects the right parietal cortex from the left (dominant)
hemisphere (Figure 18-3).

Left Ear Extinction

Patients with callosal lesions show left ear extinction when sounds are presented
simultaneously to both ears (dichotic listening). Sounds presented to the left ear
reach the right temporal cortex but, because of the callosal disconnection, are
not related to the left temporal cortex (dominant) for comprehension.

There is evidence to suggest functional specialization of different segments of the

corpus callosum. Thus lesions in the posterior part of the corpus callosum
(splenium) are associated with hemialexia, lesions in the anterior part are
associated with left ideomotor apraxia, and lesions in the middle part are
associated with left-hand agraphia; lesions in the middle and posterior parts
result in left-hand tactile anomia.

PREFRONTAL LOBE SYNDROME

The prefrontal lobe syndrome occurs in association with tumors, trauma, or
degenerative disease in the prefrontal and or bitofrontal
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cortices. The syndrome is characterized by a conglomerate of signs and
symptoms that include impairments in decision making, ability to plan, social
judgment, conduct, modulation of affect and of emotional response, and

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creativity. Such patients lose spontaneity in motor as well as mental activities.

They do not appear to realize that they are neglecting themselves and their
responsibilities at home and work. Affected patients may sit for hours looking at
objects in front of them or staring out a window. They manifest loss of inhibition
in social behavior and are usually euphoric and unconcerned. They may become
incontinent of stools and urine because of the lack of spontaneity. Patients with
prefrontal lobe syndrome exhibit inappropriate repetitive motor or speech
behavior (perseveration) because of their inability to disengage from a behavior
that is no longer useful.

Figure 18-3. Schematic diagram illustrating the mechanism of unilateral

(left) ideomotor apraxia A and of unilateral (left) tactile anomia B.

THE GRASP REFLEX

Some brain-damaged patients show, in response to tactile stimulation of their
hands or to the mere presentation of an object, a tendency to grasp at the object
without any apparent intention to use it in a purposeful manner. Two types of
grasp phenomena have been described: (1) the grasp reflex and (2) the
instinctive grasp reaction.

The grasp reflex is generally considered an index of frontal lobe pathology,

although the evidence in support of this localization is not so compelling. The
grasp reflex has been reported with pathology in the basal ganglia, temporal
lobe, parietal lobe, and parietooccipital region. In the majority of cases, however,
pathology is either in the frontal lobe or in subcortical structures. Unilateral
lesions usually result in bilateral grasping.

In contrast, the instinctive grasp reaction (forced groping) is usually ipsilateral to

the focal cerebral lesion and is seen more often with retrorolandic lesions of the
right hemisphere, suggesting that it is one of the right hemisphere behavioral
syndromes caused by disturbances of selective attention.

FORCED COLLECTIONISM
Forced collectionism is a rare prefrontal lobe syndrome characterized by
involuntary, irrepressible behavior of searching, collecting, and storing that is
goal-directed and item-selective. It results from inefficient or loss of frontal lobe

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inhibition. It is associated with bilateral damage to the orbitofrontal and polar

prefrontal cortices.

Pathologic patterns of collecting have been observed following frontal lobe injury.
They range from a tendency to grasp to the irrepressible seizure and storage of
surrounding objects (hoarding behavior). In contrast to forced collectionism,
these behaviors are not planned and not selective.

ALZHEIMER'S DISEASE
Alzheimer's disease is the example par excellence of cortical dementia. It
was first described by Alois Alzheimer, the German psychiatrist, in 1906–
1907, based on pathological findings in the brain of a patient (Auguste D) with
memory impairment. It is characterized by relentlessly progressive memory loss.
Early on in the disease, patients lose recent memory (telephone numbers,
appointments). As the disease progresses, remote memory is impaired. In the
end stage, memory loss is nearly total. With advance in the disease, patients will
be unable to recognize their family members or their familiar surroundings. The
pathologic hallmarks are neurofibrillary tangles and senile plaques. The former
are intracellular aggregates of twisted cytoskeletal filaments and abnormally
phosphorylated tau protein. The latter are abnormal neurites surrounding an
aggregated B-amyloid core in the neuropil between nerve cells. The limbic cortex
is most affected, the association cortices are heavily affected, the primary
sensory areas are minimally affected, and the motor cortex is least affected.
Within the limbic cortex, the entorhinal cortex (Brodmann area 28) is the most
heavily affected, thus disconnecting the hippocampus from association areas of
the cortex. In Alzheimer's disease, about 50% of neurons are lost.

Ninety percent of Alzheimer's disease is sporadic. The familial cases comprise

10% of cases and are related to abnormal mutations in chromosomes 21, 14, and
1. Chromosome 21 mutation is in the amyloid precursor protein and has been
associated with abnormal quantities of amyloid production. Mutations in
chromosomes 14 and 1, on the other hand, are associated with protein
presenilins that are possibly responsible for build up of amyloid.

Risk factors for Alzheimer's disease have been associated with chromosome 19,
which encodes apolipoprotein, and chromosome 12, which encodes alpha 2
macroglobulin.

BALINT'S SYNDROME
This rare syndrome is named after the Hungarian neurologist Rudolph Balint. The
syndrome is also known as Balint-Holmes syndrome, optic ataxia, ocular apraxia,
and psychic paralysis of visual fixation. It is characterized by a triad of (1)
simultanagnosia, (2) optic ataxia, and (3) ocular apraxia. Simultanagnosia, also
known as visual disorientation, is the inability of the patient to perceive the
visual field as a whole. Optic ataxia is the inability to reach for objects under
visual guidance. Ocular apraxia is the inability to direct gaze voluntarily to visual
targets. The associated cortical lesion is bilateral parietooccipital junction
(Brodmann areas 7 and 19).

GERSTMANN'S SYNDROME
This syndrome is named after Josef Gerstmann, an Austrian neuro-psychiatrist
who described the syndrome in 1930. The syndrome is also known as the Badal-
Gerstmann syndrome and the angular gyrus syndrome. Antoine-Jules Badal, a

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French ophthalmologist, had reported some features of the syndrome in 1888.

The syndrome consists of the combination of right-left disorientation, acalculia
(reduced ability to perform simple calculations), agraphia (inability to write), and
finger agnosia (inability to recognize various fingers) due to a lesion in the left
angular gyrus. Asymbolia for pain and constructional apraxia are added features
in some cases.

ANOSOGNOSIA (DENIAL SYNDROME, ANTON-

BABINSKI SYNDROME)
The term anosognosia was introduced by Josef-Franéois-Felix Babinski in 1912 for
unawareness of physical deficits or disease. This is seen most often with lesions
of the nondominant (right) parietal lobe, with unawareness of deficits of the left
side of the body. The denial syndrome may include denial that the paretic limbs
belong to the patient. Hemispatial neglect often co-occurs with anosognosia. In
hemispatial neglect, the contralateral side of the body and visual space are
ignored but can be used if attention is drawn to them. Hemispatial neglect occurs
after damage
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to either hemisphere but is typically more common and severe after right parietal
lesions. The precise location of the lesion in the parietal lobe has not been
determined, but most likely is in the inferior parietal lobule and the adjacent
intraparietal sulcus.

ANTON'S SYNDROME
Anton's syndrome traditionally refers to the clinical phenomenon of denial of
blindness (anosognosia for blindness) in a patient who has suffered acquired
cortical blindness. The most common setting is acute bilateral occipital cortex
ischemia secondary to posterior circulation insufficiency. Although classically a
manifestation of cortical blindness, Anton's syndrome has been reported in
patients with blindness from peripheral visual pathway lesions (optic nerve,
chiasm). The syndrome is named after Gabriel Anton, an Austrian neurologist who
described the syndrome in 1899.

KLUVER-BUCY SYNDROME
The Kluver-Bucy syndrome was first described in 1939 in monkeys after bilateral
temporal lobectomy. The human counterpart was described by Terzian and Dalle
Ore in 1955 after bilateral removal of the temporal lobes. The syndrome consists
of six main elements: (1) blunted affect with apathy, (2) psychic blindness or
visual agnosia with inability to distinguish between friends, relatives, and
strangers, (3) hypermetamorphosis with a marked tendency to take notice and
attend to fine and minute visual stimuli, (4) hyperorality, placing all items in the
mouth, (5) bulimia or unusual dietary habits, and (6) alteration in sexual
behavior (hypersexuality, sexual libertarianism).

SIMULTANAGNOSIA
Simultanagnosia is the inability to appreciate more than one aspect of the visual
panorama at any single time. Affected patients cannot experience a spatially
coherent visual field because of an inability to voluntarily control the shifting of
attention or to disengage from a fixed target. Objects in the visual field of
affected patients appear and disappear erratically. Affected patients fail to see a
match flame held several inches away when their attention is focused on the tip

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of a cigarette held between their lips. The term simultanagnosia was introduced
by Wolpert in 1924 to refer to a condition in which the patient is unable to
recognize or abstract the meaning of the whole (pictures or series of pictures)
even though the details are appreciated correctly. Simultanag-nosia is frequently
a component of Balint's syndrome. Isolated simultanagnosia is associated with
lesions in the unimodal visual association cortex (Brodmann area 19).

THE ALIEN HAND (LIMB) SYNDROME

The alien hand (limb) syndrome is characterized by the unwilled and uncontrolled
actions of an upper limb on either the dominant or nondominant side. The alien
hand performs auton-omous activity that the subject cannot inhibit and then
often contrasts with voluntary actions performed by the other hand. Patients
often fail to recognize ownership of the limb and state that the alien hand has a
mind of its own. The alien hand syndrome was first described in 1908 by
Goldstein. Two forms of alien hand exist: (1) an acute, transient condition in the
non-dominant hand due to callosal lesion and (2) a chronic condition resulting
from additional medial frontal lesions involving the supplementary motor area.
The combined callosal and medial frontal lesions presumably release the lateral
frontal motor system responsible for environmentally driven activity. A sensory
alien hand syndrome has also been described in which the right arm involuntarily
attacks the left side of the body, including choking movement.

TERMINOLOGY
Adversive seizures.
A variety of seizures in which there is deviation of eyes and/or head to one side
secondary to a stimulating lesion in the contralateral frontal eye field region.

Agnosia (Greek a, “negative” gnosis, “knowledge”).

Impairment of the ability to recognize stimuli that were recognized formerly
despite intact perception, intellect, and language. The term was coined by
Sigmund Freud in 1891. The lesion is usually in the posterior parietal region.

Agraphia (Greek a, “negative” grapho, “to write”).

Inability to express thoughts in writing due to a cerebral lesion. The first modern
descriptions of agraphia are those of Jean Pitres in 1884 and of Joseph-Jules
Dejerine in 1891.

Alzheimer, Alois (1864–1915).

German neuropsychiatrist and pathologist. He described Alzheimer's disease in a
lecture in 1906 and a publication in 1907. The term “Alzheimer's disease” was
coined in 1910 by Ernst Kraepelin, a German psychiatrist and co-worker of
Alzheimer.

Anomia (Greek a, “negative” onoma, “name”).

Inability to name objects or of recognizing and recalling their names.

Anton, Gabriel (1858–1933).

Austrian neurologist who described visual anosognosia (anosognosia for
blindness) in 1899. The term anosognosia was coined by Babinski in 1912.

Aphasia (dysphasia) (Greek a, “negative” phasis, “speech”).

Language impairment following cortical lesion in the left hemisphere. Either
inability to speak or to comprehend language or both.

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Apraxia (Greek a, “negative” praxis, “action”).

Inability to carry out learned skilled movements on command despite intact
motor and sensory systems and good comprehension.

Babinski, Josef-Franéois-Felix (1857–1932).

French neurologist of Polish descent. Described the “phenomenon of the toes” in
1896, which became known as the Babinski sign. Coined the terms anosognosia,
dysdiadochokinesis, and asynergia, among others.

Bastian, Henry Charlton (1837–1915).

English neurologist, who described Wernicke's aphasia in 1869, five years before
Karl Wernicke.

Circumlocution.
Convoluted, meaningless speech output, providing information rather than
defining the objects to be communicated. Characteristic of Wernicke's aphasia.

Dax, Gustav.
French physician, who, in 1865, published the observation of his father, Marc
Dax, about left hemisphere dominance for language, which was noted, but not
published, by his father in 1836.

Déjá vu (French, “already seen”).

An illusion in which a new situation is incorrectly viewed as a repetition of a
previous situation. Usually an aura of a temporal lobe seizure.

Dysphasia (Greek dys, “difficult” phasis, “speech”).

Distur-bance in communication involving language.

Dysprosody (Greek dys, “difficult” prosodos, “a solemn procession”).

Disturbance in stress, pitch, and rhythm of speech. A feature of all types of
aphasia, but especially of Broca's aphasia.
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Goldstein, Kurt (1878–1965).

German-American physician. Described the alien hand (limb) syndrome (la main
etrangere, anarchic hand).

Idiographic language.
Pictographic language such as Japanese Kanji.

Jacksonian seizures.
The spread of tonic-clonic seizure activity through contiguous body parts on one
side of the body secondary to excitation of adjacent cortical areas within the
motor or sensory homunculus. Also known as Jacksonian march and Bravais-
Jackson epilepsy. L. Bravais described this phenomenon in his graduation thesis
in 1827 from the University of Paris but did not analyze the etiology, which John
Hughlings-Jackson did.

Lichtheim, Ludwig (1845–1928).

German neurologist and pathologist. Recognized alexia as a distinct condition
separate from other language disorders. He is credited with describing
subcortical aphasia in 1885 and subacute combined degeneration of the spinal
cord in vitamin B12 deficiency (Lichteim syndrome).

Liepmann, Hugo Karl (1863–1925).

German neurologist and psychiatrist, who introduced the concept of apraxia and

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proposed its classification in 1900.

Marie, Pierre (1853–1940).

French neurologist who, in 1906, disagreed with Broca on the extent of the lesion
that produced aphasia in patient Leborgne. He and Charcot are credited with
describing peroneal muscular atrophy in 1886 (Charcot-Marie-Tooth disease).

Mayer-Gross, Willi.
German psychiatrist who provided full description of constructional apraxia in
1935.

Neologism (Greek neos, “new” logos, “word”).

A newly coined word either in response to a communicative need or as a result of
brain disorder. In the latter case, the newly coined word is a replacement of a
desired word but without meaning.

Paraphasia (Greek para, “to, at, from the side of” phasis, “speech”).
An aphasic phenomenon in which the patient employs wrong words or uses words
in wrong combinations.

Prosopagnosia (Greek prosopon, “face” gnosis, “knowledge”).

Inability to recognize familiar faces. The word was coined by Bodamer in 1947,
although the phenomenon had been recognized by Jackson and Charcot at the
end of the nineteenth century.

Simultanagnosia.
The inability to comprehend more than one element of a visual scene at the same
time or to integrate the parts into a whole.

Uncinate (Latin uncinus,”hook-shaped”).

Pertaining to the uncus of the temporal lobe. Uncinate seizures are temporal lobe
seizures in which olfactory and gustatory hallucinations occur as part of the
seizure. The name uncinate fits was applied by Jackson in 1899.

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Alexander MP et al: Broca's area aphasias: Aphasia after lesions including the
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Banks G et al: The alien hand syndrome: Clinical and postmortem findings.
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Benson DF: Aphasia. In Heilman KM, Valenstein E (eds): Clinical

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Benson DF: Aphasia, alexia, and agraphia. In Glaser GH (ed): Clinical

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Benton A: Visuoperceptive, visuospatial, and visuoconstructive disorders. In

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Damasio H, Damasio AR: The anatomical basis of conduction aphasia. Brain

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Editors: Afifi, Adel K.; Bergman, Ronald A.

Title: Functional Neuroanatomy: Text and Atlas, 2nd Edition

Copyright ©2005 McGraw-Hill

> Table of Contents > Part I - Text > 19 - Hypothalamus

19
Hypothalamus

Boundaries and Divisions

Preoptic Region
Suprachiasmatic (Supraoptic) Region Tuberal Region
Mamillary Region
Connections
Local Connections
Extrinsic Connections
Functions of the Hypothalamus
Control of Posterior Pituitary (Neurohypophysis)
Control of Anterior Pituitary
Autonomic Regulation
Temperature Regulation
Emotional Behavior
Feeding Behavior
Drinking and Thirst
Sleep and Wakefulness
Circadian Rhythm
Memory
Sexual Arousal
Blood Supply

KEY CONCEPTS

The hypothalamus is divided by the fornix into medial and lateral zones.

The hypothalamus contains the following nuclear groupings: preoptic,

suprachiasmatic (supraoptic), tuberal, and mamillary.

Hypothalamic connections are divided into local (efferent) and extrinsic (afferent
and efferent).

Local hypothalamic connections consist of the hypotha-lamohypophyseal tract and

the tuberohypophyseal (tuberoinfundibular) tract.

Afferent extrinsic connections include the retinohypothalamic, fornix,

amygdalohypothalamic, thalamohypothalamic, medial forebrain bundle, inferior
mamillary peduncle, dorsal longitudinal fasciculus (of Schütz), pallidohypothalamic,
cerebello-, spino-, and prefrontal hypothalamic.

Efferent extrinsic connections include the mamillotha-l amic, mamillotegmental,

fornix, medial forebrain bundle, dorsal longitudinal fasciculus (of Schütz), hypoth-
alamoamygdaloid, descending autonomic, hypothalamocerebellar and hypothalamo-
prefrontal.

The hypothalamus is involved in a variety of functions that include (1) control of

water reabsorption in the kidney through secretion of the antidiuretic hormone (ADH)

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or vasopressin, (2) contraction of uterine smooth muscle and ejection of milk from the
lactating nipple through secretion of oxytocin, (3) control of anterior pituitary function
through secretion of hypothalamic releasing factors, (4) control of brain stem and
spinal cord autonomic centers related to cardiovascular, respiratory, and
gastrointestinal functions, (5) control of body temperature through thermoreceptors
that are sensitive to changes in temperature of blood perfusing the hypothalamus, (6)
emotional behavior and the “fight or flight” reaction, (7) regulation of feeding behavior
through the hypothalamic satiety and feeding centers, (8) regulation of drinking and
thirst, (9) wakefulness and sleep through the hypothalamic centers for wakefulness and
sleep, (10) circadian rhythm through the connections of the suprachiasmatic nucleus,
and (11) memory through connections to the anterior thalamic nucleus and
hippocampal formation.

The blood supply of the hypothalamus is derived from perforating branches of the
anterior cerebral, anterior communicating, posterior communicating, and posterior
cerebral arteries.

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BOUNDARIES AND DIVISIONS

The hypothalamus is the area of the diencephalon ventral to the hypothalamic sulcus (see
Figure 11-1). It weighs about 4 g and comprises 0.3 to 0.5 percent of brain volume. It is
limited anteriorly by the lamina terminalis and is continuous posteriorly with the
mesencephalon. On its ventral surface, caudal to the optic chiasma, the hypothalamus narrows
to a small neck, the tuber cinereum. The ventral-most portion of the tuber cinereum constitutes
the median eminence. The median eminence blends into the infundibular stalk, which is
continuous with the posterior lobe of the pituitary gland (hypophysis). In coronal sections, the
hypothalamus is bordered medially by the third ventricle and laterally by the subthalamus (see
Figure 11-2). The fornix divides the hypothalamus into medial and lateral regions. The lateral
region contains mainly longitudinally oriented fibers of the medial forebrain bundle (which
connects the septal area, hypothalamus, and midbrain tegmentum), among which are scattered
neurons of the lateral hypothalamic nucleus. The medial region has a cluster of nuclei organized
into four major groups. In a rostrocaudal orientation (Figure 19-1), these nuclear groups are as
follows:

1. Preoptic

2. Suprachiasmatic (supraoptic)

3. Tuberal

4. Mamillary

Preoptic Region (Figure 19-2)

The gray matter in the most rostral part of the hypothalamus, just caudal to the lamina
terminalis, is the preoptic region. The preoptic region receives many fibers that carry
neuromediators, such as angiotensin II, sleep-inducing peptides, enkephalin, and endorphin,
among others. It contains medial and lateral preoptic nuclei and the preoptic periventricular
nucleus.

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Figure 19-1. Schematic diagram showing the four regions of the medial hypothalamus.

The medial preoptic nucleus contains neurons that elaborate gonadotropic releasing hormone
which reaches the anterior pituitary gland via the tuberoinfundibular tract. It is related to
reproduction, eating, locomotion, and sexual arousal. The medial preoptic nucleus is referred to
as the sexually dimorphic nucleus. It is twice as large in young males compared to females,
probably because gonadotropin release in males is constant, whereas it is cyclic in females. The
difference in size may also explain the reported greater sexual arousal to erotic stimuli
experienced by men. Functional magnetic resonance imaging (fMRI) studies have shown greater
activation in the preoptic region in men compared to women when viewing erotic films.

Suprachiasmatic (Supraoptic) Region (Figure 19-2)

Located above the optic chiasma, this nuclear group contains the supraoptic, paraventricular,
anterior hypothalamic, and suprachiasmatic nuclei. The supraoptic nucleus is located above the
optic tract, whereas the paraventricular nucleus is dorsal to it, lateral to the third ventricle
(Figure 19-3). Both nuclei contain magnocellular secretory neurons. Axons of both nuclei course
in the pituitary stalk to reach the posterior lobe of the pituitary (hypothalamoneurohypophyseal
system), transporting neurosecretory material elaborated in these nuclei and stored in axonal
swellings within the posterior lobe. The neurosecretory material consists of vasopressin ADH and
oxytocin. There is evidence to suggest that the supraoptic nucleus elaborates mainly ADH,
whereas the paraventricular nucleus elaborates mainly oxytocin. ADH acts on the distal
convoluted tubules of the kidney to increase reabsorption of water. Lesions of the supraoptic
nucleus, the hypothalamoneurohypophyseal system, or the posterior lobe of the pituitary result
in excessive excretion of urine (polyuria) of low specific gravity. This condition is known as
diabetes insipidus. Another symptom of this condition is excessive intake of water (polydipsia).
Unlike diabetes mellitus diabetes insipidus is not associated with alterations in the sugar
content of blood or
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of urine. Production of ADH is controlled by the osmolarity of the blood that bathes the
supraoptic nucleus. An increase in blood osmolarity, as occurs in dehydration, increases ADH
production, whereas the reverse occurs in states of lowered blood osmolarity, such as excessive
hydration. ADH secretion is increased by pain, stress, and such drugs as morphine, nicotine, and
barbiturates; it is decreased by alcohol intake, which explains the increase in urination with

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alcohol consumption.

Figure 19-2. Schematic diagram showing nuclei within each of the regions of the medial
hypothalamus.

Oxytocin causes contraction of uterine smooth musculature and promotes milk ejection from the
lactating mammary glands by stimulating contraction of its myoepithelial cells. Commercially
produced oxytocin (Pitocin) is used to induce labor. The function of oxytocin in males is not yet
known.

The anterior nucleus merges with the preoptic region. Stimulation of the anterior part of the
hypothalamus in animals results in excessive intake of water, suggesting that a center for thirst
is located in this region. Tumors in this region in children are associated with refusal of patients
to drink despite severe dehydration.

Figure 19-3. Schematic diagram showing the hypothalamo-neurohypophyseal system.

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The suprachiasmatic nucleus, poorly developed in humans, overlies the optic chiasma. It is
involved in regulation of sleep-wake cycle, body temperature, and day-night cycle (circadian
rhythm). It receives bilateral inputs from ganglion cells of the retina. It projects to the
paraventricular, tuberal, and ventromedial nuclei of the hypothalamus. Lesions of the nucleus in
experimental animals will disturb the cyclic variations of a number of bodily functions (e.g.,
temperature cycle, sleep-wake cycle, circadian changes of hormones).

Tuberal Region (Figure 19-2)

This is the widest region of the hypothalamus and the one in which the division of the
hypothalamus into medial and lateral areas by the fornix is best illustrated. It extends from the
infundibulum anteriorly to the mamillary body posteriorly. The tuberal region contains the
ventromedial hypothalamic, dorsomedial hypothalamic, and arcuate (infundibular) nuclei.

The ventromedial nucleus, a poorly delineated area of small neurons, is concerned with satiety.
Bilateral lesions in the ventromedial nucleus in animals produce a voracious appetite, obesity,
and savage behavior. Lesions in the lateral hypothalamus at this level produce loss of appetite.
Thus a center for satiety is believed to be associated with the ventromedial nucleus and a
feeding center with the lateral hypothalamus.

The dorsomedial nucleus is a poorly delineated mass of small neurons dorsal to the
ventromedial nucleus. The arcuate nucleus consists of small neurons located ventral to the third
ventricle near the infundibular recess. The arcuate nucleus contains dopamine, which controls
prolactin and growth hormone secretions. In addition, neurons of the arcuate nucleus stain
positively for adrenocorticotropic hormone (ACTH), beta-lipotropic pituitary hormone (β-LPH),
and beta-endorphin (β-END). These sub-stances are transmitted to the anterior pituitary via the
tubero-infundibular
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tract and the hypophyseal portal system. The arcuate nucleus is believed to play a role in
emotional behavior and endocrine function. The arcuate nucleus is a major target in the
hypothalamus for leptin action to suppress food intake. Both food promoting (orexinergic) and
food inhibiting (anorexinergic) neurons exist in the arcuate nucleus and are targets for leptin
action. The arcuate orexinergic neurons are the neuropeptide Y neurons.

Mamillary Region (Figure 19-2)

The most caudal region of the hypothalamus is the mamillary region; it contains mamillary and
posterior hypothalamic nuclei. The mamillary nuclei (bodies) are two spherical masses
protruding from the ventral surface of the hypothalamus caudal to the tuber cinereum and
rostral to the interpeduncular fossa and the anterior perforated substance. Each mamillary body
contains two nuclei, medial and lateral. The medial nucleus is especially well developed in man.
It is the main target of the fornix and the source of the mamillothalamic tract.

The posterior hypothalamic nucleus is a mass of large neurons located dorsal to the mamillary
bodies. It is the main source of descending hypothalamic fibers to the brain stem.

A. LATERAL REGION
The lateral region of the hypothalamus lies lateral to the fornix and mamillothalamic tract. It
contains the medial forebrain bundle and the lateral hypothalamic nucleus. The medial forebrain
bundle connects the hypothalamus with the septal area rostrally and brain stem reticular
formation caudally. The lateral hypothalamus is specifically responsible for feeding. Orexin
(hypocretin) peptide containing neurons are exclusively located in the lat-eral hypothalamic
region. Central administration of hypocretin-1 stimulates food intake. Hypocretin neurons in the
lateral region send a dense projection to the hypothalamic arcuate nucleus. Hypocretin inhibits
anorexinergic and excites orexinergic arcuate neurons. Hypocretin neurons also project to the
paraventricular and ventromedial hypothalamic nuclei, structures known to integrate feeding.
The orexin/hypocretin system is also the major excitatory neuromodulatory system that controls
activities of monoaminergic and cholinergic systems to control vigilance states. Destruction of
orexin/hypocretin neurons is associated with the sleep disorder of narcolepsy.

CONNECTIONS (Figure 19-3)

The hypothalamus has extensive connections reflecting its roles in endocrine, autonomic,

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and somatic integration.

Local Connections
The hypothalamus influences pituitary function via two path ways: the
hypothalamohypophyseal (supraoptic-hypophyseal) tract and the tuberohypophyseal
(tubero-infundibular) tract.

A. THE HYPOTHALAMOHYPOPHYSEAL (SUPRAOPTIC-

HYPOPHYSEAL) TRACT (Figure 19-3)
This tract arises from the large magnocellular neurons of the supraoptic and
paraventricularnuclei of the hypothalamus and terminates in the posterior lobe of the pituitary
gland (neurohypophysis). Axons in this tract transport vasopressin (ADH) from the supraoptic
nucleus and oxytocin from the paraventricular nucleus to the fenestrated capillary bed in the
neurohypophysis. Interruption of this tract results in diabetes insipidus, a condition
characterized by excessive urine excretion (poly-uria) of low specific gravity and excessive
intake of water (polydipsia) without alterations in the glucose content of blood or urine.

B. THE TUBEROHYPOPHYSEAL (TUBEROINFUNDIBULAR) TRACT

This tract arises from the small parvicellular neurons of the arcuate and periventricular nuclei
and terminates on capillaries in the median eminence and infundibular stem. Fibers in this tract
trans-mit hypothalamic releasing factors (hypophysiotropic agents) to the anterior lobe of the
pituitary gland via the hypophyseal portal system. Hypophysiotropic agents stimulate or inhibit
secretion of anterior lobe of the pituitary hormones.

Extrinsic Connections
A. AFFERENT EXTRINSIC CONNECTIONS
The following hypothalamic extrinsic inputs have been reported:

1. Retinohypothalamic tract. Fibers from ganglion cells of the retina project bilaterally to
the suprachiasmatic nuclei of the hypothalamus via the optic nerve and optic chiasma.
They reach the nucleus as direct fibers from the optic chiasm or as collaterals from
retinogeniculate fibers. This tract transmits light periodicity information to the
suprachiasmatic nucleus, which plays a role in the circadian rhythm.

2. Fornix. The fornix comprises the major input to the hypothalamus. Arising from the
hippocampal formation and subiculum, the fornix follows a C-shaped course underneath the
corpus callosum as far forward as the interventricular foramen of Monro, where it
disappears in the substance of the diencephalon to reach the mamillary bodies. Although
the major component of the fornix comes from the hippocampal formation and subiculum,
it also carries fibers from the septal area to the mamillary bodies. Its major target within
the mamillary body is the medial nucleus.

3. Amygdalohypothalamic tract. Inputs to the hypothalamus from the amygdala follow two
pathways. One is via the phylogenetically older stria terminalis, which links the amygdala
with the preoptic, anterior hypothalamic, ventromedial, and arcuate nuclei of the
hypothalamus. The other is via the phylogenetically more recent ventral amygdalofugal
fiber system, which links the amygdala with the lateral hypothalamic nucleus.

4. Thalamohypothalamic fibers. These fibers run from dorsomedial and midline thalamic nuclei
to the lateral and posterior hypothalamus and are sparse. Fibers from the anterior tha-
lamic nuclei reach the mamillary bodies via the mamillo-thalamic tract and provide a
feedback mechanism to the mamillary bodies.

5. Medial forebrain bundle. This fiber bundle runs in the lateral hypothalamus. It conveys to
the hypothalamus inputs from a variety of sources, including the basal forebrain (olfactory
cortex, septal area, nucleus accumbens septi), amygdala, premotor frontal cortex, brain
stem reticular formation, and spinal cord.

6. Inferior mamillary peduncle. This fiber bundle links the dorsal and ventral tegmental nuclei
of the midbrain with the mamillary body. It also contains indirect inputs from ascending

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sensory pathways.

7. Dorsal longitudinal fasciculus of Schütz. Afferent fibers in this fasciculus link the
periaqueductal (central) gray matter of the midbrain with the hypothalamus.

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8. Pallidohypothalamic fibers. This fiber bundle originates from the lentiform nucleus and
projects on neurons in the ventromedial hypothalamic nucleus.

9. Cerebellohypothalamic fibers. This fiber bundle originates from all deep cerebellar nuclei
and relates the cerebellum to autonomic function.

10. Other inputs. Other afferents to the hypothalamus from the brain stem include those from
the raphe nuclei (serotoninergic), locus ceruleus (noradrenergic), and nucleus solitarius.
These fibers enter the hypothalamus via the medial forebrain bundle. Input from the spinal
cord reaches the hypothalamus via the reticular formation of the brain stem.

11. Prefrontal-hypothalamic fibers. Reciprocal connections between the hypothalamus and

prefrontal cortex have been demonstrated. Prefrontal-hypothalamic fibers originate
primarily from the orbital and medial prefrontal areas and terminate primarily in the
posterior hypothalamus, with some terminations in the tuberal and anterior hypothalamus.
The origin of prefrontal-hypothalamic fibers from limbic prefrontal cortex and their targets
in the hypothalamus suggest that they are important links for autonomic response to
emotion.

B. EFFERENT EXTRINSIC CONNECTIONS

The hypothalamus sends fibers to most areas from which it receives inputs. The following
hypothalamic extrinsic efferent connections have been reported:

1. Mamillothalamic tract (tract of Vicq d'Azyr) (see Figure 11-4). This is a two-way fiber
system connecting the mamillary bodies with the anterior thalamic nucleus.

2. Mamillotegmental tract. Fibers from the mamillary bodies course caudally to terminate on
dorsal and ventral tegmental nuclei and secondarily on autonomic cranial (dorsal motor
nucleus of vagus, nucleus solitarius, nucleus ambiguus) and spinal nuclei
(intermediolateral cell column).

3. Fornix. Reciprocal fibers travel in the fornix from the mamillary body to the hippocampal
formation.

4. Medial forebrain bundle. This bundle conveys impulses from the lateral hypothalamus
rostrally to the septal nuclei and caudally to tegmental nuclei and periaqueductal (central)
gray of the midbrain.

5. Dorsal longitudinal fasciculus of Schütz. Fibers in this fasciculus link the medial
hypothalamus with the periaqueductal gray matter of the midbrain, the accessory
oculomotor nuclei, and salivary nuclei.

6. Hypothalamoamygdaloid fibers. These fibers travel via the stria terminalis and ventral
amygdalofugal fiber system and provide feedback information to the amygdaloid nucleus.

7. Descending autonomic fibers (Figure 19-4). Axons of neurons in the paraventricular

nucleus, the lateral hypothalamic area, and the posterior hypothalamus project into
autonomic cranial nerve nuclei in the brain stem (dorsal motor nucleus of the vagus,
nucleus ambiguus, nucleus solitarius) and autonomic spinal cord nuclei in the
intermediolateral cell column and the sacral autonomic cell column. Via these connections,
the hypothalamus exerts control over central autonomic processes related to blood
pressure, heart rate, temperature regulation, and digestion. Many of these fibers are
components of the dorsal longitudinal fasciculus of Schütz.

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Figure 19-4. Schematic diagram showing descending autonomic projections of the

hypothalamus.

8. Hypothalamocerebellar fibers. In the past few years, a series of investigations has revealed
the existence of a complex net-work of direct and indirect pathways between the
hypothalamus and cerebellum. The projections are bilateral with ipsilateral preponderance.
They originate from various hypothalamic nuclei and areas but principally from the lateral
and posterior hypothalamic areas. The direct pathway reaches the cerebellum via the
superior cerebellar peduncle. The indirect pathway reaches the cerebellum after relays in a
number of brain stem nuclei. The hypothalamocerebellar pathway may provide the
neuroanatomic substrate for the autonomic responses elicited from cerebellar stimulation.

9. Hypothalamothalamic fibers: This fiber system connects the preoptic hypothalamic area
with the dorsomedial thalamic nucleus.

10. Hypothalamoprefrontal fibers: These fibers originate principally from the posterior
hypothalamus with some contribu-tions from the anterior and tuberal hypothalamus. In
con-trast to the prefrontal hypothalamic connection which originates selectively from limbic
prefrontal cortex, the hypothalamus prefrontal projection is widespread to all sectors of
the prefrontal cortex.

Table 19-1 is a summary of the afferent and efferent connections of the hypothalamus.

FUNCTIONS OF THE HYPOTHALAMUS

The functions of the hypothalamus, mediated through its varied and complex connections,
involve several important bodily activities. The following is a listing of some of the most
important and best known.

Control of Posterior Pituitary (Neurohypophysis)

This is served through the hypothalamoneurohypophyseal sys-tem discussed earlier.
Approximately 100,000 unmyelinated fibers extend from the supraoptic and paraventricular
nuclei of the hypothalamus to the fenestrated capillary bed of the neurohy-pophysis. These
fibers convey two peptide hormones: vasopressin (ADH) and oxytocin. Vasopressin promotes
reabsorption of water from the kidney. In lesions of the neurohypophysis, urine output of low
specific gravity reaches 10 to 15 liters per day, a condition known as diabetes insipidus.
Oxytocin stimulates contraction of smooth muscles of the uterus and promotes ejection of milk
from the lactating mammary gland.

Table 19-1. Connections of the Hypothalamus

Pathway Afferent Efferent Origin Termination

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Hypothalamohypophyseal X Supraoptic and Neurohypophysis

tract paraventricular
nuclei

Tuberohypophyseal tract X Arcuate and Median

periventricular eminence and
nuclei infundibular
stalk

Retinohypothalamic tract X Ganglion cells Suprachiasmatic

of retina nucleus

Fornix X Hippocampal Mamillary body

formation,
subiculum

X Mamillary body Hippocampal

formation

Stria terminalis X Amygdaloid Preoptic and

nucleus arcuate nuclei

X Preoptic and Amygdaloid

arcuate nuclei nucleus

Ventral amygdalofugal X Amygdaloid Lateral

tract nucleus hypothalamic
nucleus

X Lateral Amygdaloid
hypothalamic nucleus
nucleus

Thalamohypothalamic X Dorsomedial Lateral and

and midline posterior
thalamic nuclei hypothalamus

Medial forebrain bundle X Basal Lateral

forebrain, hypothalamus
amygdala,
premotor
frontal cortex,
brain stem
reticular
formation
(raphe nuclei,
locus ceruleus,
nucleus
solitarius),
spinal cord

X Lateral Septal nuclei,

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hypothalamus tegmental
nuclei, and
periaqueductal
gray matter of
midbrain

Inferior mamillary X Tegmental Mamillary body

peduncle nuclei of
midbrain,
ascending
sensory
pathways

Dorsal longitudinal X Periaqueductal Medial

fasciculus(of Schütz) gray matter of hypothalamus
midbrain

X Medial Periaqueductal
hypothalamus gray matter of
midbrain

Pallidohyphothalamic X Lentiform Ventromedial

nucleus hypothalamic
nucleus

Cerebellohypothalamic X Deep nuclei of Lateral and

fibers cerebellum posterior
hypothalamus

Hypothalamocerebellar X Lateral and Deep cerebellar

fibers posterior nuclei and
hypothalamus cerebellar cortex

Mamillothalamic tract X Mamillary body Anterior

thalamic nucleus

Mamillotegmental tract X Mamillary body Tegmental

nuclei of
midbrain

Descending autonomic X Paraventricular Autonomic

fibers nucleus, cranial nerve
lateral and spinal cord
hypothalamic nuclei
area, posterior
hypothalamus

Prefrontal-hypothalamic X Orbitofrontal Posterior

cortex Medial hypothalamus
prefrontal Tuberal
cortex hypothalamus
Anterior

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hypothalamus

Hypothalamic-prefrontal X Posterior Prefrontal cortex

hypothalamus (wide spread)
Tuberal
hypothalamus
Anterior
hypothalamus

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Control of Anterior Pituitary

Several trophic factors (hypophysiotropins, hypothalamic releasing factors) are produced in the
hypothalamus and influence production of hormones in the anterior pituitary. Trophic factors are
released into capillaries of the median eminence, from which they reach the anterior pituitary
via the hypophyseal portal circulation. In the anterior lobe, trophic factors act on the
appropriate chromophil cell to release or inhibit the appropriate trophic hormone. The anterior
pituitary trophic hormones then act on the appropriate target gland. The serum hormone level of
the target gland has a feedback effect on hypothalamic trophic factors. The known hypothalamic
trophic factors include corticotropin-releasing factor (CRF), which influences production of ACTH
and beta-lipotropin (precursor of ACTH and of endorphins) by the pituitary basophils;
thyrotropin-releasing factor (TRF), which influences secretion of thyroid-stimulating hormone
(TSH) from the basophils; gonadotropin-releasing factor (GnRF), which influences production of
follicle-stimulating (FSH)- and luteinizing hormones (LH) from the basophils; growth hormone–
releasing factor (GHRF), which influences growth hormone (somatostatin, GH) secretion from
the acidophils; melanocyte-stimulating hormone–releasing factor (MSHRF), which influences
melanocyte-stimulating hormone (MSH) production; prolactin-inhibiting factor (PIF), which
inhibits production of prolactin from the acidophils; somatic inhibiting–releasing factor (SIRF),
also known as somatostatin (SS); growth hormone–inhibiting factor (GHIF) or somatotropin
release–inhibiting factor (SRIF), which inhibits release of GH and thyrotropin (TSH); and
melanocyte-stimulating hormone release-inhibiting factor (MIF), which inhibits the release of
MSH.

Secretion of GHRF and GHIF is stimulated by dopamine, norepinephrine, and serotonin. The PIF
is dopamine.

Autonomic Regulation
The hypothalamus is known to control brain stem and spinal cord autonomic centers.
Stimulation or ablation of the hypothalamus
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influences cardiovascular, respiratory, and gastrointestinal functions. Autonomic influences are
mediated via the dorsal longitudinal fasciculus (of Schütz) and the mamillotegmental tract.
Although definite delineation within the hypothalamus of sympathetic and parasympathetic
centers is not feasible, it is generally held that the rostral and medial hypothalamus is
concerned with parasympathetic control, whereas the caudal and lateral hypothalamus is
concerned with sympathetic control mechanisms.

Stimulation of the rostral and medial hypothalamus (preoptic and supraoptic areas) results in
parasympathetic activation, characterized by a slowing of heart rate, decrease in blood
pressure, vasodilatation, pupillary constriction, increased sweating, and in creased motility and
secretions of the alimentary tract. In contrast, stimulation of the posterior and lateral
hypothalamus (particularly the posterior) results in sympathetic activation, characterized by an
increase in heart rate and blood pressure, vasoconstriction, pupillary dilatation, piloerection,
decreased motility and secretion of the alimentary tract, bladder inhibition, and heightened
somatic reactions of shivering and running.

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Temperature Regulation
Some regions of the hypothalamus contain thermal receptors that are sensitive to changes in
the temperature of blood perfusing these regions. Anterior regions of the hypothalamus are
sensitive to a rise in blood temperature and trigger mechanisms for heat dissipation, which
include sweating and cutaneous vascular dilatation in humans. Bilateral damage to this region,
through surgery or by tumors or vascular lesions, results in elevation of body temperature
(hyperthermia). In contrast, the posterior hypothalamic region is sensitive to the lowering of
blood temperature and triggers the mechanisms for heat conservation, which include cessation
of sweating, shivering, and vascular constriction. Bilateral damage to this region results in
poikilothermia, in which body temperature fluctuates with environmental temperature.

Emotional Behavior
The hypothalamus is a major component of the central autonomic nervous system and as such
plays a role in emotional behavior. Lesions of the ventromedial hypothalamic nuclei in animals
are associated with a rage reaction, characterized by hissing, snarling, biting, piloerection,
arching of the back, and pupillary dilatation. In contrast, stimulation of lateral regions of the
anterior hypothalamus elicits a flight response. Stimulation of some hypothalamic regions elicits
a pleasurable response. Stimulation of other regions produces unpleasant responses. The role of
the hypothalamus in behavior and emotion is intimately related to that of the limbic system. The
connection between limbic prefrontal cortex and posterior hypothalamus is an important link for
autonomic response to emotion.

Feeding Behavior
As detailed earlier, bilateral lesions in the ventromedial nucleus elicit hyperphagia (excessive
feeding), whereas similar lesions in the lateral hypothalamic nucleus produce loss of hunger,
suggesting the presence of a satiety center and feeding center, respectively, in these regions.
The lateral hypothalamus has recently been found to contain orexin/hypocretin peptide
containing neurons. Central administration of orexin/hypocretin stimulates food intake.
Orexin/hypocretin neurons in the lateral hypothalamus inhibit anorexinergic and excite
orexinergic neurons in the arcuate nucleus of the hypothalamus. Orexin/hypocretin neu-rons
also project to ventromedial and paraventricular nuclei of the hypothalamus, structures known
to integrate feeding.

Drinking and Thirst

In addition to the control of body water by ADH, stimulation of the lateral and anterior regions
of the hypothalamus elicits drinking behavior that persists despite overhydration. Lesions of the
same area abolish thirst.

Sleep and Wakefulness

The hypothalamus is believed to play a role in the daily sleep-wakefulness cycle. A sleep center
is proposed to be in the anterior part of the hypothalamus and a waking center in the posterior
part. The orexin/hypocretin system in the lateral hypothalamus is the major excitatory
neuromodulatory system that controls activities of monoaminergic (dopamine, norepinephrine,
serotonin, histamine) and cholinergic systems that control vigilance states. Lesions in the
orexin/hypocretin system are associated with a state of irresistible sleep (narcolepsy).

Circadian Rhythm
Through the connections of the suprachiasmatic nucleus with the retina and brain regions
related to circadian rhythm, the hypothalamus plays an important role as an internal clock
regulating cyclic variations of a number of bodily functions such as temperature cycle, sleep-
wake cycle, and hormonal cyclic variations. The suprachiasmatic nucleus serves the function of
an endogenous pacemaker. It regulates secretion of melatonin by the pineal gland. Disruption of
release of melatonin is partially responsible for the phenomenon of jet lag.

Memory
Through its connections with the hippocampal formation and anterior thalamic nucleus, the
mamillary body of the hypothalamus plays a role in memory.

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Sexual Arousal
Several brain areas have been shown by fMRI to be associated with sexual arousal in humans.
These include the anterior cingulate, medial prefrontal, orbitofrontal, insular and
occipitotemporal cortices, as well as the amygdala, ventral striatum, thalamus, and
hypothalamus. All of these areas have reciprocal connections with the hypothalamus. fMRI
activation during sexual arousal is similar in all areas except the preoptic region of the
hypothalamus where activation is significantly greater in males. This gender difference in
activation of the hypothalamus has been correlated with the greater sexual arousal generally
experienced by men in response to erotic stimuli, and with the larger volume of the medial
preoptic nucleus (the sexually dimorphic nucleus) in young males compared to young females.
Lesions in the medial preoptic area have deleterious effect on copulation in males, while
electrical stimulation of this area has facilitatory effect on this biological function.

BLOOD SUPPLY
The preoptic and supraoptic regions, as well as the rostral part of the lateral
hypothalamus, are supplied by perforating branches from the anterior communicating
P.275
and anterior cerebral (A-1 segment) arteries. The tuberal and mamillary regions, as well as the
middle and posterior parts of the lateral hypothalamus, are supplied by perforating branches
from the posterior communicating and posterior cerebral (P-1 segment) arteries.

TERMINOLOGY
WArcuate (Latin arcuatus, “bow-shaped”).
The arcuate nucleus of the hypothalamus has an arcuate shape in coronal sections.

Diabetes insipidus (Greek diabetes, “a syphon”).

A condition of excessive production of urine from deficiency of the antidiuretic hormone. The
condition was distinguished from diabetes mellitus by Thomas Willis, the English physician in
1674. The relation of the condition to lesions in the neurohypophysis is attributed to the
German physiologist Alfred Frank.

Diabetes mellitus (Greek diabetes, “a syphon” Latin mellitus, “honey sweet”).

A disorder of carbohydrate metabolism with high levels of glucose in blood and urine. Thomas
Willis in 1674 differentiated sweet urine (diabetes mellitus) from clear, insipid urine (diabetes
insipidus).

Fornix (Latin “arch”).

The fornix is an archlike cerebral structure that connects the hippocampal formation with the
mamillary body. The fornix was noted by Galen and described by Andreas Vesalius, the
sixteenth-century Belgian anatomist. Thomas Willis introduced the name fornix cerebri.

Hypocretin.
A hypothalamic neuropeptide discovered in 1998. Like orexin, it increases food intake. The
name hypocretin derives from its hypothalamic origin and its similarity to the gut hormone
secretin.

Hypophysis (Greek hypo, “under” phyein, “to grow”).

Anything growing under or beneath. The hypophysis (pituitary gland) is under the brain.

Infundibulum (Latin “funnel”).

Andreas Vesalius, the Belgian anatomist, used this term to describe the attachment of the
pituitary gland to the brain.

Orexin (Greek, orexis “appetite”).

A hypothalamic neuropeptide discovered in 1998. Central administration of orexin potently
increases food intake.

Pituitary (Latin pituita, “phlegm or mucus”).

Pituitary gland. Jacob Berengarius, the Italian anatomist and surgeon, noted the presence of the
pituitary gland in 1524. Andreas Vesalius, the Belgian anatomist, called it “glandula pituitam
cerebri excipiens” and thought that the gland secreted mucus into the nose, an opinion held

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until the seventeenth century.

Poikilothermia (Greek poikilos, “varied” therme, “heat”).

Variation of body temperature with environmental temperature.

Polydipsia (Greek polys, “many”; dipsa, “thirst”).

Chronic excessive thirst as in diabetes insipidus and mellitus.

Polyuria (Greek polys, “many” ouron, “urine”).

The passage of a very large volume of urine, characteristic of diabetes.

Satiety (Latin satis, “sufficient” ety, “state or condition of”).

Sufficiency or satisfaction or gratification of thirst or appetite.

Vicq d'Azyr, Felix (1748–1794).

French anatomist and physician to Queen Marie Antoinette who described the mamillothalamic
tract (tract of Vicq d'Azyr) in 1781, although his observation was not published until 1805.

SUGGESTED READINGS
Braak H, Braak E: The hypothalamus of the human adult: Chiasmatic region. Anat Embryol
1987; 175:315–330.

Dietrichs E et al: Hypothalamocerebellar and cerebellohypothalamic projection circuits for

regulating nonsomatic cerebellar activity? Histol Histopathol 1994; 9:603–614.

Hatton GL: Emerging concepts of structure-function dynamics in adult brain: The

hypothalamo-neurohypophyseal system. Prog Neurobiol 1990; 34:337–504.

Holstege G: Some anatomical observations on the projections from the hypothalamus to

brain stem and spinal cord: An HRP and autoradiographic tracing study in the cat. J Comp
Neurol 1987; 260:98–126.

Hungs M, Mignot E: Hypocretin/orexin, sleep and narcolepsy. Bioessays 2001; 23:397–408.

Karama S et al: Areas of brain activation in males and females during viewing of erotic film
excerpts. Hum Brain Mapping 2002; 16:1–13.

Kordon C: Neural mechanisms involved in pituitary control. Neurochem Int 1985; 7:917–
925.

Meister B, Hakansson ML: Leptin receptors in hypothalamus and circumventricular organ.

Clin Expt Pharmac Physiol 2001; 28:610–617.

Nauta WJH, Haymaker W: Hypothalamic nuclei and fiber connections. In Haymaker W et al

(eds): The Hypothalamus. Springfield, IL, Charles C Thomas, 1969:136.

Nishino S: The hypocretin/orexin system in health and disease. Biol Psychiatry 2003; 54:87–
95.

Pickard GE, Silverman AJ: Direct retinal projections to the hypothalamus, piriform cortex,
and accessory optic nuclei in the golden hamster as demonstrated by a sensitive
anterograde horseradish peroxidase technique. J Comp Neurol 1981; 196:155–172.

Rafols JA et al: A Golgi study of the monkey paraventricular nucleus: Neuronal types,
afferent and efferent fibers. J Comp Neurol 1987; 257:595–613.

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Remple-Clower NL, Barbas H: Topographic organization of connections between the

hypothalamus and prefrontal cortex in the rhesus monkey. J Comp Neurol 1998; 398:393–
419.

Saper CB et al: Direct hypothalamo-autonomic connections. Brain Res 1976: 117:305–312.

Swaab DF et al: Structural and functional sex differences in the human hypothalamus. Horm
Behav 2001; 40:93–98.

Swanson LW: The neuroanatomy revolution of the 1970s and the hypothalamus. Brain Res
Bull 1999; 50:397.

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Editors: Afifi, Adel K.; Bergman, Ronald A.

Title: Functional Neuroanatomy: Text and Atlas, 2nd Edition

Copyright ©2005 McGraw-Hill

> Table of Contents > Part I - Text > 20 - Hypothalamus: Clinical Correlates

20
Hypothalamus: Clinical Correlates

Disorders of Water Balance

Diabetes Insipidus
Syndrome of Inappropriate Secretion of Adh (Siadh)
Disorders of Thermoregulation
Hypothermia
Hyperthermia
Poikilothermia
Disorders of Caloric Balance
Diencephalic Syndrome of Infancy (Russell Syndrome,
Batten-Russell-Collier Disease)
Fröhlich Syndrome (Babinski-Fröhlich Syndrome,
Dystrophia-Adiposogenitalis)
Disorders of Emotional Behavior
Disorders of Sleep
Kleine-Levin Syndrome
Disorders of Memory

KEY CONCEPTS

A number of clinical signs and symptoms have been

associated with lesions of the hypothalamus. They are related
to disorders of water balance, temperature regulation, caloric
balance, alertness and sleep, memory, and emotional
behavior.

Two syndromes are related to disorders of water balance:

diabetes insipidus and the syndrome of inappropriate
antidiuretic hormone (ADH) secretion (SIADH). The lesion in
the former is in the supraoptic and paraventricular nuclei or

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the supraopticohypophyseal tract. The lesion in SIADH

involves hypothalamic osmoreceptors in the re-gion of the
supraoptic and paraventricular nuclei.

Disturbances in hypothalamic thermoregulation may result

in hypothermia, hyperthermia, or poikilothermia related to
pathology in different regions of the hypothalamus. In
general, chronic hypothermia and poikilothermia are related
to posterior hypothalamic pathology, whereas sustained
hyperthermia is related to pathology in the anterior
hypothalamus.

Disturbances in hypothalamic caloric balance are

associated with two syndromes: emaciation (diencephalic
syndrome) and obesity (Fröhlich syndrome). The former is
related to pathology in the anterior hypothalamus or its
connections; the latter is related to pathology in the
ventromedial nucleus.

Disturbances in sleep are associated with

hypersomnolence (posterior hypothalamus), insomnia
(anterior hypothalamus), and the Kleine-Levin syndrome.

Disturbances in episodic memory are associated with

lesions in the mamillary body or fornix.

P.277
A large number of clinical signs and symptoms have been reported
in association with hypothalamic dysfunction. They include
disturbances in (1) water balance, (2) thermoregulation, (3) caloric
balance, (4) emotional behavior, (5) sleep, and (6) memory.

DISORDERS OF WATER BALANCE

Diabetes Insipidus
Diabetes insipidus results from lesions that destroy the majority of
neurons of the supraoptic and paraventricular nuclei (sites of ADH
secretion) or that interrupt the supraoptic-neurohypophyseal tract.
Affected patients pass large volumes of dilute urine (polyuria). Because
the thirst mechanism is intact, patients drink large amounts of fluid
(polydipsia). Such patients drink over 10 liters of water per day and
excrete a similar amount of urine. In contrast to diabetes mellitus,
values for glucose in blood and urine are normal in diabetes insipidus.
The two types of diabetes were differentiated by Thomas Willis in 1674.

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The relation of diabetes insipidus to the neurohypophysis was

recognized by the German physiologist Alfred Frank. Diabetes insipidus
can be caused by a variety of disease processes, including
hypothalamic tumors, trauma, storage diseases, and infection. A
familial variety of diabetes insipidus may be due to a defect in the
neurophysin gene precluding normal production of ADH. Treatment of
diabetes insipidus consists of intranasal administration of a long-acting
vasopressin analogue, desmopressin acetate (des-amino-D-arginine
vasopressin, DDAVP).

Syndrome of Inappropriate Secretion of ADH

(SIADH)
This syndrome is due to lesions in the region of the supraoptic and
paraventricular nuclei that impair hypothalamic osmoreceptors and that
result in elevated ADH release. The syndrome is characterized by (1)
hyponatremia, (2) low serum osmolarity, (3) normal renal excretion of
sodium, (4) elevated urine osmolarity, and (5) absence of volume
depletion.

DISORDERS OF THERMOREGULATION

Hypothermia
Hypothermia of hypothalamic origin may be chronic or periodic
(episodic). Chronic hypothermia is associated with posterior
hypothalamic injury from trauma, tumor, infection, or metabolic or
vascular disease. Episodic hypothermia (Shapiro syndrome,
diencephalic epilepsy) is characterized by spontaneous episodic
hypothermia lasting minutes to days occurring at variable intervals
(daily or decades). The hypothermia is usually associated with
polydipsia, polyuria, hypona-tremia, and autonomic paroxysms
characterized by hypertension, tachycardia, and diaphoresis. The
condition may respond to antiepileptic drug therapy. The lesion in the
hypothalamus may involve the arcuate nucleus and the premamillary
area. Agenesis of the corpus callosum is often present.

Hyperthermia
Hyperthermia of hypothalamic origin may be sustained or episodic
(periodic). Sustained hyperthermia usually is associated with head
trauma or with surgery adjacent to the anterior hypothalamus. It
usually lasts 1 to 2 days but may last up to 2 weeks. Episodic
hyperthermia has been associated with lesions in the ventromedial
hypothalamus. A reverse Shapiro syndrome has been described,
characterized by periodic hyperthermia and agenesis of the corpus
callosum.

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Poikilothermia
Fluctuations in body temperature with changes in environmen-tal
temperature are associated with bilateral posterior hypothalamic
lesions.

DISORDERS OF CALORIC BALANCE

Diencephalic Syndrome of Infancy (Russell

Syndrome, Batten-Russell-Collier Disease)
This condition is characterized by progressive emaciation during
the first year of life despite a reasonable food intake. Despite
their emaciation, such children are characteristically happy and active.
Other associated clinical signs include poor temperature regulation,
vomiting, and nystagmus. Growth hormone may be normal or elevated.
The etiology of this syndrome is usually a slowly growing tumor of the
anterior hypothalamus. Other lesions interrupting projections from or
to the anterior hypothalamus can produce the syndrome. The syndrome
was best described by A. Russell in 1951.

Fröhlich Syndrome (Babinski-Fröhlich

Syndrome, Dystrophia-Adiposogenitalis)
Fröhlich syndrome is characterized by obesity, genital hypoplasia, and
stunted growth as a result of hypothalamic or pituitary lesion. Obesity
in this syndrome is attributed to damage to the ventromedial nucleus
of the hypothalamus (satiety center) and hypogonadism to the
involvement of the adjacent infundibulum. Although the syndrome is
attributed to a report by Fröhlich in 1901, the main features of the
syndrome had been described in 1900 by Babinski and in 1840 by the
German physician Berhard Mohr.

DISORDERS OF EMOTIONAL BEHAVIOR

Lesions in the ventromedial region of the hypothalamus have been
associated with rage, whereas lesions in the posterior hypothalamus
have been associated with fear and apathy. Stimulation of the lateral
regions of the anterior hypothalamus elicits a flight response.
Pleasurable as well as unpleasant responses have been elicited from
hypothalamic stimulation. The reciprocal connections between the
limbic prefrontal cortex and the hypothalamus are an important link for
autonomic response to emotion.

DISORDERS OF SLEEP
Sleep disturbances associated with hypothalamic lesions were
attributed previously to concomitant involvement of the ascending
reticular pathways. Accumulating evidence, however, points to the

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existence of a waking center in the posterior hypothalamus and a sleep

center in the anterior hypothalamus. Lesions of the posterior
hypothalamus provoke lethargy and hypersomnia, whereas lesions in
the anterior hypothalamus cause insomnia. The lateral hypothalamus
contains a major excitatory neuromodulatory system
(orexin/hypocretin) which controls activities of monoaminergic and
cholinergic systems that control vigilance. Lesions in the
orexin/hypocretin system are associated with a state of irresistible
sleep known as narcolepsy.

Table 20-1. Hypothalamic Disorder

Hypothalamic Hypothalamic Site of pathology

function disorders

Water balance Diabetes insipidus Supraoptic and

paraventricular
nuclei

Syndrome of Supraoptic and

inappropriate paraventricular
secretion of nuclei or
antidiuretic neighborhood
hormone

Thermoregulation Hypothermia

Chronic Posterior
hypothalamus

Episodic Arcuate nucleus,

premamillary
area

Hyperthermia

Sustained Anterior
hypothalamus

Episodic Ventromedial

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hypothalamus

Poikilothermia Posterior
hypothalamus

Caloric balance Diencephalic Anterior

syndrome of hypothalamus
infancy Ventromedial
Fröhlich syndrome nucleus,
infundibulum

Emotional Rage Ventromedial

behavior Fear, apathy nucleus
Posterior
hypothalamus

Sleep Hypersomnolence Posterior

Insomnia hypothalamus
Anterior
hypothalamus

Memory Loss of episodic Mamillary

memory bodies, fornix

P.278

Kleine-Levin Syndrome
Hypothalamic lesions have been associated with Kleine-Levin syndrome
which is characterized by episodic compulsive eating (bulimia),
hypersomnolence, and hypersexuality in adolescent males and, rarely,
in females. A similar syndrome occurs with lesions in the medial
thalamus. Each episode lasts days to weeks at intervals of 3 to 6
months between episodes. The episodes decrease in frequency with age
and usually disappear by the fourth decade. Some evidence indicates
that the dopaminergic tone of the hypothalamus is reduced during the
symptomatic phase of the syndrome. Although credit is given to the
German neuropsychiatrist Kleine and the American neurologist Levin
for describing the syndrome in 1925 and 1929, a similar syndrome of
episodic hypersomnolence and morbid hunger was described by
Antimoff in 1898.

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DISORDERS OF MEMORY
Hypothalamic lesions in the posterior hypothalamus involving the
mamillary bodies or the fornix are associated with inability to
establish (encode) new memories for personally experienced, context-
and time-specific events (episodic memory) such as the memory of
eating a specific dish at a specific restaurant. The connections of the
mamillary bodies with the hippocampus (via the fornix) and with the
anterior thalamic nucleus (via the mamillothalamic tract) make them
crucial to the process of acquisition of recent memory.

The different hypothalamic disorders discussed herein and

corresponding sites of hypothalamic pathology are summarized in Table
20-1.

TERMINOLOGY
Bulimia (Greek bous, “ox”; limos, “hunger”).
A disorder of eating occurring predominantly in adolescent females,
characterized by morbid hunger and binge eating that continue until
terminated by abdominal pain, vomiting, or sleep.

Diabetes insipidus (Greek diabetes, “a syphon”).

A condition of excessive production of urine from deficiency of the
antidiuretic hormone. The condition was distinguished from diabetes
mellitus by Thomas Willis, the English physician in 1674. The relation
of the condition to lesions in the neurohypophysis is attributed to the
German physiologist Alfred Frank.

Fröhlich syndrome.
A hypothalamic syndrome characterized by obesity, genital hypoplasia,
and stunted growth. Named after Alfred Fröhlich (1871–1953), the
Viennese neurologist and pharmacologist. Also known as Babinski-
Fröhlich syndrome.

Kleine-Levin syndrome.
A hypothalamic syndrome occurring in adolescent males and, less
frequently, in females, characterized by episodic hypersomnolence,
hypersexuality, and compulsive eating. The syndrome was described by
Willi Kleine, the German neuropsychiatrist, in 1925. Max Levin, the
American neurologist, reported another case in 1929 and summarized
the features of the syndrome in 1936.

Poikilothermia (Greek poikilos, “varied”; therme, “heat”).

Variation of body temperature with environmental temperature.

Polydipsia (Greek polys, “many”; dipsa, “thirst”).

Chronic excessive thirst as in diabetes insipidus and mellitus.

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Polyuria (Greek polys, “many”; ouron, “urine”).

The passage of a very large volume of urine, characteristic of diabetes.

Shapiro syndrome.
A hypothalamic syndrome characterized by recurrent hypothermia and
agenesis of the corpus callosum. Named after W.R. Shapiro, who
described the syndrome in 1969.

SUGGESTED READINGS
Arroyo HA et al: A syndrome of hyperhidrosis, hypothermia, and
bradycardia possibly due to central monoaminergic dysfunction.
Neurology 1990; 40:556–557.

Bartter FC, Schwartz WB: The syndrome of inappropriate secretion

of antidiuretic hormone. Am J Med 1967; 42:790–806.

Bauer HG: Endocrine and other clinical manifestations of

hypothalamic disease. J Clin Endocrinol Metab 1954; 14:13–31.

Burr IM et al: Diencephalic syndrome revisited. J Pediatr 1976;

88:439–444.

Chesson AL et al: Neuroendocrine evaluation in Kleine-Levin

syndrome: Evidence of reduced dopaminergic tone during periods
of hypersomnolence. Sleep 1991; 14:226–232.

P.279

Culebras A: Neuroanatomic and neurologic correlates of sleep

disturbances. Neurology 1992; 42(suppl 6):19–27.

Gaffan EA et al: Amnesia following damage to the left fornix and to

other sites. Brain 1991; 114:1297–1313.

Gamstorp I et al: Diencephalic syndrome of infancy. J Pediatr

1967; 70:383–390.

Gillberg C: Kleine-Levin syndrome: Unrecognized diagnosis in

adolescent psychiatry. J Am Acad Child Adolesc Psychiatry 1987;
26:793–794.

Harris AS: Clinical experience with desmopressin: Efficacy and

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safety in central diabetes insipidus and other conditions. J Pediatr

1989; 114:711–718.

Hirayama K et al: Reverse Shapiro's syndrome. A case of agenesis

of corpus callosum associated with periodic hyperthermia. Arch
Neurol 1994; 51:494–496.

LeWitt PA et al: Episodic hyperhidrosis, hypothermia, and agenesis

of the corpus callosum. Neurology 1983; 33:1122–1129.

Maghnie M et al: Correlation between magnetic resonance imaging

of posterior pituitary and neurohypophyseal function in children
with diabetes insipidus. J Clin Endocrinol Metab 1992; 74:795–800.

Perry RJ, Hodges JR: Spectrum of memory dysfunction in

degenerative disease. Curr Opin Neurol 1996; 9:281–285.

Reeves AG, Plum F: Hyperphagia, rage, and dementia

accompanying a ventromedial hypothalamic neoplasm. Arch Neurol
1969; 20:616–624.

Russell A: A diencephalic syndrome of emaciation in infancy and

childhood. Arch Dis Child 1951; 26:274.

Shapiro WR et al: Spontaneous recurrent hypothermia

accompanying agenesis of the corpus callosum. Brain 1969;
92:423–436.

Shapiro WR et al: Spontaneous recurrent hypothermia

accompanying agenesis of the corpus callosumk Brain
1969;92:423–436.

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Editors: Afifi, Adel K.; Bergman, Ronald A.

Title: Functional Neuroanatomy: Text and Atlas, 2nd Edition

Copyright ©2005 McGraw-Hill

> Table of Contents > Part I - Text > 21 - Limbic System

21
Limbic System

Definition of Terms: Limbic Lobe, Limbic System, and

Rhinencephalon
Rhinencephalon (Smell Brain)
Olfactory Nerve Rootlets
Olfactory Bulb
Olfactory Tract
Olfactory Striae
Olfactory Cortex
Limbic Lobe
The Papez Circuit
Limbic System
Hippocampal Formation
Fornix
Entorhinal-Hippocampal Circuitry
Amygdala
Septal Area
Overview of the Limbic System

KEY CONCEPTS

The term limbic lobe refers to the structures that form a limbus (ring
or border) around the brain stem. These structures include the
subcallosal gyrus, cingulate gyrus, isthmus, parahippocampal gyrus, and
uncus.

The term limbic system refers to the limbic lobe and the structures
connected to it.

Limbic system structures play important roles in emotional behavior,

memory, homeostatic responses, sexual behavior, and motivation.

The term hippocampal formation refers to the hippocampus, dentate

gyrus, and subiculum.

The bulk of extrinsic input to the hippocampal formation comes from

the entorhinal area and the septal area.

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The major targets of the hippocampal formation's output are the

entorhinal cortex, the hypothalamus, and the septal area.

The entorhinal area is reciprocally connected with the hippocampus

and serves as a gateway between the cerebral cortex and the
hippocampus.

The hippocampus plays a role in declarative or associative memory,

attention and alertness, and behavioral, endocrine, and visceral
functions.

Output from the amygdala is carried in two pathways: the stria

terminalis (dorsal amygdalofugal pathway) and the ventral
amygdalofugal pathway (ventrofugal bundle).

The amygdala plays an important role in a variety of functions,

including autonomic and orienting responses, emotional behavior, food
intake, arousal, sexual activity, and motor activity.

The term septal area refers to the septum pellucidum and the
septum verum. The septum pellucidum is a thin glial partition between
the lateral ventricles; the septum verum is a group of basal nuclei that
includes the septal nuclei.

Reciprocal connections with the hippocampus (via the fornix)

constitute the major connection of the septal area. Other connections
include those with the amygdala, hypothalamus, thalamus, brain stem,
and cingulate gyrus.

The septal area plays an important role in emotional behavior,

learning, reward, autonomic responses, drinking and feeding, and sexual
behavior.

The limbic system plays a major role in integrating exteroceptive

and interoceptive information by serving as a link between cortical
sensory association areas, the subcortical autonomic and endocrine
centers, and the prefrontal association cortex. It thus mediates the
effects of emotion on motor function.

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DEFINITION OF TERMS: LIMBIC LOBE, LIMBIC

SYSTEM, AND RHINENCEPHALON
The concept of the limbic system is derived from the limbic lobe. The term le
grande lobe limbique (limbic lobe), coined by the French anthropologist,
anatomist, and surgeon Pierre-Paul Broca in 1878, refers to a number of
structures on the medial and basal surfaces of the hemisphere that form a limbus
(border or ring) around the brain stem. Broca was possibly unaware that Thomas
Willis (of Circle of Willis fame) had designated the cortical border encircling the
brain stem as the cerebri limbus in 1664, 200 years earlier. The limbic lobe and
all the structures connected to it constitute the limbic system, which plays a

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major role in visceral function, emotional behavior, and memory.

Because of the large size of the limbic lobe in phylogenetically lower animals,
Broca postulated that it might have an olfactory function; hence, the terms limbic
lobe and smell brain (rhinencephalon) were used synonymously. In humans, the
limbic lobe has very little if any primary olfactory function. The rhinencephalon,
by contrast, is primarily concerned with olfaction but has some reciprocal
relationships with parts of other limbic system regions.

RHINENCEPHALON (SMELL BRAIN)

The rhinencephalon (Figures 21-1 and 21-2) consists of the following structures:

1. Olfactory nerve rootlets

2. Olfactory bulb

3. Olfactory tract

4. Olfactory striae

5. Primary olfactory cortex

Olfactory Nerve Rootlets

The olfactory nerve is composed of unmyelinated thin processes (rootlets) of the
olfactory hair cells (receptors) in the nasal mucosa. Fascicles of the olfactory
nerve pierce the cribriform plate of the ethmoid bone, enter the cranial cavity,
and terminate on neurons in the olfactory bulb.

Olfactory Bulb
The olfactory bulb is the main relay station in the olfactory pathways.

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Figure 21-1. Ventral view of the brain showing components of the

rhinencephalon.

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Figure 21-2. Schematic diagram of olfactory pathways.

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A. LAMINATION AND CELL TYPES

In histologic sections (Figure 21-3), the olfactory bulb appears to be laminated
into the following layers:

1. The olfactory nerve layer is composed of incoming olfactory nerve fibers.

2. In the glomerular layer synaptic formations occur between the olfactory

nerve axons and the dendrites of olfactory bulb neurons (mitral and tufted
neurons).

3. The external plexiform layer consists of tufted neurons, some granule cells,
and a few mitral cells with their processes.

4. The mitral cell layer is composed of large neurons (mitral neurons).

5. The granule layer is composed of small granule neurons and processes of

granule and mitral cells; it also contains incoming fibers from other cortical
regions.

The mitral cells and tufted cells are the principal neurons of the olfactory bulb.
Their dendrites establish synaptic relation-ships with olfactory nerve fibers within

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the glomeruli.

The granule cells are the intrinsic neurons of the olfactory bulb. These cells have
vertically oriented dendrites but no axon and exert their action on other cells
solely by means of dendrites. Another type of intrinsic neuron, the short axon
neuron, is found in the glomerular layer (periglomerular short axon neu-ron) and
the granular layer.

The olfactory bulb receives fibers (input) from the following sources:

1. Olfactory hair cells in the nasal mucosa

2. Contralateral olfactory bulb

3. Primary olfactory cortex

4. Diagonal band of Broca

5. Anterior olfactory nucleus

The output from the olfactory bulb is composed of axons of mitral cells and tufted
cells (principal neurons), which project to the following areas:

1. Contralateral olfactory bulb

2. Subcallosal gyrus

3. Anterior perforated substance

4. Primary olfactory cortex

5. Anterior entorhinal cortex

Olfactory Tract
The olfactory tract is the outflow pathway of the olfactory bulb. It is composed of
the axons of principal neurons (mitral and tufted cells) of the olfactory bulb and
centrifugal axons originating from central brain regions. The olfactory tract also
contains the scattered neurons of the anterior olfactory nucleus, the axons of
which travel in the olfactory tract, cross in the anterior commissure, and project
on the contralateral anterior olfactory nucleus and the olfactory bulb. At its
caudal extremity, just anterior to the anterior perforated substance, the olfactory
tract divides into the olfactory striae.

Olfactory Striae
At its caudal extremity, just rostral to the anterior perforated substance, the
olfactory tract divides into three striae:

1. Lateral olfactory stria

2. Medial olfactory stria

3. Intermediate olfactory stria.

Each stria is covered by a thin layer of gray matter known as an olfactory gyrus.

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Figure 21-3. Schematic diagram of olfactory bulb showing laminae and

types of cells.

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The lateral olfactory stria projects to the primary olfactory cortex in the temporal
lobe. The medial olfactory stria projects on the medial olfactory area, which also
is known as the septal area, on the medial surface of the frontal lobe, ventral to
the genu and rostrum of the corpus callosum and anterior to the lamina
terminalis. The medial olfactory area is closely related to the limbic system and
thus is concerned with emotional responses elicited by olfactory stimuli. It does
not play a role in the perception of olfactory stimuli. The medial and intermediate
striae are poorly developed in humans. The intermediate stria blends with the
anterior perforated substance. The thin cortex at this site is designated the
intermediate olfactory area. The three areas of olfactory cortex are
interconnected by the diagonal band of Broca, a bundle of subcortical fibers in
front of the optic tract.

Olfactory Cortex
The olfactory cortex is located within the temporal lobe and is composed of the
pyriform cortex, the periamygdaloid area, and part of the entorhinal area. The
pyriform cortex is the region on each side of and beneath the lateral olfactory
stria; hence, it is also called the lateral olfactory gyrus. The periamygdaloid area
is dorsal and rostral to the amygdaloid nuclear complex. The pyriform cortex and
the periamygdaloid area constitute the primary olfactory cortex. The entorhinal
area, which is situated in the rostral part of the parahippocampal gyrus,
corresponds to Brodmann's area 28. It constitutes the secondary olfactory cortex.
The olfactory cortex is relatively large in some animals, such as the rabbit, but in
humans it occupies a small area. The primary olfactory cortex in humans is
concerned with the conscious perception of olfactory stimuli. In contrast to all

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other primary sensory cortices (vision, audition, taste, and somatic sensibility),
the primary olfactory cortex is unique in that afferent fibers from the receptors
reach it directly without passing through a relay in the thalamus.

The primary olfactory cortex contains two types of neurons: (1) principal neurons
(pyramidal cells) with axons which leave the olfactory cortex and project to
nearby or distant regions and (2) intrinsic neurons (stellate cells) with axons
which remain within the olfactory cortex.

The major input to the primary olfactory cortex is from (1) the olfactory bulb via
the lateral olfactory stria and (2) other central brain regions.

The output from the primary olfactory cortex is via axons of principal neurons
which project to (1) the secondary olfactory cortex in the entorhinal area, (2) the
amygdaloid nucleus, and (3) the dorsomedial nucleus of the thalamus.

The output of the secondary olfactory cortex, the entorhinal area, is to the (1)
hippocampal formation and (2) the anterior insular and frontal cortices.

The connections of the olfactory cortex with the thalamus, the amygdaloid
nucleus, the hippocampal formation, and the insular and frontal cortices provide
the anatomic basis for a role of olfaction in emotional behavior, visceral function,
and memory.

Quantitative studies of the primary olfactory cortex have revealed that (1) there
is a predominance of principal neurons (compared with the intrinsic variety) and
(2) the number of principal neurons far exceeds the number of fibers in the
lateral olfactory stria. Thus, in contrast to the olfactory bulb, in which there is a
high convergence ratio, the ratio of input to output in the primary olfactory
cortex is low. This is similar to the pattern in the neocortex and the climbing
fiber system of the cerebellar cortex.

LIMBIC LOBE
As described by Broca in 1878, the limbic lobe refers to the gray matter in
the medial and basal parts of the hemisphere that forms a limbus (border)
around the brain stem. The limbic lobe is a synthetic lobe whose component parts
are derived from different lobes of the brain (frontal, parietal, temporal). There
is no general agreement on all the parts that enter into the formation of the
limbic lobe. The following, however, are generally accepted as limbic lobe
components (Figure 21-4):

1. Subcallosal gyrus, inferior to the genu and rostrum of the corpus callosum,
just anterior to the lamina terminalis

2. Cingulate gyrus

3. Isthmus of the cingulate gyrus, posterior and inferior to the splenium of the
corpus callosum

4. Parahippocampal gyrus (and the underlying hippocampal formation and

dentate gyrus)

5. Uncus

The limbic lobe is formed of archicortex (hippocampal formation and dentate

gyrus), paleocortex (rostral parahippocampal gyrus and uncus), and

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juxtallocortex or mesocortex (cingulate gyrus).

Originally, the limbic lobe was assigned a purely olfactory function. It has been
established that only a minor part of the limbic lobe has an olfactory function.
The rest of the limbic lobe, which forms part of the limbic system, plays a role in
emotional behavior and memory.

THE PAPEZ CIRCUIT

In 1937, James Papez, an American neuroanatomist, described a closed circuit of
connections starting and ending in the hippocampus that later became known as
the Papez circuit. It was suggested that the structures connected by this circuit
play a role in emotional reactions. The circuit consisted of outflow of impulses
from the hippocampus via the fornix to the mamillary bodies of the
hypothalamus; from there, via the mamillotha-la-mic tract, to the anterior
thalamic nucleus; and, via the thalamocortical fiber system, to the cingulate
gyrus, from which impulses returned to the hippocampus via the entorhinal area.
The circuit which has been modified since its introduction, provided the basis for
the concept of the limbic system introduced by McLean in 1952.

LIMBIC SYSTEM
The limbic system is defined as the limbic lobe and all the cortical and
subcortical structures related to it. These include the following structures:

1. Septal nuclei

2. Amygdala

3. Hypothalamus (particularly the mamillary body)

4. Thalamus (particularly the anterior and medial tha-lamic nuclei)

5. Brain stem reticular formation

6. Epithalamus

7. Neocortical areas in the basal frontotemporal region

8. Olfactory cortex

9. Ventral parts of the striatum

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Figure 21-4. Midsagittal view of brain showing components of the limbic

lobe.

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This conglomerate of neural structures, which constitute the old part of the
brain and are highly interconnected, seems to play a role in the following
processes:

1. Emotional behavior

2. Memory

3. Integration of homeostatic responses such as those related to preservation

of the species, securing food, and the fight or flight response.

4. Sexual behavior

5. Motivation

The underlying mechanisms for these different functions are very complex and
are inadequately understood. Furthermore, it has become difficult to define the
extent of the limbic system with precision and to attribute common connections
and functions to its individual components. Some researchers have advocated the
theory that the limbic system is not useful as a scientific or clinical concept.

The presentation of the limbic system in this chapter focuses on the following
components: hippocampal formation, amygdala, and septal area. These are the
regions that are most closely related to the limbic lobe.

HIPPOCAMPAL FORMATION
The hippocampal formation (Figures 21-5 and 21-6) is an infolding of the

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parahippocampal gyrus into the inferior (temporal) horn of the lateral ventricle
and consists of three regions: hippocampus dentate gyrus (fascia dentata), and
subiculum. The dentate gyrus occupies the interval between the hippocampus and
subiculum part of the parahippocampal gyrus. The dentate gyrus and subiculum
are separated by the hippocampal sulcus (Fig. 21-7). The name dentate gyrus is
derived from its toothed or beaded surface. The subiculum is the part of the
parahippocampal gyrus that is in direct continuity with the hippocampus.

Of the three components of the hippocampal formation, the hippocampus is the

largest and the best studied in humans. Therefore, it is presented in this chapter
as the prototype of this segment of the limbic system.

Hippocampus
The hippocampus appears as a C-shaped structure in coronal sections, bulging
into the inferior horn of the lateral ventricle. The hippocampus is closely
associated with the adjacent dentate gyrus (Figures 21–5 to 21–7), and together
they form an S––shaped structure.

A. HIPPOCAMPAL TERMINOLOGY
In the late 1500s, the anato-mist Arantius exposed a convoluted structure in the
floor of the temporal horn of the lateral ventricle. He called this structure the
hippocampus because of its resemblance to a sea horse. A century later the term
pes hippocampus was used to describe the same structure, and two centuries
later anatomists likened the structure to a ram's horn or the horns of the ancient
Egyptian deity Ammon, who had a ram's head, hence the name Ammon's horn or
cornu Ammonis. Terminology
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over the years became abundant and often confusing. Table 21-1 lists the
preferred terminology and synonyms used for hippocampal structures.

Figure 21-5. Coronal section of the brain showing the hippocampus and
dentate gyrus (components of the hippocampal formation), the alveus, and

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fimbria. Adjacent to the hippocampal formation are the subiculum and

entorhinal cortex (components of the parahippocampal gyrus).

B. LAMINATION AND DIVISIONS

Although Ramón y Cajal described seven laminae in the hippocampus, it is
customary to combine the different laminae into three major layers (Figure 21-
7): the molecular layer, the pyramidal cell layer, and the stratum oriens
(polymorphic layer).

The pyramidal cell layer is divided into a zone in which the pyramidal cells are
compact and a zone (rostral to the compact zone) in which the pyramidal cells
are less compact. The boundary between the compact and less compact zones of
the pyramidal layer separates the two divisions of the hippocampus (Figure 21-7)
into the superior division (compact zone) and the inferior division (less compact
zone).

Figure 21-6. Schematic diagram showing the components of the

hippocampal formation.

The hippocampus has been subdivided further into fields (Figure 21-7) designated
as cornu Ammonis 1, 2, 3, and 4 (CA 1 through CA 4 ). CA 1 , the largest hippocampal
field in humans, is located in the superior division at the interface between the
hippocampus and the subiculum. CA 2 and CA 3 are in the inferior division within
the hippocampus. CA 4 constitutes the transition zone between the hippocampus
and the dentate gyrus. Field CA 1 (also known as Sommer's sector and the
vulnerable sector) is of interest to neuropathologists because its pyramidal
neurons are highly sensitive to anoxia and ischemia and because it is the trigger
zone for some forms of temporal lobe epilepsy. CA 2 and CA 3 have been referred
to as resistant sectors because they are less sensitive to anoxia. CA 4 (the Bratz
sector) is also called the medium vulnerability sector because of its medium
sensitivity to hypoxia.

C. NEURONAL POPULATION

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There are basically two types of neurons in the hippocampus: the principal
neurons (pyramidal cell) and the intrinsic neurons (polymorphic cell, basket cell)
(Figure 21-8).

1. Principal Neurons.
The pyramidal neurons in the pyramidal cell layer are the principal neurons of the
hippocampus. They are the only neurons with axons which contribute to the
outflow tract from the hippocampus. Pyramidal neurons vary in size and density
in different regions of the hippocampus. They are smaller and more densely
packed in the superior region than in
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the inferior region. The largest neurons in the inferior region are referred to as
the giant pyramidal cells of the hippocampus.

Figure 21-7. Schematic dia-gram showing layers of the hippocampus and

the division of the hippocampus into superior and inferior regions, and four
fields (CA 1 to CA 4 ).

Basal dendrites of pyramidal neurons are oriented toward the ventricular surface;
apical dendrites are oriented toward the molecular layer. Both types of dendrites
arborize extensively and are rich in dendritic spines.

Axons of pyramidal cells are directed toward the ventricular surface, where they
gather to form the alveus and fimbria and finally join the fornix as the outflow
tract from the hippocampus. Recurrent axon collaterals terminate within the
stratum oriens or reach the molecular layer. They exert a facilitatory influence.

Table 21-1. Terminology of Hippocampal Structures.

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Structure Preferred terminology Synonyms

Hippocampus Hippocampus Hippocampal

formation
Ram's horn
Ammon's horn
Cornu ammonis
Pes hippocampus
Pes hippocampus
major

Cornu ammonis Cornu ammonis Ammon's horn

Hippocampus proper
Hippocampus

Cornu ammonis 1 CA 1 Sommer's sector

Vulnerable sector

Cornu ammonis 2 CA 2

Cornu ammonis 3 CA 3 Resistent sector

Spielmeyer sector

Cornu ammonis 4 CA 4 Hilus of fascia

dentata
End folium
Bratz sector

Dentate gyrus Dentate gyrus Gyrus dentatus

Fascia dentata

Commissure of Hippocampal Psalterium

fornix commissure Lyre of David

It is estimated that the hippocampus of humans contains 1.2 million principal

neurons on each side, a figure close to the number of pyramidal tract fibers.

2. Intrinsic Neurons.
Intrinsic neurons have axons which remain within the hippocampus. Because of
the irregularity of their perikarya and dendrites, they are referred to as
polymorphic neurons. They are situated in the stratum oriens (Figure 21-8). Their
irregularly oriented dendrites arborize locally, while their axons ramify between
pyramidal neurons and arborize around the perikarya of pyramidal neurons in a
basket formation (hence the term basket cells). They are inhibitory (GABAergic)
to pyramidal cell activity. There are no estimates of the exact number of intrinsic

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neurons in the hippocampus. It has been estimated, however, that one basket
cell is related to about 200 to 500 pyramidal cells. Thus, it is believed that the
intrinsic neurons are much fewer in number than are the principal neurons.

Dentate Gyrus
Like the hippocampus, the dentate gyrus is a three-layered structure composed
of a molecular layer, a granular cell layer, and a polymorphic layer. The
molecular layer is continuous with that of the hippocampus. The granular layer is
made up of small, densely packed granular cells whose axons form the mossy
fiber system which links the dentate gyrus and the hippocampus. The cells in the
polymorphic layer are varied and include pyramidal and basket cells. Unlike the
hippocampus, the output of the dentate gyrus does not leave the hippocampal
formation.

Subiculum
Like the hippocampus and the dentate gyrus, the subiculum is composed of three
layers: a molecular layer, a pyramidal layer, and a polymorphic layer. The
polymorphic layer originates in the adjoining entorhinal cortex. Axons of
pyramidal neurons in the subiculum, like those in the hippocampus, contribute to
the output of the hippocampal formation.

Figure 21-8. Schematic diagram showing the major types of neurons in the
hippocampus and their interrelationships.

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Afferent Pathways
The bulk of extrinsic input to the hippocampal formation comes from the
entorhinal area (Brodmann's area 28) of the parahippocampal gyrus and, to
a lesser extent, the septal area (Figure 21-9). Other inputs include those from
the contralateral hippocampus, hypothalamus, amygdala, thalamus, locus
ceruleus, raphe nuclei, and ventral tegmental area of Tsai.

Fibers from the parahippocampal gyrus arise mainly from its rostral part, the

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entorhinal area (Brodmann's area 28). They constitute the major input to the
hippocampus, dentate gyrus, and subiculum, which they reach by two routes. The
main input, first described by Ramón y Cajal, travels through (perforates) the
adjacent subicular area en route to the hippocampus and dentate gyrus and is
therefore called the perforant path. A smaller input arrives in the hippocampus at
the ventricular surface, where the alveus (axons of hippocampal pyramidal
neurons) is formed, and is therefore called the alvear path. The entorhinal area
serves as an important gateway between the cerebral cortex and the
hippocampus. Information from many cortical areas (limbic, modality sensory-
specific, and multimodal association cortices) in the frontal, temporal, parietal,
and occipital lobes conveying visual, auditory, and somatosensory information
converges on the entorhinal cortex and the posterior parahippocampal gyrus. The
entorhinal cortex in turn conveys this cortical information to the hippocampus.
Reciprocally, hippocampal output originating in CA 1 and the subiculum is relayed
back to the entorhinal cortex. The entorhinal cortex is the most heavily damaged
in Alzheimer's disease and is the site of early onset of the disease.

Figure 21-9. Schematic diagram showing the major afferents to the

hippocampal formation.

Fibers from the septal nuclei reach the hippocampus via the fornix. Compared
with the input from the entorhinal area, the septal input is modest.

Axons of small pyramidal neurons (granule cells) in the dentate gyrus reach the
hippocampus via the mossy fiber pathway.

The two hippocampi are in communication via the hip-pocampal commissure

(commissure of the fornix). Interhippocampal communication in humans is
minimal, and the hippocampal commissure is thus rudimentary.

Fibers from the hypothalamus originate from cell groups in the vicinity of the
mamillary body and exert a strong inhibitory influence on the hippocampus.

Amygdalohippocampal connections travel in the adjacent temporal lobe white

matter and may form the anatomic basis for the effect of emotion on memory

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function.

Thalamic input to the hippocampus has been shown to originate in the anterior
thalamic nucleus.

Noradrenergic fibers from the locus ceruleus have been traced to the
hippocampus and the dentate gyrus.

Serotonergic fibers from the raphe nuclei and dopaminergic fibers from the
ventral tegmental area of Tsai in the midbrain also have been traced to the
hippocampus.

The noradrenergic, serotoninergic, and dopaminergic inputs exert a modulatory

effect on memory function in the hippocampus.

Efferent Pathways
The output from the hippocampal formation consists of axons of pyramidal
neurons in the hippocampus and subiculum (Figure 21-10). Axons of granule
neurons in the dentate gyrus have no extrinsic connections but terminate locally
as mossy fibers on hippocampal pyramidal neurons. Both the hippocampus and
the subiculum project on the entorhinal cortex. From there, impulses are
mediated to limbic, sensory-specific, and multimodal association cortical areas.
Another major output from the hippocampus is to the subiculum. Both the
hippocampus and the subiculum contribute fibers to the fornix, the output tract of
the hippocampal formation. Subiculum-originating fibers constitute the major
component of the fornix and are distributed, via its postcommissural division, to
the mamillary bodies of the hypothalamus and the anterior nucleus of the
thalamus. Hippocampal originating fibers in the fornix constitute its smaller
precommissural division and are distributed to the septal nuclei, the medial area
of the frontal cortex, the anterior and preoptic hypothalamic nuclei, and the
ventral striatum.

FORNIX (FIGURE 21-11)

The fornix is a fiber bundle that reciprocally connects the hippocampal formation
with a number of subcortical areas, including the thalamus, the hypothalamus,
and the septal region. It thus has both hippocampofugal and hippocampopetal
fibers. The hippocampofugal fibers are axons of pyramidal neurons in
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the subiculum and hippocampus which gather at the ventricular surface of the
hippocampus as the alveus. Fibers in the alveus converge farther on to form a
flattened ribbon of white matter, the fimbria. Traced posteriorly on the floor of
the inferior horn of the lateral ventricle, the fimbria, at the posterior limit of the
hippocampus, arches under the splenium of the corpus callosum to form the crus
of the fornix. The two crura converge to form the body of the fornix, which is
attached to the inferior surface of the septum pellucidum to the level of the
rostral thalamus. As the crura converge to form the body, a small number of
fibers cross to the other side (hippocampal commissure, fornical commissure,
lyra, psalterium). The hippocampal commissure is rudimentary in humans. Just
above the interventricular foramen of Monro, the body of the fornix splits to form
the two anterior columns of the fornix, which arch ventrally. Most of the fibers
(75 percent) in each anterior column descend caudal to the anterior commissure
to form the postcommissural fornix. The majority of fibers in this component of
the fornix terminate in the mamillary body, and the rest terminate in the anterior
nucleus of the thalamus and the midbrain tegmentum. A small component (25

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percent) of each anterior column descends rostral to the anterior commissure to

form the precommissural fornix. Fibers in this component of the fornix terminate
in the septal nuclei, medial frontal cortex, anterior hypothalamus, and ventral
striatum. Fibers in the postcommissural fornix originate in the subiculum,
whereas those in the precommissural fornix originate in both the hippocampus
and the subiculum.

Figure 21-10. Schematic diagram- showing the major efferents of the

hippocampus.

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Figure 21-11. Schematic diagram of the component parts of the fornix.

Each fornix contains 1.2 million axons of pyramidal neurons in humans.

ENTORHINAL-HIPPOCAMPAL CIRCUITRY (FIGURE

21-12)
Using a variety of neuroanatomic and neurophysiologic techniques, the
entorhinal-hippocampal-entorhinal circuit of connections has been defined.
The circuit starts in the entorhinal area, which projects via the perforant pathway
to granule cells in the dentate gyrus and pyramidal cells in the hippocampus.
Axons of granule cells in the dentate gyrus form the mossy fiber system, which
projects on pyramidal neurons in the CA 3 field of the hippocampus. The CA 3
pyramidal neurons send Schaffer collaterals to the pyramidal cells of the CA 1
hippocampal field. Axons of pyramidal neurons in CA 1 project on neurons in the
subiculum. The subiculum in turn projects back to the entorhinal area, thus
closing the circuit. The synapses in this circuit are all excitatory; the only
inhibitory synapses are those from hippocampal basket neurons in the stratum
oriens whose axons terminate on the perikarya of pyramidal neurons.

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Figure 21-12. Schematic diagram of the entorhinal-hippocampal circuit

showing the perforant pathway (1) from the entorhinal cortex to the dentate
gyrus, hippocampus, and subiculum; mossy fibers (2) connecting the dentate
gyrus with CA 3 neurons of the hippocampus; Schaffer collaterals (3) linking
CA 3 neurons with CA 1 neurons within the hippocampus; hippocampal-
subiculum pathway (4); and finally the circuit is closed by connections from
the subiculum back to the entorhinal cortex (5).

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FUNCTIONAL CONSIDERATIONS
In considering the functions of the hippocampus, it is important to emphasize the
complex relationships of the hippocampus with other brain regions, as was
outlined above. The effects of stimulation or ablation of the hippocampus cannot
be evaluated in isolation from the elaborate systems of hippocampal
communication.

The hippocampus is no longer believed to play a role in olfaction. The

hippocampus is very well developed in humans, who are microsmatic; it is also
present in the whale, which is anosmatic. No direct pathways from the primary
olfactory cortex can be traced to the hippocampus, although a multisynaptic
pathway through the primary olfactory cortex and the parahip-pocampal gyrus
(entorhinal area) exists. Olfactory bulb stimulation results in excitatory
postsynaptic potential (EPSP) activity but no ac-tion potential firing in the
hippocampus. This is consistent with a polysynaptic pathway from the olfactory
bulb to the hippocampus. It has been suggested that this subthreshold EPSP
activity may be comparable to a conditional stimulus that plays a role in memory
and learning.

Action potentials, in contrast, have been recorded in the hippocampus after

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stimulation of various areas, both centrally and peripherally. Hippocampal

responses have been elicited after visual, acoustic, gustatory, and somatosensory
stimulation as well as after stimulation of various cortical and subcortical areas.
Such responses are characteristically labile and are easily modified by a variety
of factors.

Stimulation and ablation of the hippocampus give rise to changes in behavioral,

endocrine, and visceral functions. The same effects may follow either ablation or
stimulation.

The hippocampus has been implicated in the processes of attention and alertness.
Stimulation of the hippocampus in ani-mals produces glancing and searching
movements that are associated with bewilderment and anxiety.

The important role of the hippocampus in memory was not apparent until the
late 1950s, when Scoville and Milner de-scribed memory loss following
bilateral anterior temporal lobectomies. Bilateral ablation of the hippocampus in
humans (usually involving adjacent regions as well) results in a loss of recent (60
s) memory and the inability to store newly learned facts (anterograde amnesia).
Remote or long-term memories, however, re-main intact. Unilateral ablation of
the hippocampus in humans does not affect memory to a significant degree.
Studies of humans with brain lesions indicate that the hippocampus is important
for declarative (explicit) memory, the memory of facts, words, and data that can
be brought to mind and consciously inspected. Declarative (associative) memory
includes episodic, semantic, and familiarity-based recognition, with the additional
suggestion that the hippocampus plays a time-limited role (being needed only for
recently acquired information). Episodic memory (recall of past events with a
sense of personal familiarity) is usually more severely disrupted in hippocampal
lesions than semantic memory (memory for general declarative information such
as for vocabulary or arithmetic facts). Similar to hemispheric specialization, the
left hippocampus is specialized for verbal memory and the right hippocampus for
nonverbal memory.

The hippocampus has a low threshold for seizure (epileptic) activity; however,
the spread of such epileptic activity to the nonspecific thalamic system, and
hence all over the cortex, is not usual. This may explain why temporal lobe
epilepsy (psychomotor epilepsy) in humans does not become generalized.

AMYGDALA (FIGURE 21-13)

The amygdalar (from the Greek amygdala, “almonds”) nuclei, a major component
of the limbic system, resemble almonds in shape and are located in the tip of the
temporal lobe beneath the cortex of the uncus and rostral to the hippocampus
and the inferior horn of the lateral ventricle. There are two main groups of these
nuclei: the corticomedial and central and the basolateral. The corticomedial-
central group is relatively small and is phylogenetically older. It maintains
connections with the phylogenetically older regions of the central nervous
system, such as the olfactory bulb, hypothalamus, and brain stem. The
basolateral group is larger and phylogenetically more recent. It has extensive
connections with the cerebral cortex. Several neurotransmitters have been
demonstrated in the amygdala, including acetylcholine, gamma-aminobutyric acid
(GABA), noradrenaline, serotonin, dopamine,
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substance P, and enkephalin. The amygdala was first identified by the German
physician Burdach in the early 19th century.

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Figure 21-13. Coronal section of the brain showing the amygdala and
adjacent structures.

Afferent Pathways
The amygdala receives a broad range of exteroceptive afferents (olfactory,
somatosensory, auditory, and visual) for integration with interoceptive stimuli
from a variety of autonomic areas (Figure 21-14). Most of the amygdalar
connections are reciprocal.

The basolateral nuclear group, the largest in humans, receives inputs from the
following cortical and subcortical sources: (1) cortical input from the prefrontal,
temporal, occipital, and insular cortices, which convey to the amygdala highly
processed somatosensory, auditory, and visual sensory information from
modality-specific
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and multimodal association areas as well as visceral information, (2) the
thalamus (dorsomedial nucleus), (3) the olfactory cortex, and (4) cholinergic
input from the nucleus basalis of Meynert. The basolateral nuclear group is
intimately and reciprocally connected with the prefrontal cortex via the uncinate
fasciculus.

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Figure 21-14. Schematic diagram of the major afferent connections of the

amygdala.

The corticomedial and central nuclear complex receives inputs from the following
sources: (1) olfactory bulb (directly via the lateral olfactory stria and indirectly
via the olfactory cortex), (2) thalamus (dorsomedial nucleus), (3) hypothalamus
(ventromedial nucleus and lateral hypothalamic area), (4) septal area, and (5)
brain stem nuclear groups concerned with visceral function (periaqueductal gray
matter, parabrachial nucleus, and nucleus of the solitary tract).

Efferent Pathways
A large number of amygdalar efferents terminate in nuclei that regulate
endocrine and autonomic function, and others are directed to the neocortex.
Output from the amygdala is conveyed via two main pathways: (1) stria
terminalis (dorsal amygdalofugal pathway) and (2) ventral amygdalofugal
pathway (ventrofugal bundle).

A. STRIA TERMINALIS
The stria terminalis (Figure 21-15) is the main outflow tract of the amygdala. It
arises predominantly from the corticomedial group of amygdalar nuclei. From its
sites of origin, it follows a C-shaped course caudally, dorsally, anteriorly, and
ventrally along the medial surface of the caudate nucleus to reach the region of
the anterior commissure, where it branches out to supply the following areas: (1)
septal nuclei, (2) anterior, preoptic, and ventromedial nuclei of the hypothalamus
and the lateral hypothalamic area, and (3) bed nucleus of the stria terminalis (a

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scattered group of nuclei at the rostral extremity of the stria terminalis).

Figure 21-15. Schematic diagram of the major efferent connections of the

amygdala.

B. VENTRAL AMYGDALOFUGAL PATHWAY

The ventral amygdalofugal pathway is a ventral outflow tract that originates from
the basolateral and central amygdalar nuclei. It proceeds along the base of the
brain beneath the lentiform nucleus and distributes fibers to the following areas.
Fibers originating from the basolateral amygdalar nucleus project to the following
cortical and subcortical areas: (1) prefrontal, inferior temporal (entorhinal area
and subiculum), insular, cingulate, and occipital cortices, (2) ventral striatum,
(3) thalamus (dorsomedial nucleus), (4) hypothalamus (preoptic and lateral
hypothalamic areas), (5) septal area, and (6) substantia innominata (nucleus
basalis of Meynert), from which a diffuse cholinergic system activates the
cerebral cortex in response to significant stimuli.

Fibers in the ventral amygdalofugal pathway originating in the central amygdalar

nucleus are distributed to brain stem nuclei concerned with visceral function
(dorsal motor nucleus of the vagus, raphe nuclei, locus ceruleus, parabrachial
nucleus, and periaqueductal gray matter).

The two amygdala communicate with each other through the stria terminalis and
the anterior commissure. Fibers leave one amygdaloid nuclear complex and travel
via the stria terminalis to the level of the anterior commissure, where they cross
and join the other stria terminalis and return to the contralateral amygdaloid
nuclear complex. Nuclear groups within each amygdaloid nuclear complex

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communicate with each other via short fiber systems.

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Intra-Amygdaloid Connections
Tract tracing studies have revealed extensive intranuclear and internuclear
connectivity between amygdalar nuclei. Most of the connections are
glutamatergic. These observations indicate that there is extensive local
processing of information entering the amygdala before it leads to the
appropriate behavioral outcomes.

Functional Considerations
The functions of the amygdala are somewhat elusive. Stimulation and
ablation experiments usually involve adjacent neural structures. The
intricate neural connectivity of the amygdala makes it difficult to ascribe an
observed behavior purely to the amygdala. The following manifestations,
however, have been noted to occur after stimulation or ablation of the amygdala.

A. AUTONOMIC EFFECTS
Changes in heart rate, respiration, blood pressure, and gastric motility have been
observed after amygdalar stimulation. Both an increase and a decrease in these
functions have been observed, depending on the area that is stimulated.

B. ORIENTING RESPONSE
Stimulation of the amygdala enhances the orienting response to novel events.
Such animals arrest ongoing activity and orient their bodies to the novel
situation. Animals with amygdalar lesions manifest reduced responsiveness to
novel events in the visual environment. Their responsiveness, however, is
improved if they are rewarded for the response.

C. EMOTIONAL BEHAVIOR AND FOOD INTAKE

There seem to be two regions in the amygdala that are antagonistic to each other
with regard to emotional behavior and eating. Lesions in the corticomedial
nuclear group of the amygdala result in aphagia, decreased emotional tone, fear,
sadness, and aggression. Lesions of the basolateral nuclear group, by contrast,
produce hyperphagia, happiness, and pleasure reactions. Stim-ulation of the
basolateral nuclear group of the amygdala is associated with fear and flight.
Stimulation of the corticomedial nuclear group produces a defensive and
aggressive reaction. The attack behavior elicited by amygdalar stimulation differs
from that elicited by hypothalamic stimulation in its gradual buildup and gradual
subsidence upon the onset and cessation of stimulation. Attack behavior elicited
from the hypothalamus, in contrast, begins and subsides almost immediately
after the onset and cessation of the stimulus. Of interest also is the fact that
prior septal stimulation prevents the occurrence of aggressive behavior elicited
from both the amygdala and the hypothalamus.

D. FACIAL EXPRESSION
Several areas in the brain are specialized for processing of faces. Foremost
among them are the sectors of extrastriate visual cortex, notably in the fusiform
and superior temporal gyri, and the amygdala. Whereas the extrastriate visual
cortices participate primarily in constructing detailed perceptual representation of

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faces, the amygdala is required to link the perception of the face to the retrieval
of knowledge about its emotional and social meaning. Lesions of the amygdala in
monkeys impair the ability to evaluate social and emotional meaning of visual
stimuli. Bilateral amygdalar lesions in humans result in alteration in social
behavior and social cognition, especially as related to the recognition of social
cues from faces. Bilateral amygdalar damage in humans is associated with
impaired recognition of facial expressions. Functional imaging studies have
demonstrated activation of the amygdala during presentation of emotional facial
expressions. These findings are most evident for negatively valenced emotions
(fear, anger, and sadness).

E. AROUSAL RESPONSE
Stimulation of the basolateral nuclear group of the amygdala produces an arousal
response that is similar to but independent of the arousal response that follows
stimulation of the reticular activating system of the brain stem. The amygdalar
response is independent of the reticular activating system response, since it can
be elicited after lesions have been made in the reticular formation of the brain
stem. Stimulation of the corticomedial nuclear group of the amygdala, by
contrast, produces the reverse effect (a decrease in arousal and sleep). The net
total effect of the amygdala, however, is facilitatory, since ablation of the
amygdala results in a sluggish, hypoactive animal which is placid and tame. Such
animals avoid social interaction and may become social isolates.

F. SEXUAL ACTIVITY
The amygdala contains the highest density of receptors for sex hormones.
Stimulation of the amygdala has been associated with a variety of sexual
behaviors, including erection, ejaculation, copulatory movements, and ovulation.
Bilateral lesions of the amygdala produce hypersexuality and perverted sexual
behavior.

G. MOTOR ACTIVITY
Stimulation of the corticomedial nuclear group of the amygdala produces complex
rhythmic movements related to eating, such as chewing, smacking of the lips,
licking, and swallowing.

Animal experiments support the importance of the amygdala in the organization

of fear-related behavior. Bilateral removal of the amygdala abolishes naturally
occurring fear-related responses in animals. Electric stimulation of the amygdala
elicits defensive or fear-related behavior. The amygdaloid projections to the hy-
pothalamus via the ventral amygdalofugal pathway seem to be essential for fear-
related behavior.

Stimulation of the amygdala during brain surgery in humans is associated with a

variety of autonomic and emotional reactions and a feeling of fear and anxiety.
Some of these patients report a memorylike delusion of recognition known as the
déjà vu phenomenon (a French term meaning “already seen”). The déjà vu
phenomenon, as well as olfactory and gustatory hallucinations, is frequently
experienced as auras in patients who experience temporal lobe seizures.

Destruction of both amygdalas in humans has been done to relieve intractable

epilepsy and treat violent behavior. Such patients usually become complacent and
sedate and show significant changes in emotional behavior.

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It should be pointed out that many, if not all, of these functions can be observed
after stimulation or ablation of other brain regions, notably the hypothalamus and
the septal regions. It has been proposed that the amygdala plays an integrative
role in all these functions.

SEPTAL AREA
The septal area (Figures 21-16 and 21-17) has two divisions: the septum
pellucidum and the septum verum. The septum pellucidum is a thin leaf that
separates the lateral ventricles. It is made up of glia and lined by ependyma.

Figure 21-16. Midsagittal view of the brain showing the septal area ventral
to the septum pellucidum, between the subcallosal gyrus rostrally and the
anterior commissure, hypothalamus and lamina terminalis caudally.

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Figure 21-17. Axial brain section showing septal nuclei and septum
pellucidum between the corpus callosum and fornix.

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Figure 21-18. Schematic diagram showing afferent and efferent connections

of the septal area.

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The septum verum is ventral to the septum pellucidum, be-tween the subcallosal
gyrus rostrally and the anterior commissure and the anterior hypothalamus
caudally. Most authors include the following structures in the septum verum: the
septal nuclei, the diagonal band of Broca, the bed nucleus of the stria terminalis,
and the nucleus accumbens septi.

The septal nuclei are made up of medium-size neurons which are grouped into
medial, lateral, and posterior groups. The lateral group receives most of the
septal afferents and projects to the medial septal group. The medial group gives
rise to most of the septal efferents. The posterior group receives input from the
hippocampus and directs its output to the habenular nuclei. The septal nuclei are
poorly developed in humans.

Connections
The septal area has reciprocal connections (Figure 21-18) with the following
areas: (1) hippocampus, (2) amygdala, (3) hypothalamus, (4) midbrain, (5)
habenular nucleus, (6) cingulate gyrus, and (7) thalamus.

The reciprocal connections between the septal area and the hippocampus
constitute the major connection of the septal area and travel via the fornix. The
hippocampal-septal relationship is topographically organized so that specific
areas of the hippocampus project on specific regions of the septum (CA 1 of the
hippocampus to the medial septal region; CA 3 and CA 4 of the hippocampus to the

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lateral septal region, medial septal region to CA 3 and CA 4 ). When one adds to this
the intrinsic connection between the medial and lateral septal regions and
between CA 1 and CA 3 –CA 4 of the hippocampus, it becomes evident that a neural
circuit is established connecting these two limbic regions.

The reciprocal connections between the septal area and the amygdala travel via
the stria terminalis and the ventral amygdalofugal pathway.

Reciprocal connections with the hypothalamus travel in the medial forebrain

bundle. The hypothalamic nuclei involved include the preoptic, anterior,
paraventricular, and lateral. The medial forebrain bundle is an ill-defined bundle
of short nerve fibers that courses through the lateral hypothalamus,
interconnecting nuclei located close together and extending from the septal area
into the midbrain.

Fibers between the septal area and the midbrain travel in the medial forebrain
bundle. The periaqueductal gray region and the ventral tegmental area are the
primary brain stem areas involved in this connection.

The stria medullaris thalami reciprocally connects the septal area and the
habenular nuclei. From the habenular nuclei, the habenulointerpeduncular tract
connects the septal area indirectly with the interpeduncular nucleus of the
midbrain.

The thalamic nuclei involved in the septothalamic connection are the dorsomedial
and the anterior nuclei.

Functional Considerations
The functional importance of the septal area lies in providing a site of
interaction between limbic and diencephalic structures.

Stimulation and ablation experiments have provided the following information

about the role of the septal region.

A. EMOTIONAL BEHAVIOR
Lesions of the septal area in animal species such as rats and mice produce rage
reactions and hyper-emotionality. These behavioral alterations usually are
transitory and disappear 2 to 4 weeks after the lesion.

B. WATER CONSUMPTION
Animals with lesions in the septal area tend to consume increased amounts of
water. There is evidence to suggest that this is a primary effect of the lesion and
is caused by disruption of a neural system concerned with water balance in
response to changes in total fluid volume. Chronic stimulation of the septal area
tends to decrease spontaneous drinking even in animals that have been deprived
of water for a long time.

C. ACTIVITY
Animals with septal lesions demonstrate a high initial state of activity in response
to a novel situation. This heightened activity, however, rapidly declines almost to
immobility.

D. LEARNING

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Animals with septal lesions tend to learn tasks quickly and perform them
effectively once they have been learned.

E. REWARD
Stimulation of several regions of the septal area gives rise to pleasure or
rewarding effects.

F. AUTONOMIC EFFECTS
Stimulation of the septal region has an inhibitory effect on autonomic function.
Cardiac deceleration ensues after septal stimulation and is reversed by the drug
atropine, suggesting that septal effects are mediated via the cholinergic fibers of
the vagus nerve.

Figure 21-19. Schematic diagram showing the anatomic substrate for the
integrative function of the limbic system (the limbic loop).

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G. SEPTAL SYNDROME
Destruction of the septal nuclei gives rise to behavioral overreaction to most
environmental stimuli. Behavioral changes occur in sexual and reproductive
behavior, feeding, drinking, and the rage reaction.

Relatively few discrete septal lesions or stimulations have been reported in

humans. Chemical stimulation in the septal area using acetylcholine results in
euphoria and sexual orgasm. Recordings from the septal area during sexual
intercourse have shown spike and wave activity during orgasm. Markedly
increased sexual activity has been reported in humans after septal damage.

OVERVIEW OF THE LIMBIC SYSTEM

It is evident that the limbic system is a highly complex system that is
interconnected by a multiplicity of pathways and reciprocal circuits among
its component parts, notably the hypothalamus.

The main components of the limbic system (hippocampal formation, amygdala,

septal area, and entorhinal cortex) are densely interconnected and are connected

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with neural systems that subserve somatosensory, somatomotor, and autonomic

and endocrine functions. They are thus in a unique position to integrate
exteroceptive and interoceptive information and are essential for the
maintenance of emotional stability, learning ability, and memory function. A
limbic loop (Figure 21-19) has been proposed as the anatomic substrate for the
integrative role of the limbic system. The afferent limb of the loop consists of
collaterals to the limbic system from the pathway connecting neocortical
association cortices with the prefontal cortex. Autonomic and endocrine centers
are reciprocally connected with the same limbic system centers that receive
cortical collaterals. The efferent limb of the loop consists of projections from the
limbic centers to the prefrontal association cortex. The prefrontal cortex plays a
role in guiding behavior and is indirectly involved in the initiation of movement.
The input from the limbic centers into the prefrontal cortex subserves the effects
of emotion on motor function. At best, one can define the overall functions of the
limbic system in the most general terms as subserving the following:

1. Homeostatic mechanisms for preservation of the individual (flight or

defensive response, eating, drinking) and preservation of the species
(sexual and social behavior). In this the limbic system serves a protective
function of assuring graded and considered autonomic and endocrine
responses.

2. Emotional behavior (including fear, rage, pleasure, and sadness) and feeling

3. Memory

4. Matching up sensory input with autonomic-endocrine drive-s and putting it

into the context of the situation

5. Motivation

Different functions of the limbic system are not distributed equally among its
components. The hippocampus is especially concerned with memory, the
amygdala with emotion and sexuality, the anterior cingulate gyrus with
motivation, and the orbitofrontal cortex with social behavior.

TERMINOLOGY
Alveus (Latin, “a trough or canal”).
The alveus of the hippocampus is the thin layer of white matter that covers the
ventricular surface of the hippocampus.

Amnesia (Greek, “forgetfulness”).

Lack or loss of memory. Amnesia was an old term for loss of memory. The
modern use of the word dates from about 1861 and the work of Broca, who
divided disorders of speech caused by central lesions into aphemia and verbal
amnesia. The term first appeared in English in 1862. Broca's use of the term
verbal amnesia (impaired word finding) is no longer current.

Amygdala (Greek amygdale, “almond”).

The amygdaloid nucleus is an almond-shaped nuclear mass in front of the tail of
the caudate nucleus.

Associative memory.

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The conscious recollection of specific events and facts. Also known as declarative
memory and database memory.

Bratz sector.
Cornu Ammonis field CA 4 . Also known as the medium vulnerability (to anoxia)
sector.

Broca, Pierre-Paul (1824–1880).

French anthropologist, anat-omist, and surgeon, and later a politician. He
described hemispheric dominance for language. He described muscular dystrophy
before Duchenne, and the use of hypnotism in surgery. The speech area in the
left hemisphere is named after him.

Burdach, Karl Friedrich (1776–1847).

German physician, anatomist and physiologist. He introduced the terms biology
and morphology. He is credited with naming many structures, including the
fasciculus cuneatus (Burdach column), globus pallidus, putamen, internal
capsule, lenticular nucleus, red nucleus, cingulum, cuneus, and amygdaloid
nucleus. He also classified the thalamic nuclei.

Cingulate gyrus (Latin, “belt or girdle”).

A four-layered paleo-cortex above the corpus callosum. Part of the limbic lobe.

Cornu Ammonis.
Ammon's horn. Anatomists likened the hippocampus to a ram's horn or to the
horns of the ancient Egyptian deity Ammon, who had a ram's head.

Crus fornix (Latin, “leg or shin, arch”).

The flattened band of white beneath the splenium of the corpus callosum. The
two crura join to form the body of the fornix.

Declarative memory.
The conscious recollection of specific events and facts. Also known as associative
memory and database memory.

Déjà vu (French, “already seen”).

An illusion in which a new situation is incorrectly viewed as a repetition of a
previous situation. Usually an aura of a temporal lobe seizure.

Dentate gyrus (Latin dentatus, “having teeth”; Greek gyros, “circle”).

The three-layered archicortex of the temporal lobe. A component of the
hippocampal formation.
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Entorhinal cortex.
The rostral part of the parahippocampal gyrus in the temporal lobe. It
corresponds to Brodmann's area 28.

Fimbria (Latin, “fringe, border, edge”).

The band of white matter along the medial edge of the ventricular surface of the
hippocampus. Part of the fornix.

Fornix (Latin, “arch”).

The outflow tract of the hippocampal formation is archlike. Noted by Galen and
first described by Vesalius. Thomas Willis named it the fornix cerebri.

Hippocampus (Greek, “sea horse”).

Part of the hippocampal formation. The inferiomesial part of the parahippocampal

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gyrus. So named because of its resemblance to a sea horse. The structure was
first observed by Achillini and named by Arantius.

Isthmus (Greek isthmos, “a narrow connection between two larger bodies

or parts”).
The isthmus of the cingulate gyrus is its constricted portion between the
cingulate and parahippocampal gyri.

Limbic (Latin limbus, “fringe, border, margin”).

The limbic lobe forms a margin around the brain stem.

Lyra (Greek, “lirah”).

A stringed instrument resembling the harp.

Mitral cells (Latin mitra, “a cap”).

Mitral cells in the olfactory bulb have a caplike shape.

Papez circuit.
A circuit connecting the hippocampus with the hypothalamus, thalamus, and
cingulate gyrus. Described by James Papez, an American neuroanatomist, in
1937. The circuit subsequently laid the basis for the concept of the limbic
system.

Psalterium (Greek psalterion, “harp”).

The hippocampal commissure or fornical commissure is called the psalterium.

Pyriform (Latin pirum, “a pear”; forma “shape”).

Pear-shaped. The pyriform gyrus of the temporal lobe is pear-shaped.

Rhinencephalon (Greek rhin, “nose”; enkephalos, “brain”).

The smell brain. The part of the brain concerned with the olfactory system.

Schaffer collaterals.
Collaterals of axons of pyramidal neurons in the CA 3 field of the hippocampus
that project on pyramidal cells in the CA 1 field.

Sommer's sector.
Field CA 1 of the hippocampus. Also known as the vulnerable sector because of its
sensitivity to anoxia and ischemia. Named after Wilhelm Sommer, a German
physician.

Subiculum (Latin subicere, “to raise or lift”).

An underlying or supporting structure.

Uncinate (Latin, “hook”).

The uncinate fasciculus is like a hook connecting the frontal and temporal lobes.

Uncus (Latin, “hook”).

The medially curved anterior end of the parahippocampal gyrus.

Willis, Thomas (1621–1675).

English physician who described the arterial Circle of Willis in the base of the
brain in 1664. He described the 11th cranial nerve (nerve of Willis), and carotid
occlusion headache (Willis headache), among many other observations.

SUGGESTED READINGS
Adolphs R, Tranel D: Amygdala damage impairs emotion recognition from
scenes only when they contain facial expression. Neuropsychologia 2003;

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Editors: Afifi, Adel K.; Bergman, Ronald A.

Title: Functional Neuroanatomy: Text and Atlas, 2nd Edition

Copyright ©2005 McGraw-Hill

> Table of Contents > Part I - Text > 22 - Limbic System: Clinical Correlates

22
Limbic System: Clinical Correlates

Abnormalities of Olfaction
Memory
Types of Memory
Anatomic Correlates of Memory
Types of Memory Loss (Amnesia)
Wernicke-Korsakoff Syndrome Transient Global Amnesia
Klüver-Bucy Syndrome Temporal Lobe Epilepsy
Schizophrenia Alzheimer's Disease Herpes Simplex
Encephalitis

KEY CONCEPTS

Anosmia may be the earliest clinical sign of a subfrontal

meningioma.

There are two types of memory: explicit and implicit.

Amnesia (memory loss) may be anterograde, retrograde,

global, or modality-specific. It may be transient or permanent.

Wernicke-Korsakoff's syndrome, a thiamine deficiency

syndrome seen in chronic alcoholics, is characterized by
amnesia (anterograde and retrograde) and in confabulation.

Transient global amnesia is caused by ischemia in memory

structures in the medial temporal lobe. Spreading cortical
depression in the medial temporal lobe is another, more
recently reported mechanism.

Various manifestations of the Klüver-Bucy syndrome can

be explained as defects in relating sensory information to past

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experience or in evaluating sensory stimuli in terms of their

biologic significance.

Temporal lobe epilepsy is characterized by a combination

of psychological and motor manifestations.

Schizophrenia is a mental illness with undefined

neuropathology. Cortical and subcortical limbic structures are
likely sites of the neuropathology.

Alzheimer's disease is a degenerative brain disease

characterized by severe memory loss, disorientation, and
behavioral changes. The brunt of the pathology is in the
entorhinal cortex, which isolates the hippocampal formation
from the rest of the cerebral cortex.

ABNORMALITIES OF OLFACTION
Rhinencephalic structures can be affected in several sites, resulting in
derangement of the sense of smell.

Olfactory receptors in the nose are involved in common colds,

resulting in bilateral diminution or loss of smell (anosmia).
Olfactory nerve fibers may be affected in their course through the
cribriform plate of the ethmoid bone after fractures of the plate and
severe falls. The anosmia in such cases results from the shearing of the
fine olfactory nerve fibers as they pass through the cribriform plate.
The olfactory bulb and tract may be involved in inflammatory processes
of the meninges (meningitis) or tumors (meningiomas) in the inferior
surface of the frontal lobe or the anterior cranial fossa. Unilateral loss
of smell (anosmia) may be the earliest clinical manifestation of a
subfrontal meningioma. Pathologic processes in the region of the
primary olfactory cortex (uncus of the temporal lobe) usually give rise
to hallucinations of smell (uncinate fits). The odor experienced in such
cases often is described as unpleasant. Such hallucinations may herald
an epileptic seizure or be part of it.

MEMORY
The term memory refers to the encoding, storage, and retrieval of
information. A defect in one or more of these processes results in
memory impairment (amnesia).

The role of the nervous system in memory has been studied by using
neurosurgical techniques (ablation of selective areas of

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the brain), electrophysiologic methods (neural pathways and
mechanisms), biochemical studies (the role of RNA and other proteins),
a neuropharmacologic approach (the effect of drugs on synaptic
transmission and intracellular processes), and studies of humans with a
memory deficit (amnesia). Memory seems to depend on two distinct
changes: an electric membrane event of a temporary nature and a
more stable, permanent change in the chemistry of the nervous
system. The discovery that DNA and RNA can act as codes for synaptic
transmission has led to the theory that those substances are
responsible for transforming short-term memories into permanent
stores.

Types of Memory
Memories are either explicit or implicit.

A. Explicit (Declarative) Memory

Explicit memory refers to conscious retrieval of information. It
supports the learning and retention of facts and the conscious
recollection of prior events (knowing that). Thus, it is consciously
accessed. There are two subtypes of explicit memory: (1) episodic and
(2) semantic.

Episodic (unique) memory is the memory of personally experienced

facts and events with special spatial and temporal localization, such as
the memory of eating a specific type of food in a restaurant.

Semantic (nonunique, generic) memory refers to the memory of

culturally and educationally acquired encyclopedic knowledge such as
the meaning of words, arithmetical facts, and geographic and historical
information, for example, that Paris is the capital of France and that
bistro is French for “restaurant.”

Episodic memory can be short or long term.

1. Short-Term (Immediate, Recent, Working)

Memory.
Short-term memory refers to the memory of a limited amount of
information (e.g., a seven-digit telephone number) held continuously in
consciousness for a short period (less than 60 s). This type of memory
decays in seconds if it is not refreshed continuously.

2. Long-Term (Remote) Memory.

Long-term memory refers to the memory retrieved after delays longer
than one minute, and in the case of remote memory, for more distant
past.

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B. Implicit Memory
Implicit memory supports the learning and retention of skills (knowing
how). It is the memory of experience-affected behaviors that are
performed unconsciously. There are two types of implicit memory: (1)
procedural memory and (2) priming.

1. Procedural Memory.
Procedural memory (skill learning) is the phenomenon in which
repeated performance of a motor act, such as driving or riding a bike,
enhances and automates future skill for the same act. It is
characteristically resistant to forgetting, hence its preservation in
patients who are otherwise amnesic.

2. Priming.
Priming refers to short-lived enhancement of perceptually based
performance following recent exposure to visually similar material,
such as completing a three-letter item with a word that has been
presented previously or recognizing a word or picture faster or more
accurately because of prior exposure.

Table 22-1 is a summary of the types of memory.

Immediate memory may be explained as a transient electric alteration

at the synapse; longer-lasting memory may be explained as an actual
physical or chemical alteration of the synapse. Several of these
alterations have been described in different experimental situations,
including changes in the number and size of synaptic terminals as well
as their chemical composition. Changes in postsynaptic neurons also
have been described. Such changes in the pre- or postsynaptic
components of the synapse have been thought to facilitate the
transmission of impulses at the synapse and thus establish a memory
code, or ingram.

Table 22-1. Memory Types

Explicit

Semantic

Episodic
Short term
Long term

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Anterograde
Retrograde

Implicit

Procedural

Priming

Several biochemical studies have suggested a role for protein and RNA
in memory mechanisms. Evidence for this role has been obtained from
(1) experiments in which protein and RNA syntheses were increased or
blocked by drugs, (2) measurement of the protein and RNA content of
stimulated neuronal systems, and (3) experiments in which learned
tasks were presumably transferred from a trained animal to an
untrained animal after the injection of RNA or protein from the brain of
the trained subject.

Anatomic Correlates of Memory

The different types of memory are supported by different neural
systems.

A. Episodic Memory
The mesial temporal cortex (hippocampus, entorhinal cortex, perirhinal
cortex, and parahippocampal gyrus) are critical for episodic memory.
Patients with bilateral hippocampal resection (for treatment of
intractable epilepsy) or acquired lesions (herpes simplex encephalitis)
are unable to acquire new explicit (declarative) memory (anterograde
amnesia). In these patients, no new information is ever retained
beyond the span of 40–60 seconds. Lesions extending beyond the
hippocampus to involve adjacent mesial temporal regions are
associated with severe anterograde and/or retrograde amnesia. Besides
the mesial temporal cortex, the following brain regions are implicated
in episodic memory: (1) cortico-cortical connections from posterior and
anterior neocortices to the entorhinal cortex, (2) hippocampus-
mamillary body-anterior and medial thalamic nuclei via the fornix and
mamillothalamic tract, and 3) basal forebrain cholinergic nuclei
(nucleus basalis of Meynert).

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B. Semantic Memory
The temporal, parietal, and occipital lobes, particularly the temporal
neocortex, are associated with semantic memory. Semantic memory
impairment is seen in patients with bilateral lesions in the above
cortices as occurs in herpes simplex encephalitis and Alzheimer's
disease. Right hemisphere damage is more important than left
hemisphere damage.

C. Short-Term (Working) Memory

Studies on short-term memory point to two separate neural systems
that handle verbal and nonverbal information. In patients
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with left hemisphere dominance for language, the left prefrontal cortex
subserves working memory for verbal material, and the right prefrontal
cortex subserves working memory for nonverbal material. Working
memory is unaffected in mesial temporal lesions.

D. Procedural (Skill Learning) Memory

Skill learning memory is a function of subcortical circuits, particularly
in the basal ganglia and cerebellum, and is thus unaffected by mesial
temporal pathology.

E. Priming
The neural basis of priming is not certain but is most probably related
to unimodal sensory association areas.

Types of Memory Loss (Amnesia)

Several types of amnesia are recognized: (1) retrograde, (2)
anterograde, (3) global, (4) modality-specific, (5) permanent, and
(6) transient.

Retrograde amnesia is amnesia for information learned before the

onset of an illness. Anterograde amnesia is amnesia for information
that should have been acquired after the onset of an illness.
Anterograde amnesia is the most common type of amnesia. It usually
affects verbal and nonverbal (visual) materials equally, although
unilateral left temporal lobe damage may selectively affect acquisition
of verbal information, whereas right temporal lobe damage may
selectively affect nonverbal information, such as faces and location of
items. Retrograde amnesia occurs usually in association with
anterograde amnesia and is most pronounced for events in the years
just preceding the lesion. Global amnesia is an acute, transient
(minutes to hours) severe anterograde, with variable periods of
retrograde amnesia in which information cannot be retrieved through

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any sensory channel. Transient global amnesia was first described in

1956 by Morris Bender, and the term was coined by C. Miller Fisher and
Raymond Adams in 1964. Modality-specific amnesia is the inability to
retrieve information through a specific channel, such as vision.
Amnesia may be permanent, as in Alzheimer's disease, or transient, as
in posttraumatic and global amnesia.

Much of our knowledge about memory loss has come from careful
observations of patients with amnesia. Although a relationship between
the temporal lobe and loss of memory was recognized at around the
turn of the century by the Russian neuropathologist Vladimir
Bekhterev, it was William Scoville in 1953 who established a precise
relationship between bilateral anterior temporal lobe lesions and
anterograde amnesia. Scoville's patient underwent bilateral anterior
temporal lobectomies for the treatment of intractable seizures. The
lesion included the anterior hippocampal formation and
parahippocampal gyrus and the amygdala. While the seizures
responded favorably, the patient was left with severe declarative
memory loss and anterograde memory loss. His retrograde memory and
implicit (procedural) memory were not affected.

Pathologic processes in the brain may affect one type of memory and
spare others. Older people lose the ability to recall what they ate
earlier in the day but can recall, in the minutest detail, experiences
they had many years earlier. People who suffer head trauma in a car
accident are unable to recall what transpired for minutes to hours
before the accident, but the recall of older memories remains intact.

Severe impairment of episodic memory is the hallmark of Alzheimer's

disease. However, other types of memory are affected in this disease,
including semantic memory, some aspects of implicit memory, and
short-term memory.

WERNICKE-KORSAKOFF SYNDROME
The Wernicke-Korsakoff syndrome, which was described by
Wernicke in 1881 and Korsakoff in 1887, is characterized by
severe anterograde and retrograde amnesia and confabulation. The
cause of this syndrome is vitamin B 1 (thiamine) deficiency resulting
from malnutrition associated with chronic alcohol intake. The lesion in
Korsakoff's syndrome involves the dorsomedial and midline nuclei of
the thalamus, mamillary body, and frontal cerebral cortex.

TRANSIENT GLOBAL AMNESIA

Transient global amnesia is a short-term neurologic condition that
is characterized by sudden memory loss of recent events,
transient inability to retain new information (anterograde amnesia),
and retrograde amnesia of variable extension. Immediate and very

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remote memories are unaffected. Complete recovery usually occurs

within a few hours. The term transient global amnesia was coined by
Fisher and Adams in 1964. The exact mechanism of transient global
amnesia remains controversial. This type of amnesia has been
associated with epilepsy, migraine headache, and tumor. Most reports
emphasize bilateral transient ischemia in the territory of the posterior
cerebral circulation affecting medial temporal lobe structures that are
important for memory. More recent studies on transient global amnesia
implicate spreading cortical depression in medial temporal structures in
the pathogenesis of the amnesia. The episodes of transient amnesia
may be preceded by characteristic events or activities such as
exertion, intense emotion, sexual intercourse, temperature extremes,
and bathing.

KLÜVER-BUCY SYNDROME
The Klüver-Bucy syndrome is a clinical syndrome observed in humans
and other animals after bilateral lesions in the temporal lobe that
involve the amygdala, hippocampal formation, and adjacent neural
structures. The syndrome was first described by Klüver and Bucy in
1939 in monkeys after bilateral temporal lobectomy. The human
counterpart was described by Terzian and Dalle Ore in 1955 and by
Marlowe in 1975. The syndrome is manifested by the following
symptoms:

1. Visual agnosia or psychic blindness (inability to differentiate

between friends, relatives, and strangers).

2. Hyperorality (tendency to examine all objects by mouth).

3. Hypersexuality (normal as well as perverted sexual activity). Such

patients and animals manifest heightened sexual drives toward
either sex of their own or other species and even inanimate
objects.

4. Docility.

5. Lack of emotional response, blunted affect, and apathy.

6. Increased appetite, bulimia.

7. Memory deficit.

The various manifestations of this syndrome reflect a defect in

relating sensory information to past experience or evaluating
sensory stimuli in terms of their biologic significance.

TEMPORAL LOBE EPILEPSY

Another manifestation of limbic lesions in humans is temporal lobe

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epilepsy, which also is known as psychomotor seizures,

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uncinate fits, and complex partial seizures. During the seizure, the
patient may manifest one or more of the following symptoms:

1. Olfactory hallucinations consisting of transient and recurrent

episodes of unpleasant olfactory experiences such as smelling
burning rubber.

2. Gustatory hallucinations consisting of a transient unpleasant taste

sensation.

3. Auditory hallucinations.

4. Visual hallucinations (déjà vu).

5. Rhythmic movements related to feeding (chewing, licking,

swallowing).

6. Complex motor acts such as walking, undressing, and twisting

movements of trunk and extremities.

7. Amnesia, which may last several hours or days.

8. Aggressive behavior. During the seizure, such patients may

commit violent or even criminal acts.

The pathology in temporal lobe seizures involves the hippocampus,

entorhinal cortex, and amygdala. Magnetic resonance imaging (MRI) is
useful in identifying temporal lobe pathology, such as mesial temporal
lobe sclerosis and tumor (Figure 22-1). Unexplained death has been
reported in patients with temporal lobe epilepsy. This has been
attributed to autonomic changes in cardiovascular function during a
seizure. Autonomic cardiovascular responses have been elicited on
stimulation of the insular cortex in humans. Stimulation of the right
insular cortex produces sympathetic effects on cardiovascular function
(tachycardia and pressor effects). Stimulation of the left insular cortex,
in contrast, produces parasympathetic effects (bradycardia and
depressor effects).

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Figure 22-1. Gadolinium-enhanced T1-weighted magnetic

resonance image of the brain showing an enhancing lesion (tumor)
(arrow) in the temporal lobe.

SCHIZOPHRENIA
Schizophrenia is a severe mental illness characterized by
disorganized thought processes, hallucinations, delusions, and
cognitive deficits. Vulnerability to schizophrenia is 60% genetic and
40% environmental. Although the definitive neuropathology of
schizophrenia has not been defined, it includes ventriculo-megaly,
diffuse neuronal loss and disorganization, and decreased frontal blood
flow and metabolism. Neurochemical studies have strongly supported a
dysfunctional dopaminergic neurotransmission. Thus, the pathology
involves both cortical and subcortical structures. Numerous pathologic
mechanisms have been proposed for schizophrenia. The currently
predominant hypothesis is abnormal neurodevelopment that becomes
manifest in adolescence. The alternative hypothesis is
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a neurodegenerative one. Cytoarchitectural studies in schizophrenic
brains point to abnormal laminar organization in limbic structures that

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are suggestive of abnormal neuronal migration during brain

development. Findings from different studies suggest a “miswiring” of
neural connections in the schizophrenic brain.

ALZHEIMER'S DISEASE
Alzheimer's disease is a degenerative brain disorder that is
characterized by memory loss severe enough to impair everyday
activities; disorientation to time, place, and person; and behavioral
changes such as depression, paranoia, and aggressiveness. Memory
loss starts with recent (short-term) memory such as remembering to
keep appointments, and progresses to involve remote (long-term)
memory such as forgetting names of children and spouses, and finally,
in the end stage, to nearly total loss of memory. The gross
neuropathologic hallmarks of Alzheimer's disease consist of atrophic
gyri and widened sulci (Figure 22-2) most prominent in the limbic
cortex. The association cortices are heavily affected, whereas primary
sensory cortices are minimally affected and the motor cortex is least
affected. Microscopically, the neuropathologic hallmarks of the disease
consist of neurofibrillary tangles and senile plaques. Neurochemical
studies have demonstrated abnormal accumulation in senile plaques of
a breakdown product of amyloid precursor protein known as beta-
amyloid or A4 amyloid as well as accumulation of tau protein in
neurons destined to have neurofibrillary tangles. The cognitive deficit
in Alzheimer's disease has been attributed to an abnormality in the
cholinergic system. In support of this hypothesis are the loss in
Alzheimer's brains of cholinergic projection neurons in the nucleus
basalis of Meynert and the loss throughout the cerebral cortex of
choline acetyltransferase activity.

Careful studies on the distribution of neurofibrillary tangles in

Alzheimer's brains have shown a preponderance of these tangles in
limbic and multimodal association cortices compared with primary
association, primary sensory, and primary motor cortices. The most
affected areas are the anterior parts of the parahippocampal gyrus and
particularly in the entorhinal cortex (area 28). It is well established
that the entorhinal cortex serves as a link between the hippocampal
formation (important for memory) and the rest of the cerebral cortex.
Severe neuropathology in the entorhinal cortex, as occurs in
Alzheimer's disease, thus isolates or disconnects the hippocampal
formation from the remainder of the cortex and results in severe
memory loss. Alzheimer's disease thus is a disorder where there is a
breakdown of cortical neural systems critical for higher cognitive
behaviors (thought, reasoning, memory).

Alzheimer's disease has been shown to be a polygenetic disease.

Mutations in chromosomes 21, 14, and 1 have been associated with the
disorder. All three chromosomes have been related to early onset

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autosomal dominant Alzheimer's disease. Chromosome 19 has been

associated with late onset familial and sporadic Alzheimer's disease.

HERPES SIMPLEX ENCEPHALITIS

Herpes simplex encephalitis is a viral encephalitis caused by
herpesvirus and characterized by focal seizures, focal neurologic signs,
and progressive deterioration of consciousness. It is the single most
important cause of fatal sporadic encephalitis in the United States. The
neuropathology consists of a severe focal necrotizing process with a
predilection for the limbic system. A brain biopsy is diagnostic in
showing characteristic intranuclear viral inclusions (Figure 22-3)
(Cowdry type A inclusions) and inflammation. MRI is the most sensitive
noninvasive test for the early diagnosis of herpes simplex encephalitis
and the demonstration of pathology in the limbic system (Figure 22-4).
Early diagnosis is crucial because there is an effective antiviral
treatment for this type of encephalitis.

Figure 22-2. Lateral view of the brain showing prominence of

sulci (arrows) and atrophy of gyri (stars) in Alzheimer's disease.

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Figure 22-3. Electron micrograph showing intranuclear viral

inclusions (Cowdry type A) (arrow) in brain biopsy of a patient
with herpes simplex encephalitis.

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TERMINOLOGY
Alzheimer's disease.
A progressive degenerative brain disorder characterized by severe loss
of memory, disorientation, and behavioral changes. Named after Alois
Alzheimer, a German neuropsychiatrist and pathologist who described
the disorder verbally in 1906 and in writing in 1907.

Amnesia (Greek, “forgetfulness”).

Lack of or loss of memory. Amnesia was an old term for loss of
memory. The modern use of the word dates from about 1861 and the
work of Broca, who divided disorders of speech caused by central
lesions into aphemia and verbal amnesia. The term first appeared in
English in 1862. Broca's use of the term verbal amnesia (impaired

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word finding) is no longer current.

Anosmia (Greek an, “negative”; osme, “smell”).

Absence of the sense of smell. The condition was first mentioned by
Galen.

Bekhterev, Vladimir Mikhailovitch (1857–1927).

Russian neuropathologist and psychiatrist whose contributions include
descriptions of the superior vestibular nucleus (Bekhterev nucleus), the
relationship between temporal lobe and memory, and spasmodic
laughter and weeping in hemiplegic patients (Bekhterev-Brissaud sign),
among other findings.

Bulimia (Greek bous, “ox”; limos, “hunger”).

An eating disorder characterized by episodes of binge eating that
continue until they are terminated by abdominal pain, sleep, or self-
induced vomiting.

Cribriform (Latin cribrum, “sieve”; forma, “form”).

The cribriform plate of the ethmoid bone is perforated with small
apertures, resembling a sieve. Ancient anatomists were especially
interested in the perforations of the ethmoid bone because of their
theory that pituita (mucous brain secretions) entered the nose through
these channels.

Déjà vu (French, “already seen”).

An illusion in which a new situation is incorrectly viewed as a repetition
of a previous situation. Usually an aura of temporal lobe seizures.

Klüver-Bucy syndrome.
A clinical syndrome characterized by visual agnosia, hyperorality,
hypersexuality, docility, blunted affect, bulimia, and memory deficit.
First described in monkeys by H. Klüver, and P.C. Bucy in 1937.

Korsakoff's syndrome (Wernicke-Korsakoff syndrome).

A syndrome of thiamine deficiency in chronic alcoholics that is
characterized by loss of memory and confabulation. The syndrome was
first described by Magnus Huss, a Swedish physician. Strumpell, in
1883, and Charcot, in 1884, called attention to this syndrome. Charles
Gayet described the pathology in 1875. Karl Wernicke, a German
neuropsychiatrist, described three cases in 1881 and named the
disorder acute superior hemorrhagic polioencephalitis. Sergi Korsakoff,
a Russian neuropsychiatrist, summarized the syndrome and described
it as an entity between 1887 and 1889. The role of vitamin deficiency
in the etiology of the syndrome was established by Peters in 1936.

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Figure 22-4. T2-weighted magnetic resonance image of the brain

showing increased signal intensity (arrows) in components of the
limbic system in a patient with herpes simplex encephalitis.

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Nucleus basalis of Meynert.

A group of neurons in the substantia innominata below the globus
pallidus. This nucleus is the source of cholinergic innervation of the
cerebral cortex. Loss of neurons in the nucleus occurs in patients with
Alzheimer's disease. Named after Theodor Hermann Meynert, an
Austrian psychiatrist.

Psychic blindness (visual agnosia).

A disorder in which patients with normal vision fail to comprehend the
nature or meaning of nonverbal visual stimuli.

Rhinencephalon (Greek rhin, “nose”; enkephalos, “brain”).

The smell brain.

Uncinate fits (Latin, “hook”).

Uncinate fits arise from the area of the uncus, the medially curved
(like a hook) anterior end of the parahippocampal gyrus.

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Blass JP, Gibson GE: Abnormality of a thiamine-requiring enzyme in

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Grabowski TJ et al: Cardinal symptoms of disordered cognition.

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Klüver H, Bucy PC: Preliminary analysis of functions of the

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Editors: Afifi, Adel K.; Bergman, Ronald A.

Title: Functional Neuroanatomy: Text and Atlas, 2nd Edition

Copyright ©2005 McGraw-Hill

> Table of Contents > Part I - Text > 23 - Special Senses

23
Special Senses

Olfaction
Olfactory Epithelium
Olfactory Nerve
yOlfactory Bulb
Olfactory Tract
Olfactory Striae
Primary Olfactory Cortex
Olfactory Mechanismsy
Taste
Taste Buds
Physiology of Taste
Central Transmission of Taste Sensations
Vision
The Retina
Variations in Retinal Structure
Synaptic Organization of the Retina
Photochemistry and Physiology of the Retina
Dark and Light Adaptation
Color Vision
Visual Pathways
Hearing
The Ear
Sound Transmission
Cochlea
Auditory End Organ (Organ of Corti)
Auditory Physiology
Otoacoustic Emissions
Audiometry
Deafness
Vestibular Sensation

KEY CONCEPTS

The olfactory sense organ is located in the roof of the nose and the
upper part of the lateral wall and septum.

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Olfactory nerve fibers synapse on mitral and tufted neurons of the

olfactory bulb.

The olfactory tract subdivides into three striae.

The gustatory (taste) sense organs (taste buds) are distributed in

the tongue, soft palate, oropharynx, and epiglottis.

Taste buds in different locations of the tongue respond best to

different tastes. Those at the tip of the tongue respond best to sweet
and salty substances; those at the margins and posterior part of the
tongue respond best to sour and bitter substances.

Taste sensations are transmitted centrally via three cranial nerves:

facial, glossopharyngeal, and vagus.

Central taste pathways establish synapses in several brain stem

nuclei (nucleus solitarius, reticular nuclei, ventral posterior medial)
before reaching the primary gustatory cortex in the inferior part of the
somesthetic cortex.

The visual receptor cells are located in the retina.

Axons of ganglion cells form the optic nerve.

Crossed and uncrossed optic nerve fibers join caudal to the optic
chiasma to form the optic tract.

Axons of neurons in the lateral geniculate nucleus form the

geniculocalcarine tract (optic radiation).

Geniculocalcarine fibers terminate, in a retinotopic fashion, in the

primary visual (striate) cortex in the occipital lobe.

The sense organs for hearing and equilibrium are in the inner ear.

Efferent nerves originating from the superior olivary complex

modulate activity in hair cells.
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Central auditory pathways synapse in several brain stem nuclei

before terminating in the primary auditory cortex (transverse gyri of
Heschl) in the temporal lobe.

Receptors of the vestibular sense organ are located in the inner ear
(semicircular canals, utricle, saccule).

Central vestibular pathways are directed to several neural

structures: spinal cord, cerebellum, thalamus, nuclei of extraocular
movement, and the cerebral cortex.

The vestibular system is essential for the coordination of motor

responses, eye movement, and posture.

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The different sensations perceived by the human body are grouped into two
major categories: those concerned with general sensations (touch, pressure,
pain, and temperature) and those concerned with special sensations (olfaction,
taste, vision, audition, and sense of position and movement). This chapter is
devoted to a consideration of the organs of special senses. Whereas nerve
endings concerned with general sensibility are distributed widely, those
concerned with special sensations are limited to specific areas of the body.

OLFACTION
Olfactory stimuli are received by receptors of the olfactory epithelium in the
nasal wall and are conveyed via olfactory nerve fibers through the cribriform
plate of the ethmoid bone to the olfactory bulb inside the cranial cavity (see
Figure 21-2). Within the olfactory bulb, axons of the olfactory nerve synapse with
mitral and tufted cells in a complex structure known as the olfactory glomerulus
(see Figure 21-3). Axons of mitral and tufted neurons form the olfactory tract,
which lies in the olfactory sulcus on the undersurface of the frontal lobe. Close to
the anterior perforated substance, the olfactory tract divides into the lateral,
intermediate, and medial olfactory striae (see Figures 23-1 and 23-2). The lateral
olfactory stria terminates in the primary olfactory cortex, where olfaction is
perceived. The medial olfactory stria joins the anterior commissure to reach the
contralateral olfactory tract and bulb. It also projects on limbic system
structures. The intermediate olfactory stria blends with the anterior perforated
substance. The medial and intermediate olfactory striae are not well developed in
humans and do not play a role in perception of olfactory stimuli.

Olfactory Epithelium
The olfactory epithelium is located in the mucous membrane lining the roof
of the nasal cavity on the inferior surface of the cribriform plate of the
ethmoid bone. From the roof, the olfactory epithelium extends down both sides of
the nasal cavity to cover most of the superior concha laterally and 1 cm of nasal
septum medially. Humans are microsmatic animals in whom the surface area of
olfactory mucous membrane in both nostrils is small (approximately 5 cm 2 ).
Though microsmatic, humans are able to distinguish large numbers of odors,
some at very low concentrations.

The olfactory epithelium contains three types of epithelial cells: receptor cells,
supporting cells, and basal cells (Figure 23-1). Interspersed among epithelial
cells are ducts of Bowman's glands.

A. Receptor Cells
Olfactory receptor cells are bipolar sensory neurons. Their perikarya are located
in the lower part of the olfactory epithe-lium. Each cell has a single dendrite that
reaches the surface of the epithelium and forms a knoblike expansion that
extends beyond the epithelial surface. From this expansion, 10 to 20 nonmotile
cilia project into a layer of fluid covering the epithelium. The olfactory cilia
contain receptors for odorant molecules. From the basal part of the perikaryon, a
nonmyelinated axon emerges and joins with axons of adjacent receptor cells to
form the olfactory nerve (first cranial nerve). Olfactory nerve bundles penetrate
the cribriform plate of the ethmoid bone to reach the olfactory bulb-.

It is estimated that there are more than 100 million receptor cells in the olfactory
mucosa. The specialized nerve cells of the olfactory epithelium are highly

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sensitive to different odors. Olfactory neurons are produced continuously from

basal cells of the olfactory epithelium and are lost continuously by normal wear
and tear. It is estimated that olfactory receptor cells have an average life span of
30–60 days. The presence of these nerve cells at the surface exposes them
unduly to damage; it is estimated that 1 percent of the fibers of the olfactory
nerves (axons of olfactory neurons) are lost each year of life because of injury to
the perikarya. The sense of smell thus diminishes in the elderly as a result of
exposure of the olfactory epithelium to repeated infections and trauma in life.
The presence of olfactory neurons at the surface represents the only exception to
the evolutionary rule by which nerve cell bodies of afferent neurons migrate
along their axons to take up more central and well-protected positions. The
surface of the olfactory epithelium is moistened constantly by secretions of
Bowman's glands. This moistening helps dissolve the gaseous substances,
facilitating stimulation of the olfactory
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epithelium. The continuous secretion also cleanses the receptors of accumulated
odorous substances and prevents their retention.

Figure 23-1. Schematic diagram of the cellular components of the olfactory

mucosa.

It is believed that different basic odors stimulate different olfactory neurons.

Stimulation of different combinations of receptors for basic odors is believed to
be the basis for humans' ability to recognize all the varieties of odors to which
they are exposed.

B. Supporting (Sustentacular) Cells

Supporting cells are columnar epithelial cells that separate the olfactory receptor
cells. The surface of supporting cells is specialized into microvilli that project into
the fluid layer covering the epithelium. As their name suggests, supporting cells
provide mechanical support to the receptor cells. In addition, they con-tribute,
along with Bowman's gland, to the elaboration of the overlying mucus. In
contrast to the relatively short life span of olfactory receptor cells, supporting
cells remain stable.

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C. Basal Cells
Basal cells are polygonal cells limited to the basal part of the epithelium. They
are the source of new epithelial cells. Mitotic activity persists in these cells
through maturity.

D. Bowman's Glands
Bowman's glands contain serous and mucous cells and are located beneath the
epithelium. They send their ducts in between epithelial cells to pour their
secretion onto the surface of the epithelium, bathing the cilia of receptor cells
and the microvilli of supporting cells. The secretion of Bowman's glands plays an
important role in dissolving odorous substances and diffusing them to receptor
cells.

Olfactory Nerve
The olfactory nerve (see Figure 21-2) is composed of unmyelinated thin
processes (rootlets) of the olfactory hair cells in the nasal mucosa. Fascicles
of the olfactory nerve pierce the cribriform plate of the ethmoid bone, enter the
cranial cavity, and terminate on neurons in the olfactory bulb.

Olfactory Bulb
The olfactory bulb (see Figures 21-1 and 21-2) is the main relay station in the
olfactory pathways. It is located on the cribriform plate of the ethmoid and
beneath the inferior surface of the frontal lobe.

A. Lamination and Cell Types (See Figure 21-3)

In histologic sections, the olfactory bulb appears laminated into the following
layers (see Figure 21-3):

Olfactory nerve layer. This layer is composed of incoming olfactory nerve

fibers.

Glomerular layer. In this layer, synaptic formations occur between

olfactory nerve axons and dendrites of olfactory bulb neurons (mitral and
tufted neurons).

Plexiform layer. This layer consists of tufted neurons, some granule cells,
and a few mitral cells with their processes.

Mitral cell layer. This layer is composed of large neurons (mi-tral

neurons).

Granule layer. Composed of small granule neurons and processes of

granule and mitral cells, this layer also contains incoming fibers from other
cortical regions.

The mitral and tufted cells are considered the principal neurons of the olfactory
bulb. Their dendrites establish synaptic relationships with the olfactory nerve
fibers within the glomeruli.

The granule cells (GABAergic inhibitory neurons) are considered to be the

intrinsic neurons of the olfactory bulb. These cells have vertically oriented
dendrites but no axon and exert their action on other cells solely by dendrites.

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The olfactory bulb contains two other varieties of intrinsic neurons. These are the
periglomerular short axon cells in close proximity to the glomeruli in the
glomerular layer and the deep short axon cells located in the granule layer.

Dopamine has been reported to be present in the olfactory bulb. Its depletion in
patients with Parkinson's disease may explain the decrease of the sense of smell
in patients with Parkinson's disease.

The olfactory bulb receives fibers (input) from the following sources:

1. Olfactory hair c ells in the nasal mucosa

2. Contralateral olfactory bulb

3. Primary olfactory cortex

4. Diagonal band of Broca

5. Anterior olfactory nucleus

The output from the olfactory bulb is the olfactory tract.

Olfactory Tract
The olfactory tract (see Figures 21-1 and 21-2) is the outflow pathway of the
olfactory bulb. It is composed of the axons of principal neurons (mitral and tufted
cells) of the olfactory bulb and centrifugal axons originating from the
contralateral olfactory bulb, as well as from central brain regions. The olfactory
tract also contains the scattered neurons of the anterior olfactory nucleus, the
axons of which contribute to the olfactory tract. At its caudal extremity, just
anterior to the anterior perforated substance, the olfactory tract divides into the
olfactory striae (see Figures 21-1 and 21-2).

Olfactory Striae
At its caudal extremity, just rostral to the anterior perforated substance, the
olfactory tract divides into three striae:

1. Lateral olfactory stria

2. Medial olfactory stria

3. Intermediate olfactory stria.

Each of the striae is covered by a thin layer of gray matter, the olfactory gyri.

The lateral olfactory stria projects to the primary olfactory cortex in the temporal
lobe. The medial olfactory stria projects on the medial olfactory area, also known
as the septal area, located on the medial surface of the frontal lobe, ventral to
the genu and rostrum of the corpus callosum (subcallosal gyrus) and anterior to
the lamina terminalis. The medial olfactory area is closely related to the limbic
system and hence is concerned with emotional responses elicited by olfactory
stimuli. It does not play a role in the perception of olfactory stimuli. The medial
and intermediate striae are poorly developed in humans. The intermediate stria
blends with the anterior perforated substance. The thin cortex at
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this site is designated the intermediate olfactory area. The primary terminal

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stations of the three olfactory striae (olfactory cortices) are interconnected by

the diagonal band of Broca, a bundle of subcortical fibers in front of the optic
tract, and with a number of cortical and subcortical areas concerned with visceral
function and emotion (hippocampus, thalamus, hypothalamus, epithalamus, and
brain stem reticular formation). Through these connections, the olfactory system
exerts influence on visceral function (salivation, nausea) and behavioral
reactions.

Primary Olfactory Cortex

The primary olfactory cortex is located within the uncus of the temporal lobe and
is composed of the prepiriform cortex, periamygdaloid area, and part of the
entorhinal area. The prepiriform cortex is the region on each side of and beneath
the lateral olfactory stria; hence it is also called the lateral olfactory gyrus. It is
considered the major part of the primary olfactory cortex. The primary olfactory
cortex is relatively large in some animals, such as the rabbit, but in humans it
occupies a small area. The primary olfactory cortex in humans is concerned with
the conscious perception of olfactory stimuli. In contrast to all other primary
sensory cortices (vision, audition, taste, and somatic sensibility), the primary
olfactory cortex is unique in that afferent fibers from the receptors reach it
directly without passing through a relay in the thalamus.

The primary olfactory cortex contains two types of neurons. These are (1)
principal neurons (pyramidal cells) with axons that leave the olfactory cortex and
project to nearby or distant regions and (2) intrinsic neurons (stellate cells) with
axons that remain within the olfactory cortex.

The major input to the primary olfactory cortex is from (1) the olfactory bulb via
the lateral olfactory stria and (2) other central brain regions. The output from the
olfactory cortex is via axons of principal neurons that project to nearby areas
surrounding the primary olfactory cortex, as well as to more distant areas, such
as the thalamus and hypothalamus, which play important roles in behavior and
emotion.

Olfactory Mechanisms
Olfaction is a chemical sense. For a substance to be detected, it should have the
following physical properties:

z Volatility, so that it can be sniffed

z Water solubility, so that it can diffuse through the olfactory epithelium

z Lipid solubility, so that it will interact with the lipids of the membranes of
olfactory receptors

After an odorous substance is dissolved in the fluid bathing the surface of the
olfactory mucosa, it interacts with receptor sites located on the cilia of receptor
cells. The binding of a single appropriate molecule to one receptor site causes a
change in membrane permeability. The ion flux that ensues gives rise to a slow
surface negative wave (receptor or generator potential) that can be detected at
the surface of the receptor cell. An all-or-none action potential, however, can be
detected in the axons of receptor cells.

The olfactory receptors show a marked variability in sensitivity to different odors.

They can detect methyl mercaptan (garlic odor) in a concentration of less than

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one-millionth of a milligram per liter of air but ethyl ether in a concentration of

5.8 mg per liter of air.

Olfactory receptors adapt rather quickly to a continuous stimulus. Although the

olfactory mucosa can discriminate among a large number of different odors, its
ability to detect changes in concentration of an odorous substance is rather poor.
It is estimated that the concentration of an odorous substance must change by 30
percent before it can be detected by receptor cells. The mechanism of
discrimination is poorly understood but is probably related to a spatial pattern of
stimulation of the receptor cells.

TASTE
The gustatory (taste) sense organs in higher vertebrates are limited to the
cavity of the mouth. Taste receptors are located within taste buds in the
tongue (circumvallate and fungiform papillae), as well as in the soft palate,
oropharynx, and epiglottis. Circumvallate papillae are distributed in the back of
the tongue, whereas fungiform papillae are scattered on the anterior two-thirds
of the tongue. There are about 2000 taste buds in the human tongue. This
number decreases progressively with age. It is estimated that taste buds are lost
at a rate of 1% per year with increased rate after 40 years of age. Taste
sensations are conveyed centrally via three cranial nerves: the facial (CN VII),
glossopharyngeal (CN IX), and vagus (CN X) cranial nerves.

Taste Buds (Figure 23-2)

Taste buds are barrel-like structures distributed in the epithelium of the tongue,
soft palate, oropharynx, and epiglottis. Each taste bud is composed of receptor
(neuroepithelial), supporting and basal cells, and nerve fibers.

A. Receptor Cells
Two types of receptor cells can be identified in taste buds, clear receptor cells
and dense receptor cells. Clear receptor cells contain clear vesicles; dense
receptor cells contain dense-core vesicles that store glycosaminoglycans. Both
cell types presumably function as receptors. They are believed to represent two
stages in the development of receptor elements, the dense cell being the more
mature. The apex of each receptor cell is modified into microvilli, which increase
the receptor surface area and project into an
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opening, the taste pore. Approximately 4 to 20 receptor cells are located in the
center of each taste bud. Receptor elements decrease in number with age.
Receptor cells are stimulated by substances in solution.

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Figure 23-2. Schematic diagram of the cellular components of the taste

bud.

B. Supporting Cells
These are spindle-shaped cells that surround the receptor cells. They are located
at the periphery of the taste bud. They have both an insulating function and a
secretory function. They are believed to secrete the substance that bathes the
microvilli in the taste pore.

C. Basal Cells
Basal cells are located at the base of the taste bud and, by division, replenish the
receptor cells that are lost continually with an average life span of 10–14 days.

D. Nerve Fibers
The nerve fibers in the taste bud are terminal nerve fibers of the facial (chorda
tympani branch), glossopharyngeal (lingual-tonsillar branch), and vagus nerves
(superior laryngeal branch). They are peripheral processes of sensory neurons in
the geniculate ganglion of the facial nerve and in the inferior ganglia of the
glossopharyngeal and vagus nerves (petrosal and nodose ganglia, respectively).
They enter the taste bud at its base and wind themselves around the receptor
cells in close apposition to receptor cell membranes. Synaptic vesicles cluster on
the inner surfaces of receptor cell membranes at sites of apposition to nerve
terminals.

Physiology of Taste
Although all taste buds look alike histologically, sensitivity to the four basic taste
modalities is different in different regions of the tongue. Like olfaction, the sense
of taste is a chemical sense. Although humans can taste a large number of
substances, only four primary taste sensations are identified:

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z Sour

z Salty

z Sweet

z Bitter

Figure 23-3. Schematic diagram of the gustatory pathways.

Most taste receptors respond to all four primary taste modalities at varying
thresholds but respond preferentially at a very low threshold to only one or
two. Thus taste buds at the tip of the tongue respond best to sweet and salty
substances, and those at the lateral margins and posterior part of the tongue
respond best to sour and bitter substances, respectively.

The ability of taste buds to detect changes in concentration of a substance is

poor, similar to the response of olfactory receptors. A difference in taste intensity
remains undetected until the concentration of a substance has changed by 30
percent. Substances in solution enter the pore of the taste bud and come in
contact with the surface of taste receptors located on microvilli of taste receptor
cells. This contact induces a change in the electrical potential of the membrane of
the receptor cells (receptor or generator potential). The receptor potential in turn
generates an action potential in nerve terminals in apposition to the receptor cell
surface.

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Central Transmission of Taste Sensations (Figure

23-3)
Taste sensations from the anterior two-thirds of the tongue are mediated to
the central nervous system via the chorda tympani of the seventh (facial)
cranial nerve, those from the posterior one-third of the tongue via the ninth
(glossopharyngeal) cranial nerve, and those from the epiglottis and
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lower pharynx via the tenth (vagus) cranial nerve. These nerves contain the
peripheral processes of pseudounipolar sensory nerve cells located in the
geniculate ganglion (seventh nerve), petrous ganglion (ninth nerve), and nodose
ganglion (tenth nerve). These peripheral processes enter the deep ends of the
taste buds and establish intimate contact with the neuroepithelial cells of the
buds.

The central processes of these sensory neurons project to the nucleus of the
tractus solitarius (the rostral part of the nucleus, the gustatory subnucleus)
in the brain stem. Axons of neurons in the nucleus solitarius project on a number
of reticular nuclei (especially the parabrachial nucleus in the pons) before
crossing the midline to reach the ventral posterior medial (VPM) nucleus of the
thalamus, giving on their way collateral branches to such nuclei as the nucleus
ambiguus and salivatory nuclei for reflex activity. From the VPM nucleus, axons
project (via the posterior limb of the internal capsule) to the cerebral cortex to
terminate on neurons in the inferior part of the somesthetic cortex, just anterior
to the face area (primary gustatory cortex).

VISION
Vision is by far the most important of the human senses. Most of our perception
of the environment around us comes through our eyes. Our visual system is
capable of adapting to extreme changes in light intensity to allow us to see
clearly; it is also capable of color discrimination and depth perception. The organ
of vision is the eye; accessory structures are the eyelids, lacrimal glands, and
extrinsic eye muscles.

The eye has been compared with a camera. Although structurally the two are
similar, the camera lacks the intricate automatic control mechanism involved in
vision. As an optic instrument, the eye has four functional components: a
protective coat, a nourishing lightproof coat, a dioptric system, and a receptive
integrating layer. The protective coat is the tough, opaque sclera which covers
the posterior five-sixths of the eyeball; it is continuous with the dura mater
around the optic nerve. The anterior one-sixth is covered by a transparent
cornea, which belongs to the dioptric system. The nourishing coat is made up of
the vascular choroid, which supplies nutrients to the retina and, because of its
rich content of melanocytes, acts as a light-absorbing layer. It corresponds to the
pia-arachnoid layer of the nervous system. Anteriorly, this coat becomes the
ciliary body and iris. The iris ends at a circular opening, the pupil.

The dioptric system comprises the cornea the lens the aqueous humor within the
anterior eye chamber, and the vitreous body. The dioptric system helps focus the
image on the retina. The greatest refraction of incoming light takes place at the
air-cornea interface. The lens is supported by the suspensory ligament from the
ciliary body, and changes in its shape permit change of focus. This is a function
of the ciliary muscle which is supplied by the parasympathetic nervous system. In
late middle age, the lens loses its elastic properties, and a condition known as

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presbyopia results, wherein accommodative power is diminished, especially for

near vision. The amount of light entering the eye is regulated by the size of the
pupil. Pupillary size is controlled by the action of the constrictor and dilator
smooth muscles of the iris. The constrictor muscle is supplied by the
parasympathetic nervous system and the dilator muscle by the sympathetic
nervous system.

The receptive integrating layer of the eye is the retina, which is an extension of
the brain, to which it is connected by the optic nerve. The rods and cones are the
sensory retinal receptors.

The Retina
Light rays falling on the eye pass through its refractive media (cornea, lens,
and anterior and posterior chambers) before reaching the visual receptor
cells (the rods and cones) in the retina. The refractive media help focus the
image on the retina.

The retina (Figure 23-4), an ectodermal derivative, is an outward extension of

the brain, to which it is connected by the optic nerve. The human retina is made
up of the following ten layers, starting with the outermost:

z Layer of pigment epithelium

z Layer of rods and cones

z External limiting membrane

z Outer nuclear layer

z Outer plexiform layer

z Inner nuclear layer

z Inner plexiform layer

z Layer of ganglion cells

z Optic nerve layer

z Internal limiting membrane

Five types of neurons are distributed throughout these layers:

z Receptor cells

z Bipolar cells

z Ganglion cells

z Horizontal cells

z Amacrinecells

A. Layer of Pigment Epithelium (Figure 23-4)

The pigment epithelium is a single layer of melanin-containing, pigmented
cuboidal cells firmly bound at their bases to the choroid layer. The cell membrane
at the apices of these epithelial cells is specialized into slender microvilli that
interdigitate with the outer segments of photoreceptor cells. The lateral walls
show conspicuous zonulae occludentes and zonulae adherentes as well as

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desmosomes and gap junctions. The function of this layer includes providing
nutrients and mechanical support for the photoreceptors and protecting retinal
receptors from the damaging effect of excessive light by absorption of excess
light. Retinal detachment, essentially a splitting of this layer from the other
retinal layers, is nowadays treated with laser surgery.

B. Layer of Rods and Cones (Figure 23-4)

The rods and cones are the light-sensitive parts of the photoreceptors. The
human retina contains approximately 100 million rods and 6 to 7 million cones.
The rods and cones differ in their distribution along the retina. In humans, a
modified region called the fovea contains only cones and is adapted for high
visual acuity. At all other points along the retina, rods greatly outnumber cones.

1. Rods (Figure 23-4).

The rod photoreceptor cell is a modified neuron having as components the cell
body, axonal process, and photosensitive process. The cell body contains the
nucleus. This part of the rod is located in the outer nuclear layer. The axonal
process is located in the outer plexiform layer. The photosensitive process is
located in the layer of rods and cones. The photosensitive process of the rod is
made up of two segments, outer and inner, connected by a narrow neck
containing cilia. The outer segment has been shown by electron microscopy to be
filled with stacks of double-membrane disks containing the
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visual pigment rhodopsin. The disks are not continuous with the cell membrane.
The function of the outer segment is to trap the light that reaches the retina. The
visual pigment molecules are positioned within the disk membranes in such a way
as to maximize the probability of their interacting with the path of incident light.
The extensive invagination of the disk membranes increases the total surface
area available for visual pigment. Rhodopsin is composed of a vitamin A aldehyde
(retinal) combined with the protein scotopsin. Exposure to light breaks the bond
between retinal and the protein. This chemical change triggers a change in the
electric po-tential and produces a generator (receptor) potential. The stacked
disks in the outer segment are shed continually and are replaced by the infolding
of the cell membrane. The outer segments are separated and supported by
processes from the layer of pigment epithelium.

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Figure 23-4. Schematic diagram of the layers of the retina and their cellular
components.

The inner segment of the rod's photosensitive process contains mitochondria,

glycogen, endoplasmic reticulum, and Golgi apparatus. It is the site of formation
of the protein scotopsin, which subsequently moves to the outer segment. The
inner segment is connected to the cell body of the rod fiber, which traverses the
external limiting membrane. The outer segment of rods is the photosensitive
part, where the receptor potential is generated, whereas the inner segment is the
site of metabolic activity, where protein and phospholipids are synthesized and
energy is produced. Extremely sensitive to light, rods are the receptors used
when low levels of light are available, such as at night.

2. Cones (Figure 23-4).

Cones have the same structural components as the rods (cell body, axonal
process, and photosensitive process). The photosensitive processes of cones, like

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those of rods, contain outer and inner segments. The disks in the outer
segments, unlike those of rods, are attached to the cell membrane and are not
shed. They contain iodopsin, an unstable, light-sensitive visual pigment
composed of vitamin A aldehyde conjugated to a specific protein (cone opsin).
Cones are sensitive to light of higher intensity than that required for rod vision.

C. External Limiting Membrane (Figure 23-4)

A sievelike sheet, the external limiting membrane, is fenestrated to allow the
passage of processes that connect the photosensitive processes of rods and cones
with their cell bodies. It also contains the outer processes of Müller's
(supporting) cells.

D. Outer Nuclear Layer (Figure 23-4)

The outer nuclear layer of the retina contains the cell bodies of rods and cones
with their nuclei. Cone nuclei are ovoid and limited to a single row close to the
external limiting membrane. Rod nuclei are rounded and distributed in several
layers.

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E. Outer Plexiform Layer (Figure 23-4)

Also known as the outer synaptic layer, the outer plexiform layer contains axonal
processes of rods and cones, as well as dendrites of bipolar cells and processes of
horizontal cells.

F. Inner Nuclear Layer (Figure 23-4)

The inner nuclear layer contains cell bodies and nuclei of bipolar cells and
association cells (horizontal and amacrine) as well as supporting (Müller's) cells.
The layer has three zones: an outer zone containing horizontal cells, an
intermediate zone containing bipolar cells, and an inner zone containing amacrine
cells.

Three types of bipolar cells are recognized. Rod bipolar cells are related to
several rod axons, midget bipolar cells are related to one cone axon, and flat
bipolar cells are related to several cone axons.

The horizontal association cells are larger than bipolar cells. Their axons and
dendrites are located in the outer plexiform layer. Their axons establish synapses
with rod and cone axons, whereas their dendrites establish relationships with
cone axons. Thus they connect cones of one area with cones and rods of another
area.

The amacrine association cells are pear shaped. Each has a single process that
terminates on a bipolar or ganglion cell process in the inner plexiform layer.
Müller's supporting cells send their processes to the outer plexiform layer.

G. Inner Plexiform Layer (Figure 23-4)

The inner plexiform, also called synaptic, layer contains axons of bipolar cells,
dendrites of ganglion cells, and processes of the association (amacrine) cells.

H. Layer of Ganglion Cells (Figure 23-4)

The perikarya of multipolar ganglion cells constitute the eighth layer of the

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retina. Two types of ganglion cells are recognized on the basis of their dendritic
connections: a monosynaptic (midget) ganglion cell related to a single bipolar
midget cell and a diffuse (polysynaptic) ganglion cell related to several bipolar
cells. The axons of ganglion cells traverse the inner surface of the retina and
collect at the papilla, where they penetrate the sclera to form the optic nerve.
This part of the retina contains no receptor cells and is called the blind spot. In
humans, the number of ganglion cells is estimated to be 1 million.

I. Optic Nerve Layer (Figure 23-4)

The optic nerve layer is composed of axons of ganglion cells that form the optic
nerve, as well as some Müller's fibers and neu-roglial cells. Axons of ganglion
cells in this layer are unmyelinated but have a glial sheath around them. They
run toward the posterior pole of the eye, where they form the optic disk and
penetrate the sclera to form the optic nerve.

J. Internal Limiting Membrane (Figure 23-4)

The expanded inner ends of the processes of Müller's cells form the internal
limiting membrane. Müller's cells, the cell bodies of which are located in the inner
nuclear layer, send processes both outward to the external limiting membrane
and inward to the internal limiting membrane. They are thus homologous to glial
cells of the central nervous system.

Variations in Retinal Structure

The retinal structure just described is maintained throughout the retina except at
two sites, the fovea centralis in the central area of the retina and the ora serrata
at the periphery of the retina. In both sites, the ganglion cell layer, inner
plexiform layer, and bipolar cell layer are absent.

The fovea centralis represents the area of greatest visual acu-ity, and its center
contains only cones arranged in multiple rows. The cones of the fovea are slender
and resemble rods. The thinning of the retina at the fovea centralis reduces to a
minimum tissue through which light passes, hence improving visual acuity. Cones
in this area function for sharp vision and color perception. Surrounding the fovea
centralis in the posterior pole of the eye on the temporal side of the optic disk is
a 1-mm yellowish area, the macula lutea.

Near the ora serrata, at the periphery of the retina, rods predominate, increase
in thickness, and become shorter. The cones decrease in number and also become
shorter.

The retina receives its vascular supply from two sources. The outer retina is
vascularized by the choriocapillaris layer of the choroid. The inner retina receives
its blood supply from the central artery of the retina and its branches. The foveal
area, the area of most acute vision, is vascularized mostly by the underlying
choriocapillaries of the choroid. If the retina surrounding the fovea becomes
semiopaque, as in occlusion of the central retinal artery or in some of the lipid
storage diseases (e.g., Tay-Sachs disease), the choroid underlying the thin
avascular fovea appears as a bright red circle called a cherry red spot.

Synaptic Organization of the Retina (Figure 23-5)

The human retina is considered to be a simple retina in which there is relatively
little processing of information, compared with complex retinas, such as the

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frog's, in which information processing is more extensive. The different types of

cells encountered in the retina can be divided into three categories:

z Input elements (rods and cones)

z Output elements (ganglion cells)

z Intrinsic elements (bipolar, horizontal, and amacrine cells)

It is estimated that the human retina contains 100 million rods, 6 to 7 million
cones, and 1 million ganglion cells. This provides input-to-output ratios of 100:1
for rods and 5:1 for cones. This difference correlates well with the function of
cones, namely, high-acuity vision. The input-to-output ratio is lowest
(approximately 1:1) in the fovea centralis, where visual acuity is highest.

Synaptic interaction in the retina takes place in two layers, the outer plexiform
layer and the inner plexiform layer.

A. Synaptic Interaction in the Outer Plexiform Layer

(Figure 23-5)
In the outer plexiform layer, synaptic interaction occurs both vertically and
horizontally. The vertical interaction is represented by the rod and cone terminals
on bipolar cell dendrites. The horizontal interaction is represented by the
interaction of horizontal cell processes with both rod and cone axons. Axon
terminals of rods (rod spherules) are smaller than cone terminals; the latter are
flat or pyramidal and large (cone pedicles).

1. Receptor–Bipolar Cell Interaction.

Bipolar cells provide a link between photoreceptor cells (rods and cones) and
ganglion cells.

As stated previously, there are three varieties of bipolar cells. A rod bipolar cell
forms synapses with several rod spherules. A midget bipolar cell forms synapses
with one cone pedicle. A flat bipolar cell forms synapses with several cone
pedicles.

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Figure 23-5. Schematic diagram of the types of synaptic activity within the
retina.

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2. Horizontal Cell–Receptor Interaction.

Horizontal cell processes form synapses with several cones or rods, relating
cones of one area to rods and cones of another area. Processes of horizontal cells
are not classified as either axons or dendrites and possibly transmit
bidirectionally.

Horizontal cells receive excitatory (glutaminergic) input from photoreceptor

cones, and in turn form inhibitory GABAergic contact with adjacent photoreceptor
rods and cones. They thus serve to sharpen transmission by surround inhibition.

B. Synaptic Interaction in the Inner Plexiform Layer

(Figure 23-5)
In the inner plexiform layer, synaptic interaction occurs vertically, between

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bipolar and ganglion cells, as well as horizontally, among amacrine, bipolar, and
ganglion cells.

1. Bipolar Cell–Ganglion Cell Interaction.

Rod bipolar cells project on several ganglion cells. Midget bipolar cells relate to
one ganglion cell (midget ganglion cell). Flat bipolar cells relate to several
ganglion cells.

2. Amacrine, Bipolar, and Ganglion Cell Interaction.

Amacrine cells relate to axons of bipolar cells as well as to dendrites and
perikarya of ganglion cells. Amacrine cell processes, like horizontal cell
processes, probably conduct bidirectionally.

C. Characteristics of Synaptic Interaction

It is apparent, from the preceding description, that synaptic activity in the retina
has the following characteristics:

z It is oriented both vertically (receptor-bipolar-ganglion cell axis) and

horizontally (via horizontal and amacrine cell con-nections).

z It is carried out by both diffuse (flat bipolar- or rod bipolar–polysynaptic

ganglion cell) and oligosynaptic (midget bipo-lar–midget ganglion cell)
pathways (Figure 23-5).

Photochemistry and Physiology of the Retina

The retina contains two types of photoreceptors, the rods and the cones. The
rods are highly sensitive to light, have a low threshold of stimulation, and are
thus best suited for dim-light vision (scotopic vision). Such vision, however, is
poor in detail and does not differentiate colors (achromatic). The cones, however,
have a high threshold of stimulation and function best in strong illumination
(daylight) (photopic vision). They provide the substrate for acute vision as well
as color vision.

On exposure to light, the visual pigments in the outer segments of the rods and
cones (rhodopsin and cone opsin, respectively) break down into two components,
retinal (colorless pigment) and the protein opsin. The degradation of visual
pigment
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triggers a change in the electric potential of the photoreceptors (receptor or
generator potential). The generator potential of rods and cones (unlike similar
potentials in other receptors) is in the hyperpolarizing direction. This unique
response of the photoreceptors has been attributed to the fact that the
photoreceptor membrane is depolarized in the resting state (darkness) by a
constant entry of sodium ions into the outer segment through cyclic guanosine
monophosphate (cGMP)–gated ionophores. Exposure to light closes the cGMP-
gated ionophores and reduces the permeability of the membrane to sodium ions,
lowers the electric current, and hyperpolarizes the membrane. Thus
hyperpolarizing currents in photoreceptors are produced by turning off
depolarizing sodium ion conductance, whereas the orthodox hyperpolarization—
inhibitory postsynaptic potential (IPSP)—seen in other neurons is produced by

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turning on hyperpolarizing potassium ion conductance in the neuronal membrane.

The generator potential of photoreceptors leads to hyperpolarization or

depolarization of the bipolar and horizontal cells. Neither of these cell types,
however, is capable of triggering a propagated action potential.

On the basis of their hyperpolarizing or depolarizing re-sponse, two types of

bipolar cells are identified. One type (off cell) responds by hyperpolarization to a
light spot in the center of its receptive field and by depolarization to a light spot
in the area surrounding the center (the surround). The other type (on cell)
responds in a reverse fashion by depolarization to a light spot in the center of its
receptive field and by hyperpolarization to the surround. The bipolar cell is the
first of the retinal elements to show this variation of response in relation to the
spatial position of the stimulus in its receptive field.

The amacrine cell responds to a light stimulus by a propagated, all-or-none

action potential. It is the first cell of the retinal elements to generate a
propagated action potential.

Ganglion cells discharge continuously at a slow rate in the absence of any

stimulus. On superimposition of a circular beam of light, ganglion cells may
behave in a variety of ways. Some cells increase their discharge in response to
the superimposed stimulus (“on” cells). Others inhibit their discharge in response
to the superimposed stimulus but discharge again with a burst when the stimulus
is turned off (“off” cells). Still others increase their discharge when the stimulus
is turned both on and off (“on-off” cells). Furthermore, the behavior of ganglion
cells, like that of bipolar cells, is regulated by the spatial position of the stimulus
in their receptive field. “On” cells, which increase their discharge in response to a
spot of light in the center of their receptive field, inhibit their discharge when
light is shone in the area surrounding the center. The same principle applies to
“off” cells, which inhibit their discharge in response to a light stimulus in the
center of the receptive field but increase their discharge when the stimulus is
shone in the surround.

Furthermore, some ganglion cells respond only to a steady stimulus of light in

their receptive field, whereas others respond only to a change in intensity of
illumination; still others respond only to a stimulus moving in a particular
direction.

Dark and Light Adaptation

When an individual moves from an environment of bright light to dim light or
darkness, the retina adapts and becomes more sensitive to light. This process,
called dark adaptation, takes about 20 min to become maximally effective. The
time required for maximal adaptation to darkness can be shortened by wearing
red glasses. Light waves in the red end of the spectrum do not effectively
stimulate the rods, which remain dark-adapted. Nor do red light waves interfere
with cone stimulation, so the individual can still see in bright light. The process
of dark adaptation has two components, a fast one attributed to adaptation of
cones and a slower one attributed to adaptation of rods.

Conversely, when an individual moves from a dark environment to a bright one, it

takes time to adapt to the bright environment. This process, called light
adaptation, takes about 5 min to be effective.

A. Night Blindness

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Night blindness (nyctalopia) is encountered in individuals with vitamin A

deficiency. As mentioned previously, photoreceptor pigment is formed of two
substances, vitamin A aldehyde (retinal) and the protein opsin. In vitamin A
deficiency, the total amount of visual pigment is reduced, thus decreasing the
sensitivity to light of both rods and cones. Although this reduction does not
interfere with bright-light (daylight) vision, it does significantly affect dim-light
(night) vision, because the amount of light is not enough to excite the depleted
visual pigment. This condition is treatable by administration of vitamin A.

Color Vision
Color vision is a function of the retina, lateral geniculate nucleus, and cerebral
cortex. In the retina, the cone receptors and the horizontal cells as well as
ganglion cells take part in the integration of color vision. According to the Young-
Helmholtz theory of color vision, there are three varieties of retinal cone
receptors: those which respond maximally to long wavelengths in the red end of
the spectrum (L-cones), those which respond maximally to medium wavelengths
in the green end of the spectrum (M-cones), and those which respond maximally
to short wavelengths in the blue range of the spectrum (S-cones). A
monochromatic color (red, green, or blue) stimulates one variety of cones
maximally and the other varieties of cones to a variable but lesser degree. Blue
light, for example, stimulates blue cones maximally, green cones much less so,
and red cones not at all. This pattern is interpreted centrally as blue color. Two
monochromatic colors stimulating two types of cones equally and simultaneously
are interpreted as a different color; thus, if green and red lights stimulate green
and red cones simultaneously and equally, they are interpreted as yellow.
Simultaneous and equal stimulation by red, green, and blue lights is interpreted
as white.

The horizontal cells respond to a particular monochromatic color by either

depolarization or hyperpolarization. A red-green horizontal cell responds by
depolarization to red light and by hyperpolarization to green light. Such a cell is
turned off by equal and simultaneous stimulation by red and green light. There
are also yellow-blue horizontal cells, accounting for the four hues—red, green,
blue, and yellow. The depolarization and hyperpolarization responses of
horizontal cells also explain why red with green and blue with yellow are
complementary colors, which, when mixed together in proper amounts, result in
the cancellation of color.

Ganglion cells of the retina respond in an “on-off” manner to monochromatic

light. Thus there are green “on” and red “off” ganglion cells, blue “on” and yellow
“off” ganglion cells, and so on.

Furthermore, there are color-sensitive neurons in the lateral geniculate nucleus

and occipital cortex that respond maximally to color in one part of the spectrum.
They also play a role in color discrimination. The color-contrast cells in the
striate cortex form a distinct population separate from cells concerned with
brightness contrast. As with cells concerned with brightness discrimination, the
color-contrast cells can be divided into simple, complex, and hypercomplex cells.

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A. Color Blindness
Some people have a deficiency in or lack of a particular color cone. Such people
have color weakness or color blindness, respectively. Most color-blind persons

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are red-green blind; a minority are blue blind. Among the group blind to red-
green, there is a preponderance of green color blindness.

Color blindness for red and green is inherited by an X-linked recessive gene; thus
there are more males with red-green color blindness than females. Color
blindness for blue is inherited through an autosomal gene and is much less
common. Pure red color blindness is known as protanopia. Pure green color
blindness is known as deuteranopia. Blue-yellow blindness is known as tritanopia.

Color blindness was first described, in 1794, by John Dalton, a color-blind English
chemist. The phenomenon may have been reported earlier, in 1777, by Joseph
Huddard.

Visual Pathways
Axons of ganglion cells in the retina gather together at the optic disk in the
posterior pole of the eye, penetrate the sclera, and form the optic nerve. At
the point of exit of ganglion cell axons from the retina the optic disk is devoid of
receptor elements (blind spot). There are approximately one million axons in the
optic nerve. Outside the sclera, the optic nerve is covered by extensions of the
meninges that ensheathe the brain. Marked increase in intracranial pressure from
tumors or bleeding inside the cranial cavity or an increase in cerebrospinal fluid
pressure around the nerve sufficient to interfere with venous return from the
retina results in swelling of the optic disk (papilledema). This swelling can be
seen using a special instrument, an ophthalmoscope, which views the retina
through the pupil. The optic nerve enters the cranial cavity through the optic
foramen. Thus tumors of the optic nerve (optic glioma) may be diagnosed by
taking radiographs of the optic foramen, which appears enlarged in such
conditions. Lesions of the optic nerve produce unilateral blindness on the side of
the lesion (Figure 23-6).

The two optic nerves come together at the optic chiasma where partial crossing
of optic nerve fibers takes place. Optic nerve fibers from the nasal half of each
retina cross at the optic chiasma. Fibers from the temporal halves remain
uncrossed. The optic chiasma is related to the hypothalamus above and pituitary
gland below. Thus tumors in the pituitary gland encroaching (as they do initially)
on the crossing fibers of the optic nerve cause degeneration of optic nerve fibers
arising in the nasal halves of both retinae. This results in loss of vision in both
temporal fields of vision (bitemporal hemianopia) (Figure 23-6).

The crossed and uncrossed fibers from both optic nerves join caudal to the
optic chiasma to form the optic tract. Lesions of the optic tracts, therefore,
cause degeneration of optic nerve fibers from the temporal half of the ipsilateral
retina and nasal half of the contralateral retina. This produces loss of vision in
the contralateral half of the visual field (homonymous hemianopia) (Figure 23-6).

The lateral geniculate nucleus is laminated into six layers. Not all parts of the
retina are represented equally in the lateral geniculate nucleus. Proportionally
much more of the nucleus is devoted to the representation of the central area
than of the periphery of the retina.

Axons of neurons in the lateral geniculate nucleus project to the visual

cortex in the occipital lobe via the geniculocalcarine tract (optic radiation).
Geniculocalcarine fibers from the upper halves of both retinae course directly
backward around the lateral ventricle in the inferior part of the parietal lobe to
reach the visual cortex. Geniculocalcarine fibers from the lower halves of both

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retinae course forward toward the tip of the temporal horn of the lateral ventricle
and then loop backward (Meyer's loop, Flechsig's loop, Archambault's loop) in the
temporal lobe to reach the visual cortex. Lesions of the geniculocalcarine tract
give rise to a contralateral homonymous hemianopia similar to that occurring
with lesions of the optic tract (Figure 23-6). Because of the spread of
geniculocalcarine fibers in the parietal and temporal lobes, a lesion involving part
of this fiber system at these sites produces a contralateral quadrantic visual field
defect (upper if the temporal fibers are affected and lower if the parietal fibers
are affected) (Figure 23-7).

Figure 23-6. Schematic diagram of the visual pathways showing clinical

manifestations of lesions in various sites.

The geniculocalcarine fibers project on neurons in the pri-mary visual cortex

(area 17 of Brodmann). As described in the chapter on cerebral cortex

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(Chapter 17), fibers from the upper retina terminate in the upper calcarine gyrus,
those from the lower retina in the lower calcarine gyrus, those from the macular
area of the
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retina posteriorly, and those from the peripheral retina anteriorly in the visual
cortex. Thus a lesion destroying the whole of the visual cortex on one side
produces contralateral homonymous hemianopia, whereas a lesion destroying the
upper or lower calcarine gyrus will produce only a contralateral lower or an upper
quadrantic visual field defect. As stated in Chapter 17, vascular lesions in the
occipital cortex tend to spare the macular area because of its two sources of
blood supply (posterior and middle cerebral arteries).

Figure 23-7. Schematic diagram showing the clinical manifestations of

lesions in the optic radiation in the temporal and parietal lobes.

In addition to the classic geniculostriate visual pathway that terminates in the

primary visual (striate) cortex, a second visual pathway has been described; this
is the retinocolliculopulvinar-cortical pathway, which terminates in extrastriate
cortical areas, including areas 18 and 19 and the temporal lobe. The classic
geniculostriate pathway is concerned with the identification of objects, whereas
the second visual pathway is important for processing highly abstracted visual
perceptions.

HEARING

The Ear
The ear has three compartments: external, middle, and internal. Each component
plays a specific role in the hearing process. The organs of hearing and
equilibrium are located within the internal compartment of the ear.

A. External Ear

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The external ear is formed of the auricle or pinna external auditory canal, and
tympanic membrane. The auricle collects sound and funnels it into the external
auditory meatus. The external auditory canal is a narrow tube through the
temporal bone.

The tympanic membrane (eardrum) delimits the external auditory canal medially.
The core of the tympanic membrane is tough connective tissue made up of
collagen and elastic fibers and fibroblasts.

B. Middle Ear
The middle ear (tympanic cavity) is located within the temporal bone. It
communicates with the nasopharynx anteriorly via the eustachian (auditory) tube
and with the mastoid air cells posteriorly. The tympanic membrane separates the
middle ear medially from the external ear laterally. Two windows (oval and
round) separate the middle ear from the inner ear. The middle ear cavity is
traversed by three bony ossicles. The malleus is attached to the tympanic
membrane, the stapes fits into the foramen ovale (oval window), and the incus is
in between. The three ossicles transmit sound vibrations from the tympanic
membrane to the oval window. The cavity also contains two muscles, the tensor
tympani and stapedius. The tensor tympani muscle inserts into the malleus and
the stapedius muscle into the stapes.

C. Inner Ear
The inner ear, located within the petrous portion of the temporal bone,
contains two systems of canals or cavities, the osseous labyrinth and the
membranous labyrinth. Both systems contain fluids, perilymph in the osseous
labyrinth and endolymph in the membranous labyrinth. Perilymph has a high
concentration of sodium ions, whereas endolymph has a high concentration of
potassium ions. The osseous labyrinth has a large central cavity, the vestibule,
located medial to the tym-panic cavity. Three semicircular canals open into the
vestibule posteriorly, and a coiled winding tube, the cochlea, communicates with
the vestibule anteriorly.

The membranous labyrinth, located within the osseous labyrinth, maintains a

similar configuration. The central cavity of the membranous labyrinth (within the
vestibule of the osseous labyrinth)
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contains two cavities. The utricle, the posterior cavity, communicates with the
membranous labyrinth of the semicircular canals (semicircular ducts). The
saccule, the anterior cavity, communicates with the membranous labyrinth of the
cochlea (cochlear duct). At the junction of the membranous semicircular canals
(semicircular ducts) with the utricle, the epithelium of the semicircular ducts
becomes specialized to form a receptive sensory area (neuroepithelium) for
equilibrium, the crista am-pullaris. Similar sensory receptive areas in the utricle
and saccule are the macula utriculi and the macula sacculi. The macula sacculi is
located in the floor of the saccule, whereas the macula utriculi is in the lateral
wall of the utricle at right angles to the saccule. The sensory receptive organ for
hearing is the organ of Corti within the cochlear duct.

Sound Transmission (Figure 23-8)

Our current knowledge of sound transmission started in the sixth century B.C.
when Pythagoras, the Greek mathematician, introduced the concept that sound

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was a vibration in the air. Seven centuries later, in 175 A.D., Galen, the Greek
physician, recognized that the sensation of sound was transmitted to the brain
via nerves. The gap in knowledge between Pythagoras's sound as air vibration
and Galen's nerves transmitting sound to the brain was filled in 1543 by the
Belgian anatomist Andreas Vesalius, who discovered the malleus and incus bones
in the middle ear. Several years later, in 1546, Ingrassias discovered the third
middle ear ossicle, the stapes. In 1561, the Italian anatomist Gabriello Fallopius
named the cochlea, and in 1851, Alfonso Corti, the Italian anatomist, discovered
the organ of Corti.

Sound waves traverse the external ear and middle ear before reaching the inner
ear, where the auditory end organ (organ of Corti) is located. The tympanic
membrane between the external ear and middle ear vibrates in response to
pressure changes produced by the incoming sound waves. Vibrations of the
tympanic membrane are transmitted to the bony ossicles of the middle ear
(malleus, incus, and stapes). The handle of the malleus is attached to the
tympanic membrane, and the footplate of the stapes is attached to the oval
window between the middle ear and inner ear. Vibrations of the footplate of the
stapes are then transmitted to the membrane of the oval window and
subsequently to the fluid medium (perilymph) of the inner ear.

Figure 23-8. Schematic diagram of the three compartments of the ear

showing transmission of sound waves.

The tensor tympani muscle, attached to the handle of the malleus, and the
stapedius muscle, attached to the neck of the stapes, have a damping effect on
sound waves. Loud sounds cause these muscles to contract reflexively, to prevent
strong sound waves from excessively stimulating the hair cells of the organ of
Corti; this is the tympanic reflex. When this damping effect is lost, as in lesions
of the facial nerve (which supplies the stapedius muscle), or the trigeminal nerve
(which supplies the tensor tympani) sound stimuli are augmented unpleasantly
(hyperacusis).

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Because of the marked difference in elasticity and density between air and fluid,
almost 99 percent of acoustic energy is reflected back at the air-fluid interface
between the middle ear and inner ear. This is counteracted by two mechanisms.
First, the ratio between the surface areas of the tympanic membrane and the
footplate of the stapes is approximately 25:1. However, because the tympanic
membrane is not a piston but a stretched membrane attached around its edge, its
effective area is 60 to 75 percent of its actual area. Thus the ratio between the
effective area of the tympanic membrane and the area of the footplate of the
stapes is only 14:1. Second, the lever effect counteracts energy lost at the air-
fluid interface. The movements of the tympanic membrane are transmitted to the
malleus and incus, which move as one unit. The manubrium of the malleus is a
longer lever than the long process of the incus. The force exerted at the footplate
of the stapes is thus greater than that at the tympanic membrane by a ratio of
1.3:1.

The total pressure amplification via the two mechanisms just described thus
counteracts the energy lost at the air-fluid interface. The total gain in force per
unit area achieved by conductance in the middle ear is a factor of about 18.

Cochlea
The cochlea is a snail-shaped structure consisting of two and one-half spirals
filled with fluid. It has three compartments (Figure 23-9), the scala vestibuli,
scala tympani, and scala media (cochlear duct). The three compartments wind
together in a circular pattern around a central core, the modiolus which contains
the spiral ganglion. The scala vestibuli and scala tympani are separated by a
bony shelf (osseous spiral lamina) projecting from the modiolus across the
osseous canal of the cochlea.

The scala media, lying between the scala vestibuli (above) and the scala tympani
(below), contains the auditory end organ (organ
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of Corti). The scala vestibuli and scala tympani are continuous through the
helicotrema at the apex of the coil. The oval window and round window separate,
respectively, the scala vestibuli and scala tympani from the middle ear (Figure
23-9).

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Figure 23-9. Schematic diagram showing the three components of the

cochlea and their interrelationships.

Vibrations of the oval window are transmitted to the perilymph in the scala
vestibuli and, subsequently, via Reissner's membrane (which separates the scala
vestibuli from the scala media), to the endolymph of the scala media. Vibrations
in the endolymph are then transmitted via the basilar membrane (which
separates the scala media from the scala tympani) to the perilymph of the scala
tympani and out through the round window.

Auditory End Organ (Organ of Corti)

The organ of Corti (Figure 23-10) is located in the scala media (cochlear duct),
which is separated from the underlying scala tympani by the basilar membrane
and from the scala vestibuli by Reissner's (vestibular) membrane. The cochlear
duct is part of the endolymphatic system and contains endolymph. The basilar
membrane forms the base of the cochlear duct and gives support to the organ of
Corti (Figure 23-10). The organ of Corti contains the following cellular elements
(Figure 23-11).

A. Hair Cells
The auditory receptor cells, the hair cells, are of two types: inner hair cells,
which number approximately 3500 arranged in a single row, and outer hair cells,
which number approximately 20,000 arranged in three to four rows. The
“hairs” (or stereocilia) of the hair cells are in contact with the tectorial
membrane, which transmits to them vibrations from the endolymph. The hair
cells are columnar or flask shaped, with a basally located nucleus and about 50 to
100 hairlike projections emanating from their apical surfaces. Cochlear nerve
fibers establish synapses with their basal membranes.

B. Supporting Cells
Supporting cells are tall, slender cells extending from the basilar membrane to
the free surface of the organ of Corti. They include the following cell types: pillar
or rod cells (outer and inner), phalangeal (Deiters') cells (outer and inner), and
cells of Hensen.

1. Pillar Cells.
Pillar cells are filled with tonofibrils. The apices of the inner and outer pillar cells
converge at the free surface of the organ of Corti and fan out as a cuticle to
form, along with a similar formation of Deiters' cells, a thin plate through which
the apices of the inner and outer hair cells pass. The space between inner and
outer pillar cells comprises a fluid-filled tunnel of Corti.

2. Phalangeal (Deiters') Cells.

Arranged in three to four outer rows and one inner row, Deiters' cells give
support to the outer and inner hair cells, respectively. They extend from the
basilar membrane, like all supporting cells, to the free surface of the organ of
Corti, where they contribute to the formation of the cuticular plate through which
the hairs of the hair cells pass. Phalangeal cells are flask shaped and contain

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tonofibrils. Some of the tonofibrils support the base of the hair cells; others
extend along their sides to the free surface of the organ.

3. Cells of Hensen.
Cells of Hensen are columnar cells located adjacent to the outermost row of outer
phalangeal cells. They
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constitute the outer border of the organ of Corti. They merge laterally with
cuboidal cells (cells of Claudius). Similar (cuboidal) cells adjacent to the inner
phalangeal cells, known as border cells, constitute the inner border of the organ.

Figure 23-10. Schematic diagram of the cochlear compartments showing

the organ of Corti in the scala media.

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Figure 23-11. Simplified schematic diagram of the cellular components of

the organ of Corti.

4. Tectorial Membrane.
The tectorial membrane is a gelatinous structure in which filamentous elements
are embedded. It extends over the free surface of the organ of Corti. The hairs of
the hair cells are attached to the tectorial membrane. Vibrations in the
endolymph are transmitted to the tectorial membrane, resulting in deformation of
the hairs attached to it. Such deformation initiates an impulse in the afferent
nerve fibers in contact with the basal part of the hair cells.

5. Nerve Supply.
The hair cells of the organ of Corti receive two types of nerve supply, afferent
and efferent. The afferent fibers are peripheral processes of bipolar neurons in
the spiral ganglion located in the bony core (modiolus) of the cochlear spiral.
There are about 30,000 bipolar neurons in the spiral ganglion, 90 percent of
which (type I neurons) innervate the inner hair cells. Each inner hair cell receives
contacts from about ten fibers; each fiber contacts only one inner hair cell. The
remaining 10 percent (type II neurons) innervate the outer hair cells; each fiber
di-verges to innervate many outer hair cells.

The efferent fibers originate in the contralateral superior olive and

periolivary nuclei in the pons. These fibers form the olivocochlear bundle of
Rasmussen, which leaves the brain stem via the vestibular component of the
vestibulocochlear (eighth cranial) nerve, joins the cochlear component
(vestibulocochlear anastomosis), and terminates peripherally on the outer hair
cells and the afferent terminal boutons innervating inner hair cells. These fibers
have an inhibitory effect on auditory stimuli.

Auditory Physiology
A. Conduction of Sound Waves
Sound waves may reach the inner ear via three routes:

z Ossicular route

z Air route

z Bone route

1. Ossicular Route.
The ossicular route normally conducts sound. Sound waves entering the external
auditory meatus produce vibrations in the tympanic membrane, which are
transmitted to the bony ossicles of the middle ear and through them to the
footplate of the stapes. The energy lost at the air-fluid interface in the oval
window is counteracted by the factors outlined previously.

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2. Air Route.
An alternate route, the air route, is used when the orthodox ossicular route is not
operative owing to disease of the ossicles. In this situation, vibrations of the
tympanic membrane are transmitted through air in the middle ear to the round
window. This route is not effective in sound conduction.

3. Bone Route.
Sound waves also may be conducted via the bones of the skull directly to the
perilymph of the inner ear. This route plays a minor role in sound conduction in
normal individuals but is utilized by deaf people who can use hearing aids.

B. Fluid Vibration
Vibrations of the footplate of the stapes are transmitted to the perilymph of the
scala vestibuli. Pressure waves in the perilymph are transmitted via Reissner's
membrane to the endolymph of the scala media and, through the helicotrema, to
the perilymph of the scala tympani (Figure 23-9).

C. Vibrations of Basilar Membrane

Pressure waves in the endolymph of the scala media produce traveling waves in
the basilar membrane of the organ of Corti. The basilar membrane varies in width
and degree of stiffness in different regions. It is widest and more flaccid at its
apex and thinnest and more stiff at its base.

Pressure waves in the endolymph initiate a traveling wave in the basilar

membrane that proceeds from the base toward the apex of the membrane. The
amplitude of the traveling waves varies at different sites on the membrane
depending on the frequency of sound waves. High-frequency sounds elicit waves
with highest amplitude toward the base of the membrane. With low-frequency
sounds, the waves with highest amplitude occur toward the apex of the
membrane. Similarly, each sound frequency has a site of maximum amplitude
wave on the basilar membrane. The frequency of the wave, measured in cycles
per second or hertz (Hz), determines its pitch. The amplitude of the wave is
correlated with its loudness; a special scale, the decibel (dB) scale, is used to
measure this aspect of sound. Thus the basilar membrane exhibits the
phenomenon of tonotopic localization seen along the central auditory pathways
all the way to the cortex.

D. Receptor Potential
Vibrations of the basilar membrane produce displacement of the hair cells, the
hairs of which are attached to the tectorial membrane. The shearing force
produced on the hairs by the displacement of hair cells is the adequate stimulus
for the receptor nonpropagated potential of the hair cells. Hair cells, like all
excitable nerve cells, have an excess of negatively charged ions inside and an
excess of positively charged ions in the surrounding endolymph. The
displacement of the stereocilia of hair cells opens pores on the stereocilia, which
allows positive ions to rush inside, causing depolarization. This receptor potential
is also known as the cochlear microphonic potential. It can be recorded from the
hair cells and their immediate neighborhood and is a faithful replica of the
mechanical events of sound waves described previously.

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E. Action Potential
The receptor potential causes the hair cell to release neurotransmitter substances
that interact with receptors on nerve terminals
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and thus initiates an action potential in the afferent nerves in contact with hair
cells.

Increasing the intensity of sound of a particular frequency raises the number of

hair cells stimulated, the number of afferent nerve fibers activated, and the rate
of discharge of impulses. A single nerve fiber responds to a range of frequencies
but is most sensitive to a particular frequency, called its characteristic frequency;
this is related to the region of the basilar membrane that the fiber innervates.
Fibers innervating the part of the basi-lar membrane near the oval window have
high characteristic frequencies, whereas those innervating the part of the basilar
membrane near the apex of the cochlea have low characteristic frequencies.

F. Central Transmission
Action potentials generated in the afferent nerve fibers travel via the central
components (axons) of bipolar neurons in the spiral ganglion to reach the
cochlear nuclei in the pons. The cochlear nuclei contain a variety of physiologic
cell types. In addition to cells that respond to tone bursts in a manner similar to
primary eighth nerve fibers, there are cells that respond only to the onset of the
stimulus, some in which the rate of firing builds up slowly during the course of
the stimulus and others that pause, showing no response to the onset of the
stimulus. Axons of cochlear nuclei synapse in some or all of several brain stem
nuclei (nucleus of the trapezoid body, superior olive, nucleus of the lateral
lemniscus, inferior colliculus, reticular nuclei of the brain stem, medial geniculate
nucleus) before terminating in the primary auditory cortex (transverse gyri of
Heschl) in the temporal lobe. The central auditory pathways are organized into
two systems: core pathways, and belt pathways. Core pathways are direct, fast
conducting, and tonotopically organized. Belt pathways are less tonotopically
organized.

Otoacoustic Emissions
Recent research on the cochlea has suggested that the cochlea not only receives
sounds but also produces sound. The term otoacoustic emission has been coined
to describe this observation. It is now believed that the outer hair cells are the
source of otoacoustic emissions.

Audiometry
The quantitative clinical assessment of hearing acuity is known as audiometry;
the resulting record is the audiogram. In audiometry, pure tones of known
frequency and varying intensity are presented via earphones to the individual,
who is asked to signal a response when he or she hears a tone. The examiner
records the audible frequencies and intensities on a chart. The record is then
examined to compare the audible range of the individual with that of normal
individuals.

Deafness
The range of audible frequencies in the normal adult is 20 to 20,000 Hz. With

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advancing age, there is a decrease in perception of high frequencies (high-

frequency deafness). This loss correlates with the loss of hair cells in the basal
turns of the cochlea. Similar high-frequency deafness is encountered in
individuals intoxicated by the antibiotic streptomycin. Rock band performers, on
the other hand, develop middle-frequency deafness.

Deafness disorders generally are separated into two groups, conductive deafness
and sensorineural deafness. The first group includes deafness due to obstruction
of the external auditory meatus by wax, as well as middle ear diseases, such as
chronic otitis media and ossicle sclerosis. The second group includes conditions in
which hair cells are affected (advancing age, streptomycin toxicity), as well as
diseases of the auditory nerve, such as nerve tumors (acoustic neuroma).

The two types of deafness can be identified clinically by use of the tuning fork. A
vibrating tuning fork is placed in front of the ear and then on a bony prominence
over the skull. A person with normal hearing can hear the tuning fork better when
it is placed in front of the ear. A subject with conductive deafness hears the
tuning fork better when it is placed over a bony prominence, because sound
waves bypass the site of obstruction in the external auditory meatus or the
middle ear and reach the auditory end organ via the round window or directly
through skull bones to the perilymph.

In patients with unilateral sensorineural deafness, a tuning fork placed over the
forehead will be heard best in the healthy ear, since air conduction in such
patients is better than bone conduction.

Patients with severe sensorineural deafness may be helped by cochlear implants.

VESTIBULAR SENSATION
The receptors of the vestibular sense organ are located in the semicircular
canals, utricle, and saccule in the inner ear. The utricle and saccule are
located in the main cavity of the bony labyrinth, the vestibule; the semicircular
canals, three in number, are extensions of the utricle (Figure 23-12). Vestibular
sensory receptors are located in the floor of the utricle, wall of the saccule, and
dilated portions (ampullae) of each of the three semicircular canals. The optimal
stimulus for receptors in the utricle and saccule is linear acceleration of the body
(as occurs in body motion on a swing when coupled with gravity to change the
direction and degree of the acceleration and head tilt), whereas receptors in the
semicircular canals respond to angular acceleration resulting from head or body
turns.

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Figure 23-12. Schematic diagram of the vestibular end organ.

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The vestibular receptor in the semicircular canal (crista ampullaris) is composed
of hair cells and supporting cells (Figure 23-13). The hair cells are of two types.
The type I hair cell is flask shaped and is surrounded by a nerve terminal (calyx).
The type II hair cell is cylindrical and is not surrounded by a calyx. Both types of
hair cells show on their free surfaces about 40 to 100 short stereocilia (modified
microvilli) and one long kinocilium attached to one border of the cell. The short
stereocilia increase progressively in length toward the kinocilium. The stereo-cilia
are nonmotile; the kinocilium is motile.

Supporting cells are slender columnar cells that reach the basal lamina; their free
surfaces are specialized into microvilli. The subapical parts of supporting cells are
related to adjacent hair cells by junctional complexes.

The apical processes of hair and supporting cells are embedded in a dome-
shaped, gelatinous protein-polysaccharide mass, the cupula. The cupula swings
from side to side in response to currents in the endolymph that bathes it.

The vestibular receptor organ of the utricle and saccule (macula) is similar in
structure to that of the semicircular canals. The gelatinous mass into which the
apical processes of hair and supporting cells project is the otolithic membrane. It
is flat and contains numerous small crystalline bodies, the otoliths or otoconia,
composed of calcium carbonate and protein.

The hair cells of the semicircular canals, utricle, and saccule receive both afferent
and efferent nerve terminals (Figure 23-13). The afferent terminals contain clear
vesicles, whereas efferent terminals contain dense-core vesicles. In type II hair
cells, both afferent and efferent terminals are related to the cell body and are
sites of neurochemical transmission. In type I hair cells, the calyx that surrounds
the hair cell is regarded as the afferent nerve terminal. The efferent terminals in

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type I hair cells are applied to the external surface of the calyx.

Figure 23-13. Schematic diagram of the vestibular sensory receptor.

Type I hair cells receive vestibular nerve fibers that are large in diameter and
fast conducting. Each vestibular nerve fiber innervates a small number of type I
hair cells. Thus type I hair cells are regarded as more discriminative than type II
hair cells, which receive small-diameter, slow-conducting vestibular nerve fibers
projecting on a large number of hair cells.

The stimulus adequate to discharge hair cells is movement of the cupula or

otolithic membrane, which bends or deforms the stereocilia. Deformation of
stereocilia toward the kinocilium triggers inflow of potassium ions into the hair
cells from the endolymph and depolarization of cell membrane. Deflection of
stereocilia away from the kinocilium allows potassium ions to flow out of cells and
hyperpolarization of hair cell membrane. The resting vestibular end organ has a
constant discharge of impulses detected in afferent vestibular nerve fibers. This
resting activity is modified by mechanical deformation of the stereocilia. Bending
the stereocilia toward the kinocilium increases the frequency of resting discharge,
whereas bending the stereocilia away from the kinocilium lowers the frequency.
The signals emitted by hair cells of the vestibular end organ are transmitted to
the central nervous system via processes of bipolar cells in Scarpa's ganglion
that terminate on neurons in the four vestibular nuclei in the pons. Output of
vestibular nuclei is directed to several central nervous system regions, including
the spinal cord, cerebellum, thalamus, and nuclei of extraocular movements. The
pathway to the primary vestibular cortex in the temporal lobe is not well defined

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but most likely passes through the thalamus.

Although we are normally not aware of the vestibular component of our

sensory experience, this component is essential for the coordination of
motor responses, eye movements, and posture.

TERMINOLOGY
Amacrine (Greek a, “negative” makros, “long”).
Having no long processes. The amacrine cells of the retina have no long
processes.

Bowman's gland.
Branched and tubuloalveolar glands located beneath the olfactory epithelium.
Secretions of the glands are impor-tant in dissolving odorous substances and
diffusing them to olfactory receptor cells. Named after Sir William Bowman
(1816–1892), an English ophthalmologic surgeon and anatomist.

Cells of Hensen.
Type of cells in the organ of Corti. Named after Viktor Hensen (1835–1924), a
German physiologist.

Chiasma (Greek chiasma, “two-crossing line,” from the shape of the letter
chi, “X”).
The decussation of the fibers of the optic nerve. The decussation was described
by Galen without naming it. It was named by Rufus of Ephesus.

Ciliary muscle (Latin cilium, “eyelid or eyelash”).

Smooth muscles of the ciliary body; the circumferential fibers were described by
Heinrich Müller in 1858 and the radial fibers by William Bowman in 1847.
Together they control the aperture of the pupil and the degree of curvature of
the lens.

Circumvallate (Latin circum, “around”; vallare, “to wall”).

Surrounded by a trench or wall.

Cochlea (Latin, “snail shell,” from Greek “a winding staircase”).

The coiled winding tube of the cochlea in the inner ear resembles a snail shell. It
was first described by Eustachio (1552) and named cochlea by Fallopius about
1561.
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Cornea (Latin corneus, “horny”).

The transparent structure forming the anterior part of the fibrous tunic of the
eye.

Corti, Alfonso Marchese (1822–1888).

Italian histologist who described the end organ of hearing, the organ of Corti.

Cribriform (Latin cribrum, “a sieve”; forma, “form”).

The cribriform plate of the ethmoid bone is so named because of the numerous
perforations.

Cupula. (Latin, “a small inverted cup or dome-shaped cap”). Deiters' cells.

Also known as phalangeal cells. One type of cell in the organ of Corti. Described
by Otto Friedrich Karl Deiters (1834–1863), a German anatomist.

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Deuteranopia (Greek deuteros, “second”; an, “negative”; opia, “vision”).

Complete insensitivity to green. Patients confuse red and green but are sensitive
to red light.

Eustachian tube.
The auditory tube, a connection between the middle ear and nasopharynx. Named
after Bartolommeo Eustachio, the Italian anatomist who provided the classic
description of this structure in 1563. The term eustachian tube was coined by Val
Salva in 1704. The eustachian tube was known to the ancients. Alcmaeon (500
B.C.) had dissected it. It was described by Aristotle and other early writers.

Fallopius, Gabriel (1523–1563).

Italian anatomist. Credited with description of the facial canal and of the
trochlear, trigeminal, glossopharyngeal, and vagus nerves as well as the cochlea
in the inner ear. He is believed to have, in his drawings, noted the circle of Willis
before Thomas Willis.

Flechsig, Paul Emile (1847–1929).

Bohemian neurologist and psychiatrist. Defined the dorsal spinocerebellar tract
(Flechsig tract) in 1876 and the part of the optic radiation (known as Meyer's
loop or Flechsig loop) that loops around the tip of the temporal horn.

Fovea (Latin, “a pit, a small hollow”).

The part of the macula that receives light from the central part of the visual field
and which contains high concentration of cones.

Fungiform.
Shaped like a fungus or mushroom.

Galen, Claudius (130–201 A.D.).

Greek physician and founder of the galenical system of medicine. Among his
many contributions are the descriptions of the Great Vein of Galen, seven pairs
of cranial nerves, CSF production from choroid, CSF circulation, and transmission
of sound to the brain via nerves.

Gustatory (Latin gustatorius, “pertaining to the sense of taste”).

Helicotrema (Greek helix, “a spiral”; trema, “a hole”).

The passage or hole that connects the scala vestibuli at the apex of the cochlea
with the scala tympani. First described in 1761 by Cotugno and so named by
Breschet.

Hemianopia (Greek hemi, “half”; a, “without”; opia, “eye”).

Loss of vision in one-half the visual field.

Homonymous (Greek homos, “same”; onoma, “name”).

Pertaining to the corresponding halves of the visual fields.

Incus (Latin anvil, “one of the bones in the middle ear”).

So named by Vesalius in 1543, although probably seen much earlier.

Ingrassias, Giovanni Filipo (1510–1580).

Italian anatomist. Described the stapes bone in the middle ear in 1546. He called
it “stapha.” Eustachio later asserted (1564) that he had found the bone before
Ingrassias.

Labyrinth (Greek labyrinthos, “a system of interconnecting cavities or

canals,” as in the inner ear).

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Lens (Latin lentil, “a bean”).

The lens of the eye resembles a lentil.

Macula lutea (Latin, “a small spot, yellow”).

The portion of the retina on the temporal side of the optic disk. It contains the
greatest concentration of cone receptors.

Malleus (Latin malleus, “a hammer”).

One of the bones of the middle ear. So named by Vesalius in 1543, but probably
seen much earlier.

Meatus (Latin meo, “passage”).

The external auditory meatus is a path or a way for sound waves.

Meyer, Adolph (1866–1950).

Swiss neuropsychiatrist who immigrated to the United States and was on the
faculty of Cornell and Johns Hopkins. Described the part of the optic radiation
that loops around the tip of the temporal horn (Meyer's loop).

Mitral (Latin mitra, “a kind of a hat with two cusps, a tur-ban, or head
band”).

Modiolus (Latin, “the hub of a wheel”).

The central pillar of the cochlea. Described and so named by Eustachio in 1563.
Its structure suggests the hub of the wheel with radiating spokes (lamina
spiralis) attached to it.

Nyctalopia (Greek nyx, “night”; alaos, “blind”; opia, “eye”). Night

blindness.

Olfactory (Latin olfacere, “to smell”).

Pertaining to the sense of smell. The olfactory nerve, the first cranial nerve in
today's classification, was proposed by Soemmerring (1755–1830), the German
anatomist, although it was not included as a cranial nerve by Galen. The
olfactory nerves were first noted by Theophilus Protospatharius, physician to the
Emperor Heraclius in the seventh century A.D. The function of the olfactory nerve
was correctly stated by Achillini, and its relationship to the neuroepithelium of
the nasal mucosa was demonstrated by Max Schultze in 1856.

Organ of Corti.
Auditory end organ in the inner ear. Named after Marchese Alfonso Corti (1822–
1888), the Italian histologist who is known for his investigations of the
mammalian cochlea in 1851.

Pinna (Latin, “a feather”).

The part of the external ear that projects from the side of the head. So named by
Rufus of Ephesus.

Protanopia (Greek protos, “first”; an, “negative”; opia, “vi-sion”).

Absence of red sensitive pigment in cones. Patients are insensitive to red light
and confuse red and green light.

Pythagoras.
Greek mathematician. Proposed that sound is an air vibration. He also was the
first to advance the concept that the power of reasoning is in the brain.

Reissner's membrane.
The membrane that separates the scalae vestibuli and media. Described in 1851

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by Ernst Reissner (1824–1878), a German anatomist.

Scala (Latin, “stairway or ladder”).

The scala tympani and scala vestibuli are so named because of their circular
staircase appearance.

Sclera (Greek skleros, “hard”).

The outermost, tough, fibrous coat of the eyeball. The term was first used to
refer to the whole white outer layer by Salomon Albertus, professor of anatomy in
Wittenburg in 1585.

Stapes (Latin, “a stirrup”).

The stapes of the middle ear resembles a stirrup. So named by Ingrassias in
1546.

Tectorial membrane (Latin tego, “a covering”).

Tritanopia (Greek tritos, “third”; an, “negative”; opia, “vision”).

Absence of blue sensitive pigment in retinal cones. Patients are insensitive to
blue light but do not confuse red and green.

Vesalius, Andreas (1514–1564).

Belgian anatomist. Considered one of the greatest anatomists of all time.
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SUGGESTED READINGS
Barbur JL et al: Human visual responses in the absence of the geniculo-
calcarine projection. Brain 1980; 103:905–928.

Brown KT: Physiology of the retina. In Mountcastle VB (ed): Medical

Physiology, 14th ed, vol 1. St. Louis, Mosby, 1980:504.

Goldstein MH: The auditory periphery. In Mountcastle VB (ed): Medical

Physiology, 14th ed, vol 1. St. Louis, Mosby, 1980:428.

Hubel DH, Wiesel TN: Functional architecture of macaque monkey visual

cortex. Proc R Soc Lond [B] 1977; 198:1–59.

Hubel DH, Wiesel TN: Brain mechanisms of vision. Sci Am 1979; 241(3):150–
162.

Hudspeth AJ: The hair cells of the inner ear. Sci Am 1983; 248:54–64.

Kaneko A: Physiology of the retina. Annu Rev Neurosci 1979; 2:169–191.

Lim DJ: Functional structure of the organ of Corti: A review. Hear Res 1986;
22:117–146.

Mafee MF et al: Large vestibular aqueduct and congenital sensorineural

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hearing loss. AJNR 1992; 13:805–819.

Merigan WH, Maunsell JHR: How parallel are the primate visual pathways:
Annu Rev Neurosci 1993; 16:369–402.

Nelson GM: Biology of taste buds and the clinical problem of taste loss. The
Anat Rec (New Anat) 1998; 253:70–78.

Shepherd GM: Synaptic organization of the mammalian olfactory bulb.Physiol

Rev 1972; 52:864–917.

Uesaka Y et al: The pathway of gustatory fibers of the human ascends

ipsilaterally in the pons. Neurology 1998; 50:827–828.

Zeki S: The representation of colours in the cerebral cortex. Nature 1980;

284:412–418.

Zihl J, von Cramon D: The contribution of the “second” visual system to

directed visual attention in man. Brain 1979; 102:835–856.

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Editors: Afifi, Adel K.; Bergman, Ronald A.

Title: Functional Neuroanatomy: Text and Atlas, 2nd Edition

Copyright ©2005 McGraw-Hill

> Table of Contents > Part I - Text > 24 - Special Senses: Clinical Correlates

24
Special Senses: Clinical Correlates

Disorders of Olfaction
Abnormalities in Taste
Disorders of Vision
Disorders of Hearing
Vestibular Disorders

KEY CONCEPTS

The olfactory system may be involved in disease

processes at the olfactory receptors (common cold), olfactory
nerve (fractures of the cribriform plate of the ethmoid),
olfactory bulb and tract (inflammation, tumors), and olfactory
cortex (tumor, epilepsy).

Taste may be affected in lesions of the facial,

glossopharyngeal, and vagus cranial nerves and in lesions of
or near the primary gustatory cortex. Taste loss is also
associated with a variety of medical conditions, drugs, and
radiation.

Lesions of the optic nerve are associated with monocular

blindness. Lesions of the optic chiasma are associated with
bitemporal hemianopia. Lesions of the optic tract are
associated with contralateral homonymous hemianopia.

Lesions of the optic radiation in the temporal and parietal

lobes are associated with contralateral quadrantanopia.

Lesions of the upper or the lower bank of the calcarine

sulcus are associated with contralateral quadranta-nopia.

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Lesions of the primary visual cortex (both banks of the

calcarine sulcus) are associated with contralateral homony-
mous hemianopia.

In vascular lesions of the primary visual cortex (occlusion

of posterior cerebral artery), macular (central) vision is
preserved (macular sparing).

Sensorineural deafness results from disorders that

interfere with function of the auditory end organ, cochlear
nerve, cochlear nuclei, or central auditory pathways.

Vestibular disorders (peripheral and central) are

associated with vertigo, nystagmus, and truncal ataxia.

DISORDERS OF OLFACTION
The olfactory system can be affected in several sites with resulting
derangements in the sense of smell. Olfactory receptors are
decreased in number with age and are affected in common colds,
resulting in bilateral diminution or loss of smell (anosmia). Olfactory
nerve fibers may be affected in their course through the cribriform
plate of the ethmoid bone in fractures of the plate.

The olfactory bulb and tracts may be involved in inflammatory

processes of the meninges (meningitis) or tumors (meningioma) in the
frontal lobe or the anterior cranial fossa. Unilateral loss of smell may
be the earliest clinical manifestation in such processes. Loss of
dopamine in the olfactory bulb of Parkinson's patients is responsible for
the decrease of the sense of smell in such patients.

Pathologic processes in the region of the primary olfactory cortex (the

uncus of the temporal lobe) usually give rise to hallucinations of smell
(uncinate fits). The odor experienced in such cases is often described
as unpleasant. Such hallucinations may herald an epileptic seizure or
be part of it. They also may be a manifestation of a tumor in that
region.

ABNORMALITIES IN TASTE
Abnormal taste sensations (usually unpleasant sensations) occur
preceding a temporal lobe seizure or as part of the seizure, especially if
the epileptic focus is close to the uncus of the temporal lobe (uncinate
seizures) or to the primary gustatory cortex in the inferior part of the

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somesthetic cortex.

Taste loss (ageusia), decrease in taste (hypogeusia), and

abnormal taste (dysgeusia) are common disorders.
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They occur as a natural phenomenon of aging or in association with
pregnancy, menopause, and a variety of illnesses.

Taste sensations are impaired ipsilateral to lesions in the facial (CN

VII), glossopharyngeal (CN IX), and vagus (CN X) nerves. These nerves
convey taste sensations from the anterior two-thirds of the tongue (CN
VII), posterior third of the tongue (CN IX), and the epiglottis (CN X).

Patients with xerostomia (dry mouth), Sjögren syndrome (salivary

glands inflammation) diabetes, and zinc deficiency may experience loss
of taste.

Chemotherapeutic agents (methotrexate) used in the treatment of

cancer, as well as numerous drugs (dexamethasone, antihypertensive
agents, H 2 receptor agonists, antimicrobial agents), can also induce
loss of taste.

Taste loss usually follows radiation therapy to the oral cavity.

DISORDERS OF VISION
The visual system can be affected in several sites. Alterations in length
of the eyeball result in refraction errors. Normally, distant objects are
brought to focus on the retina. In persons with elongated eyeballs,
distant objects are brought to focus in front of the retina (myopic
eyes). In such persons, only near objects can be brought to focus on
the retina (nearsightedness). In persons with flattened eyeballs,
distant objects are brought to focus behind the retina (hyperopic
eyes). Both conditions can be corrected by use of appropriate lenses.

Night blindness (nyctalopia) is encountered in individuals with vitamin

A deficiency. Photoreceptor pigment is formed of vitamin A aldehyde
and a protein. Thus, in vitamin A deficiency states, the total amount of
visual pigment is reduced, decreasing the sensitivity to light of both
rods and cones. This reduction in visual pigment, while not affecting
bright-light (daylight) vision, does significantly interfere with dim-light
(night) vision. This condition is treatable by vitamin A administration.

Color blindness is associated with deficiency or lack of a particular

color cone. Most color blind persons are red-green blind; a minority are
blue blind. Color blindness for red and green is inherited by X-linked
recessive gene; hence it is more prevalent in males. Color blindness for
blue is inherited by autosomal recessive gene.

Lesions of the optic nerve (tumor, demyelination) (see Fig. 23-6)

result in monocular blindness (blindness in one eye). Lesions of

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the optic chiasma (see Fig. 23-6), where partial crossing of optic nerve
fibers occurs, result in bitemporal hemianopia (blindness in both
temporal visual fields) due to involvement of the crossing fibers. Such
a visual defect is seen in association with lesions in the pituitary gland
(pituitary adenoma) or tumors in the hypothalamus. Lesions in the
optic tract result (see Fig. 23-6) in homonymous hemianopia
contralateral to the lesion in the optic tract due to involvement of
crossed fibers from the contralateral retina and uncrossed fibers from
the ipsilateral retina.

Lesions of the direct path of the optic radiation in the parietal

lobe or of the indirect path of the optic radiation (Meyer's loop) in
the temporal lobe (see Fig. 23-6) result in quadrantic hemianopia. The
inferior quadrants of the visual field will be affected in parietal lobe
lesions and the superior quadrants in temporal lobe lesions.

Similarly, lesions of the upper or lower banks of the calcarine

sulcus will result in a quadrantic visual field defect, inferior in
upper bank lesions and superior in lower bank lesions.

Lesions of the primary visual cortex (upper and lower banks) (see
Fig. 23-6) result in contralateral homonymous hemianopia.

If the lesion is vascular (occlusion of posterior cerebral or

calcarine arteries), there will be macular sparing due to collateral
supply of the macular area from the middle cerebral artery.

DISORDERS OF HEARING
Disorders of hearing are generally of two types: conductive and
sensorineural. Conductive hearing loss is associated with processes
that interfere with conduction of sound waves in the external and
middle ears. Such processes include wax (cerumen) accumulations in
the external auditory meatus, chronic otitis media, and ossicle
sclerosis (otosclerosis).

Sensorineural hearing loss is associated with lesions of the hair

cells in the organ of Corti, the cochlear nerve (tumors of the
nerve, such as in cerebellopontine angle tumors, labyrinthine artery
occlusion), cochlear nuclei in the pons, or the central auditory
pathways. Hearing loss is ipsilateral to the lesion in disorders of the
hair cells, cochlear nerve, and cochlear nuclei. Lesions of the central
auditory pathways (lateral lemniscus, medial geniculate body, auditory
cortex) result in a bilateral decrease in hearing more marked
contralateral to the lesion. Ringing, buzzing, hissing, or paper crushing
noises (tinnitus) in the ear are early signs of diseases of the cochlea.

The two types of hearing disorders (conductive and sensorineural) are

differentiated by placing a vibrating tuning fork on the vertex in the
midline of the skull (Weber test) or alternately on the mastoid process

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and next to the auricle (Rinne test). Using the Weber test, a person
with normal hearing will hear the sound of the vibrating tuning fork
equally well in both ears. A person with conductive deafness in one ear
will hear the sound louder in the deaf ear because the masking effect
of environmental noises is absent on the affected side. A person with
sensorineural deafness will hear the sound louder in the normal ear.
With the Rinne test, a person with normal hearing will continue to hear
the sound of the vibrating tuning fork placed next to the ear (air
conduction) after he or she stops hearing the sound of the tuning fork
placed on the mastoid process (bone conduction). A person with
conductive deafness will not hear the vibrations of the tuning fork in
air after bone conduction is over. A person with sensorineural deafness
will continue to hear vibrations in air after bone conduction is over.

Cochlear implants are used today to treat patients with sensorineural

loss resulting from cochlear disease provided the auditory nerve and
central auditory pathways are intact.

VESTIBULAR DISORDERS
The vestibular system can be affected in several sites, including
the peripheral end organ in the inner ear, vestibular nerve,
vestibular nuclei, and central vestibular pathway, and by a variety of
disease processes, including infection, demyelination, vascular
disorders, and tumor. Disorders of the vestibular system are
manifested by an illusory sensation of motion (vertigo), oscillatory
involuntary eye movements (nystagmus), and postural disequilibrium
(truncal ataxia).

Lesions of the semicircular canals induce rotatory vertigo, whereas

disease of the utricle or saccule produces sensations of tilt or
levitation. An example of end-organ vertigo is sea sickness, which is
caused by irregular continuous movement of endolymph in susceptible
individuals. Vertigo also may occur with disease of vestibular
structures in the brain stem. This is usually
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associated with other signs of brain stem damage such as hemiparesis,
hemisensory loss, and cranial nerve signs.

Both central and peripheral vestibular lesions induce nystagmus, an

involuntary back-and-forth movement of the eyes in horizontal,
vertical, or rotatory pattern. Peripheral and central nystagmus are
differentiated from each other by the following: (1) fixation of the eyes
suppresses peripheral but not central nystagmus, and (2) pure vertical
or torsional nystagmus is usually central.

Truncal (vestibular) ataxia occurs in association with peripheral and

central vestibular disease. A dramatic feature of such patients is the
inability to stand upright without support and a staggering gait with a

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tendency to fall toward the side of the lesion.

TERMINOLOGY
Anosmia (Greek a, “negative”; osme, “smell”).
Loss of sense of smell.

Calcarine (Latin calcarinus, “spur-shaped”).

Pertaining to the calcar, a structure resembling a spur.

Cribriform plate (Latin cribrum, “a sieve”; forma, “form”).

The cribriform plate of the ethmoid bone has many holes (like a sieve)
through which olfactory nerve fibers pass.

Gustatory (Latin gustatorius, “pertaining to the sense of taste”).

Relating to the sense of taste.

Hemianopia (Greek hemi, “half”; an, “negative”; opia, “eye”).

Loss of vision in one-half the visual field of each eye.

Homonymous (Greek homo, “same”; onoma, “name”).

Per-taining to the corresponding halves of the visual field.

Hyperopia (Greek hyper, “above”; opia, “eye”).

An error of refraction (farsightedness) in which the entering light rays
are focused behind the retina as a result of a short eyeball from front
to back.

Meyer's loop.
Also known as Flechsig loop. The part of the optic radiation that loops
around the tip of the temporal horn before reaching the primary visual
cortex in the occipital lobe. Named after Adolph Meyer (1866–1950), a
Swiss-American neurologist and psychiatrist who described this loop.

Myopia (Greek myein, “to shut”; opia, “eye”).

An error of refraction (shortsightedness) in which light rays fall in
front of the retina as a result of a too long eyeball from front to back.

Nyctalopia (Greek nyx, “night”; alaos, “blind”; opia, “eye”).

Impairment of night vision. The original Greek usage referred to the
ability to see by night only. Galen changed the meaning to impairment
of night vision.

Nystagmus (Greek nystagmos, “drowsiness,” from nystazein, “to

nod”).
Involuntary, rapid rhythmic oscillations of the eyes.

Otosclerosis (Greek otos, “ear”; sklerosis, “hardening”).

Conductive hearing loss due to sclerosis of the ossicles in the middle
ear.

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Rinne test.
Hearing test to compare air and bone conduction of sound by placing a
vibrating tuning fork on the mastoid process and in front of the ear.
Named after H. A. Rinne (1819–1868), a German otolaryngologist who
described the test.

Tinnitus (Latin “ringing”).

Hallucinatory sound associated with cochlear disorders.

Uncinate (Latin, “hooked”).

Pertaining to the uncus. Uncinate fits are complex partial seizures in
which olfactory or gustatory hallucinations occur. The term was used
by Hughlings-Jackson, a British neurologist in 1899.

Vertigo (Latin vertigo, “turning or whirling around”).

Hallucination of movement, a sign of peripheral or central vestibular
system disorders.

Weber test.
A hearing test to differentiate conductive and sensorineural deafness
by placing a vibrating tuning fork on the vertex of the skull. Named
after Ernest Heinrich Weber, a German anatomist who described the
test in 1834.

SUGGESTED READINGS
Borruat FX et al: Congruous quadrantanopia and optic radiation
lesion. Neurology 1993; 43:1430–1432.

Brandt T: Man in motion: Historical and clinical aspects of

vestibular function. Brain 1991; 114:2159–2174.

Brandt T, Daroff RB: The multisensory physiological and

pathological vertigo syndromes. Ann Neurol 1980; 7:195–203.

Collard M, Chevalier Y: Vertigo. Curr Opin Neurol 1994; 7:88–92.

D'Amico DJ: Disease of the retina. N Engl J Med 1994; 331:95–106.

Luxon LM: Disorders of hearing. In Asbury AK et al (eds): Diseases

of the Nervous System: Clinical Neurobiology. Philadelphia,
Saunders, 1992:434.

Masdeu JC: The localization of lesions in the oculomotor system. In

Brazis PW et al (eds): Localization in Clinical Neurology. Boston,

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Little, Brown, 1985:118.

Nelson GM: Biology of taste buds and the clinical problem of taste
loss. The Anat Rec (New Anat) 1998; 253:70–78.

Newman NJ: Neuro-ophthalmology: The afferent visual system.

Curr Opin Neurol 1993; 6:738–746.

Sharpe JA, Johnston JL: Vertigo and nystagmus. Curr Opin Neurol
Neurosurg 1990; 3:789–795.

Troost BT: Nystagmus: A clinical review. Rev Neurol 1989;

145:417–428.

Zeki S: The visual image in mind and brain. Sci Am 1992; 267
(September):69–76.

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Editors: Afifi, Adel K.; Bergman, Ronald A.

Title: Functional Neuroanatomy: Text and Atlas, 2nd Edition

Copyright ©2005 McGraw-Hill

> Table of Contents > Part I - Text > 25 - Central Nervous System Development

25
Central Nervous System Development

Development
Embryogenesis
Histogenesis
Regional Development
Myelination
Prenatal Brain Performance
Postnatal Development and Growth
Functional Maturation
Cerebral Oxygen Consumption
Cerebral Blood Flow
Cerebral Metabolic Rate for Glucose
Postnatal Brain Performance
Myths and Facts
Aging
Morphologic Alterations
Functional Alterations

KEY CONCEPTS

Embryogenesis includes three developmental events: induction,

neurulation, and vesicle formation.

Almost all of the central nervous system develops by primary

neurulation. The sacral and coccygeal spinal cord segments develop by
secondary neurulation.

Dysraphic (neural tube) defects result from defective neurulation.

Histogenesis includes two processes: cellular differentiation and

cellular maturation.

Cells migrate from the ventricular zone to other zones of the neural
tube by using glial cell guides (radial glia).

Exposure of a fetus to radiation or infection early in development

leaves the fetus with serious defects.

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The alar plate of the neural tube gives rise to sensory structures in
the spinal cord and brain stem. The basal plate gives rise to motor
structures.

Layers II to VI of the cerebral hemisphere develop from the cortical

plate by an “inside-out” process.

Cerebral commissures develop from the commissural plate, a

specialized area in the lamina terminalis.

Myelination follows a caudal-rostral sequence in which motor and

sensory systems myelinate before association systems do.

DEVELOPMENT
The development of the central nervous system occurs in two stages: (1)
embryogenesis and (2) histogenesis.

Embryogenesis
Embryogenesis includes the following developmental events: (1) induction,
(2) neurulation, and (3) vesicle formation.

A. Induction
Induction is a process of cell-to-cell signaling by which the underlying mesoderm
induces the ectoderm to become neuroectoderm and form the neural plate, which
gives rise to most of the nervous system. Neuroectodermal induction is believed
to be due to the actions of hormones, neurotransmitters, and growth factors. The
specific biochemical mechanisms are unknown. The process of induction takes
place in the ectoderm of the head
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process overlying the notochord at about the seventeenth day of intrauterine life.

B. Neurulation
The process by which the neural plate folds over on itself and fuses in a
zipperlike fashion to become a neural tube is known as neurulation (Figure
25-1). There are two eurulation processes: (1) primary, by which most of the
neural tube is formed, and (2) secondary, by which the most caudal part of the
neural tube is formed.

1. Primary Neurulation.
Primary neurulation is the process by which the brain and most (cervical,
thoracic, upper lumbar) of the spinal cord form. Primary neurulation begins when
the notochord induces the overlying embryonic ectoderm to form a neural plate.
On about the eighteenth day of intrauterine life, the neural plate begins to
thicken at its lateral margins. Rapid growth at these margins results in elevation
of the margins and formation of neural folds as well as invagination of the neural
plate to form the neural groove. The elevated lateral margins of the neural tube

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(the neural folds) then approximate each other in the midline and fuse to form
the neural tube.

In the human embryo, fusion of the margins of the neural groove begins on the
twenty-first day in the region of the fourth somite (middle of the embryo,
presumptive cervical region) and proceeds in both directions; it is completed by
the twenty-fifth day. Two orifices delimit the completed neural tube, one at its
rostral end (anterior neuropore) and the other at its posterior end (posterior
neuropore).

Figure 25-1. Schematic diagram showing the stages of formation of the

neural tube.

Through these orifices, the lumen of the neural tube (the neural canal)
communicates with the amniotic cavity. The anterior neuropore closes on about
the twenty-fourth day of intrauterine life, and the posterior neuropore closes 2
days later. The neural canal persists as the future ventricular system.

2. Secondary Neurulation.
Secondary neurulation is the process by which the caudal parts of the spinal cord
(lower lumbar, sacral, and coccygeal segments) are formed. Secondary
neurulation begins on about the twenty-sixth day of intrauterine life as the
posterior neuropore is closing. At about that time a mass of cells, the caudal

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eminence, develops caudal to the neural tube. The caudal eminence then enlarges
and develops a cavity within itself. Eventually, the caudal eminence joins the
neural tube and its cavity becomes continuous with that of the neural tube.

Defective primary neurulation leads to a group of congenital central nervous

system malformations known as dysraphic defects. They include
anencephaly, in which the brain fails to form; encephalocele, in which the
intracranial contents, including the brain, herniate through a defect in the
cranium; and spina bifida cystica, in which the contents of the spinal canal,
including the spinal cord, herniate through a defect in the vertebral column.
Defects associated with secondary neurulation (myelodysplasias) include the
tethered cord syndrome, in which the conus medullaris and the filum terminale
are abnormally fixed to the vertebral column.

Two theories have been proposed for fusion sites in the formation of the neural
tube. The traditional theory (zipper model) states that the neural tube closes in a
continuous bidirectional process beginning in the cervical region. The other
theory (multisite closure model) states that neural tube fusion occurs at multiple
sites along the neural tube.

3. Neural Crest.
As the neural tube is being formed, a cluster of ectodermal cells that originally
was at the margins of the neural groove separate to form the neural crest. The
neural crest gives rise to the dorsal root (spinal) ganglia, including their satellite
cells; the sensory ganglia of cranial nerves V, VII, VIII, IX, and X; the
parasympathetic ganglia of cranial nerves VII, IX, and X; the autonomic ganglia
(paravertebral, prevertebral, enteric); the Schwann cells; the melanocytes; the
chromaffin cells of the adrenal medulla; and the pia and arachnoid layers of the
meninges.

C. Vesicle Formation
After closure of the anterior neuropore at about the twenty-fourth day of
intrauterine development, the rostral, larger portion of the neural tube subdivides
into three vesicles (Figure 25-2): the prosencephalon (forebrain), mesencephalon
(midbrain), and rhombencephalon (hindbrain).

At about the thirty-second day, the prosencephalon and rhombencephalon

subdivide further into two parts each, while the mesencephalon remains
undivided. The prosencephalon divides into an anterior telencephalon and a
posterior diencephalon. The telencephalon differentiates further into two
telencephalic vesicles which extend beyond the anterior limit of the original
neural tube (lamina terminalis) and eventually become the cerebral hemispheres.
From the diencephalon, two secondary bulges (the optic vesicles) appear, one on
each side. These structures differentiate to form the optic nerves and retinas.
The rhombencephalon divides into an anterior metencephalon and a posterior
myelencephalon. The metencephalon eventually becomes the pons and
cerebellum, and the myelencephalon is differentiated into the medulla oblongata.

Thus, the five vesicles that develop from the rostral part of the neural tube
eventually give rise to the whole brain. Table 25-1
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summarizes the sequence of events leading to the development of the various
regions of the brain.

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Figure 25-2. Schematic diagram showing the vesicle stages of brain

development.

As a result of the unequal growth of the different parts of the developing brain,
three flexures appear (Figure 25-3).

1. Midbrain Flexure.
The midbrain flexure develops in the region of the midbrain. As a result, the
forebrain (prosencephalon) bends ventrally until its floor lies almost parallel to
the floor of the hindbrain (rhombencephalon).

2. Cervical Flexure.
The cervical flexure appears at the junction of the hindbrain (rhombencephalon)
and the spinal cord.

3. Pontine Flexure.
The pontine flexure appears in the region of the developing pons.

The midbrain and cervical flexures are concave ventrally, whereas the pontine
flexure is convex ventrally.

D. Ventricular System
After the appearance of the three vesicles in the rostral part of the neural tube,
cavities develop within the vesicles. Initially, three cavities are visible,
corresponding to the three vesicles: (1) the prosocele, the cavity of the
prosencephalon; (2) the mesocele, the cavity of the mesencephalon; and (3) the
rhombocele, the cavity of the rhombencephalon.

Simultaneous with the division of the prosencephalon into the two telencephalic
vesicles and the diencephalic vesicle, the prosocele undergoes corresponding
divisions (Figure 25-4), resulting in the formation of the following structures:

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Table 25-1. Developmental Sequence of Brain Regions

Three-vesicle stage Five-vesicle stage Brain region

Prosencephalon Telencephalon Cerebral hemisphere

Diencephalon Diencephalon
Optic nerve and retina

Mesencephalon Mesencephalon Mesencephalon

Rhombencephalon Metencephalon Pons

Cerebellum

Myelencephalon Medulla oblongata

Figure 25-3. Schematic diagram showing the formation of flexures in brain

development.

1. Two telencephalic cavities, one on each side (lateral teloceles)

2. A midline cavity between the telencephalic vesicles (median telocele)

3. A diencephalic cavity (diocele)

The two lateral teloceles develop into the two lateral ventricles. The median
telocele and the diocele develop into the third ventricle. The cavity of the
mesencephalon (mesocele) remains undivided (Figure 25-4) and eventually

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becomes the aqueduct of Sylvius.

After the division of the rhombencephalon into a metencephalon and a

myelencephalon, its cavity (rhombocele) divides into the metacele, the cavity of
the metencephalon, and the myelocele, the cavity of the myelencephalon (Figure
25-4). The metacele and myelocele become the fourth ventricle.

As the different parts of the brain change shape, corresponding changes in the
cavities follow. The connections between the
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lateral ventricles and the third ventricle become smaller and constitute the
interventricular foramina of Monro. The median aperture (of Magendie) in the
roof of the fourth ventricle appears during the third month of intrauterine life,
followed by the appearance of the lateral apertures (of Luschka). Table 25-2
summarizes the sequence of events leading to the formation of the various
ventricles.

Figure 25-4. Schematic diagram showing the formation of brain cavities.

E. Choroid Plexus
The choroid plexus develops in the floor and roof of the lateral ventricle, and the
roofs of the third and fourth ventricles by a process of invagination of blood
vessels. As the neural tube thickens, the blood vessels on the surface of the pia
mater penetrate the brain surface carrying the pia mater with them. At sites of
formation of choroid plexus in the ventricles, the pial sheaths remain apposed to
the penetrating blood vessels and are adherent to the ependymal lining of the
ventricles. The choroid plexus is thus formed by a core of blood vessels
surrounded by pia which is adherent to the ependymal lining of the ventricles.

Histogenesis
Neurons and macroglia arise from a single precursor cell from which two
lineage cells arise: the neuroblast, which gives rise to neurons, and the
glioblast, from which macroglia (astrocytes and oligodendroglia) develop.
Microglia are derived not from neuroectoderm but from mesoderm-derived

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monocytes. Histogenesis includes two main processes: (1) cellular differentiation

and (2) cellular maturation.

A. Cellular Differentiation
Once it has been determined that a region will become part of the nervous
system, its cells begin to differentiate. Differentiation involves three phases:
cellular proliferation, migration of cells to characteristic positions, and
maturation of cells with specific interconnections.

When the neural tube is formed, the cells of the germinating epithelium
around the lumen of the tube (ventricular zone) proliferate actively between
the seventh and sixteenth weeks of gestation to form an ependymal layer of
columnar cells lining the cavity of the neural tube. Some of these cells migrate
pe-ripherally to form the intermediate (mantle) layer. Processes of cells in the
mantle layer extend to the periphery to form the marginal layer. Cell migration
from the periventricular zone to the periphery of the neural tube occurs between
the twelfth and twenty-fourth weeks of gestation and utilizes transient glial cell
guides (radial glia). Radial glia subsequently disappear and may be transformed
into astrocytes. As development continues, the central cavity diminishes in size,
the mitotic activity of the ependymal cells decreases, and three distinct layers
are established (Figure 25-5): the ependymal, intermediate (mantle), and
marginal. The intermediate (mantle) and marginal layers are the primordia of the
future gray and white matter, respectively.

Table 25-2. Developmental Sequence of Ventricular Cavities

Three-vesicle stage Five-vesicle stage Adult structure

Prosocele Lateral telocele Lateral ventricle

Median telocele Third ventricle
Diocele

Mesocele Mesocele Aqueduct of Sylvius

Rhombocele Metacele Fourth ventricle

Myelocele

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Figure 25-5. Schematic diagram of the three basic layers of the neural
tube.

A full-term fetus is born with a full complement of neurons. It has been

estimated that roughly 20,000 neurons are formed each minute during the
period of prenatal development. The rate varies in different growth periods. In
general, there are two growth spurts in the human embryo. The first extends
from the tenth week to the eighteenth week of gestation. The second begins in
the thirtieth week of gestation and extends through the second year of life. The
first growth spurt is vulnerable to irradiation, chromosomal anomalies, and viral
infections; these factors may leave the fetus with serious defects. Congenital
infection with toxoplasma, rubella, cytomegalovirus (CMV), and herpes simplex at
this stage may damage the developing heart, brain, and eyes of the fetus,
resulting in a newborn with congenital heart disease, mental retardation, and
blindness. The second growth spurt is sensitive to factors such as malnutrition.
Within any given neural region, different cell types are generated during specific
periods. In general, large nerve cells develop before small cells do, motor
neurons develop before sensory neurons do, and interneurons are the last to
develop. Glial cells proliferate after the neurons and continue to grow rapidly
after birth.

During histogenesis, one and a half to two times more neurons are produced than
are present in the mature brain. The excess neurons are disposed of during
development by a genetically determined process of programmed cell death
(apoptosis). Apoptosis is characterized morphologically by condensation of
nuclear chromatin, fragmentation of DNA, and formation of encapsulated cell
fragments that are then phagocytosed. Apoptosis in the spinal cord occurs before
25 weeks of gestation, whereas cortical apoptosis occurs late in gestation.
Apoptosis serves two purposes: (1) elimination of redundancy in number of
neurons and (2) regulation of neural connectivity, matching the size of input
population of neurons (usually in excess) with the number or size of the target
population.

B. Cellular Maturation
Neuronal maturation consists of four stages: (1) outgrowth and elongation of
axons, (2) elaboration of dendritic processes, (3) expression of appropriate

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biochemical properties, and (4) formation of synaptic connections.

Figure 25-6. Schematic diagram showing the stage of plate formation in

central nervous system development.

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Axons grow out before any other sign of neuronal maturation occurs. Axonal
growth is guided by specialized structures that are rich in actin filaments
important for motility at the tip of the growing process (growth cones) and is
influenced by factors that guide the neuron toward its target (tropic factors) and
factors that maintain the metabolism of the neuron (trophic factors). Axonal
growth is not random but is aimed toward a specific target.

Dendrites grow after axons have developed. Unlike axons, which have few
branches if any, dendrites may form elaborate branches.

When axonal growth cones arrive at their targets, they undergo biochemical and
morphologic changes to establish synapses. Similarly, the target cells undergo
changes to enhance synaptic interaction involving neurotransmitter receptors and
second messenger molecules. Normally, more synapses are produced than are
needed. Subsequently, many synapses are lost. The use and disuse of synapses
are important factors in their growth and regression.

Regional Development
A. Alar and Basal Plates
During the formation of the neural tube, a longitudinal groove appears on each
side of the lumen. This groove, known as the sulcus limitans, divides the neural
tube into a dorsal area, the alar plate, and a ventral area, the basal plate (Figure
25-6). Alar and basal plates give rise to all the elements destined to make up the
spinal cord, medulla oblongata, pons, and mesencephalon. The regions of the
brain rostral to the mesencephalon (diencephalon and cerebral cortex) develop
from the alar plate, as does the cerebellum. The mantle layer of the alar plate
generally gives rise to sensory neurons and interneurons, whereas that of the
basal plate gives rise to motor neurons and interneurons.

B. Spinal Cord

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The adult spinal cord maintains the organizational pattern of the

embryologic neural tube, with a central canal (neural canal), the ependyma
(ventricular zone), and central gray matter (intermediate, or mantle, zone)
surrounded by white matter (marginal zone). The cervical, thoracic, and upper
lumbar segments develop from the neural tube by the process of primary
neurulation. The lower lumbar, sacral, and coccygeal segments develop from the
caudal eminence by the process of secondary neurulation. The cord matures from
the cervical region caudally. The basal and alar plates give rise to the ventral
(motor) and dorsal (sensory) horns of the adult spinal cord, respectively. The
intermediate zone of the adult spinal cord develops from the interface of the alar
and basal plates. By the fourteenth week of gestation all the cell groups in the
central gray matter can be recognized. Axons of motor neurons in the ventral
horn develop in the fourth week of gestation and form the ventral root. Later in
the fourth week, axons from the dorsal root ganglia grow into the dorsal horn.

Early in development, the spinal cord and the vertebral column, which develop
from the surrounding mesoderm, grow at the same rate. At the end of the first
trimester of pregnancy, the spinal cord occupies the entire length of the vertebral
column and the spinal nerves travel at right angles to exit at their corresponding
intervertebral foramina. In the fourth month of gestation, however, growth of the
spinal cord slows in comparison with that of the vertebral column. By term, the
tip of the spinal cord lies at the level of the third lumbar vertebra, and in the
adult it lies at the lower border of the first or second lumbar vertebra. As a
result, the spinal roots, which originally were horizontal, become oblique, being
dragged down by the growth of the vertebral column. The degree of obliquity
increases from the lower cervical segment caudally, particularly in the lumbar
and sacral segments, where the roots form the cauda equina, extending well
below the end of the cord.

C. Medulla Oblongata and Pons

The medulla oblongata and the pons are derivatives of the embryologic
myelencephalon and metencephalon, respectively. At the junction of the spinal
cord and the medulla oblongata, the central canal opens to form the fourth
ventricle. This forces the alar plate to rotate dorsolaterally. Thus, sensory
neurons of the alar plate come to lie lateral or dorsolateral to motor neurons of
the basal plate (Figure 25-7). A thin single cell layer of ependyma (roof plate)
also is formed, supported by a richly vascularized mesenchymal tissue (tela
choroidea). The sulcus limitans, which disappears in the spinal cord during
development, is retained in the floor of the fourth ventricle between alar plate
and basal plate neuronal derivatives. The same pattern of organization is
maintained in the pons. The alar plate gives rise to the following cranial nerve
nuclei in the medulla and pons: spinal trigeminal nucleus, principal (main)
sensory trigeminal nucleus, nucleus solitarius, and vestibular and cochlear nuclei.
The alar plate also gives rise to the following structures in the medulla and pons:
the
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inferior olivary nucleus of the medulla and the pontine nuclei in the basis pontis.
The basal plate gives rise to the following cranial nerve nuclei in the medulla and
pons: hypoglossal nucleus, nucleus ambiguus, dorsal motor nucleus of the vagus,
inferior salivatory nucleus, abducens nucleus, superior salivatory nucleus,
trigeminal motor nucleus, and facial motor nucleus.

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Figure 25-7. Schematic diagram showing reorganization of basal and alar

plate derivatives induced by formation of the fourth ventricle.

D. Cerebellum
The cerebellum, like the pons, is a derivative of the metencephalon. It arises
from an alar plate structure (the rhombic lip) in the dorsolateral wall of the
fourth ventricle, which also gives rise to the inferior olive, cochlear, and
vestibular nuclei. The cerebellar primordia in each rhombic lip grow outward to
form the cerebellar hemispheres and inward toward the midline, where they meet
to form the cerebellar vermis in the roof of the fourth ventricle.

Neurons of the cerebellum are derived from neuroblasts in the ventricular zone of
the cerebellar primordium. Some of these neuroblasts migrate outward along
radial glia to form the deep cerebellar nuclei (dentate, emboliform, globose, and
fastigii) and the Purkinje and Golgi cells. Another group of periventricular
neuroblasts from the lateral edges of the rhombic lip move across the rhombic lip
to the subpial zone and from there to the external surface of the cerebellum to
form the external granular layer. These neuroblasts retain their proliferative
potential and give rise to cells that migrate inward to form the granule, basket,
and stellate cells of the adult cerebellum. Some external granular layer cells
(those destined to form granule cells of the internal granular layer) develop
tangentially oriented axonal processes (future parallel fibers of granule cells)
before migrating inward along radial glial guides to form the granule cells of the
internal granular cell layer in the adult cerebellum. The external granular layer
generates neurons throughout the last 7 months of gestation and the first 7
months of postnatal life. The cerebellum remains relatively small during
development; the main growth spurt in humans occurs from 30 weeks of
gestation through the first year of postnatal life.

E. Mesencephalon (Midbrain)
The midbrain is a derivative of the embryologic mesencephalic vesicle. The
tectum (superior and inferior colliculi) and the central (periaqueductal) gray
matter are derivatives of the alar plate; the tegmentum, which contains the
oculomotor and trochlear nuclei, the red nucleus, and the substantia nigra, is a
derivative of the basal plate. Some authors limit the basal plate derivatives to

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the oculomotor and trochlear nuclei and suggest that the red nucleus and
substantia nigra are derived from alar plate neuroblasts that migrate to the basal
plate. Thickening of the walls of the embryologic mesencephalon reduces the
central ventricular space into a narrow passage, the aqueduct of Sylvius.

F. Diencephalon
The diencephalon develops solely from the alar plate. Three swellings in the wall
of the central cavity (future third ventricle) develop into the future epithalamus,
thalamus, and hypothalamus. After further development, the area of the
epithalamus diminishes in size, whereas the thalamus and hypothalamus grow.
The two thalami are connected across the midline (massa intermedia) in about 80
percent of individuals. The hypothalamic sulcus separates the thalamus and
hypothalamus. This sulcus is not a rostral continuation of the sulcus limitans,
which terminates at the rostral mesencephalon. Within the thalamus, laterally
placed nuclei (lateral and medial geniculate, ventral lateral, ventral anterior, and
ventral posterior) develop before the medially placed nuclei (dorsomedial,
anterior) do.

G. Basal Ganglia
The caudate and putamen nuclei develop from a ventral telencephalic swelling,
the ganglionic eminence, in the floor of the future cerebral hemispheres. In
addition to the caudate and the putamen, the ganglionic eminence contributes
cells to the amygdaloid nucleus and the bed nucleus of the stria terminalis.
Initially, the caudate and putamen appear as a single cellular mass. With the
development of the internal capsule, which connects the cerebral hemispheres
with subcortical structures, the single cell mass is divided into a medial caudate
nucleus and a lateral putamen.

The derivation of the globus pallidus is controversial. It is probably derived from

telencephalic anlage as well as diencephalic anlage. The external (lateral)
segment of the globus pallidus is derived partly from the telencephalic ganglionic
eminence and partly from the diencephalon, whereas the internal segment of the
globus pallidus is derived from the diencephalon. The portions of the globus
pallidus that are derived from the diencephalon are subsequently incorporated in
the telencephalon.

H. Cerebral Hemisphere
The cerebral hemispheres develop from the telencephalic vesicles. Early in
development, each telencephalic vesicle is composed of three zones:
ventricular, intermediate (mantle), and marginal. The marginal zone develops
into the acellular, most superficial layer I of the mature cerebral cortex. Layers II
to VI develop from the cortical plate, a group of cells that migrate from the
ventricular zone to the outer part of the intermediate (mantle) zone (Figure 25-
8). The development of layers II to VI from the cortical plate is accomplished by
an “inside-out” sequence in which newly arrived cells migrate outward past their
predecessors in the cortical plate. Thus, in the mature adult cerebral cortex,
acellular layer I is the oldest; cellular layer VI is formed by the first wave of
neuroblast migration, followed in chronologic sequence by cellular layers V, IV,
III, and II (Table 25-3). Unlike the spinal cord, where gray matter is centrally
placed compared with white matter, the reverse is true in the cerebral cortex,
where gray matter is superficial to the white matter core. Defects in the inside-
out migration sequence result in a variety of developmental brain disorders, such

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as heterotopias, lissencephaly, and schizencephaly. Because

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of the rapid accumulation of cells, the telencephalic vesicles grow rapidly
forward, upward, and backward to form the frontal, parietal, occipital, and
temporal lobes. In the process of rapid growth, the newly formed cortex covers
cortical and subcortical structures such as the insula and the diencephalon. Local
variations in the rate of growth result in the formation of the gyri, sulci, and
fissures that demarcate different cortical convolutions and lobes. The sylvian
fissure is the first to develop, at about the fourteenth week of gestation. The
central (rolandic) and calcarine sulci appear between 24 and 26 weeks of
gestation. The formation of the cortical gyri proceeds rapidly near the thirtieth
week of gestation, and the entire hemisphere surface is gyrated by the thirty-
second week of gestation.

Figure 25-8. Schematic diagram showing origin of mature cerebral cortical

layers from the telencephalic vesicle.

Table 25-3. Development of Cortical Layers: The Inside-Out Process

Layer Origin Chronologic age

I Periventricular layer Oldest

II Cortical plate Fifth wave of neuroblast migration

III Cortical plate Fourth wave of neuroblast migration

IV Cortical plate Third wave of neuroblast migration

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V Cortical plate Second wave of neuroblast migration

VI Cortical plate First wave of neuroblast migration

I. Cerebral Commissures
At about the sixth week of gestation, the dorsal part of the lamina terminalis
(site of the embryologic anterior neuropore) thickens to form a densely
cellular cell mass, the lamina reuniens (lamina of His). The lamina reuniens
increases rapidly in size to form the commissural plate, from which the cerebral
commissures and the septum pellucidum develop. Pioneer cerebral commissure
fibers cross the midline with the help of early glial cells and are guided either by
cell surface markers or by chemotactic substances that are expressed into the
extracellular space. The anterior commissure is the first to form at about the
sixth gestational week and the first to cross in the anterior portion of the
commissural plate at about the tenth week of gestation. The hippocampal
commissure is the next structure to form. It crosses further dorsally in the
commissural plate at about the eleventh week of gestation. The first fibers of the
corpus callosum begin to cross at approximately the twelfth gestational week.
Growth of the corpus callosum continues over the next 5 to 7 weeks in an
anterior to posterior direction with the formation of the genu anteriorly followed
by development of the body and, finally, the splenium. The rostrum is the last
part of the corpus callosum to form after the genu, body, and splenium. This
sequence of callosal growth is reflected in patients with callosal hypogenesis, who
may manifest the presence of the early formed portions of the corpus callosum
(genu, body, splenium) and the absence of the portion that forms later
(rostrum).

The septum pellucidum, another derivative of the commissural plate, is a thin

structure that separates the anterior horns of the lateral ventricles. At about 8
weeks of gestation, the central part of the commissural plate undergoes cystic
necrosis and forms the thin leaves of the septum pellucidum with the cavum
septum pellucidum between them.

Congenital absence of the corpus callosum and septum pellucidum is at times

associated with hypothalamic abnormalities. This can be explained by the fact
that the septal nuclei, which are related anatomically and functionally to the
anterior hypothalamus, arise from an area of the anterior diencephalon just
ventral to the lamina reuniens.

Myelination
In the central nervous system, myelin is formed by oligodendrocytes. Myelin

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formation in the central nervous system begins at about the sixth month of
gestation and continues into adulthood. The factors that initiate myelin formation
have not been fully elucidated. It is known, however, that myelination is retarded
when the conduction of nerve impulses through axons is interrupted and that
myelin production by oligodendrocytes is enhanced when neural cell extracts are
added to cultures. It appears that both neural impulses and some unknown
cellular communication between neurons and oligodendrocytes (surface markers,
chemotactic factors) stimulate the process of myelination. Different fiber systems
myelinate at different developmental periods. In general, motor and sensory
tracts myelinate before association tracts do. Myelination proceeds in a caudal-
to-rostral order. The spinal cord and spinal nerve roots begin to myelinate during
the second trimester in utero. Toward the end of the second trimester and the
beginning of the third trimester, myelination begins in the brain stem. No myelin
is detectable in the cerebral hemisphere until the first postnatal month.

Using T1-weighted magnetic resonance imaging, myelin appears at birth in the

posterior limb of the internal capsule and middle cerebellar peduncle (brachium
pontis). Myelin appears in the anterior limb of the internal capsule and in the
centrum semiovale between the second and fourth months. The splenium of the
corpus callosum myelinates between the third and fourth months and the genu
follows at between the fourth and sixth months. Myelin appearance is evident in
the occipital white matter between the fourth and seventh months and in the
frontal white matter between the fourth and eleventh months. Myelin appearance
on T2-weighted magnetic resonance imaging usually occurs 1 to several months
after its appearance on T1-weighted images.

Myelination undergoes dramatic changes in the first 2 postnatal years. Multiple

rules govern the chronologic and topographic sequences of central nervous
system myelination during this period. These rules include the following: (1)
Sensory pathways myelinate before motor pathways, (2) projection pathways
myelinate before association pathways, (3) central telencephalic sites myelinate
before telencephalic poles, (4) occipital poles myelinate before frontal and
temporal poles, (5) the posterior limb of the internal capsule myelinates earlier
and faster than the anterior limb, (6) the body and splenium of the corpus
callosum myelinate earlier and faster than the rostrum, and (7) the central
segment of the cerebral peduncle myelinates earlier than both the lateral and
medial segments. The lateral segment (from posterior cerebral hemisphere sites)
myelinates before the medial segment (from anterior cerebral hemisphere sites)
does.

PRENATAL BRAIN PERFORMANCE

The cardiovascular and nervous systems are the first systems to function in an
embryo. The heart begins to beat 3 weeks after conception. The earliest
detectable reflex in the nervous system appears in about the eighth week of
intrauterine life. If a stimulus is applied to the lip region at this time, the hand
region exhibits a withdrawal reflex. Touching the lips at 11 weeks of gestation
elicits swallowing movements. At 14 weeks of gestation, the reflexogenic
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zones spread so that touching the face of the embryo results in a complex
sequence of movements consisting of head rotation, grimacing, stretching of the
body, and extension of the extremities. At 22 weeks of gestation, the embryo
manifests stretching out movements and pursing of the lips; at 29 weeks, sucking
movements become apparent. At birth almost all reflexes are of brain stem

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origin; cortical control of these reflexes is minimal.

POSTNATAL DEVELOPMENT AND GROWTH

The brain of a human newborn weighs 350 g, which is approximately 10 percent
of its body weight; in contrast, the brain of an adult weighs about 1400 g
(roughly 2 percent of body weight). This difference in weight between the adult
brain and the newborn brain is accounted for by the laying down of myelin, which
occurs mainly in the first 2 years of life, as well as by an increase in the size of
neurons, the number of glial elements, and the complexity of neuronal processes.
Virtually no neurons are added after birth, since the human newborn has the full
complement of neurons. Structurally, in the brain of a newborn all the lobes are
clearly distinguishable. The central lobe (insula, island of Reil) is not covered by
the frontal and temporal opercula. The color of the cortex at birth is pale,
approximating that of white matter. Histologically, a newborn brain shows the
six-layered cytoarchitectonic lamination of the adult cerebral cortex. In contrast
to the adult cortex, however, the cells of the newborn cortex are tightly packed
together with few if any processes to separate them. Nissl substance is sparse in
cortical neurons and abundant in brain stem and spinal cord neurons. Dendritic
development in the newborn cortex is poor, and this correlates with the absence
of alpha activity in the electroencephalogram of a newborn. At birth, most of the
synapses are of the axodendritic variety; axosomatic synapses develop later.

At 3 months of age, the brain weighs approximately 500 g. The island of Reil is
completely covered by the frontal and temporal opercula. Although the gray
matter and white matter remain poorly demarcated and the cortical Nissl
substance remains scanty, the neurons are not as closely packed as they are in
the newborn brain.

At 6 months of age, the brain weighs approximately 660 g. The cytoplasm of

neurons is more abundant. Nissl material is more prominent, and the distinction
between gray matter and white matter can be made easily.

At 1 year of age, the brain weighs approximately 925 g. The density of cortical
neurons is reduced as a result of an increase in neuronal and glial processes
between neuronal perikarya; Nissl substance within the cell bodies is well
developed.

By the third postnatal year, average brain weight (1080 g) triples compared to
birth weight, and by 6 to 14 years, average brain weight (1350 g) approximates
that of an adult. Even when adult brain weight has been reached, maturational
changes continue to occur in the brain. Although active myelination in the human
brain continues throughout the first decade, remodeling of myelin continues
throughout life. The electroencephalogram and stimulus-evoked potentials
undergo maturational changes that continue into the second decade of life.

FUNCTIONAL MATURATION

Cerebral Oxygen Consumption

Oxygen consumption is relatively low in the newborn brain and increases
gradually with maturation. It reaches approximately 5 ml/100 g of brain tissue
per minute, which is equivalent to about 50 percent of the child's total oxygen
consumption. With further development, cerebral oxygen consumption decreases
to reach the adult level of 3.5 ml/100 g of brain tissue per minute. The low
cerebral oxygen consumption of the brain at birth explains the ability of a

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newborn brain to tolerate states of anoxia. This tolerance to anoxia also may be
explained by the dependence of the brain before birth on anaerobic glycolysis as
a source of energy. Just before birth, the level of enzymes needed for aerobic
glycolysis (succinodehydrogenase, succinoxidase, adenylphosphatase, etc.)
increases in preparation for the change in brain metabolism from anaerobic to
aerobic processes.

Cerebral Blood Flow

Cerebral blood flow in a newborn brain is low. It increases with age to reach a
maximum of 105 ml/100 g per minute between the ages of 3 and 5 years. It then
decreases to reach the adult rate of 54 ml/100 g per minute.

Cerebral Metabolic Rate for Glucose

Studies using positron emission tomography to study local cerebral metabolic
rates for glucose in infants and children have shown a pattern of glucose
utilization in the neonatal brain that is markedly different from that in the adult
brain. Typically, four brain regions are metabolically prominent: sensorimotor
cortex, thalamus, brain stem, and cerebellar vermis. By 1 year of age, local
cerebral metabolic rates for glucose resemble qualitatively those of young adults.
Quantitatively, however, glucose metabolic rates mature slowly. In a neonate,
the local cerebral metabolic rate for glucose is 70 percent that of an adult. It
increases and exceeds the adult rate by 2 to 3 years of life. It remains at these
high levels until 9 or 10 years of life, and then it declines to reach the adult rate
by 16 to 18 years. The stage of decline in the cerebral metabolic rate for glucose
between 9 and 18 years of age corresponds to the stage of a notable decrease in
brain plasticity after injury.

POSTNATAL BRAIN PERFORMANCE

Brain performance after birth proceeds through several stages of increasing
complexity.

The first stage spans the first 2 years of life. During this stage, the infant
changes from a baby with no awareness of the environment to a child who is
aware of the environment and is able to discriminate among varying
environmental stimuli.

The second stage occurs between 2 and 5 years of age. This is a stage of
preconceptual representation in which the child develops picture images as
symbols and begins to use language as a system of symbol signs.

The third stage is noted between 5 and 8 years of age. This is a stage of
conditional representation in which the child becomes aware that he or she is not
alone in the universe and begins to interact with other features and forces of the
universe.

The fourth stage, which extends from 7 to 12 years of age, is a stage of

operational thinking in which the child begins to recognize the relationships
between objects and appreciate their relative values, such as more or less,
heavier or lighter, and longer or shorter.

Along with these stages of behavioral development, the child proceeds through
stages of motor and sensory development of increasing complexity. In general,
motor development precedes sensory development. Starting as a subcortical
creature at 1 month

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of age, the child proceeds to grasp, raise its head, smile, focus its eyes, hear,
roll over, crawl, pick up small objects, stand, and walk.

Table 25-4. Brain Development: Anatomic, Functional, and Behavioral

Correlations

As these behavioral, motor, and sensory developments proceed, the central

nervous system develops nerve processes, synapses, and myelinated pathways.
It is difficult, however, to match each of these developmental stages with a
definitive structural change.

Table 25-4 presents a simplified summary correlating anatomic, functional, and

behavioral developments in the first year of life.

Functional imaging studies have revealed that early stimulation enhances brain
function whereas lack of early stimulation leads to loss of brain function.
Developmental research has shown that there are developmental windows of
opportunity for different brain functions. Thus, the windows of opportunity are 0
to 2 years for emotional development, 0 to 4 years for mathematics and logic, 0
to 10 years for language, and 3 to 10 years for music. It has been found that
accent-free second language acquisition is not possible after mid adolescence.
Another example of a critical period effect relates to absolute pitch, a skill
important for musicians, which is unlikely to develop if music training is started
after the age of 10 years.

MYTHS AND FACTS

Several myths about brain development have been corrected by new knowledge:

Myth #1: Brain develops at a steady pace throughout childhood.

Fact: Brain development is not linear but episodic, with windows of

opportunity to be utilized.

Myth #2: Brain development is affected primarily by biological factors.

Fact: Brain development can be altered by abuse, neglect, poverty, and

institutionalization.

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Myth #3: Brain development is very slow before age 3 years.

Fact: Brain development during the first 3 years is rapid.

Myth #4: Genes control brain development.

Fact: Genes and experience determine brain development.

AGING
Aging in the nervous system is associated with characteristic morphologic and
functional alterations.

Morphologic Alterations
The following structural alterations have been described in the aging nervous
system.

1. Cortical atrophy manifested by broadening of sulci, a decrease in the size of

gyri, and widening of ventricular cavities.

2. A reduction in the number and size of neurons. This is best seen in larger
neurons such as the pyramidal cells of Betz and Purkinje neurons.

3. A reduction in the amount of Nissl material.

4. Thickening and clumping together of neurofibrils.

5. An increase in the number of amyloid bodies (corpora amylacea),

particularly around the ventricular surface. The origin of amyloid bodies has
not been established with certainty, but they are believed to represent
products of neuronal degeneration.

6. An increase in lipofuscin pigment in both neurons and glia. Among the glia,
the astrocytes are particularly affected, whereas the oligodendroglia and
microglia are relatively spared. The predominant involvement of astrocytes
in this aging process has a deleterious effect on neuronal function.

7. Thickening of the walls of cerebral blood vessels.

Functional Alterations
The following functional alterations are believed to contribute to some of these
structural alterations or result from such structural modifications.

1. A decrease in cerebral blood flow. The reduction in cerebral blood flow can
be the end product of the thickening of blood vessel walls, which in turn can
lead to ischemia and dropout of neuronal elements.

2. A reduction in oxygen utilization by cerebral tissues.

3. A reduction in glucose utilization by cerebral tissues.

4. An increase in cerebrovascular resistance.

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TERMINOLOGY
Anencephaly (Greek an, “negative”; enkephalos, “brain”).
Congenital absence of the cranial vault with failure of the cerebral hemispheres
to develop as a result of a defect in the development of the rostral neural tube. A
condition incompatible with life.

Apoptosis (Greek apo, “off”; ptosis, “fall”).

A genetically determined process of cell death. The fragmentation of a cell into
membrane-bound particles that are then eliminated by phagocytosis.
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Aqueduct of Sylvius (Latin aqua, “water”; ductus, “canal”).

The narrow passage in the midbrain linking the third and fourth ventricles.
Described by Jacques Dubois (Sylvius) in 1555.

Cauda equina (Latin, “horse's tail”).

A bundle of lumbosacral nerve roots beyond the tip of the spinal cord that form a
cluster in the spinal canal which resembles the tail of a horse.

Corpora amylacea (Latin corpus, “body”; amylaceus, “starchy”).

Starchlike bodies. Basophilic structures found in astrocytic processes with
advancing age and in various degenerative diseases. The name was applied by
Virchow to certain “amyloid” bodies in the central nervous system that had been
noted by Purkinje.

Cortical plate.
The part of the intermediate (mantle) zone of the telencephalic vesicle that gives
rise to layers II to VI of the cerebral hemispheres.

Diocele (Greek dis, “twice”; koilos, “hollow”).

The cavity of the diencephalon, the third ventricle.

Dysraphic defects (Greek dys, “abnormal, disordered”; raphe, “seam”).

Defects caused by incomplete closure of the neural tube, such as anencephaly
and spina bifida cystica.

Embryogenesis (Greek embryo, “seed that develops into an individual”;

genesis, “production, generation”).
The process of embryo formation.

Encephalocele (Latin encephalon, “brain”; Greek kele, “hernia”).

A congenital developmental defect characterized by extracranial herniation of
part of the cerebral hemisphere through a midline skull defect.

Ganglionic eminence.
A swelling in the ventral telencephalon from which the basal ganglia develop.

Grasp reflex.
Flexion of the fingers when an object is placed gently in the palm. Normally
present in infants from birth to about 6 months of age. It is also found in adults
with bifrontal lesions.

Heterotopia (Greek heteros, “other, different”; topos, “place”).

Displacement of parts; the presence of tissue in an abnormal location. Neuronal
heterotopia refers to the presence of gray matter within white matter as a result
of abnormal neuronal migration during histogenesis.

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His, Wilhelm (1831–1904).

A Swiss anatomist who was interested in the development of the nervous system.
He described the lamina reunions (lamina of His) from which cerebral
commissures develop. He is also credited for originating the following terms:
dendrite, neuropil, neuroblast, and spongioblast.

Histogenesis (Greek histos, “web”; genesis, “production, generation”).

The formation of tissues from undifferentiated germinal cells in the embryo.

Induction (Latin inductio, “the process of inducing or causing to occur

through the influence of organizers”).
The formation of the neural plate is induced by the underlying mesoderm.

Lamina reuniens (lamina of His).

The dorsal part of the lamina terminalis, from which the cerebral commissures
develop. Described by Wilhelm His (1831–1904), a Swiss anatomist.

Lissencephaly (Greek lissos, “smooth”; enkephalos, “brain”).

A developmental brain anomaly characterized by a smooth brain surface devoid
of gyral convolutions or a paucity of convolutions. Also known as agyria. A defect
of neuronal migration.

Mesencephalon (Greek mesos, “middle”; enkephalos, “brain”).

The midbrain. Developed from the middle of the three primary brain vesicles of
the embryologic neural tube.

Mesocele (Greek mesos, “middle”; koilos, “hollow”).

The cavity of the mesencephalon, the aqueduct of Sylvius.

Metacele (Greek meta, “after, beyond, over”; koilos, “hollow”).

The cavity of the metencephalon.

Metencephalon (Greek meta, “after, beyond, over”; enkephalos, “brain”).

The anterior portion of the most caudal primary vesicle of the embryologic neural
tube (the rhombencephalon). Develops into the pons and the cerebellum.

Moro's reflex.
Abduction and extension of the arms and opening of the hands followed by
adduction of the arms in response to sudden withdrawal of support of the head.
Normally present from birth to 5 months of age. Named after E. Moro, an
Austrian pediatrician who described it in 1918.

Myelencephalon (Greek myelos, “medulla, marrow”; enkephalos, “brain”).

The caudal part of the rhombencephalon. Develops into the medulla oblongata.

Myelocele (Greek myelos, “medulla, marrow”; koilos, “hollow”).

The cavity of the myelencephalon. The fourth ventricle.

Myelodysplasia (Greek myelos, “medulla, marrow”; dys, “abnormal”;

plassein, “to form”).
Defective development of the caudal spinal cord and vertebral column.

Neurulation.
A stage of embryogenesis that includes the formation and closure of the neural
tube.

Prosencephalon (Greek prosos, “before”; enkephalos, “brain”).

The most anterior of the three primary brain vesicles of the embryologic neural

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tube. Gives rise to the diencephalon and the cerebral hemispheres.

Prosocele (Greek prosos, “before”; koilos, “hollow”).

The foremost cavity of the brain. The ventricular cavity of the prosencephalon.

Rhombencephalon (Greek rhombos, “rhomb”; enkephalos, “brain”).

The most caudal of the three primary brain vesicles. Gives rise to the medulla
oblongata, pons, and cerebellum.

Rhombic lip.
Part of the alar plate in the dorsolateral wall of the fourth ventricle. Gives rise to
the cerebellum.

Rhombocele (Greek rhombos, “rhomb”; koilos, “hollow”).

The cavity of the rhombencephalon.

Rooting reflex.
Mouth opening and head turning in response to stroking of the corner of the
mouth. An exploratory reflex of the mother's skin to locate the nipple. A normal
reflex from birth to 6 months of life.

Schizencephaly (Greek schizein, “to divide”; enkephalos, “brain”).

A developmental brain anomaly characterized by the presence of unilateral or
bilateral clefts in the cerebral hemisphere. A neuronal migration defect.

Tela choroidea (Latin tela, “a web”; chorion, “membrane”; epidos,

“form”).
A membrane of pia and ependyma that contributes to the formation of choroid
plexus inside the ventricles.

Telencephalon (Greek telos, “end”; enkephalos, “brain”).

The anterior of the two vesicles that develop from the prosencephalon. Gives rise
to the cerebral hemispheres.

Telocele (Greek telos, “end”; koilos, “hollow”).

The cavity of the telencephalon. The lateral ventricles.

Tethered cord.
A developmental defect of the caudal spinal cord in which the conus medullaris is
low in the vertebral canal and is anchored to the sacrum.

SUGGESTED READINGS
Bangert BA: Magnetic resonance techniques in the evaluation of the fetal and
neonatal brain. Semin Pediatr Neurol 2001; 8:74–88.

Barkovich AJ et al: Formation, maturation, and disorders of white matter.

AJNR 1992; 13:447–461.

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Chugani HT: Functional maturation of the brain. Int Pediatr 1992; 7:111–117.

Cowan WM: The development of the brain. Sci Am 1979; 241:112–133.

Crelin ES: Development of the nervous system. Ciba Clin Symp 1974; 26:2–

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32.

Dorovini-Zis K, Dolman CL: Gestational development of the brain. Arch Pathol

Lab Med 1977; 101:192–195.

Friede RL: Gross and microscopic development of the central nervous system.
In Friede RL (ed): Developmental Neuropathology. Berlin, Springer-Verlag,
1989; 2–20.

Hayflick L: The cell biology of human aging. Sci Am 1980; 242:58–65.

Hutchins JB, Barger SW: Why neurons die: Cell death in the nervous system.
Anat Rec 1998; 253:79–90.

Huttenlocher PR: Basic neuroscience research has important implications for

child development. Nat Neurosci 2003; 6:541–543.

Leech RW: Normal development of central nervous system. In Leech RW,

Brumback RA (eds): Hydrocephalus, Current Clinical Concepts. St. Louis,
Mosby Year Book, 1991:9–17.

Link E: Time is of the essence: Early stimulation and brain development. Care
for Kids EPSDT Newsletter 1998; 5:1,2,6. Available at
http://www.medicine.uiowa.edu/uhs/EPSDT/archive.cfm#1998.

Marin-Padilla M: Prenatal development of human cerebral cortex: An

overview. Int Pediatr 1995; 10(suppl):6–15.

Moore K: The nervous system. In Moore K (ed): The Developing Human.

Philadelphia, Saunders, 1982:375–412.

Naidich TP: Normal brain maturation. Int Pediatr 1990; 5:81–86.

Norman MG et al: Embryology of the central nervous system. In Norman MG

et al (eds): Congenital Malformations of the Brain: Pathological,
Embryological, Clinical, Radiological, and Genetic Aspects. New York, Oxford
University Press, 1995:9–50.

O'Rahilly R, Muller F: The Embryonic Human Brain: An Atlas of Developmental

Stages. New York, Wiley-Liss, 1994.

Rockstein M: Development and Aging in the Nervous System. New York,

Academic Press, 1973.

Yakovlev PI, Lecours AR: The myelogenetic cycles of regional maturation of

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the brain. In Mikowski A (ed): Regional Development of the Brain in Early

Life. Philadelphia, Davis, 1967:3–70.

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Editors: Afifi, Adel K.; Bergman, Ronald A.

Title: Functional Neuroanatomy: Text and Atlas, 2nd Edition

Copyright ©2005 McGraw-Hill

> Table of Contents > Part I - Text > 26 - Central Nervous System
Development: Clinical Correlates

26
Central Nervous System
Development: Clinical Correlates

Neurulation (Neural Tube) Defects

Primary Neurulation Defects
Secondary Neurulation Defects
Neuronal and Glial Proliferation Defects
Microcephaly (Micrencephaly)
Macrocephaly (Megalencephaly)
Hemimegalencephaly
Neuroblast Migration Defects
Lissencephaly (Agyria)
Pachygyria (Macrogyria)
Polymicrogyria
Cortical Heterotopias
Schizencephaly
Midline Defects
Holoprosencephaly
Agenesis of the Corpus Callosum
Septo-optic Dysplasia (DeMorsier Syndrome)

KEY CONCEPTS

Congenital malformations of the brain have exogenous

and endogenous causes and occur in 0.5 percent of live
births.

Malformations associated with defective neurulation

include anencephaly, encephalocele, myelomeningocele,
diastematomyelia, and tethered cord.

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Neural tube defects can be detected prenatally by

examining alpha-fetoprotein and acetylcholinesterase in the
amniotic fluid and by ultrasonography.

Malformations associated with neuroblast migration

include lissencephaly (agyria), pachygyria, polymicrogyria,
cortical heterotopias, and schizencephaly.

Agenesis of the corpus callosum is commonly associated

with other congenital brain malformations. It may be total or
partial.

Congenital malformations of the brain occur in approximately 0.5

percent of live births and 3 percent of stillbirths. They are
generally attributed to one of two types of causes: exogenous and
endogenous. Exogenous causes include nutritional factors, radiation,
viral infections, chemicals, ischemic insults, and medications.
Endogenous causes are mainly genetic. The different etiologic factors
affect the embryo adversely during specific periods of development.
Since the same malformation may be produced by both exogenous and
endogenous causes, it is customary to classify the different
malformations according to the developmental stage at which they
occur.

NEURULATION (NEURAL TUBE) DEFECTS

Congenital malformations associated with defective neurulation
are among the most commonly encountered malformations in
humans. They include (1) anencephaly, (2) encephalocele, (3)
myelomeningocele, (4) diastematomyelia, and (5) tethered cord. The
first three are associated with primary neurulation defects, and the last
two with secondary neurulation defects.

Two features of human neural tube defects point to failure of closure of

the neural tube as the more likely cause of malformations: (1)
Pathologic studies show that the neural tube is open at the area of the
defect, with continuity of the neural epithelium and surface epithelium,
suggesting failure of fusion of the neural tube, and (2) neural tube
malformations occur mostly at the rostral and caudal regions of the
neural tube just proximal to the areas of final neural tube fusion,
suggesting that the malformations result from a defect in neural tube
closure.

In experimental animals, neural tube defects can be produced by

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introducing a variety of teratogens during the stage of closure of the

anterior and posterior neuropores.

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Early prenatal detection of neural tube defects is possible by the
determination of alpha-fetoprotein (AFP) and acetylcholinesterase
in amniotic fluid. AFP is synthesized in fetal liver and excreted in urine.
It increases in amount in the amniotic fluid in patients with various
malformations, in particular those resulting from neural tube defects.
AFP elevation in maternal serum is not as reliable as similar elevations
in amniotic fluid. Acetylcholinesterase is produced in nervous tissue, is
excreted in cerebrospinal fluid, and passes into the amniotic fluid only
in cases of neural tube defects. Neural tube defects also can be
detected early by ultrasonography.

The incidence of neural tube defects varies worldwide from about 1 to

about 9 per 1000 births. The incidence in the United States is 1 per
2000 births. Northern Ireland and South Wales are among the areas
with the highest incidence (8.6 and 7.6 per 1000 births, respectively).
The incidence also varies with ethnic origin. In the United States,
African Americans have lower incidence rates than whites. Asian
Americans have lower incidence rates than African Americans or
whites. Hispanic Americans have the highest incidence rates. Neural
tube defects are known to cluster in families. The occurrence in
siblings of an affected child is approximately 3 percent, and it doubles
with the birth of each additional child with a neural tube defect.

The risk of neural tube malformation can be reduced by daily intake of

folic acid.

Primary Neurulation Defects

Primary neurulation refers to the formation of the neural tube from
approximately the caudal lumbar level to the cranial end of the
embryo. Most of the central nervous system is thus developed by
primary neurulation, which occurs during the third and fourth weeks of
gestation. Three malformations are generally associated with defective
primary neurulation: (1) anencephaly, (2) encephalocele, and (3)
myelinomeningocele.

A. Anencephaly
Anencephaly (Figure 26-1) is characterized by the absence or
underdevelopment of the cranial vault, maldevelopment of the skull
base, and a constant anomaly of the sphenoid bone that resembles “a
bat with folded wings.” The orbits are shallow, causing protrusion of
the eyes. The anomaly of the skull imparts a froglike appearance to the
patient when viewed face on. The forebrain is absent and is replaced
by a reddish irregular mass of vascular tissue with multiple cavities

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containing cerebrospinal fluid. The primary defect is failure of closure

of the rostral part of the neural tube. The onset of the malformation is
estimated to occur no later than at 24 days of gestation. Anencephaly
was known in Egyptian antiquity. Affected infants are stillborn or die
early (a few days) in the neonatal period. The incidence of anencephaly
varies from 0.5 to 2.0 per 1000 live births, and anencephaly accounts
for approximately 30 percent of all major abnormal live births. Females
are affected more frequently than are males. Epidemiologic studies
have shown a high incidence of anencephaly in Northern Ireland and
South Wales. Both environmental and genetic factors operate in the
genesis of the malformation. Familial cases have been reported; the
mode of transmission, however, is poorly understood.

The incidence of anencephaly has been declining. This has been

attributed to early detection by ultrasonography, AFP, and
acetylcholinesterase determination, and elective termination of
pregnancy when the fetus is found to have anencephaly.

Figure 26-1. Photograph of a neonate with anencephaly.

B. Encephalocele (Encephalomeningocele)
An encephalocele (Figure 26-2) consists of a protrusion of brain and
meninges through a skull defect. Rarely, only the meninges

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(meningocele) protrude through the skull defect (Figure 26-3).

Encephaloceles may occur in the occipital, parietal, frontal, nasal, and
nasopharyngeal sites but are most common (75 to 85 percent) in the
occipital area. The incidence of encephaloceles is approximately 0.8 to
3.0 per 10,000 births. They account for 0.07 percent of all pediatric
admissions and about 10 percent of all craniospinal malformations.
Occipital encephaloceles are more common in females, whereas
encephaloceles in other sites occur more frequently in males. Most
encephaloceles occur sporadically. They typically present at birth and
usually come to medical attention within the first days or weeks of life.
Encephaloceles typically have an intact skin cover but are variable in
size, shape, and consistency. Occipital encephaloceles are usually
large. The outcome is poor. Seventy-five percent of occipital
encephalocele and 100 percent of parietal encephalocele infants die or
are severely retarded.

C. Myelomeningocele
A myelomeningocele (Figure 26-4) is characterized by herniation of the
lower spinal cord and overlying meninges through a large midline
defect in the vertebral column. The protruding mass consists of a
distended meningeal sac filled with cerebrospinal fluid containing spinal
cord tissue. The sac is covered by a thin membrane or skin. The
malformation results from a defect in closure of the caudal neural tube.
Approximately 80 percent of myelomeningoceles are in the lumbar
region, the last region of the neural tube to close.

Figure 26-2. Magnetic resonance image (MRI) of the brain

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showing an occipital encephalomeningocele (arrow).

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The onset of the malformation occurs not later than the twenty-sixth
day of gestation. The incidence is approximately 2 to 3 per 1000
births. As with anencephaly, the incidence is higher in Ireland and
Wales. Most cases are sporadic. There is increased risk of the
malformation in families with a history of neural tube defects. Females
are affected about twice as often as are males. Other frequently
associated malformations include the Arnold-Chiari malformation,
hydrocephalus, syringohydromyelia, and diastematomyelia. The clinical
picture is characterized by sensorimotor deficits in the lower
extremities. IQ is normal in 90 percent of patients. Recent advances in
the care of children with myelomeningocele have resulted in increased
survival. Early surgery involves closure of the spinal lesion and
frequently the placement of a shunt.

Figure 26-3. Photograph of a child with frontal meningocele.

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Figure 26-4. MRI of the spinal canal showing a myelomeningocele

(arrow).

Secondary Neurulation Defects

Secondary neurulation refers to the process by which the sacral and
coccygeal segments of the spinal cord are developed. Two
malformations are generally associated with defective secondary
neurulation: diastematomyelia and tethered cord.

A. Diastematomyelia
Diastematomyelia is characterized by the presence of two hemicords
within a single dural sac separated by a vascular mass of connective
tissue or in two separate dural sacs between which there may be a
bony septum. The malformation usually occurs in the lower thoracic or
lumbar cord segments but may occur at any spinal level. Seventy
percent of cases occur between the first and fifth lumbar cord
segments. The cord is normal above and below the level of the split.
The central canal bifurcates to extend into each hemicord and reunites
below the split. Similarly, the anterior cerebral artery divides at the
level of the split so that each hemicord has an independent arterial
supply. This condition may be

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asymptomatic in neonates and become symptomatic later in childhood,
between 2 and 10 years of age. Females are affected more than males
are. Although not an inherited disorder, diastematomyelia has been
reported to occur in members of the same family. The malformation
frequently is associated with spina bifida.

On imaging studies, diastematomyelia may be difficult to distinguish

from diplomyelia, a rare condition characterized by a duplicated spinal
cord instead of two facing hemicords, as in diastematomyelia.

The oldest known specimen of diastematomyelia, dating back to the

Roman period, approximately A.D. 100, was recovered from a burial
site in the Negev desert in Palestine. The term diastematomyelia was
coined by Ollivier, a French neurologist, in 1837.

B. Tethered Cord
The tethered cord malformation (Figure 26-5) is characterized by an
abnormally low conus medullaris tethered (anchored) by one or more
forms of intradural abnormalities, such as a short thickened filum
terminale, fibrous bands, or adhesions, or a totally intradural lipoma.
The underlying pathologic anomaly is a dural defect through which the
spinal cord comes in contact with the subcutaneous tissue early in
embryonic development. The spinal cord thus is anchored to
subcutaneous tissue, preventing its upward displacement. The clinical
picture is characterized by progressive motor and sensory deficits in
the lower extremities, scoliosis, back pain, and a neurogenic bladder.
Associated cutaneous signs in the lumbosacral region include a hairy
skin patch, a hemangioma, and a dimple.

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Figure 26-5. MRI of the spinal canal showing a low-lying conus

medullaris (arrow) in a tethered cord.

NEURONAL AND GLIAL PROLIFERATON

DEFECTS

Microcephaly (Micrencephaly)
Microcephaly is a term used generally to describe head circumference 2
standard deviations (SD) or less below the mean, or head
circumference below the third percentile. It refers to a small cranial
vault of varying etiologies. Micrencephaly, in contrast, refers to small
brain size (head circumference 5 to 6 SD below the mean).
Micrencephaly may occur as a result of genetic impedance of neuronal
proliferation or environmental factors that interfere with brain

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development. In practice, the two terms are used interchangeably.

Micrencephalic children have a small cranial vault, compared with the
size of the face, and thickened skull bones. Affected children are
developmentally delayed. Micrencephaly occurs sporadically or in
families with autosomal recessive, autosomal dominant, or X-linked
transmission.

Macrocephaly (Megalencephaly)
Macrocephaly is generally used to describe head circumference of more
than 2 SD above the mean, irrespective of etiology. Megalencephaly,
however, implies increased brain weight secondary to an increase in
neural elements, both neuronal and glial. The term megalencephaly
was introduced in 1900 by Fletcher to designate true hyperplasia of
brain tissues. Megalencephalic brains have bulky gyri with increased
cortical thickness and white matter volume. Ventricles are usually of
normal size. No significant microscopic alterations are found in the
cortex. Minor migrational anomalies (heterotopias) may be present.

Hemimegalencephaly
Hemimegalencephaly is a rare congenital malformation of the brain in
which an enlarged hemisphere is the main pathologic finding (Figure
26-6). Traditionally regarded as a defect in neuroblast migration, it is
now believed to be a defect in cellular proliferation, cellular lineage,
and establishment of hemispheral symmetry (which occurs in the third
week of gestation). Hemimegalencephaly may be isolated or may be
part of a neurological syndrome (syndromic). It is associated with
mental retardation, intractable epilepsy, macrocephaly, and
hemiparesis. Magnetic resonance imaging (MRI) reveals a dysplastic
hemisphere with overall increased size of the involved hemisphere,
increased volume of white matter of the affected hemisphere, abnormal
gyral pattern, ventriculomegaly, and displacement of the occipital lobe
across the midline (occipital sign).

The first description of hemimegalencephaly was by Sims in 1835.

Hemimegalencephaly may occur alone or associated with hypertrophy
of the face or entire half body.

NEUROBLAST MIGRATION DEFECTS

Neuroblast migration is a critical stage in normal histogenesis in which
neuroblasts migrate, guided by radial glial processes, from the
ventricular or periventricular zone to their proper position. In many
regions, the migratory pathway is long and migration
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occurs over a protracted period. The time involved is the third month
to the sixth month of gestation.

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Figure 26-6. Axial MRI showing a hemimegalencephalic dysplastic

left cerebral hemisphere (stars).

Congenital malformations associated with defective neuroblast

migration include (1) lissencephaly (agyria), (2) pachygyria, (3)
polymicrogyria, (4) cortical heterotopias, and (5) schizencephaly. The
causes of these malformations are varied and include genetic
(maternal), and environmental factors. Many are associated with
agenesis or hypoplasia of the corpus callosum.

Lissencephaly (Agyria)
Lissencephaly (Figure 26-7) is characterized by a smooth brain surface
resulting from the absence or paucity of gyri and sulci. The cerebral
cortex is composed of four layers, similar to that of a 3-month fetus:
(1) an outermost, relatively acellular molecular layer, (2) a thick,
richly cellular intermediate (mantle) zone, (3) an innermost thin band
of white matter, and (4) a layer of periventricular gray matter. The
migratory defect of this malformation occurs between 12 and 16 weeks
of gestation. It has been proposed that late-migrating neuroblasts that
are destined to become cortical layers II and IV are arrested by a deep
cortical and subcortical laminar necrosis at about the fourth fetal
month. Neurologic abnormalities are evident at birth or shortly
afterward. Affected infants are hypotonic and microcephalic and have
intractable seizures. Neurologic development is severely impaired. Most
cases of lissencephaly are sporadic; some are associated with genetic

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syndromes such as the Miller-Dieker and Walker-Warburg syndromes.

Inheritance pattern may be autosomal dominant, autosomal recessive,
or X-linked. Most cases of lissencephaly are secondary to a deletion of
17p13 chromosome. Genes involved with lissencephaly include LIS1,
located at 17p13.3 (Miller-Dieker syndrome), and double cortin (DCX,
XLIS), located at Xq22.3 (X-linked lissencephaly). Recurrence risk in
lissencephaly varies between 5 and 12 percent and may be as high as
25 percent in recessive cases. Cases not caused by 17p13 deletion
show higher recurrence risk.

A prevalence for lissencephaly of 11.7 per million births has been

ascertained.

Pachygyria (Macrogyria)
Pachygyria (Figure 26-8) is characterized by a reduced number of
coarse, broad, shallow gyri and sulci. The gyral malformation differs
from lissencephaly only in degree. Both malformations may be found in
different areas of the same hemisphere. The pachygyric cortex is made
up of four layers: (1) an outermost normal-appearing molecular layer,
(2) a layer of neurons of decreased population which has not received
its full complement of neurons by radial migration, (3) a much thicker
layer of neurons, usually poorly organized and arranged in broad
columns, which represent heterotopic neurons arrested in their
migration, and (4) a relatively thin layer of white matter encroached
on by heterotopic neurons. The migration defect resulting in pachygyria
occurs at a slightly later stage of development than is the case in
lissencephaly. Affected infants are hypotonic at birth, develop seizures
within the first year of life, and are severely neurologically retarded.

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Figure 26-7. MRI of the brain showing the smooth surface of the
cerebral hemisphere (arrows) in a patient with lissencephaly.

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Polymicrogyria
Polymicrogyria is characterized by a large number of very small gyri
without intervening sulci or with shallow sulci bridged by the overlying
molecular layers of adjacent gyri. Polymicrogyria results when neurons
reach the cortex but distribute in an abnormal fashion. Because of this,
some classify polymicrogyria as a malformation of abnormal cortical
organization rather than a malformation of abnormal neuronal
migration. The appearance of the polymicrogyric cortex has been
compared to that of a cauliflower. The polymicrogyric malformation
may cover the entire surface of the hemisphere or occur in limited
areas of one or both hemispheres. It is most commonly seen in the
perisylvian region. On imaging studies, polymicrogyria appears as
cortical thickening with multiple small gyri. In some cases, the gyri are
so small that the appearance is one of broad, flat gyri with shallow
sulci simiar to pachygyria. The migration defect that leads to
polymicrogyria occurs in the fifth month of gestation, later than that
responsible for lissencephaly and pachygyria. The clinical presentation

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of patients with polymicrogyria varies with the extent of the

malformation. Patients with diffuse polymicrogyria involving the entire
cortex present with microcephaly, hypotonia, seizures, and
developmental retardation, similar to the presentation in patients with
lissencephaly. Patients with bilateral
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focal polymicrogyria usually are moderately developmentally delayed
and spastic. Patients with unilateral focal polymicrogyria most often
have congenital hemiplegia, mild to moderate developmental delay,
and focal motor seizures.

Figure 26-8. MRI of the brain showing wide gyri (arrows) in

pachygyria.

Cortical Heterotopias
A cortical heterotopia (Figure 26-9) is characterized by islands of gray
matter along the route of neuroblast migration. The islands consist of a
collection of normal neurons in abnormal locations secondary to an
arrest of the radial migration of neuroblasts. The onset of the
migration defect occurs no later than the latter part of the fifth month
of gestation. Heterotopias have been associated with a wide variety of
genetic, vascular, and environmental causes. Heterotopias are clinically
divided into three groups: (1) subependymal, periventricular (nodular),
(2) focal subcortical (laminar), and (3) diffuse (band) (double cortex).
Subependymal (nodular) heterotopias are subependymal masses of
gray matter which form clusters of rounded nodules that are well
separated from the cortex by normally myelinated white matter. They
usually are localized at the corners of the lateral ventricles. Focal
subcortical (laminar) heterotopias are separated from both the cortex

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and the ventricles by thick layers of white matter. Diffuse (band)

heterotopias (double cortex) consist of bilateral symmetric layers of
heterotopic neurons between the lateral ventricles and the cerebral
cortex. The heterotopic neurons are separated from the cortex by a
band of white matter, giving the appearance of double cortex. Patients
with subependymal heterotopias tend to have normal development and
mild clinical symptoms. The onset of seizures usually occurs in the
second decade of life. Patients with focal subcortical heterotopias have
variable symptoms and signs that depend on the extent of their
heterotopias. Those with large heterotopias have moderate to severe
developmental delay and hemiplegia, whereas those with smaller or
thinner subcortical heterotopias may have normal development and
motor function. Patients with diffuse band heterotopias (double cortex)
have moderate or severe developmental delay and intractable seizures.

Figure 26-9. MRI of the brain showing cortical heterotopia

(arrows).

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Figure 26-10. MRI of the brain showing schizencephalic cleft

(arrows).

Schizencephaly
The term schizencephaly (Figure 26-10) was coined by Yakovlev and
Wadsworth in 1946 to describe gray matter–lined clefts in the cerebral
hemispheres extending from the pia to the ependymal lining of the
lateral ventricle. The walls of the clefts may be in apposition (closed
lip, type I) or separated (open lip, type II). The onset of the
malformation is considered to occur at 3 to 5 months of gestation. A
focal watershed infarct in the cerebral mantle during early development
has been proposed as a cause of schizencephaly. Familial occurrence
raises the possibility of a genetic mechanism in the causation of this
malformation. Previous reports of this malformation, derived primarily
from pathologic specimens, suggested that this malformation was
extremely rare, seen primarily in institutionalized patients with severe
motor and intellectual deficits. The introduction of and improvements
in imaging techniques such as computed tomography (CT) and MRI
have enhanced awareness and increased recognition of the disorder.
The clinical presentation varies with the extent of the malformation.

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Patients with bilateral malformations usually are

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developmentally delayed and have seizures. Patients with unilateral
malformations may have only a motor deficit (hemiplegia) and seizures
or may be developmentally delayed, depending on the extent of the
malformation. Patients with small unilateral clefts, particularly those
not involving the frontal lobe, usually have no symptoms.

Mutations in the human homeobox gene, EMX2 (empty spiracles 2), are
responsible for familial schizencephaly, and the inheritance may be
autosomal dominant with variability.

MIDLINE DEFECTS

Holoprosencephaly
Holoprosencephaly is a midline malformation caused by failure of
cleavage of the prosencephalon into discrete telencephalic and
diencephalic structures. The malformation develops between the fourth
and sixth weeks of gestation, when the hemispheric vesicles cleave. It
is a rare malformation occurring in 1 per 16,000 live births. The term
holoprosencephaly was introduced in 1963 by DeMyer and Zeman. The
malformation was recognized in 1882 by Kundrat, who described it as
arhinencephaly, a term not now generally accepted. Yakovlev in 1959
proposed the term holotelencephaly to describe the malformation. The
malformation is extremely heterogeneous, with both teratogenic and
genetic etiologies. Maternal diabetes, alcohol, salicylates, and
anticonvulsants have been associated with the malformation. Eighteen
to 25 percent of holoprosencephaly cases have a recognized monogenic
syndrome. Estimates of frequency of chromosomal aberrations range
from 24 to 45 percent. Most cases of holoprosencephaly, however, are
sporadic.

Because formation of the face parallels the formation of the forebrain,

malformations of the face are frequently noted in holoprosencephaly.
Traditionally, holoprosencephaly has been divided into three types: (1)
alobar, (2) semilobar, and (3) lobar. Alobar cases (Figure 26-11) have
a single large, horseshoe-shaped ventricle, no interhemispheric fissure,
and absent corpus callosum. They are the most severe type. Semilobar
cases have partially formed interhemispheric fissure and falx cerebri
posteriorly and remnant lobes. The monoventricle shows minimal
differentiation and rudimentary temporal horns. Lobar cases (the least
severe) have normal lobes, interhemispheric fissure, and falx, but the
frontal lobes are fused and communication between ventricles persists.

Agenesis of the Corpus Callosum

Corpus callosum malformations are commonly associated with
other congenital brain malformations, suggesting a causal

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relationship. Both neurulation and migration defect malformations have

been associated with agenesis of the corpus callosum (Figure 26-12).
Agenesis of the corpus callosum may be total or partial. In total
absence of the corpus callosum, the medial surface of the hemisphere
has an abnormal radial gyral pattern. The cingulate gyrus is poorly
outlined, and most of the gyri extend perpendicularly to the roof of the
third ventricle. The axons destined to form the corpus callosum instead
turn parallel to the interhemispheric fissure and form the longitudinal
callosal bundles of Probst (Figure 26-13). The bundle
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of Probst indents the superomedial borders of the lateral ventricles,
giving them a characteristic crescent shape. In partial agenesis, the
posterior portion (splenium) or the rostrum (late to develop) is
missing. Absence of the corpus callosum may be an isolated anomaly
with no clinical symptoms or may be associated with mental
retardation and seizures. Sporadic as well as familial cases have been
reported.

Figure 26-11. Coronal brain section showing a single ventricle

(arrow) in holoprosencephaly.

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Figure 26-12. MRI of the brain showing agenesis of the corpus

callosum (arrows).

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Figure 26-13. Coronal MRI showing Probst bundle (stars) in a

patient with agenesis of the corpus callosum.

Septo-optic Dysplasia (DeMorsier Syndrome)

Septo-optic dysplasia is a congenital malformation of the anterior
midline structures of the brain that occurs between 4 and 6 weeks of
gestation. The malformation includes agenesis of septum pellucidum
and optic nerve hypoplasia. Pituitary gland and hypothalamic
insufficiencies may be present. Agenesis of the septum pellucidum was
first described by Tenchini in 1881 and in association with optic nerve
hypoplasia by Reeves in 1941. DeMorsier in 1956 reported the frequent
association of optic nerve hypoplasia and agenesis of the septum
pellucidum, and coined the term septo-optic dysplasia.

The malformation has been associated with a wide variety of cerebral

anomalies but most consistently with schizencephaly. Approximately
half of patients with septo-optic dysplasia will have schizencephaly.
Patients usually present with congenital nystagmus or decrease in
visual acuity. Some may also have endocrine abnormalities.

TERMINOLOGY
Agyria (Greek a, “negative”; gyros, “ring”).
A malformation in which the brain surface is devoid of gyri and has a
smooth appearance. Also known as lissencephaly.

Anencephaly (Greek an, “negative”; enkephalos, “brain”).

Congenital absence of the cranial vault with failure of the cerebral
hemispheres to develop as a result of a defect in the development of
the rostral neural tube. A condition incompatible with life.

Arnold-Chiari malformation.
A brain malformation characterized by cerebellar and brain stem
elongation and protrusion through the foramen magnum. This
malformation was first observed by Cleland in 1883 but was more
definitively described by Hans Chiari, an Austrian pathologist, in 1891
and by Julius Arnold, a German physician, in 1894.

Bundle of Probst.
An anomalous bundle of nerve fibers associated with agenesis of the
corpus callosum. Fibers destined to cross in the commissure instead
course rostrocaudally in the superior medial part of the lateral
ventricle parallel to the cingulate bundle.

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Diastematomyelia (Greek diastema, “cleft”; myelos, “marrow,

cord”).
Splitting of the spinal cord by a connective tissue septum or bony
septum.

Diplomyelia (Greek diploos, “double”; myelos, “marrow”).

Doubling of the spinal cord.

Encephalocele (Latin encephalon, “brain”; Greek kela, “hernia”).

A congenital developmental defect characterized by extracranial
herniation of part of the cerebral hemisphere through a midline skull
defect.

Heterotopia (Greek heteros, “other, different”; topos, “place”).

Displacement of parts; the presence of tissue in an abnormal location.
Neuronal heterotopia refers to the presence of gray matter within
white matter as a result of abnormal neuronal migration during
histogenesis.

Lissencephaly (Greek lissos, “smooth”; enkephalos, “brain”).

A developmental brain anomaly characterized by a smooth brain
surface devoid of gyral convolutions or a paucity of convolutions. Also
known as agyria. A defect of neuronal migration.

Miller-Dieker syndrome.
The association of lissencephaly (smooth brain) with dysmorphic facial
features, renal anomalies, polydactyly, seizures, and microcephaly.
Described by J. Q. Miller in 1963 and H. Dieker in 1969. The term was
introduced by Jones in 1980.

Myelomeningocele (Greek myelos, “marrow”; meninx,

“membrane”; koilos, “hollow”).
A severe defect of neural tube closure in which the spinal cord and
meninges herniate through a midline defect in the vertebral column.

Neurulation.
A stage of embryogenesis that includes the formation and closure of
the neural tube.

Pachygyria (Greek pachys, “thick”; gyros, “ring”).

Thick, broad, shallow gyral convolutions in the cerebral hemisphere.

Polymicrogyria (Greek polys, “many”; mikros, “small”; gyros,

“ring or circle, convolution”).
A malformation of the brain characterized by numerous small gyri.

Schizencephaly (Greek schizein, “to divide”; enkephalos,

“brain”).
A developmental brain anomaly characterized by the presence of
unilateral or bilateral clefts in the cerebral hemisphere. A neuronal

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migration defect.

Syringohydromyelia (Greek syrinx, “pipe or tube”; hydor,

“water”; myelos, “marrow”).
A cavitation within the spinal cord filled with cerebrospinal fluid.

Teratogenic (Greek teratos, “monster”; genesis, “production”).

Tending to produce anomalies of formation.

Tethered cord.
A type of spinal dysraphism in which the lower part of the spinal cord
(conus medullaris) is anchored to the sacrum.

Walker-Warburg syndrome.
A lethal autosomal recessive congenital syndrome with brain, eye, and
muscle abnormalities. Most of these children die in the neonatal period
secondary to defects in brain development. Those who survive are
severely mentally retarded.

SUGGESTED READINGS
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Barkovich AJ, Kjos BO: Schizencephaly: Correlation of clinical

findings with MR characteristics. AJNR 1992; 13:85–94.

Barkovich AJ et al: A classification scheme for malformations of

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Barkovich AJ et al: Formation, maturation, and disorders of brain

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Barkovich AJ et al: Formation, maturation, and disorders of white

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Barkovich AJ et al: Gray matter heterotopia. Neurology 2000;

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Barth PG: Disorders of neuronal migration. Can J Neurol Sci 1987;

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Fitz CR: Holoprosencephaly and related entities. Neuroradiology

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findings and serial EEG studies. Dev Med Child Neurol 1987;
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(eds): The Tethered Spinal Cord. New York, Thieme-Stratton,
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Larroche JC: Malformations of the nervous system. In Adams JH et

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The declining incidence among white infants. J Child Neurol 1991;
6:304–305.

Storrs BB et al: The tethered cord syndrome. Int Pediatr 1990;

5:99–103.

Van der Knaap MS, Valk J: Classification of congenital

abnormalities of the CNS. AJNR 1988; 9:315–326.

Volpe JJ: Normal and abnormal human brain development. Clin

Perinatol 1977; 4:3–30.

Whiting S, Duchowny M: Clinical spectrum of cortical dysplasia in

childhood: Diagnosis and treatment issues. J Child Neurol 1999;
14:759–771.

Williams RS: Cerebral malformations arising in the first half of

gestation. In Evrard P, Minkowski (eds): Developmental
Neurobiology. New York, Raven Press, 1989:11–20.

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Editors: Afifi, Adel K.; Bergman, Ronald A.

Title: Functional Neuroanatomy: Text and Atlas, 2nd Edition

Copyright ©2005 McGraw-Hill

> Table of Contents > Part I - Text > 27 - Cerebral Circulation

27
Cerebral Circulation

Sources of Supply
Internal Carotid Artery
Vertebral Artery
Basilar Artery
Circle of Willis
Conducting and Penetrating Vessels
Histology of Cerebral Vessels
Collateral Circulation
Cerebral Venous Drainage
Superficial Venous System
Deep Venous System
Cerebral Dural Venous Sinuses
Factors Regulating Cerebral Circulation
Extrinsic Factors
Intrinsic Factors
Neural Factors
Neuropeptides
Mean and Regional Cerebral Blood Flow
Steal Syndrome
Autoregulation and Hypertension
Cerebral Blood Flow in Epilepsy
Cerebral Blood Flow in Coma

KEY CONCEPTS

Irreversible brain damage (brain death) occurs if blood supply to the

brain is interrupted for more than a few minutes.

The internal carotid arteries provide blood supply to the rostral parts
of the brain, whereas the vertebral arteries provide blood supply to the
posterior parts of the brain.

The anterior cerebral artery and its branches provide blood supply to
the medial surface of the hemisphere as far back as the parietooccipital
fissure.

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The middle cerebral artery and its branches provide blood supply to
most of the lateral surface of the hemisphere.

The posterior cerebral artery, the terminal branch of the basilar

artery, supplies the medial surfaces of the occipital, temporal, and the
caudal part of the parietal lobes.

The circle of Willis comprises the major site of intracranial collateral

circulation.

Two prominent superficial anasiomotic venous channels are the

anastomotic vein of Trolard and the inferior anastomotic vein of Labbi.

The deep venous system drains via two main veins (the internal
cerebral vein and the basal vein of Rosenthal) into the great cerebral
vein of Galen.

The dural venous sinuses include the superior and inferior sagittal,
straight, confluence, transverse, sigmoid, occipital, petrosal, and
cavernous sinuses.

Extrinsic factors that regulate cerebral circulation include systemic

blood pressure, blood viscosity, and vessel lumen.

Intrinsic factors that regulate cerebral circulation include

autoregulation (the most effective) and biochemical alterations in carbon
dioxide, oxygen, and pH.

The constantly active brain requires a rich blood supply to sustain its
ongoing activity. Irreversible brain damage (brain death) results if the blood
supply to the brain is interrupted for more than a few minutes; consciousness is
lost if the blood supply is interrupted for about 5 s. Lesions of the nervous
system due to interruption of blood supply constitute the most common type of
central nervous system disorders.

It is estimated that about 15 percent of cardiac output reaches the brain; about
20 percent of oxygen utilization of the body is consumed by the adult brain and
as much as 50 percent by the
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infant brain. The blood flow through the human brain is estimated to be 800
ml/min, or approximately 50 ml/100 g of brain tissue per minute. This average
value increases with an increase in functional activity of the brain or regions
within it. The blood flow is markedly increased in the sensory motor area on
vigorous exercise of the contralateral limb. Cerebral blood flow is faster in gray
matter (70 to 80 ml/100 g per min) than in white matter (30 ml/100 g per min).
Irreversible brain damage will occur if the cerebral blood flow is less than 15
ml/100 g per min.

SOURCES OF SUPPLY
The brain receives its blood supply from four arterial trunks: two internal carotid

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arteries and two vertebral arteries. On the right side, the brachiocephalic trunk
gives rise to the right subclavian and right common carotid arteries. The right
subclavian artery gives rise to the right vertebral artery, and the right common
carotid artery bifurcates into the right internal and external carotid arteries. On
the left side, the vertebral artery arises from the left subclavian artery, and the
internal carotid artery arises from the left common carotid artery. A knowledge of
normal cerebral vascular anatomy is essential for understanding and localizing
cerebrovascular disorders. This chapter will focus on blood supply of the cerebral
cortex. It is worth noting that nomenclature of the various branches of cerebral
vessels varies from author to author. Blood supplies of the spinal cord and brain
stem are discussed in their respective chapters: Chapters 3, 5, 7, 9, 11, 13, and
15.

Internal Carotid Artery

The internal carotid arteries arise at the bifurcation of the common carotid
arteries in the neck (Figure 27-1), ascend in front of the transverse
processes of the upper three cervical vertebrae, and enter the base of the skull
through the carotid canal. Within the cranium, the internal carotid artery lies in
the cavernous sinus. It then pierces the dura to begin its subarachnoid course.
The internal carotid artery gives rise to the ophthalmic, anterior choroidal,
anterior cerebral, middle cerebral, and posterior communicating branches. Within
the cavernous sinus, the internal carotid artery lies close to the medial wall
immediately adjacent to the abducens nerve (CN VI). Other cranial nerves in the
sinus, situated along the lateral wall include the oculomotor (CN III), trochlear
(CN IV), ophthalmic, and maxillary divisions of the trigeminal (CN V).

Figure 27-1. Lateral view of carotid arteriogram showing the four segments
of the internal carotid artery and four of its intracranial branches:
ophthalmic, anterior choroidal, anterior cerebral, and middle cerebral.

From its site of origin from the common carotid artery to its site of bifurcation
into the anterior and middle cerebral arteries, the internal carotid artery is
divided into four segments: (1) the cervical segment extends from the origin of

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the internal carotid artery from the common carotid to the site where it enters
the carotid canal, (2) the intrapetrosal segment is the part of the artery as it
courses through the petrous portion of the temporal bone, (3) the intracavernous
segment courses through the cavernous sinus, and (4) the cerebral (supraclinoid)
segment extends from the site of exit of the artery from the cavernous sinus to
its bifurcation into the anterior and middle cerebral arteries. The intracavernous
and cerebral segments are collectively known as the carotid siphon because of
their characteristic S-shaped configuration. All the major branches of the internal
carotid artery arise from the cerebral segment.

A. OPHTHALMIC ARTERY
The ophthalmic artery is the first intracranial branch of the internal carotid as it
courses through the cavernous sinus (Figure 27-1). The ophthalmic artery
supplies the optic nerve and gives rise to the central artery of the retina. Thus
interruption of the blood supply from the internal carotid system may result in
disturbances in visual acuity. The ophthalmic artery is also of importance because
of its anastomotic connections with branches of the external carotid system; this
anastomotic relationship is essential in establishing collateral circulation when
the internal carotid system is occluded in the neck.

B. ANTERIOR CHOROIDAL ARTERY

The anterior choroidal artery arises from the internal carotid artery after it
emerges from the cavernous sinus (Figure 27-1). It
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passes ventral to the optic tract and supplies the optic tract, cerebral peduncles,
lateral geniculate body, posterior part of the posterior limb of the internal
capsule, tail of the caudate nucleus, uncus, amygdala, anterior hippocampus,
choroid plexus of the temporal horn, and sometimes the globus pallidus. The
anterior choroidal artery is prone to occlusion by thrombus because of its small
caliber.

C. ANTERIOR CEREBRAL ARTERY

The anterior cerebral artery (Figures 27-1, Figures 27-2, and 17–26) originates
from the internal carotid artery lateral to the optic chiasm and courses dorsal to
the optic nerve to reach the interhemispheric fissure, where it curves around the
genu of the corpus callosum and continues as the pericallosal artery dorsal to the
corpus callosum. As the two anterior cerebral arteries approach the
interhemispheric fissure, they are joined by the anterior communicating artery.
The following are among its major branches.

1. Recurrent Artery of Heubner (Medial Striate Artery)

(Figure 27-2).
This artery arises from the anterior cerebral artery either proximal or distal to
the anterior communicating artery. It supplies the anterior limb and genu of the
internal capsule and parts of the head of the caudate, rostral putamen, and
globus pallidus. It also provides blood supply to the posterior portions of the
gyrus rectus and orbitofrontal cortex. Thus occlusion of this artery will result in
subcortical and cortical infarcts. The recurrent artery of Heubner varies in
number from one to three.

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2. Orbitofrontal Artery (Figure 27-2).

This branch arises distal to the anterior communicating artery and supplies the
orbital gyri at the base of the frontal lobe and part of the septal area. The
orbitofrontal artery or its branches may be displaced by subfrontal tumors, thus
providing a clue, in cerebral angiograms, to the extracerebral location of the
tumor (e.g., subfrontal meningioma).

Figure 27-2. Midsagittal view of the brain showing anterior cerebral artery
distribution.

3. Frontopolar Artery (Figure 27-2).

Arising at the level of the genu of the corpus callosum, this artery supplies most
of the pole of the frontal lobe.

4. Callosomarginal Artery (Figure 27-2).

This is the major branch of the anterior cerebral artery. It passes backward and
upward and gives off internal frontal branches before terminating in the
paracentral branch around the paracentral lobule.

5. Pericallosal Artery (Figure 27-2).

This is the terminal branch of the anterior cerebral artery. It courses fairly close
to the corpus callosum. It ordinarily gives rise to the paracentral artery, which
also may be derived from the callosomarginal artery. The pericallosal artery
terminates as the precuneal branch, which supplies the precuneus gyrus of the
parietal lobe.

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The anterior cerebral artery supplies the medial surface of the cerebral
hemisphere as far back as the parietooccipital fissure. This area includes the
paracentral lobule, which contains cortical centers for movement and sensation
from the contralateral lower extremity, and the ventromedial prefrontal cortex
important for executive functions, including short-term memory, planning, and
decision making. Unilateral occlusion of the anterior cerebral artery is manifested
in contralateral lower extremity weakness or paralysis and sensory deficit.

Occlusion of both anterior cerebral arteries results in bilateral lower extremity

paralysis and impaired sensations that mimic a spinal cord lesion.

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Because of the bilateral involvement of the ventromedial prefrontal cortex in such
lesions, affected patients show loss of initiative and spontaneity, apathy, memory
and emotional disturbances, and difficulty in control of their urinary and anal
sphincters.

D. MIDDLE CEREBRAL ARTERY

The middle cerebral artery (Figures 27-1, Figures 27-3, and 17–27) is a
continuation or the main branch of the internal carotid artery. It is divided
into four segments: the M 1 (sphenoidal) segment courses posterior and parallel to
the sphenoid ridge; the M 2 (insular) segment lies on the insula (island of Reil);
the M 3 (opercular) segment courses over the frontal, parietal, and temporal
opercula; and the M 4 (cortical) segment spreads over the cortical surface. It
courses within the lateral (sylvian) fissure and divides into a number of branches
that supply most of the lateral surface of the hemisphere. The middle cerebral
artery territory does not reach the occipital or frontal poles or the upper margin
of the hemisphere along the superior longitudinal fissure but does extend around
the inferior margin of the cerebral hemisphere onto the inferior surfaces of the
frontal and temporal lobes. The following are some of the more important
branches.

1. Cortical Branches.
These include the frontal branch, including the rolandic (which supplies the
primary sensory motor cortex); the temporal branch; and the parietal branch,
including the angular (which supplies the supramarginal and part of the angular
gyri). The most rostral cortical division of the middle cerebral artery is known as
the candelabra branch because of its division into two segments, resembling a
candelabra.

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Figure 27-3. Lateral Surface of the cerebral hemisphere showing the middle
cerebral artery and its cortical branches.

2. Central (Perforating) Branches.

These include the lenticulostriate arteries, which supply the major parts of the
caudate, putamen, globus pallidus, internal capsule, and thalamus. The
perforating branches are involved in basal ganglia and internal capsule
hemorrhages and infarcts. Charcot's artery, the artery of cerebral hemorrhage, is
one of the perforating branches of the middle cerebral artery.

The perforating arteries range in number from two to twelve and in size from 80
to 1400 µm.

The middle cerebral artery thus supplies the following important neural
structures: primary and association motor and somatosensory cortices, Broca's
area of speech, prefrontal cortex, primary and association auditory cortices
(including Wernicke's area), and the major association cortex (supramarginal and
angular gyri). Occlusion of the middle cerebral artery results in contralateral
paralysis (more marked in the upper extremity and face), contralateral loss of
kinesthesia and discriminative touch, changes in mentation and personality, and
aphasia when the left (dominant) hemisphere is involved.

E. POSTERIOR COMMUNICATING ARTERY

The posterior communicating artery (Figure 27-4) connects the internal carotid
artery with the posterior cerebral artery. Some anatomists consider the posterior
cerebral artery as a continuation of the posterior communicating artery. Branches
of the posterior communicating artery supply the genu and anterior part of the

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posterior limb of the internal capsule, the anterior part of the thalamus, and
parts of the hypothalamus and subthalamus.

Figure 27-4. Schematic diagram of the major branches of the vertebral and
basilar arteries and the circle of Willis and arteries that contribute to the
formation of the circle.

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Vertebral Artery
The vertebral artery arises from the subclavian artery. It ascends within the
foramina of the transverse processes of the upper six cervical vertebrae
(intraosseous segment), curves backward around the lateral mass of the atlas
(atlantoaxial segment), and enters the cranium through the foramen magnum
(intracranial segment). Within the cranium, the vertebral arteries lie on the
inferior surface of the medulla oblongata (Figure 27-4). The two vertebral
arteries join at the caudal end of the pons to form the basilar artery. The
vertebral artery gives rise to the posterior spinal, anterior spinal, and posterior
inferior cerebellar branches. Meningeal branches supply the meninges of the
posterior fossa, including the falx cerebelli.

The intraosseous segment is affected by osteoarthritis and atherosclerosis. The

atlantoaxial segment is affected in fractures, dislocations, subluxations, birth
trauma, and chiropractic adjustments. The intracranial segment is involved more
frequently than other segments in thrombotic occlusions.

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A. POSTERIOR SPINAL ARTERY

The two posterior spinal arteries pass caudally over the medulla and the posterior
surface of the spinal cord. They supply the posterior aspect of the medulla below
the obex, as well as the posterior column and posterior horns of the spinal cord.
One or both posterior spinal arteries may arise from the posterior inferior
cerebellar arteries.

B. ANTERIOR SPINAL ARTERY

The anterior spinal artery (Figure 27-4) starts as two vessels that join to form a
single artery that descends on the ventral aspect of the medulla and into the
anterior median fissure of the spinal cord. It supplies the medullary pyramids and
the paramedian medullary structures, as well as the anterior two-thirds of the
spinal cord. Occlusion of this artery in the spinal cord results in sudden onset of
paralysis below the occlusion.

C. POSTERIOR INFERIOR CEREBELLAR ARTERY (PICA)

Asymmetric in level of origin and diameter, these arteries (Figure 27-4) follow an
S-shaped course over the olive and inferior cerebellar peduncle to supply the
inferior surface of the cerebellum, dorsolateral surface of the medulla oblongata,
choroid plexus of the fourth ventricle, and part of the deep cerebellar nuclei.
Occlusion of this artery gives rise to a characteristic group of signs and
symptoms comprising the lateral medullary syndrome (Wallenberg syndrome).
The posterior inferior cerebellar artery may have common origin with the anterior
inferior cerebellar artery from the basilar artery.

Basilar Artery
Formed by the union of the two vertebral arteries at the caudal end of the pons,
the basilar artery (Figure 27-4) runs in the pontine groove on the ventral aspect
of the pons and terminates at the rostral end by dividing into the two posterior
cerebral arteries. Branches include a series of paramedian (penetrating) arteries
that supply the paramedian zone of the basilar portion of the pons (basis pontis)
and the adjacent pontine tegmentum and a series of short and long
circumferential arteries.

A. PARAMEDIAN PENETRATING ARTERIES

These branches travel for variable distances caudally before penetrating the brain
stem; hence a lesion in the brain stem may appear at levels more caudal than
that of the occluded vessel.

B. SHORT CIRCUMFERENTIAL ARTERIES

These branches supply the anterolateral and posterolateral parts of the pons.

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C. LONG CIRCUMFERENTIAL ARTERIES

There are three long circumferential arteries.

1. Auditory (Labyrinthine) Artery.

This artery (Figure 27-4) accompanies the facial (CN VII) and vestibulocochlear

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(CN VIII) cranial nerves and supplies the inner ear and root fibers of the facial
nerve. Occlusion of this artery gives rise to deafness. It has variable origin from
the basilar, anterior inferior cerebellar, and the posterior inferior cerebellar
arteries.

2. Anterior Inferior Cerebellar Artery (AICA).

This artery (Figure 27-4) supplies the inferior surface of the cerebellum, the
brachium pontis, and the restiform body, as well as the tegmentum of the lower
pons and upper medulla. It may arise from a common stem with the auditory
artery or the posterior inferior cerebellar artery.

3. Superior Cerebellar Artery.

This is the last branch of the basilar artery before its terminal bifurcation into the
two posterior cerebral arteries (Figure 27-4). The oculomotor nerve exits the
brain stem between the superior cerebellar and posterior cerebral arteries. It
supplies the superior surface of the cerebellum, part of the dentate nucleus, the
brachium pontis and conjunctivum, the tegmentum of the upper pons, and the
inferior colliculus.

D. POSTERIOR CEREBRAL ARTERIES (Figures 27-5 and

17-26)
These constitute the terminal branches of the basilar artery in 70 percent of
cases; they may arise from the carotid artery of one side in 20 to 25 percent
of cases and on both sides in 5 to 10 percent of cases. They pass around the
cerebral peduncle and supply the medial surfaces of the occipital lobe, including
the primary and association visual cortices, temporal lobe, caudal parietal lobe,
and the splenium of the corpus callosum. The main trunk of the posterior cerebral
artery bifurcates into medial and lateral branches (Figure 27-5). The lateral
branch gives rise to anterior and posterior temporal branches, which supply the
medial surface of the temporal lobe except for its most rostral part, which is
supplied by the middle cerebral artery. The medial branch gives rise to
parietooccipital and occipital (including calcarine) branches, which supply the
medial surface of the occipital lobe, part of the posterior parietal lobe, and the
splenium of the corpus callosum.

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Figure 27-5. Medial and inferior view of the cerebral hemisphere showing
the posterior cerebral artery and its branches.

Occlusion of one posterior cerebral artery results in contralateral loss of vision

(homonymous hemianopia), with sparing of macular vision because of collateral
circulation from the middle cerebral artery to the occipital pole, where macular
vision is represented. Bilateral occlusion of the posterior cerebral artery results
in prosopagnosia (loss of face recognition) and achromatopsia (loss of color
vision). Perforating branches supply the cerebral peduncle, mamillary bodies, and
the mesencephalon. Other branches include the thalamogeniculate artery, which
supplies the lateral geniculate body and posterior thalamus, and the posterior
choroidal artery, which supplies the choroid plexus of the third and lateral
ventricles, tectum, and thalamus. Posterior cerebral artery branches also pass
over the dorsal edge of the cerebral hemisphere to supply a small part of the
lateral surface of the caudal parietal lobe and occipital lobe and the inferior
temporal gyrus. The posterior cerebral artery may be compressed by herniation
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of the uncus in cases of increased intracranial pressure. As a consequence, the
circulation of the visual cortex is impaired, resulting in cortical blindness.

CIRCLE OF WILLIS
The proximal portions of the anterior, middle, and posterior cerebral arteries
connected by the anterior and posterior communicating arteries form a circle, the
circle of Willis (Figure 27-4), around the infundibulum of the pituitary and the
optic chiasm. The circle constitutes an important anastomotic channel between
the internal carotid and the vertebral basilar systems.

When either the internal carotid arteries (anterior circulation) or the vertebral

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basilar system (posterior circulation) becomes occluded, collateral circulation in

the circle of Willis will provide blood to the area deprived of blood supply. The
circle of Willis is complete in only 20 percent of individuals. In the majority of
individuals, variation in size and/or origin of vessels is the rule.

CONDUCTING AND PENETRATING VESSELS

The arteries of the brain fall into two general types. The conducting or superficial
arteries are those which run in the pia arachnoid and include the internal carotid
and vertebral basilar systems and their branches. These vessels receive
autonomic nerves and function as pressure-equalization reservoirs to maintain an
adequate perfusion pressure for the penetrating arteries. It is estimated that the
drop in the pressure head from large vessels to the penetrating arterioles does
not exceed 10 to 15 percent. The penetrating arterioles supply the cortex and
white matter and are organized in vertical and horizontal patterns. These are
presumed to be the primary sites of regional autoregulation and do not receive a
significant neural supply.

HISTOLOGY OF CEREBRAL VESSELS

Cerebral arteries differ from arteries elsewhere in the body in the following
features:

1. Thinner walls

2. Absent external elastic laminae

3. Presence of astrocytic processes

4. Presence of a perivascular reticular sheath consisting of arachnoid

trabeculae (the latter acquire an outer pial membrane when the vessel
penetrates the brain substance).

Cerebral capillaries are structurally similar to capillaries elsewhere, except for

being surrounded by perivascular glial (astrocytic) processes. Cerebral veins have
thinner walls and are devoid of valves and muscle fibers. The absence of valves
allows reversal of blood flow when occlusion of the lumen occurs in disease.

COLLATERAL CIRCULATION
Anastomotic channels are present in all parts of both the arterial and venous
circulations. Their main purpose is to ensure a continuing blood flow to the brain
in case of a major occlusion of a feeding vessel. Some of these channels,
however, are not very effective in collateral circulation because of their small
caliber. The following are the major sites of collateral circulation.

1. Extracranial anastomoses are found between cervical vessels, such as the

vertebral and external carotids of the same side.

2. Extracranial-intracranial anastomoses occur between branches of the

external carotid and the ophthalmic artery. This is a major site of
communication between extracranial and intracranial circulations. Thus,
when the internal carotid is obstructed proximal to the origin of the
ophthalmic artery, flow is reversed in the ophthalmic artery. Another site of
extracranial-intracranial anastomosis is through the rete mirabile, a group

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of small vessels that connect meningeal and ethmoidal branches of external

carotid arteries with leptomeningeal branches of cerebral arteries.

3. Intracranial anastomoses occur in the circle of Willis. Under normal

conditions, there is very little side flow or flow from posterior to
anterior segments in the circle of Willis. In the presence of major occlusion,
however, the communications across the anterior or posterior
communicating artery become a very important channel for collateral
circulation. Other sites of intracranial anastomoses include those among the
superior cerebellar, anterior inferior cerebellar, and posterior inferior
cerebellar in the cerebellum.

CEREBRAL VENOUS DRAINAGE

Cerebral venous drainage occurs through two systems, the superficial and the
deep.

Superficial Venous System

The superficial system of veins (Figure 27-6) is divided into three groups.

A. SUPERIOR CEREBRAL GROUP

These veins drain the dorsolateral and dorsomedial surfaces of the
hemisphere and enter the superior sagittal sinus at a forward angle against
the flow of blood. Conventionally, the most prominent of these veins in the
central sulcus is called the superior anastomotic vein of Trolard, which
interconnects the superior and middle groups of veins.

B. MIDDLE CEREBRAL GROUP

These veins run along the sylvian fissure, drain the inferolateral surface of the
hemisphere, and open into the cavernous sinus.

Figure 27-6. Schematic diagram of lateral surface of the cerebral

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hemisphere showing the system of superficial venous drainage.

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C. INFERIOR CEREBRAL GROUP

These veins drain the inferior surface of the hemisphere and open into the
cavernous and transverse sinuses. The middle and inferior groups are
interconnected by the inferior anastomotic vein of Labbé, which crosses the
temporal lobe about 5 cm behind its tip. The medial surface of the hemisphere is
drained by a number of veins that open into the superior and inferior sagittal
sinuses, as well as into the basal vein and the great cerebral vein of Galen.

Deep Venous System

The deep venous system (Figure 27-7) consists of a number of veins that drain
into two main tributaries; these are the internal cerebral vein and the basal vein
(of Rosenthal). The two join beneath the splenium of the corpus callosum to form
the great cerebral vein of Galen, which opens into the straight sinus.

A. INTERNAL CEREBRAL VEIN

This vein receives two tributaries.

1. Terminal Vein (Thalamostriate).

Draining the caudate nucleus and possibly the thalamus, this vein passes forward
in a groove between the caudate nucleus and thalamus in the body of the lateral
ventricle and empties into the internal cerebral vein at the interventricular
foramen of Monro.

2. Septal Vein.
This vein drains the septum pellucidum, the anterior end of the corpus callosum,
and the head of the caudate nucleus and passes backward from the anterior
column of the fornix to open at the interventricular foramen into the internal
cerebral vein.

The internal cerebral vein of each side runs along the roof of the third ventricle in
the velum interpositum. It extends from the region of the foramen of Monro
rostrally to between the pineal body (below) and the splenium of the corpus
callosum (above) caudally. The two internal cerebral veins join below the
splenium of the corpus callosum to form the great vein of Galen.

B. BASAL VEIN OF ROSENTHAL

This vein begins under the anterior perforated substance near the medial part of
the anterior temporal lobe and runs backward to empty into the great cerebral
vein. It drains blood from the base of the brain.

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Figure 27-7. Schematic diagram of the deep system of venous drainage of

the brain.

Visualization of the cerebral veins, particularly the deep group, is used during
cerebral angiography in the localization of deep brain lesions.

C. GREAT CEREBRAL VEIN (OF GALEN)

This vein receives the internal cerebral vein and the basal vein of Rosenthal and
a number of other smaller veins (occipital, posterior callosal) and extends for a
short distance under the splenium of the corpus callosum to empty into the
straight sinus (rectus sinus).

Because of the many anastomotic interconnections within the deep venous

system, only simultaneous obstruction of the great cerebral vein of Galen and the
basal vein of Rosenthal will effectively obstruct deep venous flow. This can occur
in tentorial herniation associated with displacement of the midbrain as a result of
brain edema, bleed, or tumor. Complete obstruction of the vein of Galen and
basal vein leads to rapid death.

CEREBRAL DURAL VENOUS SINUSES

Cerebral dural venous sinuses (see Figure 27-4) are lined by endothelium and are
devoid of valves. They lie between the periosteal and meningeal layers of the
dura mater. They serve as low-pressure channels for venous blood flow back to
the systemic circulation.

The superior sagittal sinus and the inferior sagittal sinus lie in the superior
and inferior margins of the falx cerebri, respectively. The superficial cerebral
veins drain into the superior and inferior sagittal sinuses. The superior sagittal
sinus, in addition, drains cerebrospinal fluid from the subarachnoid space via
arachnoid granulations, evaginations of the arachnoid matter (arachnoid villi),
into the superior sagittal sinus. Caudally, the inferior sagittal sinus is joined by
the great cerebral vein of Galen to form the straight sinus (rectus sinus) located

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at the junction of the falx cerebri and tentorium cerebelli. The straight sinus
drains into the confluence of sinuses. The two transverse sinuses arise from the
confluence of sinuses (torcular Herophili) and pass laterally and forward in a
groove in the occipital bone. At the occipitopetrosal junction, they curve
downward and backward as the sigmoid sinus, which drains into the internal
jugular vein. The occipital sinus connects the confluence of sinuses (torcular
Herophili) to the marginal sinus at the foramen magnum. The superior petrosal
sinus lies in the dura at the anterior border of the tentorium cerebelli. It
connects the pe-trosal vein and transverse sinus to the cavernous sinus. The
inferior petrosal sinus joins the cavernous sinus to the jugular bulb and extends
between the clivus and the petrous bone. The cavernous sinus lies on each side
of the sphenoid sinus, the sella turcica, and the pituitary gland. The medial wall
of the sinus contains the internal carotid artery and the abducens cranial nerve.
The lateral wall contains the oculomotor and trochlear cranial nerves and the
ophthalmic and maxillary divisions of the trigeminal cranial nerve. The two
cavernous sinuses intercommunicate via the basilar venous plexuses and via
venous channels anterior and posterior to the pituitary gland. Anteriorly, the
ophthalmic vein drains into the cavernous sinus. Posteriorly, the cavernous sinus
drains into the superior and inferior petrosal sinuses. Laterally, it joins the
pterygoid plexus at the foramen ovale.

FACTORS REGULATING CEREBRAL CIRCULATION

Cerebral blood flow is a function of the pressure gradient and cerebral vascular
resistance. The pressure gradient is determined primarily by arterial pressure.
Resistance is a function of blood viscosity and size of cerebral vessels.

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Extrinsic Factors
A. SYSTEMIC BLOOD PRESSURE
Arterial pressure is regulated by several circulatory reflexes, the most
important of which are the baroreceptor reflexes. Baroreceptors in the aortic
arch and carotid sinus are tonically active when arterial pressure is normal and
vary their impulse frequency directly with fluctuations in blood Pressure. An
increase in arterial pressure increases impulses from baroreceptors, with
inhibition of sympathetic efferents to the cardiovascular system and stimulation
of the cardiac vagus nerve, leading to a decrease in arterial pressure. The
reverse occurs if the arterial pressure is decreased. Baroreceptor regulation of
arterial pressure ceases when arterial pressure falls below 50 to 60 mmHg.

Fluctuations in systemic arterial blood pressure in the healthy young individual

have very little, if any, effect on cerebral blood flow. Cerebral blood flow will be
maintained with fluctuations in systolic blood pressure between 200 and 50
mmHg. A fall in systolic blood pressure below 50 mmHg may be accompanied by
a reduction in cerebral blood flow; however, because more oxygen is extracted,
consciousness is usually not impaired. Cerebral blood flow also may decrease if
systolic pressure rises above 200 mmHg or diastolic pressure rises above 110 to
120 mmHg. The range of blood pressure fluctuations beyond which cerebral blood
flow is affected is narrower in individuals with arteriosclerosis of cerebral vessels.

B. BLOOD VISCOSITY
Cerebral blood flow is inversely proportional to blood viscosity in humans. A

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major factor controlling blood viscosity is the concentration of red blood cells. A
reduction in blood viscosity, as occurs in anemia, will increase cerebral blood
flow. On the other hand, an increase in viscosity, as occurs in polycythemia, will
decrease cerebral blood flow. Venesection in polycythemic patients has been
shown to increase cerebral blood flow by 30 percent concomitant with a drop in
viscosity and hematocrit.

C. VESSEL LUMEN
Minor reductions in the lumina of carotid and vertebral arteries are without effect
on cerebral circulation. The vessel lumen must be reduced by 70 to 90 percent
before a reduction in cerebral circulation occurs.

Intrinsic Factors
A. AUTOREGULATION
The single most important factor controlling cerebral circulation is the
phenomenon of autoregulation, by which smooth muscles in small cerebral
arteries and arterioles can change their tension in response to intramural
pressure to maintain a constant flow despite alterations in perfusion pressure.
Thus cerebral blood vessels constrict in response to an increase in intraluminal
pressure and dilate in response to a reduction in intraluminal pressure. This
phenomenon is particularly useful in shunting blood from healthy regions where
intraluminal pressure is higher to ischemic regions where a reduction in blood
flow has occurred, resulting in a reduction in intraluminal pressure.
Autoregulation operates independently of but synergistically with other intrinsic
factors such as biochemical changes. The mechanism of autoregulation is poorly
understood. In general, three theories have been proposed; these are the
neurogenic, myogenic, and metabolic theories.

B. BIOCHEMICAL FACTORS
Several biochemical factors regulate cerebral circulation.

1. Carbon Dioxide.
Arterial PCO 2 is a major factor in the regulation of cerebral blood flow.
Hypercapnia (high PCO 2 ) produces marked vasodilatation and an increase in
cerebral blood flow. The reverse occurs in hypocapnia (low PCO 2 ). Thus inhalation
of carbon dioxide increases cerebral blood flow, whereas hyperventilation
decreases cerebral blood flow. Under normal conditions, it is estimated that a
change of 1 mmHg in PCO 2 will induce a 5 percent change in cerebral blood flow.

The control of cerebral blood flow by carbon dioxide is mediated via the
cerebrospinal fluid bathing cerebral arterioles. The pH of the cerebrospinal fluid
(CSF) reflects the arterial PCO 2 and is also influenced by the level of bicarbonate
in the CSF.

The effect of carbon dioxide on cerebral blood flow is important in dampening the
effects of tissue PCO 2 in areas of brain ischemia. The increase in cerebral blood
flow in such areas helps to wash out metabolically produced carbon dioxide and
thus reestablishes homeostasis of brain pH.

2. Oxygen.

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Moderate changes in arterial PO 2 do not alter cerebral blood flow. However, more
marked changes in arterial PO 2 alter cerebral blood flow in a manner that is the
reverse of that described for PCO 2 . Thus low PO 2 (below 50 mmHg) will increase
cerebral blood flow, and high PO 2 will decrease cerebral blood flow. Although the
exact mechanism of this effect is not known, it is believed to be independent of
changes in PCO 2 .

3. pH.
Cerebral blood flow increases with the lowering of the pH and decreases in
alkalosis.

Neural Factors
A. SYMPATHETIC SUPPLY
Sympathetic innervation of conducting vessels is amply documented from the
cervical sympathetic chain. In contrast, very few, if any, penetrating vessels
receive adrenergic nerves. Both myelinated preganglionic and unmyelinated
postganglionic nerve plexuses have been demonstrated in the periadventitial
tissue. Synaptic terminals also have been traced to the outer part of the
muscular media. The number of nerve plexuses and terminals decreases with
reduction in the caliber of the conducting vessel. Stimulation of the sympathetic
system produces vasoconstriction and a decrease in cerebral blood flow. The
effect is greater in the internal carotid artery system than in the vertebral basilar
system.

B. PARASYMPATHETIC SUPPLY
Although parasympathetic nerve fibers have been demonstrated in cerebral
vessels of the conducting variety, a physiologic role for this system in the
regulation of cerebral circulation is yet to be found. The vasoactive effects of
sympathetic stimulation are counteracted by a minor change in pH. Thus neural
factors in the regulation of cerebral blood flow are believed to be of minor
importance when compared with the biochemical factors.

Neuropeptides
Nerve fibers containing neuropeptide Y, vasoactive intestinal peptide (VIP),
substance P (SP), and calcitonin gene-related peptide (CGRP) have been reported
in adventitia or at the adventitia–media border of human cerebral arteries. In
vitro studies reveal that neuropeptide Y causes vasoconstriction, whereas VIP,
SP, and CGRP cause relaxation of precontracted vessels. The effect of
neuropeptides on cerebral blood vessels is not mediated via adrenergic,
cholinergic, or histaminergic receptors.

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MEAN AND REGIONAL CEREBRAL BLOOD FLOW

Mean cerebral blood flow is rather constant during the performance of daily
physiologic activities, such as muscular exercise, changes in posture, mental
activity, and sleep. It is altered, however, in some pathologic conditions such as
convulsions (increased), coma (decreased), anemia (increased), and cerebral
vessel sclerosis (decreased). In contrast, regional cerebral blood flow is altered
during the performance of physiologic activities; thus the regional blood flow in

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the occipital cortex is increased with visual activity and in the motor cortex
during limb movement. Studies of regional cerebral blood flow in normal
individuals have contributed significantly to a better understanding of the role of
different brain regions in the performance of physiologic activities, such as
reading, speaking, hearing, and movement. Determinations of regional cerebral
blood flow also have elucidated regional derangements of distribution of blood
flow in disease states, such as cerebral stroke.

Steal Syndrome
Ischemia of brain tissue, in which cerebral blood flow is below 20 ml/100 g per
min, results in accumulation of lactic acid and secondary loss of tone of the
regional blood vessels. These vessels are not capable of responding normally, in
view of vasomotor paralysis, to factors that alter cerebral blood flow, such as
carbon dioxide and oxygen. In such patients, administration of a vasodilator drug
or induction of a state of hypercapnia dilates the normal vessels and increases
blood flow in the brain regions supplied by such vessels at the expense of the
ischemic region (steal syndrome). These agents should be used with great
caution in such patients to avoid a serious and possibly fatal reduction in cerebral
blood flow in the already ischemic region.

Autoregulation and Hypertension

Cerebral blood flow is normal in patients with moderate hypertension. Such
patients therefore do not have cerebral symptoms. It has been found that the
autoregulatory mechanism in such patients is set at a higher threshold than that
in normal individuals. However, if the blood pressure is increased acutely, then
autoregulatory mechanisms break down and cerebral symptoms appear.

Cerebral Blood Flow in Epilepsy

During an epileptic attack, mean cerebral blood flow increases two- to threefold.
This is a response to increased metabolic demands of brain tissues during such
attacks.

Cerebral Blood Flow in Coma

The mean cerebral blood flow is severely reduced in states of unconsciousness.
Attempts to correlate the degree of reduction of cerebral blood flow with the
chances of recovery from the comatose state have not been successful.

TERMINOLOGY
Basal vein of Rosenthal.
A deep cerebral vein that serves as a landmark for neuroradiologists in
identifying pathology in deep cerebral structures. It was described by Friedrich
Rosenthal, a German anatomist.

Carotid (Greek karotis, “deep sleep”).

The arteries of the neck are so called because it was known in ancient times that
animals became sleepy when these vessels were compressed.

Cavernous (Latin cavernosus, “containing caverns or hollow spaces”).

Circle of Willis.

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The anastomotic ring of arteries that encircles the pituitary stalk. It was first
depicted by Johann Vesling in 1647 and further defined by Thomas Willis in 1664.

Great cerebral vein of Galen.

A major deep cerebral vein that drains into the straight sinus. Named after
Claudius Galen, the Roman physician and founder of the galenical system of
medicine.

Recurrent artery of Heubner.

A branch of the anterior cerebral artery. Named after Otto Johann Leonhard
Heubner, a German pediatrician.

Torcular Herophili (Latin torcula, “wine press”).

A cistern or well to collect the liquor from the wine press. Herophilus was the
ancient Greek anatomist who described this region of the brain. The confluence of
sinuses.

Vein of Labbé.
An anastomotic cerebral vein that interconnects the middle and inferior groups of
superficial cerebral veins. Named after Charles Labbé, the French anatomist.

Vein of Trolard.
An anastomotic cerebral vein that interconnects the superior and middle groups
of superficial cerebral veins. Named after Paulin Trolard, professor of anatomy in
Algiers, who described the vein in his graduation thesis from the University of
Paris in 1868.

SUGGESTED READINGS
Andeweg J: Consequences of the anatomy of deep venous outflow from the
brain. Neuroradiology 1999; 41:233–241.

Brown MM et al: Fundamental importance of arterial oxygen content in the

regulation of cerebral blood flow in man. Brain 1985; 108:81–93.

Damasio H: A computed tomographic guide to the identification of cerebral

vascular territories. Arch Neurol 1983; 40:138–142.

Edvinsson L et al: Peptide-containing nerve fibers in human cerebral arteries:

Immunocytochemistry, radioimmunoassay, and in vitro pharmacology. Ann
Neurol 1987; 21:431–437.

Gibo H et al: Microsurgical anatomy of the middle cerebral artery. J

Neurosurg 1981; 54:151–169.

Glasberg MD et al: Increase in both cerebral glucose utilization and blood flow
during execution of a somatosensory task. Ann Neurol 1988; 23:152–160.

Ingvar DH, Schwartz MS: Blood flow patterns induced in the dominant
hemisphere by speech and reading. Brain 1974; 97:273–288.

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Lassen NA: Control of cerebral circulation in health and disease. Circ Res
1974; 34:749–760.

Lister JR et al: Microsurgical anatomy of the posterior inferior cerebellar

artery. Neurosurgery 1982; 10:170–199.

Kuschinsky W, Wahl M: Local chemical and neurogenic regulation of cerebral

vascular resistance. Physiol Rev 1978; 58:656–689.

Marinkovic SV et al: Perforating branches of the middle cerebral artery:

Microanatomy and clinical significance of their intracerebral segments. Stroke
1985; 16:1022–1029.

Marinkovic S et al: Anatomical bases for surgical approach to the initial

segment of the anterior cerebral artery: Microanatomy of Heubner's artery
and perforating branches of the anterior cerebral artery. Surg Radiol Anat
1986; 8:7–18.

Marinkovic S et al: Interpeduncular perforating branches of the posterior

cerebral artery: Microsurgical anatomy of their extracerebral and
intracerebral segments. Surg Neurol 1986; 26:349–359.

Marinkovic SV et al: Distribution of the occipital branches of the posterior

cerebral artery: Correlation with occipital lobe infarcts. Stroke 1987; 18:728–
732.

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Marinkovic S et al: Anatomic and clinical correlations of the lenticulostriate

arteries. Clin Anat 2001; 14:190–195.

Martin RG et al: Microsurgical relationships of the anterior inferior cerebellar

artery and the facial–vestibulocochlear nerve complex. Neurosurgery 1980;
6:483–507.

Soh K et al: Regional cerebral blood flow in aphasia. Arch Neurol 1978;
35:625–632.

Tatu L et al: Arterial territories of the human brain: Cerebral hemispheres.

Neurology 1998; 50:1699–1708.

Waddington MM: Atlas of Cerebral Angiography with Anatomic Correlation.

Boston: Little, Brown, 1974.

Wade JPH: Transport of oxygen to the brain in patients with elevated

hematocrit values before and after venesection. Brain 1983; 106:513–523.

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Zhang R et al: Autonomic neural control of dynamic cerebral autoregulation in

humans. Circulation 2002; 106:1814–1820.

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Editors: Afifi, Adel K.; Bergman, Ronald A.

Title: Functional Neuroanatomy: Text and Atlas, 2nd Edition

Copyright ©2005 McGraw-Hill

> Table of Contents > Part I - Text > 28 - Cerebral Va scular Syndromes

28
Cerebral Vascular Syndromes

Cerebrovascular Occlusion Syndromes

Middle Cerebral Artery Syndrome
Lenticulostriate Artery Syndrome
Anterior Cerebral Artery Syndrome
Recurrent Artery of Heubner Syndrome
Internal Carotid Artery Syndrome
Anterior Choroidal Artery Syndrome
Posterior Cerebral Artery Syndrome
Vertebral-Basilar Artery Syndromes
Lacunar Syndromes
Cerebral Hemorrhage Syndromes

KEY CONCEPTS

Cerebrovascular disorders include cerebral infarcts (most common) and

cerebral hemorrhages.

The clinical picture of cerebral infarcts reflects the affected vessel, the
location, and the size of the lesion.

Fairly consistent, though not absolute, anatomicoclinical correlations occur

for each of the following vascular occlusion syndromes: middle cerebral
artery, lenticulostriate artery, anterior cerebral artery, recurrent artery of
Heubner, internal carotid artery, anterior choroidal artery, posterior cerebral
artery, and vertebral-basilar arteries.

Lacunar syndromes result from occlusion of small penetrating end

arteries. Five well-defined lacunar syndromes occur: pure motor, pure
sensory, ataxic hemiparesis, dysarthria–clumsy hand, and état lacunaire.

Intracranial hemorrhage results from rupture of an arterial wall because of

longstanding hypertension, congenital aneurysm, arteriovenous malformation,
trauma, or a bleeding disorder.

Cerebrovascular disorders (strokes) constitute the most common cause of brain

lesions. The most common cerebrovascular disorders are cerebral infarcts
resulting from occlusion of cerebral vessels by thrombosis or embolism. Less common
is hemorrhage, usually from rupture of a congenitally abnormal sacculation of a
cerebral blood vessel (aneurysm). Strokes are characterized by a relatively abrupt

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onset of a focal neurologic deficit. The conglomeration of sensory, motor, and

behavioral clinical signs of the neurologic deficit usually reflects the affected vessel as
well as the location and size of the cerebral lesion.

Despite this predictable pattern of clinical signs with specific arterial territory,
there is also sufficient variation in vascular patterns to produce perplexing
clinicoanatomic and clinicopathologic syndromes.

CEREBROVASCULAR OCCLUSION SYNDROMES

Middle Cerebral Artery Syndrome (Figure 28-1)

This is the most frequently encountered stroke syndrome. The clinical picture varies
according to the site of occlusion of the vessel and to the availability of collateral
circulation. The conglomerate clinical signs and symptoms of this syndrome consist of
the following:

1. Contralateral hemiplegia or hemiparesis (complete or partial paralysis) affecting

primarily the face and upper extremity
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and, to a lesser degree, the lower extremity. Weakness is greatest in the
contralateral hand because more proximal limb and trunk muscles as well as facial
muscles have greater representation in both hemispheres.

Figure 28-1. Coronal brain section showing middle cerebral artery territory
infarct and secondary enlargement of the lateral ventricle (star).

2. Contralateral sensory deficit, also more prominent in the face and upper extremity
than in the lower extremity. Position, vibration, deep touch, two-point
discrimination, and stereognosis are more affected than pain and temperature
because the latter two sensory modalities may be perceived at the thalamic level.

3. Contralateral visual field deficit because of damage to the optic radiation, the
tract that connects the lateral geniculate nucleus with the visual cortex.
Depending on where the lesion in the optic tract is located, the visual field deficit
may be a homonymous hemianopia (half-field deficit) or a quadrantanopia
(quadrant-field deficit). In general, parietal lesions are associated with inferior
quadrantanopia, whereas temporal lesions are associated with superior

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quadrantanopia. Occipital lesions are usually associated with a hemianopia.

4. Contralateral conjugate gaze paralysis because of the involvement of the frontal

eye field (area 8 of Brodmann). The gaze paralysis is usually transient for 1 to 2
days. The reason for this transient duration is not clear.

5. Aphasia (with impairment of repetition) if the dominant (left) hemisphere is

involved. The aphasia may be of Broca's, Wernicke's, or global variety depending
on the involved cortical region. Lesions in the inferior frontal gyrus affecting
Broca's area are associated with Broca's aphasia. Lesions affecting Wernicke's
area in the superior temporal gyrus are associated with Wernicke's aphasia.
Global aphasia is usually associated with extensive lesions involving much of the
dominant hemisphere.

6. Inattention and neglect of the contralateral half of body or space and denial of
illness if the nondominant (right) hemisphere is involved.

7. Spatial perception disorders if the right, nondominant hemisphere is involved.

This includes such difficulties as copying simple pictures or diagrams
(constructional apraxia), interpreting maps or finding one's way out
(topographagnosia), and putting on clothes properly (dressing apraxia).

8. Gerstmann syndrome (finger agnosia, acalculia, right-left disorientation, and pure

dysgraphia).

Language and spatial perception deficits tend to follow occlusion not of the proximal
stem of the middle cerebral artery but of one of its several main branches. In such
circumstances, other signs such as weakness or visual field defects may not be
present. Similarly, occlusion of the rolandic branch of the middle cerebral artery
produces motor and sensory deficits without disturbances of vision, language, or
spatial perception. Hearing is unimpaired because of its bilateral representation.

Lenticulostriate Artery Syndrome

Infarction in the territory of the lenticulostriate artery, a branch of the middle cerebral
artery, is associated with pure motor hemiplegia because of involvement of the internal
capsule.

Anterior Cerebral Artery Syndrome

The clinical manifestations of this syndrome vary according to the site of occlusion
along the artery, the availability of collateral circulation, and whether there is
unilateral or bilateral occlusion.

A. UNILATERAL ANTERIOR CEREBRAL ARTERY SYNDROME

Unilateral occlusion of the anterior cerebral artery is associated with the following
clinical picture:

1. Contralateral hemiplegia or hemiparesis affecting primarily the lower extremity

and to a lesser extent the upper extremity

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2. Contralateral sensory deficit affecting primarily the lower extremity and to a
lesser extent the upper extremity

3. Transcortical motor aphasia when the left (dominant) hemisphere is affected

B. BILATERAL ANTERIOR CEREBRAL ARTERY SYNDROME

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(Figure 28-2)
This syndrome occurs when both anterior cerebral arteries arise anomalously from a
single trunk. In addition to the signs encountered in the unilateral syndrome, the
following signs and symptoms occur in the bilateral syndrome due to involvement of
orbitofrontal cortex, limbic structures, supplementary motor cortex, and cingulate
gyrus:

1. Loss of initiative and spontaneity

2. Profound apathy

3. Memory and emotional disturbances

4. Akinetic mutism (complete unresponsiveness with open eyes only)

5. Disturbance in gait and posture

6. Grasp reflex

7. Disorder of sphincter control

The explanation for the occurrence of sphincter control disorder is not certain. It has
been variably attributed to involvement of the motor and sensory cortices on the
medial surface of the hemisphere (paracentral lobule) or to involvement of more
anterior regions of the frontal lobe concerned with inhibition of bladder emptying.

Involvement of the anterior part of the corpus callosum may cause apraxia and tactile
anomia of the left arm attributed to disconnection of the left (dominant) hemisphere
language area from the right motor and sensory cortices.

Figure 28-2. Coronal brain section showing bilateral anterior cerebral artery
territory infarct (stars).

Recurrent Artery of Heubner Syndrome

Infarction in the territory supplied by the recurrent artery of Heubner (medial striate
artery), which is a branch of the anterior cerebral artery, results in the following signs:

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1. Contralateral face and arm weakness without sensory loss

2. Behavioral and cognitive abnormalities, including abulia, agitation, neglect, and

aphasia

The clinical signs reflect involvement of the anterior limb of the internal capsule,
rostral basal ganglia (caudate nucleus and putamen), and the basal frontal lobe.

Internal Carotid Artery Syndrome

Occlusion of the internal carotid artery in the neck may be asymptomatic in the
presence of adequate collateral circulation and slow occlusion or may result in the
following clinical picture:

1. Transient monocular blindness (amaurosis fugax) due to involvement of the

ophthalmic artery, the first intracranial branch of the internal carotid artery

2. Contralateral motor and sensory deficits equally severe in the face, upper
extremity, and lower extremity

3. Contralateral visual field deficit (homonymous hemianopia)

4. Aphasia if the dominant hemisphere is involved

5. Perceptual deficits if the nondominant (right) hemisphere is involved

The internal carotid artery syndrome is thus a combination of the middle and anterior
cerebral artery syndromes to which is added transient monocular blindness.

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Anterior Choroidal Artery Syndrome (Figure 28-3)

Occlusion of the anterior choroidal artery, a branch of the internal carotid artery, may
be asymptomatic or may result in one or more of the following:

1. Contralateral motor deficit (hemiplegia) involving the face, arm, and leg due to
involvement of the posterior part of the posterior limb of the internal capsule and
the cerebral peduncle. This is the most consistent and persistent deficit.

2. Contralateral hemisensory deficit, usually transient, involving, in most cases, all

sensory modalities (hemianesthesia) due to involvement of the sensory tracts
within the posterior limb of the internal capsule.

3. Contralateral visual field defect (hemianopia or quadrant-anopia) due to

involvement of the retrolenticular part of the internal capsule (visual radiation) or
the lateral geniculate nucleus. This is the most variable feature of the syndrome.

Posterior Cerebral Artery Syndrome (Figure 28-4)

The clinical picture of posterior cerebral artery occlusion is variable depending on
whether it is unilateral or bilateral, the site of occlusion, and the availability of
collateral circulation. Only a few large series of posterior cerebral artery stroke exist,
and clinical features and causes have not been studied as extensively as in other
vascular territories.

A. UNILATERAL POSTERIOR CEREBRAL ARTERY SYNDROME

Unilateral occlusion of the posterior cerebral artery is associated with the following:

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1. Contralateral visual field deficit (hemianopia) due to involvement of the calcarine

cortex. Macular (central) vision is usually spared because macular representation
in the occipital pole receives additional blood supply from the middle cerebral
artery.

2. Visual and color agnosia, the inability to name a color or point to a color named
by the examiner because of involvement of the inferiomesial aspect of the
occipitotemporal lobe in the dominant hemisphere.

3. Contralateral sensory loss of all modalities with concomitant pain (thalamic

syndrome) due to involvement of the ventral posterolateral and ventral
posteromedial nuclei of the thalamus, which are supplied by deep penetrating
branches of the posterior cerebral artery.

4. Pure alexia (alexia without agraphia) with a left-sided lesion affecting the
posterior corpus callosum and the left visual cortex.

As a rule, the posterior cerebral artery syndrome is not associated with motor deficit.
The hemiplegia reported occasionally in
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these patients is attributed to involvement of the midbrain by the infarct.

Figure 28-3. T2-weighted magnetic resonance image (MRI) showing bright signal
intensity infarct (arrow) in the anterior choroidal artery territory.

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Figure 28-4. T2-weighted MRI showing bright signal intensity infarct (arrow) in
the posterior cerebral artery territory.

B. BILATERAL POSTERIOR CEREBRAL ARTERY SYNDROME

This syndrome results from occlusion at the point of origin of both posterior cerebral
arteries from the basilar artery. The syndrome is characterized by the following:

1. Cortical blindness, visual loss in both eyes in the presence of normal pupillary
reactivity and normal fundus examination

2. Disturbance in facial recognition (prosopagnosia) due to bilateral involvement of

the inferior occipitotemporal region (lingual and fusiform gyri)

3. Balint syndrome (optic ataxia, psychic paralysis of fixation), the inability to look
to the peripheral field with disturbance of visual attention

4. Anton's syndrome, denial of blindness and confabulation of what the patient sees
if the lesion extends to both parietal lobes

5. Agitated delirium and memory loss due to bilateral involvement of mesiotemporal

territory

C. SYNDROMES OF PENETRATING BRANCHES OF

POSTERIOR CEREBRAL ARTERY
The clinical pictures associated with occlusion of penetrating branches of the posterior
cerebral artery (thalamogeniculate and thalamoperforating) have been discussed in
Chapter 12.

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Vertebral-Basilar Artery Syndromes

Occlusion of the vertebral-basilar arterial system usually results in brain stem infarcts.
The clinical picture varies according to the specific branch affected and the brain stem
territory involved (e.g., lateral medullary syndrome, medial medullary syndrome,
Benedikt syndrome, Weber's syndrome, etc.). Common to all vertebral-basilar artery
syndromes are the following:

1. Bilateral long tract (motor and sensory) signs

2. Crossed motor and sensory signs (e.g., facial weakness or numbness combined
with contralateral extremity weakness or numbness)

3. Cerebellar signs

4. Cranial nerve signs

5. Alteration in state of consciousness (stupor or coma)

6. Disconjugate eye movements

In general, the presence of “the four Ds with crossed findings” suggests a brain stem
stroke from vertebrobasilar occlusion. The four Ds are diplopia, dysarthria, dysphagia,
and dizziness.

Table 28-1 is a simplified comparison of the major signs and symptoms in internal
carotid system and vertebrobasilar system occlusions.

Lacunar Syndromes
Lacunar syndromes result from occlusion of small penetrating end arteries
(variably called lenticulostriate, thalamogeniculate, or thalamoperforator) from
the proximal anterior cerebral, middle cerebral, posterior cerebral, and basilar arteries
or the circle of Willis. They occur usually in patients with longstanding hypertension
and cerebral vessel atherosclerosis. Symptomatic lacunae most often involve the
following brain
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regions: putamen, caudate nucleus, posterior limb of the internal capsule, thalamus,
and basis pontis. Several discrete lacunar syndromes exist. The five well-recognized
lacunar syndromes are

Table 28-1. Major Signs and Symptoms in Internal Carotid System and
Vertebrobasilar System Occlusions

Symptom of Sign Internal Carotid Vertebrobasilar

Motor deficit Contralateral Bilateral, crossed

Sensory deficit Contralateral Bilateral, crossed

Visual deficit Monocular blindness Bilateral, cortical

contralateral field blindness
defect

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Speech deficit Present Absent

(aphasia)

Cranial nerve Absent Present

deficit

1. Pure motor (hemiparesis) syndrome, involving the contralateral face, arm, trunk,
and leg due to a lacuna (small infarct) in the corticospinal tract within the internal
capsule or basis pontis. There are no sensory, speech, or visual deficits.

2. Pure sensory syndrome, involving the contralateral face, arm, trunk, and leg with
loss or diminution of all sensory modalities (hemianesthesia) due to a lacuna in
the sensory thalamic nuclei (ventral posterior lateral, ventral posterior medial).
There are no motor, speech, or visual deficits.

3. Ataxic hemiparesis syndrome, characterized by weakness, pyramidal signs, and

cerebellar-like ataxia involving the limbs on the same side due to a lacuna in one
of the following sites: (a) contralateral posterior limb of the internal capsule, (b)
basis pontis, or (c) red nucleus with extension of the lesion to the adjacent
cerebral peduncle. The internal capsule lesion involves the corticospinal
(hemiparesis) and corticopontine fibers (cerebellar-like ataxia). The basis pontis
lesion involves corticospinal (hemiplegia) and pontocerebellar (ataxia) fibers. The
red nucleus lesion interrupts the cerebellothalamic fibers in the brachium
conjunctivum (ataxia), and its extension into the cerebral peduncle explains the
hemiparesis.

4. Dysarthria–clumsy hand syndrome, characterized by central (supranuclear) facial

weakness, dysarthria, dysphagia, and hand paresis and clumsiness due to a
lacuna in the basis pontis.

5. État lacunaire syndrome. This syndrome is associated with bilateral numerous

lacunae in the frontal lobes. It is characterized by progressive dementia, shuffling
gait, emotional lability (abrupt laughing and crying), and pseudobulbar palsy
(hyperactive palate and gag reflex, lingual and pharyngeal paralysis, and difficulty
swallowing).

CEREBRAL HEMORRHAGE SYNDROMES

Intracranial hemorrhage may result from (1) spontaneous rupture of an arterial
wall because of longstanding hypertension, (2) rupture of a congenital saccular
outpouching of a vessel wall (aneurysm) (Figure 28-5), (3) rupture of an arteriovenous
malformation (Figure 28-6), (4) trauma to the head, or (5) a bleeding disorder.
Hemorrhage may occur (1) within the brain parenchyma, (2) into the ventricular
system, or (3) into meningeal spaces (subarachnoid, subdural, epidural). The ensuing
clinical picture varies depending on the location, size, cause, and rate of development
of the hemorrhage. About 15 to 20 percent of strokes are due to hemorrhage, and
roughly half of these are due to subarachnoid hemorrhage. Subarachnoid hemorrhage
usually results from leakage or rupture of a congenital aneurysm. The clinical picture is

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characterized by sudden onset of severe headache, neck stiffness, and loss of

consciousness. The diagnosis is established by computed tomographic (CT) scan, which
shows blood in the subarachnoid space (Figure 28-7).
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Parenchymal hemorrhage is usually due to rupture of an arterial wall in hypertensive
patients. In some cases, the hemorrhage may burst into the ventricular system.
Subdural and epidural hemorrhages usually are associated with trauma. Subdural
hemorrhage is due to rupture of bridging veins in the subdural space (Figure 28-8).
Epidural hemorrhage, a life-threatening situation, is due to rupture of the middle
meningeal artery in the epidural space. Bleeding from arteriovenous malformations
may occur into the cerebral parenchyma, into the subarachnoid or subdural spaces, or
into the ventricles (Figure 28-9).

Figure 28-5. Three-dimensional computed tomography (CT) image showing an

aneurysm (star).

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Figure 28-6. Arteriogram showing an arteriovenous malformation (arrow).

Figure 28-7. Axial CT image showing blood (arrows) in the sylvian fissure.

TERMINOLOGY
Agraphia (Greek a, “negative”; graphein, “to write”).
Inability to express thoughts in writing. The first modern descriptions were those of
Jean Pitres in 1884 and Dejerine in 1891.

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Figure 28-8. MRI showing blood in the subdural space, subdural hematoma
(stars).

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Figure 28-9. CT image showing blood in the ventricular system (arrows).

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Akinetic mutism (persistent vegetative state).

The state in which patients appear awake and maintain a sleep-wake cycle but are
unable to communicate in any way. The term was introduced by H. Cairns in 1941.

Alexia (Greek a, “negative”; lexis, “word”).

Loss of the power to grasp the meaning of written or printed words.

Amaurosis fugax (Greek amaurosis, “darkening”).

Transient episode of monocular blindness. Used by Hippocrates for “a becoming dull of
sight.”

Aneurysm (Greek aneurysma, “a widening”).

A widening, dilatation, or ballooning out of an artery due to weakness in its walls. The
condition was known to Galen.

Anton's syndrome.
Denial of blindness. Described by Gabriel Anton, an Austrian neurologist, in 1899.
Although unable to see, patients with this syndrome deny their blindness and tend to
confabulate about things seen.

Aphasia (Greek a, “negative”; phasis, “speech”).

Impairment of language function, inability either to speak (motor aphasia) or to
comprehend (sensory, receptive, aphasia).

Apraxia (Greek a, “negative”; pratto, “to do”).

Inability to perform complex, purposeful movements, although muscles are not
paralyzed.

Hemianopia (Greek hemi, “half”; an, “negative”; opia, “vision”).

Loss of vision in one-half the visual field.

Homonymous (Greek homo, “same”; onoma, “name”).

Loss of vision in the same half field in each eye.

Infarct (Latin infarcire, “to stuff or fill in”).

Regional death of tissue caused by loss of blood supply. Originally described by
Virchow.

Optic ataxia (Balint syndrome).

Severe impairment of visually guided movements, such as when trying to reach for an
object. Originally described by Rudolph Balint, a Hungarian neurologist, in 1909.

Prosopagnosia (Greek prosopon, “face”; gnosia, “to know”).

Inability to recognize familiar faces.

Stereognosis (Greek stereos, “solid”; gnosis, “know”).

Three-dimensional tactile feeling.

Topographagnosia (Greek topo, “place”; graphein, “to write”; gnosis, “know”).

Failure to localize a point on the body or read maps.

SUGGESTED READINGS
Archer C, Horenstein S: Basilar artery occlusion: Clinical and radiological

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correlation. Stroke 1977; 8:383–390.

Ausman JI et al: Vertebrobasilar insufficiency: A review. Arch Neurol 1985;

42:803–808.

Biller J: Vascular syndromes of the cerebrum. In Brazis PW et al (eds): Localization

of Clinical Neurology. Boston: Little, Brown, 1985:362.

Brandt T et al: Posterior cerebral artery territory infarcts: Clinical features, infarct
topography, causes and outcome. Multicenter results and a review of the literature.
Cerebrovasc Dis 2000; 10:170–182.

Caplan LR: Intracranial branch atheromatous disease: A neglected, understudied,

and underused concept. Neurology 1989; 39:1246–1250.

Fisher CM: Lacunar strokes and infarcts: A review. Neurology 1982; 32:871–876.

Fisher CM: The posterior cerebral artery syndrome. Can J Neurol Sci 1986; 13:232–
239.

Ghika J et al: Infarcts in the territory of the deep perforators from the carotid
system. Neurology 1989; 39:507–512.

Glass JD et al: The dysarthria–clumsy hand syndrome: A distinct clinical entity

related to pontine infarction. Ann Neurol 1990; 27:487–494.

Goodwin JA et al: Symptoms of amaurosis fugax in atherosclerotic carotid artery

disease. Neurology 1987; 37:829–832.

Helgason C et al: Anterior choroidal artery–territory infarction: Report of cases and

review. Arch Neurol 1986; 43:681–686.

Helweg-Larsen S et al: Ataxic hemiparesis: Three different locations of lesions

studied by MRI. Neurology 1988; 38:1322–1324.

Hommel M et al: Hemiplegia in posterior cerebral artery occlusion. Neurology 1990;

40:1496–1499.

Hupperts RMM et al: Infarcts in the anterior choroidal artery territory: Anatomical
distribution, clinical syndromes, presumed pathogenesis, and early outcome. Brain
1994; 117:825–834.

Melo TP et al: Pure motor stroke: A reappraisal. Neurology 1992; 42:789–798.

Nighoghossian N et al: Pontine versus capsular pure motor hemiparesis. Neurology

1993; 43:2197–2201.

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Wolfe N et al: Frontal systems impairment following multiple lacunar infarcts. Arch
Neurol 1990; 47:129–132.

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Editors: Afifi, Adel K.; Bergman, Ronald A.

Title: Functional Neuroanatomy: Text and Atlas, 2nd Edition

Copyright ©2005 McGraw-Hill

> Table of Contents > Part I - Text > 29 - Cerebrospinal Fluid and the Barrier System

29
Cerebrospinal Fluid and the Barrier System

Anatomy of the Ventricular System

Subarachnoid Cisterns
Choroid Plexus
Cerebrospinal Fluid
Classic Concepts
Current Concepts
Spinal (Lumbar), Cisternal, and Ventricular Taps (Punctures)
Brain Barrier System

KEY CONCEPTS

The ventricular system is composed of four interconnected spaces:

two lateral ventricles, a third ventricle, and a fourth ventricle. The
foramen of Monro connects the lateral and third ventricles. The aqueduct
of Sylvius connects the third and fourth ventricles.

Certain sites within the ventricular system contain choroid plexus.

These include the body, trigone, and inferior horns of the lateral
ventricle, the foramen of Monro, the roof of the third ventricle, and the
posterior part of the roof of the fourth ventricle.

Subarachnoid cisterns are dilations within the subarachnoid space.

They include the cisterna magna, medullary cistern, cisterna pontis,
cisterna interpeduncularis, suprasellar cistern, superior cistern, cisterna
ambiens, and lumbar cistern.

Besides the choroid plexus, the CSF is formed in the ependyma,

cerebral pial surface, and cerebral extracellular space.

CSF is formed by a variety of processes that include diffusion, active

transport, and free passage of water.

CSF is resorbed primarily through the arachnoid granulations into the

superior sagittal sinus. Other sites include the leptomeningeal vessels,
ependyma lining the ventricles, and sheaths of cranial and spinal nerves.

CSF has three functions: buoyancy of the brain, physical buffer

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between brain and skull, and chemical buffer between the blood and
brain.

Access to the CSF via the lumbar subarachnoid space is

contraindicated in states of increased intracranial pressure.

The brain barrier system has three components: blood-brain barrier,

blood-CSF barrier, and blood-nerve barrier.

Certain areas of the brain are devoid of brain barrier system. They
include area postrema, neurohypophysis, pineal gland, organ
vasculosum, median eminence, subcommissural organ, and subfornical
organ. Collectively, these areas are known as the circumventricular
organs.

ANATOMY OF THE VENTRICULAR SYSTEM

The brain contains four ependyma-lined cavities known as cerebral
ventricles; these are the right and left lateral ventricles, the third ventricle,
and the fourth ventricle (Figure 29-1). The four cavities communicate with each
other and with the subarachnoid space: the lateral and third ventricles through
the foramen of Monro, named after Alexander Monro, who described it in 1783
(Figures 29-1 and 29-2), the third and fourth ventricles through the aqueduct of
Sylvius (cerebral aqueduct or iter) (Figure 29-2), and the fourth ventricle and the
subarachnoid space through the foramina of Magendie and Luschka. The term fifth
ventricle is sometimes used to refer to the cavity (Figures 29-3 and 29-4) that
develops within the septum
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pellucidum (the cavum septum pellucidum). This, however, is a misnomer
because the cavity is lined with astrocytes and does not have the ependymal
lining characteristic of ventricular cavities, nor does it contain cerebrospinal fluid
(CSF).

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Figure 29-1. Schematic diagram in composite sagittal view showing the

ventricular cavities of the brain with intraventricular sites of choroid plexus.

Cavum septum pellucidum is found in all premature newborns. It begins to close

just before birth in full-term newborns and is frequently seen in brain images
[computed tomographic (CT) scans and magnetic resonance imaging (MRI)] in
neonates. Its incidence at 6 months of age and beyond falls to about 6 percent.

Posterior extension of the cavum septum pellucidum (Figures 29-3 and 29-4)
above the fornix and posterior to the foramen of Monro constitutes the cavum
vergae (sixth ventricle), named after the Italian anatomist Andrea Verga, who
described the cavum in 1851. It communicates with the cavum septi pellucidi.

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Figure 29-2. Midsagittal view of the brain showing the foramen of Monro,
third ventricle, aqueduct of Sylvius, and fourth ventricle.

Figure 29-3. T2-weighted axial magnetic resonance image (MRI) showing

cavum septum pellucidum and cavum vergae.

The cavum veli interpositi (interventricular cavum) is a triangular cavity located

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rostral to the superior (quadrigeminal) cistern below the fornix and above the
thalamus and the roof of the third ventricle (Figure 29-4). The cavity develops as
a result of abnormal separation of the limbs of the fornix. The cavity tends to be
large in infants and becomes small beyond 2 years of age. The cavum veli
interpositi communicates with the subarachnoid space, in contrast to the cavum
vergae, which communicates with the ventricle. The two cavities also can be
differentiated by their relationship to the fornix. The cavum vergae is located
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above the fornix, whereas the cavum interpositi is beneath the fornix. A
composite schema of the cava septum pellucidum, vergae, and interpositum is
shown in Figure 29-4. The lateral ventricles have an archlike configuration
corresponding to the shape of the hemisphere. Each lateral ventricle is
subdivided into five segments (Figure 29-1):

Figure 29-4. Schematic composite diagram showing the location and

relationship, in midsagittal view, of the cavum septum pellucidum (medium
gray), cavum vergae (dark gray), and cavum velum interpositum (light
gray). CC, corpus callosum; TH, thalamus; FM, foramen of Monro; P, pineal
gland; SC, superior cistern; MB, midbrain; P, pons; V 4 , fourth ventricle; CBL,
cerebellum.

1. Frontal (anterior) horn

2. Body

3. Atrium (trigone)

4. Occipital (posterior) horn

5. Temporal (inferior) horn

The frontal (anterior) horn is the part of the lateral ventricle rostral to the
foramen of Monro (Figures 29-1 and 29-2). In sections, this part of the ventricle
has a butterfly configuration, with the corpus callosum forming its roof, the

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septum pellucidum and fornix constituting its medial wall, and the caudate
nucleus bulging into the lateral wall. This characteristic bulge of the caudate
nucleus into the lateral wall disappears in degenerative diseases of the brain
involving the caudate nucleus such as in Huntington's chorea.

The body of the lateral ventricle (Figure 29-1) extends from the foramen of
Monro posteriorly to the trigone. The atrium or trigone (Figure 29-1) is the area
of confluence of the posterior part of the body with the occipital and temporal
horns. The atrium is the most expanded subdivision of the ventricle and the site
of early ventricular enlargement in degenerative diseases of the brain.

The occipital (posterior) horn (Figure 29-1) extends from the atrium backward
toward the occipital pole. It is the most variable subdivision in shape and size,
with the left usually larger than the right, and may be rudimentary or altogether
absent. The calcarine fissure produces an impression in the medial wall of the
occipital horn known as the calcar avis.

The temporal (inferior) horn (Figure 29-1) extends from the atrium downward
and forward into the temporal lobe and ends approximately 3 cm behind the
temporal tip.

The lateral ventricles communicate with the third ventricle through the
interventricular foramen of Monro (Figure 29-1). The cavity of the third ventricle
is enclosed between the two thalami and hypothalami. It is bounded anteriorly by
the lamina terminalis (Figure 29-2) and the anterior commissure, superiorly by
ependyma fused with the overlying leptomeninges of the embryonic diencephalon
(velum interpositum or tela choroidea) incorporating numerous blood vessels,
posteriorly by the epithalamus, and inferiorly by hypothalamic structures
(infundibular recess, tuber cinereum, and mamillary body).

The third ventricle has a number of recesses that are important in localizing
lesions in the region of the third ventricle. These recesses include the pineal
(suprapineal) recess above the posterior commissure, the optic recess above the
optic chiasma, and the infundibular recess into the infundibulum (Figures 29-2
and 29-5).

The aqueduct of Sylvius (cerebral aqueduct or iter) is a narrow canal that

connects the third and fourth ventricles through the midbrain (Figure 29-2). It is
about 1.5 to 2.0 cm long and 1 to 2 mm in diameter. Stenosis (narrowing) or
complete obstruction of the aqueduct, which may occur congenitally or as a
consequence of inflammatory processes, results in accumulation of CSF, an
increase in cerebrospinal pressure, and ventricular dilatation rostral to the site of
obstruction (in the third and lateral ventricles).

The fourth ventricle lies between the anterior surface of the cerebellum and the
posterior (dorsal) surfaces of the pons and medulla oblongata (Figures 29-1 and
29-2). The fourth ventricle boundaries are discussed in the chapter on the
medulla oblongata (Chapter 5). The fourth ventricle communicates with the
subarachnoid space through three foramina in its roof. These are a midline
foramen of Magendie and two lateral foramina of Luschka.

Ventricular cavities are lined by ependymal epithelium. In some specific

sites, the ependymal lining is invaginated by a vascular pial fold known as
the choroid plexus. Such choroid plexus sites are encountered in the body,
atrium, inferior horn of the lateral ventricle, foramen of Monro, roof of the third
ventricle, and posterior part of the roof of the fourth ventricle (Figure 29-1). The
choroid plexus achieves its largest size in the anterior part of the atrium

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(trigone), an area referred to as the glomus. The absence of choroid plexus from
the anterior horn makes it an appropriate site for placement of shunt tubes for
drainage of CSF in hydrocephalus.

Figure 29-5. Schematic diagram of the ventricular system showing recesses

of the third ventricle.

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SUBARACHNOID CISTERNS
The subarachnoid cisterns are dilatations in the subarachnoid spaces located
principally at the base of the brain. Radiologic visualization of the
subarachnoid cisterns is important in localization of pathologic processes,
especially those due to tumors in the base of the brain. The clinically relevant
cranial subarachnoid cisterns include the following:

1. The cisterna magna (cisterna cerebellomedullaris), largest of the

subarachnoid cisterns, is located between the medulla oblongata, the
cerebellum, and the occipital bone (Figure 29-6). CSF from the fourth
ventricle reaches the cisterna magna via the foramina of Magendie and
Luschka. The cisterna magna is continuous anteriorly with the cisterna
pontis. The cisterna magna is occasionally accessed to obtain CSF (cisternal
puncture). A special needle for this purpose is inserted suboccipitally
through the posterior atlanto-occipital membrane to the cisterna magna.

2. The medullary cistern lies ventral and lateral to the medulla oblongata
(Figure 29-6). The vertebral arteries are located in this cistern.

3. The cisterna pontis (Figure 29-6) is located between the basis pontis and
the clivus. It has a midline segment and two lateral extensions. The midline
segment is important in localizing pathologic processes in the pontine area,
whereas the lateral extensions are useful in localization of pathologic

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processes in the cerebellopontine angle. The basilar artery and sixth

(abducens) nerve run in the cisterna pontis.

4. The cisterna interpeduncularis (Figure 29-6) extends between the cerebral

peduncles and is helpful in localization of pathology in that region. The third
(oculomotor) nerve exits the midbrain through the interpeduncular cistern.

5. The suprasellar cistern (Figure 29-6) is located dorsal to the sella turcica
and communicates with the cisterna interpeduncularis. Some authors divide
the suprasellar cistern into prechiasmatic and postchiasmatic parts. The
former is located anterior to and above the optic chiasma, whereas the
latter is located behind and below the optic chiasma. The suprasellar cistern
is thus useful in localizing pathologic processes in or around the sella turcica
and optic chiasma.

6. The superior (quadrigeminal) cistern (Figure 29-6) is located dorsal to the

midbrain. It contains the vein of Galen.

The interpeduncular and superior (quadrigeminal) cisterns are connected along

the lateral surface of the midbrain by the ambient cistern (cisterna ambiens).

The clinically relevant spinal subarachnoid cistern is the lumbar cistern, site of
lumbar puncture (spinal tap).

CHOROID PLEXUS
The choroid plexus is one of the sites for production of CSF. It is composed of
villi extending from the ventricular wall into the CSF. It is distributed in the body,
trigone, and inferior horn of the lateral ventricle, foramen of Monro, roof of the
third ventricle, and posterior part of the roof of the fourth ventricle (Figure 29-
1). Each villus is composed of an extensive network of fenestrated capillaries
embedded in connective tissue stroma (Figure 29-7). Villi are lined by a single
layer of choroidal cuboidal epi-thelium in continuity with the ependymal cell
lining of the ventricular wall (Figure 29-7). The apical surfaces of the choroidal
epithelium in contact with CSF are specialized into microvilli that increase their
ventricular surface. Choroidal epithelial cells are attached to each other by tight
junctions that constitute an effective barrier to the free passage of substances
from the blood vessels in the core of the villus into the CSF (blood-CSF barrier).
Hydrostatic pressure within the fenestrated capillaries of choroid plexus forces
water, solutes, and proteins out into the connective tissue core of the villus.
Macromolecular substances, however, are prevented from free passage to the CSF
by the tight junctions between the lining choroidal epithelial cells.

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Figure 29-6. T2-weighted midsagittal MRI showing the major subarachnoid

cisterns.

Figure 29-7. Schematic diagram of the components of the choroid plexus.

FC, fenestrated capillary; CT, connective tissue stroma; CE, choroidal
epithelium with tight junctions.

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CEREBROSPINAL FLUID
The classic concepts of formation, circulation, and absorption of CSF elaborated

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early in this century have since undergone major modifications.

Classic Concepts
According to the classic concepts elaborated between 1914 and 1918 by Cushing,
Weed, and Dandy, the CSF is formed by the choroid plexus and circulates by bulk
flow in the lateral ventricles, the foramen of Monro, the third ventricle, the
aqueduct of Sylvius, and the fourth ventricle. It flows via the foramina of
Magendie and Luschka to the cisterna magna and subarachnoid spaces, where it
is finally absorbed through the arachnoid granulations in the superior sagittal
sinus into the venous circulation (Figure 29-8).

Current Concepts
A. FORMATION
Although the choroid plexus remains one of the major sites of CSF
formation, CSF production can be maintained in the absence of the choroid
plexus. Sites of CSF production and their relative contribution to the overall CSF
volume are not yet resolved. While there is clear evidence for a ventricular
source (from the choroid plexus), there is equal evidence for extraventricular
sites of production (cerebral pial surface, cerebral extracellular space, perineural
space, etc). Approximately 60 percent of CSF is formed in the ventricles. About
half the CSF formed in the ventricles comes from the choroid plexus; the rest
comes from the ependymal lining. In humans, CSF is formed at the rate of 0.35
ml/min (about 15 to 20 ml/hr, 500 ml/day) by the choroid plexus and to a much
lesser degree by the ependyma. Its average volume in the adult is about 140 ml,
with most of the fluid filling the cranial subarachnoid spaces. Approximately 30
ml of CSF is located in the ventricles and about 30 ml is in the spinal
subarachnoid space. It is estimated that the turnover rate of CSF is four to five
times per day.

The rate of CSF formation is rather constant and is not generally affected by
alterations in CSF pressure below 280 mm of CSF. There is evidence, however, to
suggest a decrease in CSF formation rate in chronic, experimentally produced, or
human hydrocephalus in which CSF pressure is very high. CSF formation from the
choroid plexus is also decreased with local arteriolar vasoconstriction or
hypotension. Almost total cessation of CSF formation from the choroid plexus
may result following vasoconstriction induced by low P C O 2 during hyperventilation.
On the other hand, vasodilatation induced by carbon dioxide inhalation has been
shown to result in a substantial increase in CSF formation. Drugs acting on
enzyme systems may influence CSF formation by interfering with active transport
mechanisms. Drugs that inhibit carbonic anhydrase, such as Diamox, can partially
or completely inhibit CSF formation. Ouabain, an ATPase inhibitor, can produce
effects similar to those of Diamox. Glucocorticoids have been shown to exert an
inhibitory effect on the
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rate of CSF formation. Several diuretic agents also have been shown to reduce
the rate of CSF formation. Although both respiratory and metabolic alkalosis have
been shown to depress the rate of CSF formation, the former is more effective
than the latter. CSF formation is known to increase with maturation; this may
reflect the maturation of the enzyme systems involved in the secretory process.

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Figure 29-8. Schematic diagram showing by arrows the pattern of

cerebrospinal fluid circulation from the lateral ventricles to the superior
sagittal sinus. LV, lateral ventricle; V 3 , third ventricle; AS, aqueduct of
Sylvius; V 4 , fourth ventricle; SC, spinal cord; SAS, subarachnoid space; AG,
arachnoid granulations; SSS, superior sagittal sinus.

B. MECHANISM OF FORMATION
CSF was considered to be an ultrafiltrate of plasma. Recent evidence seems to
suggest, however, that CSF is formed by the following mechanisms:

1. Diffusion.
The rate of diffusion depends on particle size and the lipid solubility of the
compound. Diffusion is the primary mechanism of transport for respiratory gases

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and some central nervous system active drugs such as diazepam (Valium),
phenobarbital, and phenytoin. Ethanol is also transported by diffusion. Water
enters the CSF readily by diffusion.

2. Active Transport.
Major cations that pass through the choroid plexus into the CSF are sodium and
potassium. The concentration of sodium is higher in CSF than in plasma, whereas
that of potassium is lower. Of all the cations in CSF, sodium is found in the
greatest amount and is used to stabilize the pH and total cation concentration in
CSF. Most of the sodium in CSF enters via the choroid plexus, and only a very
small fraction traverses the brain capillaries and brain substance. The
concentration of potassium in CSF is very stable and is not affected by
fluctuations in blood or CSF pH. A proper balance between intracellur
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and extracellular potassium is critical to nerve cell function. Excess CSF
potassium is quickly incorporated by neural tissue, whereas reduction in CSF
potassium is compensated by movement of potassium from neural tissue to CSF.
Chloride constitutes the major anion in CSF and seems to diffuse passively
through the choroid plexus, although this passage is closely regulated by sodium
and potassium transport.

Certain metabolic substances of low lipid solubility, such as glucose and some
amino acids, reach CSF by means of specific carrier-mediated transport systems.
The carrier systems for amino acids are independent of the glucose carriers.
Glucose is the major energy substrate for the brain. Entry into the CSF is
facilitated by an insulin-dependent GLUT-1 glucose transporter. Reduced GLUT-1
transport may be associated with seizures, impaired brain development, and
mental retardation.

Large molecules, such as plasma proteins, are almost completely blocked by the
choroid plexus from entering CSF. Studies using perfusion techniques have shown
that albumin transfer from blood to CSF is only partially dependent on bulk flow.
The major mechanism for protein entry into the CSF is receptor-mediated
transcytosis. In this mechanism, protein binds to a receptor on the luminal
surface of brain capillaries, is then internalized and forms intracellular vesicles
similar to pinocytotic vesicles. The protein then reaches the abluminal surface of
the blood-brain barrier. Immunoglobulins enter the CNS by this mechanism.

C. CIRCULATION
CSF flows from the lateral ventricles through the foramen of Monro to the third
ventricle and then through the aqueduct of Sylvius to the fourth ventricle, where
it reaches the subarachnoid space of the brain and spinal cord through the
foramina of Magendie and Luschka (Figure 29-8).

Using isotope cisternography, CSF circulation can be followed from the lateral
ventricles to the superior sagittal sinus, where it is resorbed. CSF reaches the
basal cisterns in a few minutes, flowing from there into the rostral subarachnoid
space and sylvian fissure and finally into the convexity of the brain. Isotopes
injected into the lumbar subarachnoid space can be detected in basal cisterns
within 1 hour.

Three factors seem to facilitate CSF circulation.

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1. Drift.
The drift of CSF from areas of positive balance to areas of negative balance
facilitates circulation. Although CSF production and absorption are in almost
perfect balance when the total CSF space is considered, any one point in the
system may be at positive or negative balance. CSF will therefore drift from areas
of positive balance to those of negative balance. This drift will contribute to CSF
flow.

2. Oscillation.
CSF is also in a continuous state of oscillation, with a to-and-fro movement the
amplitude of which increases as the fluid approaches the fourth ventricle. This
oscillation contributes to the flow of CSF, and the increase in amplitude in the
fourth ventricle facilitates the flow of CSF into the cisterna magna.

3. Pulsatile Movement.
Rhythmic movements synchronous with arterial pulse have been described in
CSF. These pulsatile oscillations assume an upward and downward movement in
the fourth ventricle and basal cisterns. The origin of these oscillations is believed
to be the expansion of the cerebrum and its arteries during systole rather than
choroid plexus pulsations, as previously assumed. The CSF pulsations occur
roughly simultaneously with intracranial arterial pulsations, and both begin about
150 ms into the cardiac cycle.

D. RESORPTION
The classic concept of CSF resorption states that the fluid is resorbed through the
arachnoid granulations into the venous system of the superior sagittal sinus
(Figure 29-8) and in the lacunae lateralis in the parasagittal dura. Arachnoid
granulations are not discernible in the newborn. They become evident by the
eighteenth month and become numerous and widely disseminated by the third or
fourth year of life. They are most common along the superior sagittal sinus but
occur at or near other sinuses as well.

Although the arachnoid granulations and lacunae lateralis constitute the

major resorption sites for CSF, other alternative sites have been described.
They are (1) arachnoid membrane, (2) adventitia of leptomeningeal blood
vessels, (3) cranial and spinal nerve root sleeves, (4) capillary endo-thelium, (5)
choroid plexus, (6) leptomeningeal vessels, (7) peri-neural sheaths of cranial and
spinal nerves, and (8) ependyma of the ventricles.

The controversy over reconciling the behavior of CSF outflow with its structural
basis remains unresolved. Earlier studies suggest that substances varying widely
in molecular weight and lipid solubility pass readily from CSF pathways to the
blood. Such studies are at variance with ultrastructural observations of the
arachnoid granulations, which show the presence of intact endothelium with tight
junctions effectively separating CSF and blood compartments. More recent
studies, however, may have resolved this controversy by suggesting a mechanism
for CSF resorption in the arachnoid granulations similar to that described for
drainage of ocular fluid in the canal of Schlemm. According to this hypothesis,
exit of CSF via the arachnoid granulations is pressure dependent. Endothelial
cells of the arachnoid villus undergo vacuolation on the CSF side. Vacuoles
increase in size because of the differential pressure gradient between CSF

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(higher) and blood compartments (lower) and ultimately reach the blood side of
the endothelial cells, where they rupture and create a patent channel between
CSF and blood. Such a hypothesis has been confirmed by electron microscopic
observations of the behavior of arachnoid granulations.

In addition to this filtration route, it is believed that substances are resorbed by

the two other routes of diffusion and active transport.

E. FUNCTION
CSF serves three principal functions:

1. It supports the weight of the brain within the skull. This buoyancy
function is disturbed when CSF is withdrawn, resulting in headache
because of more traction on vessels and nerves.

2. It acts as a buffer or cushion between the brain and adjacent dura and
skull; it protects the brain from physical trauma during injury to the skull by
dampening the effects of trauma.

3. It provides a stable chemical environment for the central nervous system.

The chemical composition of CSF is rather stable even in the presence of
major changes in the chemical composition of plasma.

F. COMPOSITION
CSF is a clear, colorless fluid composed of the following substances and
elements:

1. Water.
Water is the major constituent of CSF.

2. Protein.
The value of protein in normal CSF is approximately 15 to 45 mg/dl. The lower
value (15 mg/dl) reflects protein
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value in ventricular CSF; the higher value (45 mg/dl) reflects protein value in the
lumbar subarachnoid space. Protein values increase in various disease states of
the nervous system (infection, tumor, hemorrhage), as well as after obstruction
of CSF pathways. Three proteins account for the bulk of CSF protein content:
albumin and beta and gamma globulins. The presence of oligoclonal bands
(electrophoretic bands in the immunoglobulin G region) and myelin basic proteins
in the CSF suggest a demyelinating process such as multiple sclerosis.

3. Sugar.
The amount of glucose in normal CSF is approximately two-thirds that of the
blood. Glucose value is slightly higher (75 mg/dl) in ventricular fluid than in
lumbar subarachnoid space fluid (60 mg/dl). Ratio of CSF glucose to blood
glucose is higher in newborns and premature infants, probably because of the
immaturity of the blood-CSF barrier. The value decreases in meningitis and after
meningeal infiltration by tumors.

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4. Cells.
A normal sample of CSF contains up to three lymphocytes per cubic millimeter.
An increase in the number of white cells in CSF occurs in infectious processes. In
general, leukocytes predominate in bacterial infections (bacterial meningitis) and
lymphocytes in viral infections (viral meningitis and encephalitis). Normal CSF
contains no red blood cells (RBCs). The presence of RBCs in CSF occurs as a
result of trauma during its collection or secondary to hemorrhage into the CSF.
Traumatic RBCs are usually present in samples of CSF obtained early in the
process of CSF collection and disappear in samples collected subsequently. RBCs
from pathologic bleeding (e.g., subarachnoid hemorrhage) render the CSF grossly
bloody and xanthochromic (yellow). The xanthochromia is due to release of
bilirubin from the RBCs. Neoplastic cells may occur in some types of central
nervous system neoplasms, particularly those associated with leptomeningeal
dissemination.

5. Electrolytes.
CSF contains sodium, potassium, chloride, magnesium, and calcium. Sodium and
potassium constitute the major cations, whereas chloride constitutes the major
anion. The concentration of sodium, chloride, and magnesium ions is higher in
CSF than in plasma, whereas the concentration of potassium and calcium ions is
lower.

6. Peptides.
Numerous peptides are also found in the CSF. They include luteinizing hormone–
releasing factor, cholecystokinin, angiotensin II, substance P, somatostatin,
thyroid hormone–releasing hormone, oxytocin, and vasopressin.

G. PHYSICAL PROPERTIES

1. Specific Gravity.
The specific gravity of normal CSF varies between 1.006 and 1.009. An increase
in the protein content of the CSF raises its specific gravity. Mean CSF density is
reported to be significantly lower in women than men. This difference in density
may modify subarachnoid distribution of local anesthetics and other drugs.

2. Pressure.
Normal CSF pressure measured in the lumbar subarachnoid space varies between
50 and 200 mm of CSF (up to 8 mmHg), measured with the patient in the lateral
recumbent position and relaxed. The normal pressure range is higher (200 to 300
mm of CSF) when measured in the upright seated position. CSF pressure is
increased in central nervous system infections (meningitis), tumors, hemorrhage,
thrombosis, and hydrocephalus.

Spinal (Lumbar), Cisternal, and Ventricular Taps

(Punctures)
The examination of CSF is of major value in neurologic diagnosis. Access to
CSF for diagnosis dates back to 1891 when Quinke introduced the lumbar
puncture. CSF can be obtained from three sites: (1) the spinal subarachnoid
space (spinal or lumbar puncture), (2) the cisterna magna (cisternal puncture),

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and (3) the lateral ventricles (ventricular puncture). The first route is used most
commonly. In this procedure (spinal or lumbar tap), a special needle is
introduced using sterile techniques and local anesthesia in the L-2 and L-3, L-3
and L-4, or L-4 and L-5 vertebral space. The needle is gently eased into the
subarachnoid space, and CSF is withdrawn. Since the conus medullaris of the
spinal cord ends at the L-1 or L-2 vertebral level and the meninges extend to the
S-1 or S-2 vertebral level, the space between L-2 and L-3 vertebrae constitutes a
safe area into which to introduce the lumbar tap needle without the danger of
injuring the spinal cord. The cisterna magna is accessed by a suboccipital route
through the posterior atlanto-occipital membrane. The lateral ventricles are
accessed through the brain substance. Withdrawal of CSF from the lumbar
subarachnoid space is contraindicated in the presence of increased intracranial
pressure. Spinal taps in such conditions may lead to herniation of the uncus of
the temporal lobe through the tentorium or the cerebellar tonsils through the
foramen magnum with resulting coma and death. The lumbar subarachnoid space,
the cisternal space, and the ventricles are entered not only to obtain CSF for
examination but also to inject air, contrast material, or drugs for either diagnosis
or treatment of neurologic disorders.

BRAIN BARRIER SYSTEM

The concept of a barrier system between blood and brain dates back to
1885, when it was found that intravenously injected acidic dyes stained all
organs of the body except the brain. It was later observed that when these acidic
dyes were injected into the CSF, the brain was stained. Thus a barrier was
assumed to be located at the blood-brain interface that prevented entry of acidic
dyes into the brain. It has since been discovered that these acidic dyes bind
themselves to serum albumin and that the barrier to their entry to the brain is
the low permeability of brain capillaries to the albumin to which the dyes are
bound.

Although earlier studies conceived of only one barrier, at the blood-brain

interface, studies dating back to the 1930s have elucidated the existence of other
brain barrier sites. Consequently, the term blood-brain barrier has been replaced
by the more useful term brain barrier system. Two separate barriers compose this
system: (1) the blood-brain barrier, located at the interface between the capillary
wall and brain substance, and (2) the blood-CSF barrier, located in the choroid
plexus. The blood-brain barrier forms a unique anatomic structure very different
from other blood-organ barriers (Figure 29-9). The major difference is the
impermeable construction of endothelial cells. The fenestrations in endothelial
cells lining capillaries of other organs are absent in the brain except in some
locations (circumventricular organs). Additionally, brain endothelial cells adhere
to each other by means of tight junctions. Brain endothelial cells are coated with
a glycocalyx (P-glycoprotein) that maintains a negative charge on the luminal
surface and ejects certain undesired substances. Another special feature of the
blood-brain barrier is a layer of astrocytic foot processes (glia limitans) that
cover almost the entire abluminal surface of brain capillaries. A striking feature
of the blood-brain barrier is the high number of mitochondria in endothelial cells.
They provide the high level of energy needed to maintain the blood-brain barrier
function. The blood-brain barrier is the more extensive of the barriers. It
separates blood within
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the capillaries from brain substance. The blood-brain barrier impedes entry from
blood to brain of virtually all molecules except those that are small (less than 20

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kDa) and are lipophilic. There are, however, small and large hydrophilic
molecules that cross the barrier. They do so by means of active carrier-mediated
transport and receptor-mediated transcytosis.

Figure 29-9. Schematic diagram of the anatomic substrate of the blood-

brain barrier.

During inflammation or an immune-mediated pathologic process the blood-brain

barrier breaks down and allows access of cells and other substances into the
brain. The increased permeability of the blood-brain barrier during inflammation
depends on several factors: opening of tight junctions, gaps across endothelial
cells, increase in receptor-mediated transcytosis, and increase in pinocytosis.

It was originally believed that the brain is an immune-privileged organ. It has

since been shown that T lymphocytes can cross the blood-brain barrier in small
numbers. Once in the brain, lymphocytes that react to neural antigens will remain
in the brain and initiate inflammation. T lymphocytes that do not react to neural
antigens exit quite rapidly. The T lymphocytes that migrate into the brain are the
CD4+ variety.

In the blood-CSF barrier, tight junctions that join choroidal epithelial cells (Figure
29-7) constitute the barrier at this site. The surface area of the blood-CSF barrier
is only 0.02 percent of the surface area of the blood-brain barrier. The
ependymal cells lining the ventricles are not joined together by tight junctions
(Figure 29-7) and thus do not constitute a barrier between the CSF and brain. A
third barrier, the blood-nerve barrier, comprises the perineurium and capillaries
of the endoneurium. Walls of capillaries are nonfenestrated, and endothelial cells
have tight junctions. This barrier is most effective in dorsal root ganglia and
autonomic ganglia.

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Studies on the mechanisms of the barrier system have shown that the anatomic
substrates of the barrier (endothelial lining, basement membrane, glial
processes, tight junctions) cannot account for all the observed phenomena of the
barrier system. It is thus conceivable that other factors are operative in the
barrier system. These factors include the following:

Blood flow. This factor is operative in the entry to the brain of substances
of high lipid solubility. The rate of blood flow to a brain region will
determine the amount of entry of such substances.

Metabolic requirement. The rate of entry of some substances into the

brain seems to be dependent on the metabolic requirement of that region of
the brain for the particular substance. Cholesterol, for example, is
accumulated in the brain during myelin formation and decreases when
myelination is completed.

The brain barrier system is more permeable in newborn infants than in adults. As
the brain matures with age, the barrier system becomes less permeable. The
brain of the newborn, for example, is permeable to bilirubin. A rise in bilirubin
levels in the blood of a newborn is detrimental to brain function. In contrast, an
excessive rise in serum bilirubin in the adult does not affect the brain.

Certain areas of the brain are devoid of a barrier system. These areas,
known as circumventricular organs include (1) the area postrema, a
chemoreceptor center in the caudal medulla oblongata; (2) the neurohypophysis;
(3) the organ vasculosum of the lamina terminalis (superior and rostral to the
optic chiasma), which is sensitive to plasma osmolarity, (4) the median eminence
of the hypothalamus; (5) the subcommissural organ located ventral to the
posterior commissure at the junction of the third ventricle and aqueduct of
Sylvius; (6) the subfornical organ (under the fornix), which is sensitive to
circulating angiotensin II; and (7) the pineal gland. In some circumventricular
organs, neurons have specialized receptors for specific proteins. These include
the area postrema, subfornical organ, and organ vasculosum. Other
circumventricular organs have neurons with secretory properties. These include
the median eminence, neurohypophysis, subcommissural organ, and pineal gland.
All these areas are characterized by rich vascularity. Unlike vessels elsewhere in
the brain, the endothelial lining of vessels in these areas is fenestrated.

TERMINOLOGY
Aqueduct of Sylvius.
Narrow passage linking the third and fourth ventricles. Named after Franciscus de
la Boe Sylvius, who described it in 1650.

Cavum vergae.
Intraventricular cystic space in the body of the lateral ventricle and continuous
with the cavum septum pellucidum. Named after Andrea Verga, the Italian
anatomist who described it in 1851.

Cisternal puncture.
Accessing CSF in the cisterna magna by inserting a needle in the suboccipital
region through the atlanto-occipital membrane. The procedure was introduced by
Oberga in 1908.

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Foramen of Luschka.
Paired openings in the lateral recesses of the arachnoid roof of the fourth
ventricle through which CSF from the fourth ventricle reaches the cisterna
magna. Named after Hubert von Luschka, the German anatomist, in 1863.

Foramen of Magendie.
Median aperture in the roof of the fourth ventricle connecting it with the cisterna
magna. Named after Franéois Magendie, the French physiologist, who described
the foramen in 1842.

Foramen of Monro.
Site of communication between the lateral and third ventricles. First described by
Alexander Monro, the
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Scottish anatomist, in 1753. Before that time, it was assumed that the lateral
and third ventricles communicated by a hole or passage at the upper end of the
third ventricle called the vulva or by a place under the fornix called the anus.
There had been no demonstration of these apertures. They were presumed to
occur by necessity.

Lumbar puncture.
A method of accessing CSF in the lumbar subarachnoid space by introducing a
needle between the lumbar vertebrae. The procedure was introduced in 1891 by
Heinrich Quinke, a German physician who obtained CSF for the first time from a
living patient. William Gowers disapproved of the procedure and discouraged its
use at the National Hospital in London until after his retirement.

SUGGESTED READINGS
Alami SY, Afifi AK: Cerebrospinal fluid examination. In Race GJ (ed):
Laboratory Medicine, vol 4, chap 2. Hagerstown, MD, Harper & Row, 1973:1.

Bradbury M: The structure and function of the blood-brain barrier. Fed Proc
1984; 43:186–190.

Egnor M et al: A model of intracranial pulsations. Pediatr Neurosurgery 2001;

35:284–298.

Fox RJ et al: Anatomic details of intradural channels in the parasagittal dura:

a possible pathway for flow of cerebrospinal fluid. Neurosurgery 1996;
39:84–90.

Friede RL: Hydrocephalus-special pathology. In: Developmental

Neuropathology. New York, Springer-Verlag, 1989:240–241.

Goldstein G, Betz A: The blood-brain barrier. Sci Am 1986; 255:74–83.

Gomez DG et al: The spinal cerebrospinal fluid absorptive pathways.

Neuroradiology 1974; 8:61–66.

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Hughes RA et al: Caves and cysts of the septum pellucidum. Arch Neurol
Psychiatry 1955; 74:259–266.

Johnston I, Teo C: Disorders of CSF hydrodynamics. Child Nerv Syst 2000;

16:776–799.

Kempe LG, Busch E: Clinical significance of cisterna veli interpositi. Acta

Neurochir 1967; 16:241–248.

Leech RW: Normal anatomy of ventricles, meninges, subarachnoid space, and

venous system. In Leech RW, Brumback RA (eds): Hydrocephalus: Current
Clinical Concepts. St Louis, Mosby–Year Book, 1991:18.

Leech RW: Normal physiology of cerebrospinal fluid. In Leech RW, Brumback

RA (eds): Hydrocephalus: Current Clinical Concepts. St Louis, Mosby–Year
Book, 1991:30.

Leslie W: Cyst of the cavum vergae. Can Med Assoc J 1940; 43:433–435.

Mori K: Subcallosal midline cysts in anomalies of the central nervous system.

In Nadjmi M (ed): Neuro-radiologic Atlases. New York, Thieme-Stratton,
1985:69.

Pryse-Phillips W: Companion to Clinical Neurology. Boston: Little, Brown,

1995.

Rubin LL, Staddon JM: The cell biology of the blood-brain barrier. Annu Rev
Neurosci 1999; 22:11–28.

Sage MR, Wilson AJ: The blood-brain barrier: An important concept in

neuroimaging. AJNR 1994; 15:601–622.

Saunders NR et al: Barrier mechanisms in the brain: I. Adult brain. Clin Exp
Pharmacol Physiol 1999; 26:11–19

Schiffer E et al: Influence of sex on cerebrospinal fluid density in adults. Br J

Anaesth 1999; 83:943–944.

Schwidde JT: Incidence of cavum septi pellucidi and cavum vergae in 1032
human brains. Arch Neurol Psychiatry 1952; 67:625–632.

Segal MB: The choroid plexuses and the barriers between the blood and the
cerebrospinal fluid. Cell Molec Neurobiol 2000; 20:183–196.

Selmaj K: Pathophysiology of the blood-brain barrier. Semin Immunopathol

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1996; 18:57–73.

Tyler HR, Tyler KL: Communication between lateral and third ventricle: First
description. Neurology 1985; 35:1298.

Vastola EF: CSF formation and absorption estimates by constant flow infusion
method. Arch Neurol 1980; 37:150–154.

Whitelaw A: A new view on the CSF-circulation with the potential for

pharmacological treatment of childhood hydrocephalus. Acta Paediatr 1997;
86:125–132.

Zellweger H, Van Epps EF: The cavus veli interpositi and its differentiation
from cavum vergae. AJR 1959; 82:793–805.

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Editors: Afifi, Adel K.; Bergman, Ronald A.

Title: Functional Neuroanatomy: Text and Atlas, 2nd Edition

Copyright ©2005 McGraw-Hill

> Ta ble of Con tents > Part I - Text > 30 - Cerebrosp in al Fluid an d the Ba rrier S ystem : Clin ical Correla tes

30
Cerebrospinal Fluid and the Barrier System: Clinical
Correlates

Cerebrospinal Fluid in Disease

Ventriculomegaly
Hydrocephalus
Normal-Pressure Hydrocephalus (Hakim-Adams Syndrome)
Benign External Hydrocephalus
Idiopathic Intracranial Hypertension (Pseudotumor Cerebri) and Benign Intracranial
Hypertension
Intraventricular Neuroepithelial Cysts
The Bobble-Head Doll Syndrome
Dandy-Walker Syndrome (Malformation)

KEY CONCEPTS

Ventriculomegaly is associated with overproduction of CSF, brain atrophy, developmental failure of

growth of the cerebral mantle, and obstruction of CSF flow or absorption.

Hydrocephalus refers to an increased amount of CSF in the ventricle, with or without a concomitant
increase in CSF pressure. Hydrocephalus is classified into communicating and noncommunicating
varieties.

Normal-pressure hydrocephalus refers to uniform enlargement of the ventricular system without a

concomitant increase in CSF or intracranial pressure.

Benign external hydrocephalus refers to the accumulation of CSF in the subarachnoid spaces around
the brain without significant enlargement of the ventricular cavities.

Idiopathic intracranial hypertension is characterized by increased intracranial pressure without

hydrocephalus or a brain tumor, small ventricular cavities, and a favorable response to acetazolamide
or corticosteroids.

Intraventricular cysts may occur in any of the ventricular cavities but are most common in the third
ventricle (colloid cysts of the third ventricle).

Bobble-head doll syndrome is associated with third ventricular cysts and less commonly is
associated with aqueductal stenosis and shunt obstruction.

Dandy-Walker syndrome is characterized by the triad of large cystic dilation of the fourth ventricle,
agenesis of the cerebellar vermis, and enlargement of the posterior fossa.

CEREBROSPINAL FLUID IN DISEASE

CSF examination in patients with neurologic disorders can provide valuable information about the nature of the
disease process. This is particularly true in infections (meningitis, encephalitis), autoimmune disorders (multiple
sclerosis, Guillain-Barré polyneuritis), tumors, and hemorrhage.

Normal CSF obtained from the lumbar subarachnoid space is clear and colorless, is under 50 to 200 mm of CSF
pressure in the recumbent relaxed state, and contains three cells (lymphocytes) or fewer per cubic millimeter,
15 to 45 mg of protein, and 60 to 80 mg/dl of glucose.

In bacterial meningitis the CSF is cloudy and turbid, is under considerably increased pressure (200 to 500 mm of
CSF pressure), and contains an increased number of cells, almost all polymorphonuclear leukocytes (2000 to
10,000/mm 3 ), increased protein (100 to 1000 mg), and low glucose (below 20 mg/dl). Examination of fluid by
Gram stain and culture reveals the organism responsible for the meningitis.

In viral encephalitis the CSF usually is clear, is under normal or slightly elevated pressure, and contains either a

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normal or a slightly increased number of cells (five to several hundred, mostly lymphocytes), normal or slightly
increased protein (50 to 200 mg/dl), and normal glucose. Gram staining shows no bacteria. Culture of the CSF
may reveal the viral agent involved.

In multiple sclerosis the CSF is clear, is under normal pressure, and contains a normal or an increased number
(50 to 300) of cells, predominantly lymphocytes, normal or moderately increased protein including oligoclonal
and myelin basic proteins, increased gamma globulins, and normal glucose.

In Guillain-Barré the CSF is characterized by albuminocytologic dissociation in which protein is moderately to

markedly
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elevated in the presence of normal cells. The fluid is clear, is under normal pressure, and contains a normal
amount of glucose.

In brain tumors the CSF is clear, is under increased pressure, and contains a normal or increased number of
cells, an increased amount of protein, and normal glucose. Spinning of the CSF may reveal the presence of
tumor cells in the sediment. Seeding of tumor cells along the meninges is associated with an increase in cells
and protein. Lumbar puncture is contraindicated in the presence of increased intracranial pressure to avoid
herniation.

In spinal cord tumors the CSF may have a yellowish tinge as a result of the marked increase in protein, is under
normal pressure, and contains a normal or slightly increased number of cells, a marked increase in protein, and
normal glucose. Tumor cells may be found in the sediment.

In subarachnoid hemorrhage the CSF is bloody, is under markedly increased pressure, and contains a large
number of red blood cells, a very high amount of protein (as a result of the presence of blood), and low glucose.

Table 30-1 summarizes CSF findings in health and disease.

VENTRICULOMEGALY
Enlargement of the ventricles (ventriculomegaly) usually is associated with one of the following conditions:
(1) overproduction of CSF, as occurs in tumors of the choroid plexus (choroid plexus papilloma), (2)
atrophy of the brain with secondary (compensatory) enlargement of the ventricles (hydrocephalus ex vacuo), as
in Alzheimer's disease; (3) developmental failure of growth of the cerebral mantle (the brain between the
ventricle and the brain surface), as in the condition known as colpocephaly; or (4) obstruction of CSF flow or
absorption, as in obstructive hydrocephalus.

The mechanism of ventriculomegaly in hypersecreting tumors of the choroid plexus (Figure 30-1) is not clear. It
may be due to overproduction of CSF in excess of resorption, overproduction of protein, or both.

Ventriculomegaly associated with brain atrophy may be focal (as in infarction) (Figure 30-2) or generalized (as
in Alzheimer's disease and hypoxic ischemic encephalopathy) and is a compensatory mechanism that fills the
space created by the loss of brain substance. Hence, it is called hydrocephalus ex vacuo. It usually is associated
with concomitant enlargement of the subarachnoid spaces.

Developmental ventriculomegaly is due to failure of growth of the cerebral mantle. In an 8-week-old embryo,
the ventricles are large and the cerebral mantle is thin. With normal development, the cerebral mantle grows
faster than do the ventricles, so that by mid gestation the ventricles become relatively small. If the cerebral
mantle fails to grow normally, the ventricles remain relatively large, a condition known as colpocephaly (Figure
30-3), a term coined by Yakovlev and Wadsworth in 1946 to refer to disproportionate enlargement of the
occipital horns.

HYDROCEPHALUS
Hydrocephalus is a condition characterized by an increased amount of CSF in the ventricles (Figure 30-4).
Hippocrates was one of the first physicians to deal with hydrocephalus, advocating the use of laxatives and
sneeze-inducing substances for its treatment. The surgical approach to the treatment of hydrocephalus, though
suggested by Hippocrates and others, was not accepted as the most effective mode of treatment until the
nineteenth century.

There are two types of hydrocephalus: communicating and noncommunicating. In communicating

hydrocephalus there is free communication between the ventricles and the subarachnoid space. The
obstruction to the flow of CSF in this type of hydrocephalus is usually distal to the ventricular system, in the
subarachnoid spaces (as a result of fibrosis from previous infection) or the arachnoid granulations (as a result of
a lack of or abnormalities in those structures). This results in CSF accumulation and enlargement of all the
ventricular cavities as well as the subarachnoid spaces.

In noncommunicating hydrocephalus CSF in the ventricular cavities cannot reach the subarachnoid spaces
because of obstruction of CSF flow in the foramen of Monro (Figure 30-5), the aqueduct of Sylvius (Figure 30-6),
or the foramina of Magendie and Luschka. Obstruction of the foramen of Monro—for example, by tumor—blocks
the flow of CSF from the lateral ventricle to the third ventricle, resulting in an accumulation of CSF and
enlargement of the lateral ventricle on the side of obstruction (Figure 30-5). Obstruction of the aqueduct of
Sylvius by tumor,
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inflammation, or congenital atresia results in accumulation of CSF and enlargement of the ventricular cavities
draining into the aqueduct (third ventricle and both lateral ventricles) (Figure 30-6). Obstruction at the foramina

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of Magendie and Luschka by tumor, inflammation, or congenital atresia results in CSF accumulation and
enlargement of the fourth, third, and both lateral ventricles.

Table 30-1. Cerebrospinal Fluid Findings in Health and Disease

Condition color Pressure Cells/mm 3 Protein Glucose other

(mmCSF) (mg/dl) (mg/dl)

Normal Clear 50–200 0–3 15–45 60–80 —

Bacterial Cloudy ↑ ↑(neutrophils) ↑ ↓ Organism by

meningitis Gram stain and
culture

Viral Clear Normal Normal or ↑ Normal or Normal Organism by

encephalitis or ↑ (lymphocytes) ↑ culture

Multiple Clear Normal Normal or ↑ Normal or Normal Oligoclonal bands,

sclerosis ↑ and myelin basic
(increased proteins
gamma
globulins)

Guillain- Clear Normal Normal ↑ Normal Albuminocytologic

Barré disassociation
syndrome

Brain tumor Clear ↑ Normal or↑ ↑ Normal Tumor cells in

sediment

Spinal tumor Yellow Normal Normal or ↑ ↑ Normal Tumor cells in

sediment

Subarachnoid Bloody ↑ ↑ (red cells) ↑ ↓ —

hemorrhage

Figure 30-1. Parasagittal gadolinium enhanced magnetic resonance image (MRI) showing choroid plexus
papilloma and ventriculomegaly.

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In adults in whom the skull sutures have closed, hydrocephalus is associated with a marked increase in
intracranial pressure. This is associated with headache, vomiting, dizziness, a decrease in the state of
consciousness, and edema of the optic disks. In these patients, the lateral margins of the lateral ventricles
become rounded and there is an outflow of CSF across the ependyma into the periventricular spaces
(transependymal flow) (Figure 30-7). Pressure exerted on the corticospinal fibers that innervate the lower
extremities, which travel in proximity to the lateral ventricles, results in lower extremity weakness.

If hydrocephalus develops in early childhood, before closure of the skull sutures, the skull yields to the
increased pressure by widening of the sutures and a progressive increase in head circumference. A rapid
increase in intracranial pressure in these children may result in a decreased level of consciousness and
alertness, vomiting, irritability, and the “setting-sun” sign, in which the upper lids are retracted and the globes
are directed downward.

Figure 30-2. Coronal section of the brain showing cerebral infarct and secondary focal ventriculomegaly.

Figure 30-3. T1-weighted parasagittal MRI showing disproportionate enlargement of the occipital horn in
colpocephaly.

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Normal-Pressure Hydrocephalus (Hakim-Adams Syndrome)

Normal-pressure hydrocephalus (a type of communicating hydrocephalus) is a disorder of the elderly
characterized by uniform enlargement of the ventricular system without a concomitant increase in CSF
pressure or intracranial pressure. The pathophysiology of normal-pressure hydrocephalus is poorly understood.
Impaired resorption of CSF is believed to be the cause of CSF accumulation and ventricular enlargement.
Clinically, the condition is characterized by dementia, urinary incontinence, and gait disturbance. These signs

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sometimes improve
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after shunting of the CSF to extracranial sites. Normal-pressure hydrocephalus is thus considered a treatable
dementing disorder. The condition can be diagnosed by radioisotope scans, which demonstrate reflux of the
radioisotope into the ventricles after its injection into the lumbar subarachnoid space.

Figure 30-4. T2-weighted axial MRI showing enlarged ventricular cavities (ventriculomegaly) due to
hydrocephalus.

Figure 30-5. T1-weighted axial MRI showing unilateral enlargement of the lateral ventricle with
displacement of the septum pellucidum across the midline due to obstruction of the foramen of Monro by
atresia.

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Figure 30-6. T1-weighted midsagittal MRI showing selective enlargement of the lateral and third ventricles
due to aqueductal stenosis. The fourth ventricle is normal in size.

Figure 30-7. T2-weighted axial MRI showing transependymal flow of cerebrospinal fluid to the adjacent
brain substance in hydrocephalus.

Benign External Hydrocephalus

Benign external hydrocephalus is a disorder of childhood characterized by the accumulation of CSF in the
subarachnoid space over the brain surface, particularly over the frontal lobes and in the interhemispheric
fissure, without significant involvement of the ventricular cavities (Figure 30-8). The condition was first
described in the eighteenth century by Underwood, who also observed its benign nature. The condition was
rediscovered after the advent of newer imaging techniques. It is a self-limited condition which usually resolves
spontaneously without sequelae.

IDIOPATHIC INTRACRANIAL HYPERTENSION (PSEUDOTUMOR

CEREBRI) AND BENIGN INTRACRANIAL HYPERTENSION
Idiopathic intracranial hypertension (IIH), which was described by Quincke in 1891, is a disorder
characterized by increased intracranial pressure without hydrocephalus or brain tumor. It is more common
in adult obese women of childbearing age and affects both sexes equally in childhood. These patients complain
of headache, papilledema, and transient visual obscuration. Imaging studies usually show small ventricles. The
condition responds to acetazolamide (Diamox), a carbonic anhydrase inhibitor, and to corticosteroids, both of

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which reduce or inhibit the formation of CSF. Studies of CSF hydrodynamics in pseudotumor cerebri differentiate
two types: type I with normal CSF conductance and type II with very low conductance and high CSF pressure.
Type I is believed to result from extracellular brain edema, and type II from impaired CSF resorption through
the arachnoid granulations. CSF hydrodynamic studies suggest that patients with type II IIH share a common
physiologic mechanism with patients who have normal-pressure hydrocephalus.

INTRAVENTRICULAR NEUROEPITHELIAL CYSTS

Intraventricular cysts are rare developmental cysts lined by neuroepithelium. The precise origin of these
cysts is controversial. They are believed to arise from choroid plexus tissue derived from primitive
neuroepithelium. They have been reported to occur in all the ventricular cavities, but most commonly in the
third ventricle (colloid cysts of the third ventricle). A variety of names have been used to describe these cysts,
including epithelial cysts, ependymal cysts, choroid plexus cysts, choroidal epithelial cysts, and subarachnoid
ependymal cysts. The term neuroepithelial cysts was introduced by Fulton and Bailey in 1929. Intraventricular
cysts contain a clear serous liquid resembling CSF with a mildly elevated protein content. The fluid in colloid
cysts of the third ventricle is usually viscid with a gelatinous or mucinous appearance. Intraventricular cysts are
clearly visible on magnetic resonance imaging (Figure 30-9). They usually are asymptomatic and are found
accidentally on neuroimaging studies. Some may enlarge and become symptomatic.

Figure 30-8. Computed tomography scan showing accumulation of cerebrospinal fluid in the subarachnoid
space over the frontal lobe and in the interhemispheric fissure as seen in benign external hydrocephalus.

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THE BOBBLE-HEAD DOLL SYNDROME

The bobble-head doll syndrome is a disorder of childhood characterized by a to-and-fro, 2- to 3-Hz
rhythmic nodding of the head similar to that in a doll with a weighted head attached to a coil-spring neck.
The movement disappears in the supine position and during sleep. This disorder was described by Benton in
1966. In most cases the syndrome is associated with an intraventricular cyst in the region of the anterior third
ventricle (Figure 30-10) or an arachnoid cyst in the suprasellar region. The phenomenon results from
intermittent obstruction of the foramen of Monro by the cyst. The head bobbing is believed
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to be a learned behavior which relieves the obstruction by means of posterior displacement of the cyst away
from the foramen of Monro. The syndrome has less commonly been described in association with aqueductal
stenosis and shunt obstruction. The syndrome is treated by shunting or fenestration of the cyst.

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Figure 30-9. T1-weighted parasagittal MRI showing a neuroepithelial cyst in the posterior part of the
lateral ventricle.

Figure 30-10. T2-weighted axial MRI showing a third ventricle cyst in the bobble-head doll syndrome.

DANDY-WALKER SYNDROME (MALFORMATION)

The Dandy-Walker malformation (Figure 30-11) consists of the triad of (1) large cystic dilatation of the
posterior part of the
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fourth ventricle, (2) complete or partial agenesis of the cerebellar vermis, and (3) enlargement of the posterior
fossa with upward displacement of the tentorium, torcula, and transverse sinus. Hydrocephalus, though
common, is not an essential feature of the syndrome. The syndrome was described by Sutton in 1887 and was
recognized as a distinct entity in 1914 by Dandy and Blackfan, who attributed it to atresia of the foramina of
Magendie and Luschka. In 1942 Taggart and Walker documented the entity and supported the proposed etiology
of atresia. The term Dandy-Walker syndrome was proposed in 1954 by Benda, who recognized that atresia of the
foramina of Magendie and Luschka is not an essential feature of the syndrome. The pathogenesis of the
syndrome remains controversial. The syndrome arises early in gestation, at about 4 weeks, and involves
multiple developmental defects of the central nervous system. Foraminal atresia may be a contributing factor in
some cases. The cystic dilatation of the fourth ventricle is attributed to the persistence of the anterior
membranous area that forms the roof of the fetal fourth ventricle, which ordinarily regresses and disappears as
the choroid plexus and vermis develop.

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Figure 30-11. T1-weighted midsagittal MRI showing features of the Dandy-Walker syndrome.

Various treatment modalities have been tried with varying success, including ventriculoperitoneal shunting,
opening of the fourth ventricle, and excision of the cyst membrane. Current treatment consists of shunting of
the cyst to the peritoneum (cystoperitoneal shunt) combined with shunting of the lateral ventricles to the
peritoneum (ventriculoperitoneal shunt).

TERMINOLOGY
Alzheimer's disease.
A type of cortical dementia named after Alois Alzheimer, the German neuropsychiatrist and pathologist who
described the disease in 1906. The term Alzheimer's disease was coined by Ernst Kraepelin, a German
psychiatrist, in 1910.

Aqueduct of Sylvius.
A narrow passage linking the third and fourth ventricles. Named after Franciscus de la Boe Sylvius, who
described it in 1650.

Bobble-head doll syndrome.

A syndrome of to-and-fro rhythmic movement of the head associated with anterior third ventricle cysts or
tumors. The movement is believed to be a learned behavior that relieves obstruction of the foramen of Monro.

Colpocephaly.
A developmental condition characterized by failure of development of the cerebral mantle and secondary
ventriculomegaly with disproportionate enlargement of the occipital horns of the lateral ventricle. The term was
coined by Yakovlev and Wadsworth in 1946.

Communicating hydrocephalus.
A type of hydrocephalus in which obstruction to CSF flow occurs between the roof of the fourth ventricle and the
arachnoid granulations.

Dandy-Walker syndrome.
A developmental malformation characterized by large cystic dilatation of the fourth ventricle, agenesis of the
cerebellar vermis, and upward displacement of the tentorium cerebelli, torcula, and transverse sinus. The
condition was first described by J. B. Sutton in 1887 and was recognized as a distinct entity by Dandy and
Blackfan in 1914 and by Taggert and Walker in 1942. The term Dandy-Walker syndrome was proposed by Benda
in 1954.

Foramen of Luschka.
Paired openings in the lateral recesses of the fourth ventricle through which cerebrospinal fluid flows from the
fourth ventricle to the cisterna magna. Named after Hubert von Luschka, a German anatomist, in 1863.

Foramen of Magendie.
The median aperture in the roof of the fourth ventricle, connecting it with the cisterna magna. Named after
Fran¸ois Magendie, a French physiologist who described it in 1842.

Foramen of Monro.
The site of communication between the lateral and third ventricles. Named after Alexander Monro, a Scottish
anatomist who described it in 1753.

Guillain-Barré syndrome.
An acute inflammatory demyelinating polyneuropathy. Described by George Guillain, Jean Alexander Barré, and

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Andre Strohl, French physicians, in 1916.

Hydrocephalus (Greek hydro, “water”; kephalé, “head”).

Dilatation of the cerebral ventricles. Known to Hippocrates, it was described accurately by Vesalius in 1550.

Hydrocephalus ex vacuo.
An increase in the volume of CSF and ventriculomegaly secondary to brain atrophy.

Noncommunicating hydrocephalus.
A type of hydrocephalus caused by obstruction of cerebrospinal fluid flow between the sites of its formation and
the roof of the fourth ventricle.

Pseudotumor cerebri.
A condition consisting of a rise in intracranial pressure in the absence of an intracranial mass or hydrocephalus.
Known by other terms, including idiopathic intracranial hypertension, hydrops, serous meningitis, Julien-Marie-
See syndrome, Dupré's syndrome, and Symonds syndrome. First described by Quincke in 1891.

Setting-sun sign.
Depression of the eyeball with failure of upward gaze and retraction of upper lid. Seen in children with
hydrocephalus and pressure on the dorsal tectum.

Visual obscuration.
Transient dimming of vision caused by increased intracranial pressure.

SUGGESTED READINGS
Benda CE: The Dandy-Walker syndrome or the so-called atresia of the foramen of Magendie. J Neuropathol
Exp Neurol 1954; 13:14–29.

Benson DF et al: Diagnosis of normal pressure hydrocephalus. N Engl J Med 1970; 283:609–615.

Benton JW et al: The bobble-head doll syndrome. Neurology 1966; 16:725–729.

Coker SB: Bobble-head doll syndrome due to trapped fourth ventricle and aqueduct. Pediatr Neurol 1986;
2:115–116.

Czervionke LF et al: Neuroepithelial cysts of the lateral ventricle: MR appearance. AJNR 1987; 8:609–613.

Dandy WE, Blackfan KD: Internal hydrocephalus: An experimental, clinical, and pathological study. Am J Dis
Child 1914; 8:406–482.

Dell S: Further observation on the “bobble-head doll syndrome.” J Neurol Neurosurg Psychiatry 1981;
44:1046–1049.

Hart MN et al: The Dandy-Walker syndrome: A clinicopathological study based on 28 cases. Neurology 1972;
22:771–780.

Herskowitz J et al: Colpocephaly: Clinical, radiologic, and pathogenetic aspects. Neurology 1985; 35:1594–
1598.

Leech RW, Goldstein E: Hydrocephalus: Classification and mechanisms. In Leech RW, Brumback RA (eds):
Hydrocephalus: Current Clinical Concepts. St. Louis, Mosby 1991:45–70.

New PFJ, Davis KR: Intraventricular noncolloid neuroepithelial cysts. AJNR 1981; 2:569–576.

Norman MG et al: Dandy Walker syndrome. In Norman MG et al. (eds): Congenital Malformations of the
Brain: Pathological, Embryological, Clinical, Radiological, and Genetic Aspects. New York, Oxford University
Press, 1995:343–347.

Norman MG et al: Hydrocephalus. (eds): Congenital Malformations of the Brain: Pathological, Embryological,
Clinical, Radiological, and Genetic Aspects. New York, Oxford University Press, 1995:333–339.

Papazian O et al: The history of hydrocephalus. Int Pediatr 1991; 6:233–235.

Pryse-Phillips W: Companion to Clinical Neurology. Boston, Little, Brown, 1995.

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Puden RH: The surgical treatment of hydrocephalus: An historical review. Surg Neurol 1981; 15:15–26.

Sahar A et al: Choroid plexus papilloma: Hydrocephalus and cerebrospinal fluid dynamics. Surg Neurol 1980;
13:476–478.

Sarnat HB: Dandy-Walker malformation. In Norman MG et al (eds): Cerebral Dysgenesis: Embryology and
Clinical Expression. New York, Oxford University Press, 1992:305–316.

Sutton JB: The lateral recesses of the fourth ventricle: Their relation to certain cysts and tumors of the
cerebellum and to occipital meningocele. Brain 1887; 9:352–361.

Taggart JK, Walker AE: Congenital atresia of the foramens of Luschka and Magendie. Arch Neurol Psychiatr
1942; 48:583–612.

Wiese JA et al: Bobble-head doll syndrome: Review of the pathophysiology and CSF dynamics. Pediatr Neurol
1985; 1:361–366.

Williams MA, Razumovsky AY: Cerebrospinal fluid circulation, cerebral edema, and intracranial pressure.
Curr Opin Neurol 1996; 6:847–853.

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Editors: Afifi, Adel K.; Bergman, Ronald A.

Title: Functional Neuroanatomy: Text and Atlas, 2nd Edition

Copyright ©2005 McGraw-Hill

> Table of Contents > Part I - Text > 31 - Major Sensory and Motor Pathways

31
Major Sensory and Motor Pathways

Major Sensory Pathways

Pathway for Conscious Proprioception
Pathways for Nonconscious Proprioception
Pathway for Pain and Temperature
Trigeminal Pathways
Major Motor Pathways
Cortical Origin
Subcortical Origin

KEY CONCEPTS

Posterior column fibers ascend ipsilateral to their side of entry into

the spinal cord and synapse on the nuclei gracilis and cuneatus in the
medulla oblongata. Second-order fibers from the nuclei gracilis and
cuneatus cross in the medulla oblongata (sensory, lemniscal
decussation) to form the medial lemniscus. Medial lemniscal fibers
terminate on neurons in the ventral posterior lateral nucleus of the
thalamus.

The dorsal spinocerebellar tract reaches the cerebellum via the

restiform body. The ventral spinocerebellar tract reaches the cerebellum
via the brachium conjunctivum.

The spinothalamic fibers are somatotopically organized so that sacral

originating fibers are lateral in the tract and cervical originating fibers
are medial in the tract. Spinothalamic fibers terminate on neurons in the
ventral posterior lateral nucleus of the thalamus.

Trigeminal pathways convey exteroceptive and proprioceptive

sensations from the face.

Corticospinal fibers originate principally from the motor and

premotor areas, descend throughout the neuraxis, mostly decussate in
the medulla oblongata (motor decussation), and terminate on
interneurons or alpha motorneurons in the spinal cord.

Corticopontocerebellar fibers constitute the largest component of

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corticofugal fibers. They originate principally from primary sensory and

motor cortices and synapse on pontine nuclei. Second-order neurons
from the pontine nuclei terminate in the cerebellum.

Cortically originating (cortifugal) motor pathways include the

corticospinal (pyramidal), corticopontocerebellar, corticobulbar,
corticothalamic, corticostriate, and corticohypothalamic tracts.

Subcortically originating fibers include the rubrospinal,

vestibulospinal and reticulospinal.

MAJOR SENSORY PATHWAYS

Pathway for Conscious Proprioception

The pathway for kinesthesia (position and vibration sense) and discriminative
touch (well-localized touch and two-point discrimination) is the posterior column–
medial lemniscus system (Figure 31-1).

Nerve fibers that contribute to this pathway have their cell bodies in the dorsal
root ganglia. The receptors for this system are (1) cutaneous mechanoreceptors
(hair follicles and touch pressure receptors) which convey the sensations of
touch, vibration, hair movement, and pressure and (2) proprioceptive receptors
(muscle spindle, Golgi tendon organ, and joint receptors). Muscle receptors
(muscle spindles and Golgi tendon organs) are the primary receptors that convey
position sense. Joint receptors may be concerned with signaling joint movement
but not joint position.

Impulses arising in the receptors travel via the thickly myelinated large
nerve fibers that enter the spinal cord as the dorsolateral division of the
posterior (dorsal) root and occupy the posterior funiculus of the spinal cord.
Those arising below the sixth thoracic spinal segment form the medial part of the
posterior funiculus (gracile tract, tract of Goll). Those arising above the sixth
thoracic segment form the lateral part of
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the posterior funiculus (cuneate tract, Burdach column). Fibers in the gracile and
cuneate tracts project on neurons in the posterior column nuclei of the medulla
oblongata (nuclei gracilis and cuneatus). Axons of neurons in the posterior
column nuclei (second-order neurons, internal arcuate fibers) decussate in the
tegmentum of the medulla oblongata (sensory, lemniscal decussation) to form the
medial lemniscus, which ascends throughout the medulla oblongata, pons, and
midbrain to terminate on neurons of the ventroposterolateral (VPL) nucleus of the
thalamus. The axons of neurons in this thalamic nucleus (third-order neurons)
project on the terminal station of this pathway in the somesthetic (primary
sensory) cortex of the parietal lobe.

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Figure 31-1. Schematic diagram of the pathway for kinesthesia and

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discriminative touch.

Lesions in the posterior column–medial lemniscus system are manifested

clinically by the following signs:

1. Inability to identify the position of a limb in space with the eyes closed.
These patients are unable to tell whether a joint is in a position of flexion or
one of extension.

2. Inability to identify objects placed in the hands, such as keys and coins,
from their shape, size, and texture with the eyes closed.

3. Loss of two-point discrimination. These patients are unable to recognize two

stimuli simultaneously applied to the skin when the stimuli are separated by
the minimal necessary distance for their proper identification as two stimuli.

4. Inability to perceive vibration when a vibrating tuning fork is applied to a

bony prominence.

5. Inability to maintain a steady standing posture when the eyes are closed
and the feet are placed close together (Romberg test). These patients begin
to sway and may fall when they close their eyes, eliminating visual
compensation.

Some of the fibers in the posterior funiculus send collateral branches that
terminate on neurons in the gray matter of the posterior horn. These collaterals
give the posterior column system a role in modifying sensory activity in the
posterior horn. This role is inhibitory to pain impulses. Thus, lesions in the
posterior funiculus decrease the threshold to painful stimuli. Nonpainful stimuli
become painful, and painful stimuli are triggered by lower stimulation thresholds.

In addition to its classical role in sensory transmission, the dorsal column plays a
role in certain types of motor control. The dorsal column transmits to the motor
cortex sensory information from muscle spindles, joint receptors, and cutaneous
receptors that is necessary in planning, initiating, programming, and monitoring
tasks that involve manipulative movements by the digits.

Pathways for Nonconscious Proprioception

Nonconscious proprioception is mediated via the two spinocerebellar tracts
(Figures 31-2 and 31-3), the posterior (dorsal) and the anterior (ventral).

The posterior spinocerebellar tract conveys impulses from the muscle spindle and
the Golgi tendon organ. Such impulses travel
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via groups Ia, Ib, and II nerve fibers; enter the spinal cord in the dorsolateral,
thickly myelinated, large-diameter fiber portion of the posterior root; and project
on the ipsilateral nucleus dorsalis (Clarke's nucleus, Stilling column, Stilling
nucleus, nucleus thoracicus) and the accessory cuneate nucleus. Axons of
neurons in the nucleus dorsalis (second-order neurons) form the posterior
spinocerebellar tract, which ascends in the lateral funiculus of the spinal cord and
the medulla oblongata to reach the cerebellum via the inferior cerebellar
peduncle (restiform body). Axons of neurons in the accessory cuneate nucleus

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form the cuneocerebellar tract, which reaches the cerebellum via the restiform
body. Information relayed to the cerebellum via the posterior spinocerebellar
tract and the cuneocerebellar tract relates to muscle contraction, including the
phase, rate, and strength of contraction.

Figure 31-2. Schematic diagram of the posterior spinocerebellar pathway.

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Figure 31-3. Schematic diagram of the anterior spinocerebellar pathway.

The anterior spinocerebellar tract conveys impulses from the Golgi tendon
organ via Ib afferents. Incoming fibers project on neurons in the posterior
horn of the spinal cord (laminae V to VII). Axons of neurons in these laminae
decussate to the contralateral lateral funiculus to form the anterior
spinocerebellar tract, which ascends throughout the spinal cord, medulla
oblongata, and pons; loops backward to join the superior cerebellar peduncle
(brachium conjunctivum); and enters the cerebellum. The anterior

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spinocerebellar tract conveys to the cerebellum information related to

interneuronal activity and the effectiveness of descending pathways.

Lesions in the spinocerebellar pathways (such as those which occur in hereditary

spinocerebellar degeneration) result in incoordinate movement. These patients
tend to walk with a wide base, stagger, and frequently fall.

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Pathway for Pain and Temperature

Small-diameter, unmyelinated, or thinly myelinated fibers (C fibers and A
delta fibers) that convey pain and thermal sensations (Figure 31-4) enter
the spinal cord via the ventrolateral division of the dorsal (posterior) root. Within
the spinal cord they ascend for one or two segments and project on neurons in
several laminae (I to VI) in the posterior horn. From tract neurons in laminae I
and V to VII, axons cross in the anterior white commissure and form the lateral
spinotha-lamictract in the lateral funiculus. Sacral fibers are laterally placed in
the tract, and cervical fibers are more medially placed. The spinothalamic tract
ascends throughout the spinal cord and brain stem to project on neurons in the
VPL of the thalamus. Axons of VPL neurons project, via the posterior limb of the
internal capsule, to the somesthetic cortex.

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Figure 31-4. Schematic diagram of the pathway for specific pain and
temperature sensations.

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Lesions of the spinothalamic tract result in diminution or loss of pain and thermal
sense contralateral to the lesion. When the tract is affected in the spinal cord,
the sensory deficit begins one or two segments below the level of the lesion.

The spinothalamic tract may be sectioned surgically (cor-dotomy) to relieve

intractable pain.

Trigeminal Pathways
The trigeminal pathways convey exteroceptive and proprioceptive sensations
from the face to the thalamus. They thus correspond to the spinothalamic
and posterior column–medial lemniscus pathways, which convey similar
sensations from the rest of the body.

Exteroceptive fibers are general somatic sensory fibers that convey pain,
temperature, and touch sensations from the face and the anterior aspect of the
head. Neurons of origin of these fibers are located in the semilunar (gasserian)
ganglion (see Figure 7-18). Peripheral processes of neurons in the ganglion are
distributed in the three divisions of the trigeminal nerve: ophthalmic, maxillary,
and mandibular. Central processes of these unipolar neurons enter the lateral
aspect of the pons and distribute themselves as follows.

Some of these fibers descend in the pons and the medulla and down to the level
of the second or third cervical spinal segment as the descending (spinal) tract of
the trigeminal nerve. They convey pain and temperature sensations. Throughout
their caudal course these fibers project on neurons in the adjacent nucleus of the
descending tract of the trigeminal nerve (spinal trigeminal nucleus). Axons of
neurons in the spinal trigeminal nucleus cross the midline and form the ventral
secondary ascending trigeminal (ventral trigeminothalamic) tract, which courses
rostrally to terminate in the ventral posterior medial nucleus of the thalamus.

Other incoming fibers of the trigeminal nerve bifurcate on entry into the pons
into ascending and descending branches. These fibers convey touch sensation.
The descending branches join the spinal tract of the trigeminal nerve and follow
the course that was outlined above. The shorter ascending branches project on
the main (principal) sensory nucleus of the trigeminal nerve (see Figure 7-18).
From the main sensory nucleus, second-order fibers ascend ipsilaterally and
contralaterally as the dorsal ascending trigeminal (dorsal trigeminothalamic) tract
to the ventral posterior medial nucleus of the thalamus. Some crossed fibers also
travel in the ventral ascending trigeminal tract. Once formed, both secondary
trigeminal tracts (dorsal and ventral) lie lateral to the medial lemniscus between
it and the spinothalamic tract. A schematic summary of the afferent and efferent
trigeminal roots and their nuclei is shown in Figure 7-19. Recent studies of
trigeminothalamic fibers have revealed that the bulk of these fibers arise from
the main sensory nucleus and the interpolaris segment of the spinal nucleus.

Proprioceptive fibers from deep structures of the face are peripheral processes of
unipolar neurons in the mesencephalic
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nucleus of the trigeminal located at the rostral pontine and caudal mesencephalic
levels. Proprioceptive fibers to the mesencephalic nucleus convey pressure and
kinesthesia from the teeth, periodontium, hard palate, and joint capsules as well
as impulses from stretch receptors in the muscles of mastication. The output
from the mesencephalic nucleus is destined for the cerebellum, the thalamus, the
motor nuclei of the brain stem, and the reticular formation. The mesencephalic

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nucleus is concerned with mechanisms that control the force of the bite.

MAJOR MOTOR PATHWAYS

Cortical Origin
A. CORTICOSPINAL (PYRAMIDAL) TRACT
The corticospinal tract (Figure 31-5) is the most important descending tract.
From its origin in the cerebral cortex it descends through all levels of the
neuraxis except the cerebellum. It arises primarily from the motor (area 4) and
premotor (area 6) cortices and passes through the internal capsule, the cerebral
peduncle, the basis pontis, and the pyramids of the medulla oblongata. In the
caudal medulla, about 75 to 90 percent of the fibers decussate through the motor
or pyramidal decussation to form the lateral corticospinal tract in the lateral
funiculus of the spinal cord. About 8 percent of pyramidal fibers remain
uncrossed and form the anterior corticospinal tract (Türck's bundle) in the
anterior funiculus of the spinal cord. Fibers in the anterior corticospinal tract
decussate at segmental spinal levels. In the final analysis, therefore, roughly
about 98 percent of fibers in the pyramidal tract are crossed. The remaining 2
percent remain ipsilateral and form the tract of Barnes. Pyramidal tract fibers
influence alpha motor neurons directly or via interneurons. They facilitate flexor
motor neurons and inhibit extensor motor neurons. Lateral corticospinal tract
fibers terminate on motor neurons in the lateral part of the ventral horn that
supply the distal limb musculature. Anterior corticospinal tract fibers terminate
on motor neurons in the medial part of the ventral horn that supply the neck, the
trunk, and the proximal limb musculature.

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Figure 31-5. Schematic diagram of corticospinal pathway. F, face; A, arm;

L, leg.

The corticospinal tract is essential for skill and precision in movement and the
execution of discrete fine finger movements. However, it cannot initiate these
movements by itself; other corticofugal (cortically originating) fibers are needed
for this. The corticospinal tract also regulates sensory relay processes and the
selection of the sensory modality that reaches the cortex. The selection function
is achieved via terminations of corticospinal tract fibers on primary afferent fibers
and sensory relay neurons in the posterior (dorsal) horn of the spinal cord.

Lesions in this tract result in paralysis. If the lesion is above the level of the
motor decussation, the paralysis is contralateral to the site of the lesion. In
lesions of the pyramidal tract below the decussation, the paralysis is ipsilateral to
the site of the lesion. In addition to paralysis, lesions in the corticospinal tract
result in a conglomerate of neurologic signs, including (1) spasticity, (2)
hyperactive myotatic reflexes (hyperreflexia), (3) Babinski's sign, and (4) clonus.

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Collectively, this conglomerate of signs is referred to as upper motor neuron

signs.

B. CORTICOPONTOCEREBELLAR TRACT
The corticopontocerebellar tract (Figure 31-6) constitutes by far the largest
component of the cortically originating descending fiber system. It has been
estimated to contain approximately 19 million fibers, in contrast to the pyramidal
tract, which contains approximately 1 million. The tract originates from wide
areas of the cerebral cortex, but primarily from the primary sensory and motor
cortices, and descends in the internal capsule, cerebral peduncle, and basis
pontis, from which its fibers project on pontine nuclei. Second-order neurons
from pontine nuclei cross to the contralateral side of the basis pontis, enter the
middle cerebellar peduncle (brachium pontis), and project on the cerebellum.

Although the pontocerebellar projection is primarily crossed, it has been

estimated that 30 percent of the pontine projection to the cerebellar vermis and
10 percent of the projection to the cerebellar hemisphere are ipsilateral. The
density of projection to the cerebellar hemisphere is three times that to the
vermis. The corticopontocerebellar tract is somatotopically organized. The
primary motor cortex projects to the medial pontine nuclei, the primary sensory
cortex projects to the lateral pontine nuclei, the arm area of the sensory motor
cortex projects to the dorsal pontine nuclei and the leg area projects to the
ventral pontine nuclei, the caudal pontine nuclei project to the anterior lobe of
the cerebellum, and the rostral pontine nuclei project to the posterior lobe of the
cerebellum. The corticopontocerebellar tract is one of several pathways by which
the cerebral cortex influences the cerebellum; it plays a role in the rapid
correction of movement. Lesions of the corticopontocerebellar pathway result in
ataxia. The ataxia that
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occurs contralateral to frontal or temporal lobe pathology is explained by
interruption of the corticopontine pathway.

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Figure 31-6. Schematic diagram of corticopontocerebellar tract.

C. CORTICOBULBAR TRACT
Corticobulbar fibers (Figure 31-7) originate from the face areas of the cerebral
cortex. They descend in the genu of the internal capsule, the cerebral peduncle
(where they occupy a dorsolateral corner of the corticospinal segment of the
peduncle as well as a small area in the medial part of the base of the peduncle),
and the basis pontis (where they intermix with corticospinal fibers) and pyramid
but do not reach the spinal cord. At different levels of the neuraxis, they project
on cranial nerve nuclei. Some corticobulbar fibers project directly on cranial
nerve nuclei (trigeminal, facial, and hypoglossal); the majority, however, project
on reticular nuclei before reaching the cranial nerve nuclei. This system is known
as the corticoreticulobulbar tract. The majority of cranial nerve nuclei receive
bilateral cortical input. Bilateral interruption of the corticobulbar or
corticoreticulobulbar fiber system results in paresis (weakness) of the muscles
supplied by the corresponding cranial nerve nucleus. This condition is known as
pseudobulbar palsy.

D. OTHER CORTICOFUGAL TRACTS

Other corticofugal tracts include the corticothalamic, corticostriate, and
corticohypothalamic tracts, which serve as feedback mechanisms from the cortex
to these sites.

Corticothalamic fibers arise from cortical areas that receive thalamic

projections. They descend in the internal capsule and enter the thalamus via
the thalamic radiation, which also includes reciprocal thalamocortical fibers.

Corticostriate fibers can be direct or indirect. Direct corticostriate projections

reach the neostriatum via the internal and external capsules. Indirect
corticostriate pathways include the corticothalamostriate and the collaterals of
the corticoolivary and corticopontine pathways. Almost all cortical areas
contribute to the corticostriate projections. Corticostriate pathways are
somatotopically organized so that cortical association areas project preferentially
to the caudate nucleus, whereas sensorimotor cortical areas preferentially project
to the putamen.

Corticohypothalamic fibers arise from the prefrontal cortex, cingulate gyrus,

olfactory cortex, hippocampus, and septal area. They reach the hypothalamus via
the internal capsule.

Subcortical Origin
Tracts of subcortical origin arise from the midbrain, pons, and medulla
oblongata.

A. MIDBRAIN
The major motor pathway from the midbrain is the rubrospinal tract (see Figure
3-20). This tract originates from neurons in the caudal (magnicellular) part of the
red nucleus, crosses in the ventral tegmental decussation of the midbrain, and
descends in the midbrain, pons, medulla, and spinal cord, where it occupies a

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position in the lateral funiculus in close proximity to the lateral corticospinal

tract. The rubrospinal tract is considered an indirect corticospinal tract. Like the
corticospinal tract, the rubrospinal tract facilitates flexor motor neurons and
inhibits extensor motor neurons. In most mammals the rubrospinal tract is the
major output of the red nucleus. With evolution the output of the red nucleus to
the spinal cord decreased, and in humans the red nucleus sends its major output
to the inferior olive, which in turn projects to the cerebellum.

B. PONS
The major motor pathways emanating from the pons are the lateral and medial
vestibulospinal and pontine reticulospinal tracts.

1. Lateral Vestibulospinal Tract.

The lateral vestibulospinal tract (see Figure 3-21) originates from the lateral
vestibular nucleus and descends ipsilaterally in the pons, medulla, and spinal
cord, where it occupies a position in the lateral funiculus. The lateral
vestibulospinal tract terminates on interneurons in laminae VII and VIII, with
some direct terminations on alpha motorneuron dendrites in the same laminae.
The lateral vestibulospinal tract facilitates extensor motor neurons and inhibits
flexor motor neurons.

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Figure 31-7. Schematic diagram of the corticobulbar pathway.

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2. Medial Vestibulospinal Tract (see Figure 3-22).

The neurons of origin of the medial vestibulospinal tract are located in the medial
vestibular nucleus. From their neurons of origin, fibers join the ipsilateral and
contralateral medial longitudinal fasciculus, descend in the anterior funiculus of
the cervical cord segments, and terminate on neurons in laminae VII and VIII.
They exert a facilitatory effect on flexor motor neurons. This tract plays a role in
controlling head position.

3. Pontine Reticulospinal Tract (see Figure 3-23).

The pontine reticulospinal tract arises mainly from the medial group of pontine
reticular nuclei (nuclei reticularis pontis caudalis and oralis), descends primarily
ipsilaterally through the pons and medulla oblongata, and occupies a position in
the anterior funiculus of the spinal cord. It facilitates extensor motor neurons and
inhibits flexor motor neurons.

C. MEDULLA OBLONGATA
The major descending pathway from the medulla oblongata is the medullary
reticulospinal tract (see Figure 3-23). It arises mainly from the medial (central)
group of medullary reticular nuclei (nucleus reticularis gigantocellularis),
descends primarily ipsilateral to its site of origin, and occupies a position in the
lateral funiculus of the spinal cord. It facilitates flexor motor neurons and inhibits
extensor motor neurons.

TERMINOLOGY
Ataxia (Greek taxis, “order”).
Lack of order. Lack of coordination with unsteadiness of movement.

Burdach, Karl Friedrich (1776–1847).

German anatomist and physiologist. Described many of the tracts of the brain
and spinal cord and especially the posterior column of the spinal cord which he
designated as fasciculus cuneatus. Although the tract was previously described
by Rosenthal, the description of Burdach was more accurate.

Clarke, Jacob Augustus Lockhart (1817–1880).

English anat-omist who described the nucleus dorsalis in 1851 in a memoir to the
Royal Society, published in the Philosophical Transactions.

Corticofugal (cortex; Latin, fugere, “to flee”).

Moving away from the cortex.

Cuneatus (Latin, “wedge”).

The fasciculus cuneatus is so named because of its wedge shape.

Decussation (Latin decussare, “to cross like an X”).

X-shaped crossing of nerve fiber tracts in the midline, as in the motor
(pyramidal) and sensory (lemniscal) decussations.

Exteroceptive (Latin, “to take outside”).

Received from outside. Exteroceptive receptors receive impulses from the
outside.

Funiculus (Latin funis, “cord”).

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A bundle of white matter containing one or more tracts.

Ganglion (Greek, “swelling, knot”).

A collection of nerve cells outside the central nervous system, as in the gasserian
(trigeminal) ganglion.

Golgi tendon organ.

Specialized stretch receptors in the tendons. Named after Camillo Golgi, an
Italian anatomist.

Goll, Friedrich (1829–1903).

Swiss anatomist. Described the fasciculus gracilis in the posterior column in
1862.

Gracilis (Latin, “slender, thin”).

The fasciculus or tractus gracilis is so named because it is slender.

Kinesthesia (Greek kinesis, “motion”; aisthesis, “sensation”).

The sense of perception of movement.

Nucleus dorsalis (Clarke's nucleus).

A nucleus in the intermediate zone of the spinal cord gray matter that gives rise
to the dorsal spinocerebellar tract. Named after Jacob Augustus Lockhart Clarke,
an English anatomist who described this nucleus in 1851.

Paralysis (Greek para, “beside”; lyein, “to loosen”).

Loss of voluntary movement.

Paresis (Greek parienai, “to relax, to let go”).

Slight or incomplete paralysis.

Proprioception (Latin propius, “one's own”; perceptio, “perception”).

The sense of position and movement.

Receptor (Latin recipere, “to receive”).

A sensory nerve ending or sensory organ that receives sensory stimuli.

Restiform body (Latin restis, “a rope”; forma, “form” or “shape”).

The restiform body (inferior cerebellar peduncle) is a compact bundle of nerve
fibers connecting the medulla oblongata
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and the cerebellum. It was described and named by Humphrey Ridley, an English
anatomist, in 1695.

Romberg test.
A test for conscious proprioception. The inability to maintain a steady standing
posture when the eyes are closed and the feet are placed close together. Named
after Moritz Heinrich Romberg, a German physician who described the test in
1840.

Rubro (Latin, ruber, “red”),

The rubrospinal tract originates from the red nucleus.

Somatotopic (Greek soma, “body”; topos, “place”).

Representation of parts of the body in corresponding parts of the brain or spinal
cord.

Stilling, Benedikt (1810–1879).

German anatomist and surgeon. Described nucleus dorsalis of the spinal cord and

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reported that it extended from C 8 –L 3 – 4 .

Türck's Bundle.
Anterior corticospinal tract. Described by Ludwig Türck, an Austrian anatomist
and neurologist, in 1849.

SUGGESTED READINGS
Brodal P: The corticopontine projection in the Rhesus monkey: Origin and
principles of organization. Brain 1978; 101:251–283.

Brodal P: The pontocerebellar projection in the Rhesus monkey: An

experimental study with retrograde axonal transport of horseradish
peroxidase. Neuroscience 1979; 4:193–208.

Cherubini E et al: Caudate neuronal responses evoked by cortical stimulation:

Contribution of an indirect corticothalamic pathway. Brain Res 1979;
173:331–336.

Davidoff RA: The dorsal column. Neurology 1989; 39:1377–1385.

Davidoff RA: The pyramidal tract. Neurology 1990; 40:332–339.

Iwatsubo T et al: Corticofugal projections to the motor nuclei of the

brainstem and spinal cord in humans. Neurology 1990; 40:309–312.

Matsushita M et al: Anatomical organization of the spinocerebellar system in

the cat as studied by retrograde transport of horseradish peroxidase. J Comp
Neurol 1979; 184:81–106.

Nathan PW et al: The corticospinal tract in man: Course and location of fibers
at different segmental levels. Brain 1990; 113:303–324.

Smith MC, Deacon P: Topographical anatomy of the posterior column of the

spinal cord in man: The long ascending fibers. Brain 1984; 107:671–698.

Wiesendanger R et al: An anatomical investigation of the corticopontine

projection in the primate (Macaca fascicularis and Saimiri sciureus): II. The
projection from frontal and parietal association areas. Neuroscience 1979;
4:747–765.

Willis WD: Studies of the spinothalamic tract. Tex Rep Biol Med 1979; 38:1–
45.

Yeterian EH, VanHoesen GW: Cortico-striate projections in the Rhesus

monkey: The organization of certain cortico-caudate connections. Brain Res
1978; 139:43–63.

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Editors: Afifi, Adel K.; Bergman, Ronald A.

Title: Functional Neuroanatomy: Text and Atlas, 2nd Edition

Copyright ©2005 McGraw-Hill

> Table of Contents > Part I - Text > 32 - Reticular Formation, Wakefulness, and Sleep

32
Reticular Formation, Wakefulness, and Sleep

Nomenclature
Organization
Connections
Raphe Nuclei
Medial Group
Paramedian Group
Lateral Group
Reticular Nucleus of Thalamus
Chemically Specified Systems
Cholinergic System
Monoaminergic System
Functions
Somatic Motor Function
Somatic Sensory Function
Visceral Motor Function
Arousal and Alertness
Ascending Reticular Activating System (ARAS)
Sleep
Phases and Stages of Sleep
Sleep and Arousal Mechanisms

KEY CONCEPTS

The reticular formation of the brain stem is organized into four nuclear groups:
median raphe, paramedian, medial, and lateral.

The caudal raphe nuclei are concerned with pain mechanism while the rostral raphe
nuclei relate to wakefulness, alertness and sleep.

The medial group of reticular nuclei have descending (caudal) and ascending
(rostral) connections. The former play a role in motor control, whereas the latter relate
to consciousness and alertness.

The paramedian reticular nuclei have reciprocal connections with the cerebellum;
hence they are designated as precerebellar nuclei.

The lateral group of reticular nuclei is related to locomotion and autonomic

regulation. They also relay inputs from several sites to the medial group of reticular
nuclei.

The reticular nucleus of thalamus plays a role in integrating and gating activities of
other thalamic nuclei.

Two chemically specified systems have been identified within the reticular
formation: cholinergic and monoaminergic. The latter includes dopaminergic,
noradrenergic, adrenergic, and serotonergic subsystems.

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The reticular formation plays important roles in somatic motor and visceral motor
functions, somatic sensory functions, and in arousal and alertness.

There are two phases of sleep: slow wave (non-REM) sleep, and REM (rapid eye
movement) sleep. Slow sleep is divisible into four stages ranging from light to deep
sleep.

The sleep-promoting, ventrolateral preoptic nucleus and the aminergic arousal

system nuclei are reciprocally inhibitory to each other.

Orexin (hypocretin) neurons in the hypothalamus facilitate the aminergic arousal

system. They are active during wakefulness. Narcolepsy is associated with orexin
(hypocretin) neuron lesions.

The term reticular formation refers to a mass of neurons and nerve fibers extending from the
caudal medulla to the rostral midbrain and continuous with the zona incerta of the subthalamus
and midline, intralaminar and reticular nuclei of the thalamus. Although older accounts of the
reticular formation described it as a mass of intermeshed, poorly organized neurons and nerve
fibers, it has now been established that the reticular formation is organized into definite nuclear
groups with known afferent and
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efferent connections. As a whole, the reticular formation comprises a neural system with
multiple inputs and multisynaptic system of impulse conduction. Current methodologies such as
histo- and immunofluorescent techniques, orthograde and retrograde fiber tracing methods, and
intra- as well as extracellular microphysiology have enriched our knowledge of the
organizational precision and complexity of this system.

NOMENCLATURE
There is no entirely satisfactory term to designate the complex of cell pools, neuropil fields and
associated fiber systems which make up the reticular core of the brain stem. The term reticular
formation was used by early neuroscientists to describe the reticulated appearance of the core
formed by a nonpatterned mixture of neurons and myelinated fibers. Another designation, the
nonspecific system, differentiates it from the specific system represented by the medial
lemniscus and the spinothalamic tracts. A term that gained popularity in the fifties and sixties is
the ascending reticular activating system, which focused attention on the core's role in wakeful
and alert states. It is now known that the functions of this system transcend this behavioral
role. In the absence of a fully satisfactory term, the term “brain stem reticular core” remains in
common use.

ORGANIZATION (Figure 32-1)

Several different systems for naming nuclei of the brain stem reticular formation have been
used, resulting in confusion and controversy. In general, the reticular formation of the brain
stem is divided into the following nuclear groups (Table 32-1):

1. Median raphe

2. Paramedian reticular

3. Medial reticular

4. Lateral reticular

The median raphe nuclear group includes the following midline nuclei: raphe obscurus and raphe
pallidus in the medulla oblongata; raphe magnus in the caudal pons and rostral medulla; raphe
pontis in the pons; and the dorsal raphe and superior central (Bekhterev) nuclei in the midbrain.
The neurotransmitter of most raphe nuclei is serotonin.

The paramedian reticular nuclei are located lateral to the medial longitudinal fasciculus and the

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medial lemniscus. They include the paramedian reticular nucleus in the rostral medulla and
caudal pons, and the reticulotegmental nucleus in the rostral pons and caudal midbrain.

The medial reticular nuclear group includes the nucleus reticularis gigantocellularis in the
medulla oblongata, and the nucleus
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reticularis pontis caudalis and nucleus reticularis pontis oralis in the pons.

Figure 32-1. Schematic representation of the different groups of reticular nuclei.

Table 32-1. Reticular Nuclei.

Median Raphe Paramedian Medial Lateral

Medulla Raphe obscurus Reticularis Reticularis

Raphe pallidus giganto parvocellularis
cellularis Reticularis
lateralis

Rostral Raphe magnus Paramedian

medulla reticular
caudal
pons

Pons Raphe pontis Reticularis Reticularis

pontis parvocellularis
caudalis
Reticularis
pontis
oralis

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Rostral Reticulotegmental Parabrachial

pons– Pedunculopontine
caudal
midbrain

Midbrain Dorsal Raphe Cuneiform

(nucleus Subcuneiform
supratrochlearis)
Superior central
(Bekhterev)

The lateral reticular nuclear group includes the following nuclei: nucleus reticularis
parvocellularis and nucleus reticularis lateralis in the medulla oblongata; the nucleus reticularis
parvocellularis in the pons; parabrachial and pedunculopontine nuclei in the rostral pons and
caudal midbrain; and the cuneiform and subcuneiform reticular nuclei in the midbrain.

The reticular formation of the brain stem continues into the diencephalon. The reticular nucleus
of thalamus, located lateral to the internal capsule, is a continuation of the brain stem reticular
formation.

CONNECTIONS

Raphe Nuclei
Raphe nuclei of the medulla oblongata (raphe magnus, obscurus, pallidus) receive inputs from
the spinal cord, trigeminal sensory nuclei (second-order sensory input), and the periaqueductal
gray matter of midbrain.

Raphe nuclei of the medulla oblongata project to the cerebellum, dorsal horn of spinal cord
(spinothalamic neurons), and trigeminal nuclei.

The facilitatory input from the periaqueductal gray matter to the medullary raphe nuclei, and
the inhibitory projections of the latter on spinothalamic neurons in the dorsal horn of spinal cord
constitute the anatomic substrate for the analgesic effect of electrical stimulation of the
midbrain periaqueductal gray.

Raphe nuclei of the rostral pons and midbrain (raphe pontis, dorsal raphe, superior central)
receive inputs from the prefrontal cortex, the limbic system, and hypothalamus and project
widely to the forebrain, cerebellum, and brain stem.

It becomes evident from their connections that the caudal raphe nuclei are involved in pain
mechanisms while the rostral raphe nuclei are part of the reticular activating system
concerned with wakefulness, alertness, and sleep.

Medial Group
In addition to the medial group of nuclei in the medulla oblongata and pons (nuclei reticularis
gigantocellularis, pontis caudalis and oralis), two nuclei of the lateral group of reticular nuclei in
the midbrain (cuneiform and subcuneiform) are included here because of similar connectivity
pattern.

Input to this group of reticular nuclei originates from the spinal cord (spinoreticular), collaterals
from ascending sensory systems (spinothalamic and second-order axons from trigeminal and
auditory nuclei), superior colliculus (tectoreticular), cerebellum (vestibulocerebellum)
hypothalamus, and cerebral cortex. Descending projections from the medial group of reticular
nuclei project to the spinal cord (pontine and medullary reticulospinal tracts located in the
ventral and lateral funiculi of the spinal cord respectively). Ascending projections are destined
to the intralaminar nuclei of the thalamus (centromedian and parafascicular), and to the basal
cholinergic nuclei (nucleus basalis of Meynert, nucleus of the diagonal band).

The descending projections of this group of reticular nuclei suggest a role in motor control,
whereas the ascending projections relate these nuclei to consciousness and alertness. The

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nucleus reticularis pontis caudalis has been associated with paradoxical sleep. Bilateral lesions
in the nucleus result in complete elimination of paradoxical sleep.

Paramedian Group
The paramedian group of reticular nuclei (paramedian reticular and reticulotegmental)
receives inputs from the spinal cord (spinoreticular), cerebral cortex, and vestibular nuclei
and project to the cerebellum. They are designated, by some, as precerebellar nuclei.

Lateral Group
The lateral group of reticular nuclei in the medulla and pons (parvocellularis and lateralis)
constitute the receptive component of reticular nuclei. They receive inputs from the
contralateral red nucleus, spinal cord (spinothalamic and spinoreticular tracts) and second-order
neurons of trigeminal, auditory and vestibular sensory systems. They, in turn, project to both
cerebellar hemispheres (mostly homolateral) and to the medial group of reticular nuclei.

An expiratory center has been located experimentally within the parvocellular reticular area of
the medulla oblongata.

The pedunculopontine nucleus (rostral pons-caudal midbrain) receives inputs from the cerebral
cortex, the medial segment of globus pallidus, and substantia nigra (pars reticulata). It projects
to the thalamus and pars compacta of the substantia nigra. The nucleus lies in a region from
which walking movements can be elicited on stimulation (locomotor center).

The parabrachial nucleus (rostral pons-caudal midbrain) receives input from the amygdala, and
the nucleus solitarius and projects to the hypothalamus, preoptic area, amygdala and
intralaminar thalamic nuclei. It is believed that the nucleus plays a role in autonomic
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regulation. The involvement of the parabrachial nucleus in Parkinson's disease may explain the
autonomic disturbances that occur in that disease.

As stated previously, the cuneiform and subcuneiform reticular nuclei have similar connections
to the medial group of reticular nuclei.

Reticular Nucleus of Thalamus

The reticular nucleus of thalamus is a continuation of the reticular formation of the brain
stem into the diencephalon. It receives inputs from the cerebral cortex and other thalamic
nuclei. The former are collaterals of corticothalamic projections, and the latter are collaterals of
thalamocortical projections. The reticular nucleus projects to other thalamic nuclei. The
inhibitory neurotransmitter in this projection is GABA. The reticular nucleus is unique among
thalamic nuclei in that its axons do not leave the thalamus. Based on its connections, the
reticular nucleus plays a role in integrating and gating activities of thalamic nuclei.

CHEMICALLY SPECIFIED SYSTEMS

Two chemically specified systems have been identified among the rich ensemble of reticular
neurons; these are the cholinergic and monoaminergic systems.

Cholinergic System
Cholinergic neurons are found in two locations: (1) rostral pons-caudal midbrain, and (2) basal
forebrain.

The pedunculopontine reticular nucleus and the adjacent lateral dorsal tegmental nucleus lie
within the tegmentum of the pontomesencephalic junction, dorsolateral to and overlapping the
lateral margin of the superior cerebellar peduncle, between it and the lateral lemniscus. They
play roles in arousal and movement. The two nuclei belong to a region (locomotor center) from
which electrical stimulation causes coordinated walking movements. Neurons of the
pedunculopontine nucleus are affected in patients with progressive supranuclear palsy, a
degenerative central nervous disease.

The nucleus basalis of Meynert, located in the basal forebrain, sends axons to almost the entire
cerebral cortex. Degeneration of cholinergic neurons in this area is associated with memory
decline in Alzheimer's disease.

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Monoaminergic System
Four types of monoamine neurons have been identified within the brain stem reticular core:
dopaminergic, noradrenergic, adrenergic, and serotonergic.

Dopaminergic neurons form small clusters at several brain loci. Many of these neurons are found
in the ventral tegmentum of the midbrain (ventral tegmental area of Tsai) and the adjacent
substantia nigra (pars compacta). Projections of this area follow three pathways: (1)
mesostriatal (nigrostriatal), from the substantia nigra to the striatum (caudate and putamen).
Interruption of this system is associated with Parkinson's disease. (2) mesolimbic, from the
ventral tegmental area to limbic nuclei. Overactivity of this system is associated with
schizophrenic hallucinations. (3) mesocortical, from the ventral tegmental area to the prefrontal
cortex. Lesions in this system are associated with cognitive deficits in Parkinson's disease.

Noradrenergic neurons of the brain stem are divided into two major components. The first is the
norepinephrine system of the locus ceruleus (catecholamine neuron cell group A6). The second
is the lateral tegmental norepinephrine system, comprising another series of noradrenergic cell
groups scattered in the pons and medulla (groups A1 to A7). Axons of these neurons are
directed to the spinal cord, brain stem, cerebellum, diencephalon, and telencephalon. The
ascending noradrenergic system is involved in modulation of attention, sleep-wake state and
mood. Noradrenergic enhancing drugs are used in treatment of attention deficit disorder and in
sleep disorders such as narcolepsy. Noradrenergic projections to the brain stem, cerebellum,
and spinal cord are involved in modulation of autonomic (sympathetic) functions as in regulation
of blood pressure.

Adrenergic neurons are located in the same regions of the caudal medulla as the noradrenergic
neurons. They project to the spinal cord, brain stem, thalamus, and hypothalamus. This system
is small in comparison with the dopaminergic and nor-adrenergic systems and represents a
minor component of the monoaminergic system.

Serotonergic neurons comprise nine cell groups designated B1 to B9. The vast majority of
serotonergic neurons lie within the raphe nuclei of the midbrain, pons and medulla oblongata.
The rostral pontine and mesencephalic serotonergic raphe neurons project to the entire
forebrain, whereas the caudal pontine and medullary serotonergic raphe neurons project to the
cerebellum, medulla, and spinal cord. The rostral raphe serotonergic system plays a role in
psychiatric disorders (depression, obsession-compulsion, aggression, anxiety). The projection
from the nucleus raphe magnus of the medulla oblongata to the spinal cord has received much
attention. This projection has been shown to inhibit dorsal horn neurons that give rise to the
spinothalamic tract. Serotonin containing neurons (as noradrenergic neurons) play a role in
sleep. Inhibition of serotonin synthesis or destruction of serotonin containing neurons in the
raphe system leads to insomnia.

The dopaminergic system neurons have a discrete topography and restricted area of terminal
distribution, whereas the noradrenergic, adrenergic, and serotonergic neuron systems have a
more diffuse and wide-spread projection.

FUNCTIONS
The reticular formation has somatic motor, somatic sensory, visceral motor, and arousal
and sleep functions.

Somatic Motor Function

Somatic motor function is mediated via reticular connections to motor neurons of the spinal cord
and cranial nerve nuclei. These effects are triggered by activities in the cerebral cortex and
cerebellum.

The role of the reticulospinal tracts in control of somatic motor activity has been outlined in the
chapters on spinal cord and major motor and sensory pathways. Descending reticulospinal
pathways modify both alpha and gamma motor neuron activity, exerting facilitatory as well as
inhibitory effects on both reflex and cortically induced motor activity. In general, the pontine
reticular formation exerts facilitatory influences, whereas the medullary reticular formation
exerts inhibitory influences.

The paramedian pontine reticular formation (PPRF) integrates horizontal eye movements
through its connections to the ipsilateral abducens nucleus and from there via the medial

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longitudinal fasciculus to the contralateral medial rectus subnucleus

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of the oculomotor nucleus. A similar group of neurons in the rostral midbrain control vertical
eye movements.

Somatic Sensory Function

The reticular formation exerts an effect on the transmission of sensory impulses. As in the case
of somatic motor function, the effect of the reticular formation on sensory transmission is
triggered by cortical activity. This effect is both facilitatory and inhibitory and is exerted on
sensory nuclei of the spinal cord and brain stem, including cranial nerve nuclei. Modulation of
activity in the posterior column nuclei by the reticular formation is one such example. The role
of the nucleus raphe magnus of the medulla oblongata in the inhibition of pain transmission is
well established. Fibers from the nucleus raphe magnus descend in the brain stem and spinal
cord to terminate on the spinal trigeminal nucleus and substantia gelatinosa neurons. Axon
terminals liberate serotonin which facilitates enkephalinergic interneurons which in turn exerts
pre- and postsynaptic inhibition of the nociceptive neurons in these sites. Electrical stimulation
of the nucleus raphe magnus, in animals, produces analgesia. The analgesia produced by
stimulation of the periaqueductal gray is mediated by facilitatory input from the periaqueductal
gray to the nucleus raphe magnus.

Visceral Motor Function

Physiologic data suggest the presence of centers in the reticular formation for the control and
regulation of several visceral functions.

Stimulation of the medial group of reticular nuclei in the medulla oblongata elicits an inspiratory
response and depressor effect on the circulatory system (slowing of the heart rate and reduction
in blood pressure).

Stimulation of the lateral group of reticular nuclei elicits the opposite effect, namely an
expiratory response and pressor circulatory effect (acceleration of the heart rate and elevation
in blood pressure).

A pontine reticular center (pneumotaxic center) which regulates respiratory rhythm has been
identified in the area of parabrachial–Kölliker-Fuse nuclei located dorsal to the motor nucleus of
the trigeminal nerve. Direct connections from the pontine respiratory center to the medullary
respiratory centers have been demonstrated.

Arousal and Alertness

The reticular formation plays a role in arousal and alertness through the ascending reticular
activating system (ARAS) which was originally described in the late 1940s by Morruzi in Italy
and Magoun in the USA.

ASCENDING RETICULAR ACTIVATING SYSTEM (ARAS)

This multisynaptic pathway from the reticular formation to the diencephalon (intralaminar nuclei
of thalamus) and subsequently to the cortex plays a major role in cortical arousal and in
sharpening the attentiveness of the cortex to incoming sensory stimuli. This phenomenon of
cortical arousal is associated with a characteristic electroencephalographic (EEG) pattern
consisting of low voltage, high frequency waves known as a desynchronization pattern.

Stimulation of the ascending reticular activating system produces a state of arousal, alertness,
and attentiveness. Experiments have shown that learning is greatly enhanced during stimulation
of the reticular activating system. Destruction of this system, on the other hand, produces a
state of somnolence or coma.

Activity in the ascending reticular activating system is a tonic one maintained by incoming
afferent stimuli. Although the reticular activating system responds in a nonspecific fashion to all
incoming sensory stimuli, some stimuli are more effective than others. Auditory stimuli are more
effective than visual stimuli. Impulses from pain receptors are more effective than those from
other receptors. Trigeminal stimuli are particularly effective. Animals in which the brain stem
has been sectioned below the level of the trigeminal nerve in the pons retain the arousal
response. However, if a cut is made at the level of the trigeminal nerve, such animals lose the

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arousal response and become stuporous.

The convergence of various sensory inputs on the reticular formation, its multisynaptic
connections, and the divergence of its projections to wide areas of the cerebral cortex, make
this system best suited for arousal.

It should be emphasized, however, that the reticular activation system receives constant
feedback from the cerebral cortex and the peripheral receptors. These feedback mechanisms
help maintain the state of arousal. The depression in the state of consciousness seen in
degenerative brain disease is due in part to interruption of the feedback from the cortex to the
reticular formation.

The reticular activating system is particularly sensitive to general anesthetics and tranquilizing
drugs. These drugs may either suppress or attenuate transmission in this system, thus
producing sleep or tranquilization. They do not, however, suppress transmission along the
specific lemniscal system.

Interest in the reticular activating system has focused on the substrate for selective awareness
(how attention is selectively focused toward one sensory stream to the exclusion of other
inputs). Anatomic and physiologic evidence suggests that the reticular nucleus plays a central
role in selective awareness. The reticular nucleus of the thalamus, activated by volleys
ascending along thalamocortical axons, in turn projects back upon tha-lamic nuclei and the
mesencephalic tegmentum, exerting tonic and/or phasic inhibition of cell groups in the thalamus
and mesencephalic tegmentum. Physiologic studies have demonstrated facilitatory influences of
the frontal cortex upon units in the reticular nucleus of thalamus. Thus, a concept has emerged
of a reticularis complex selectively gating interactions between the specific thalamic nuclei and
the cerebral cortex under the control of the brain stem reticular formation and frontal cortex.
This gating mechanism seems highly selective: depending on the nature of the alerting stimulus
or locus of central stimulation, only that portion of the reticular nucleus of thalamus which
controls the appropriate thalamic sensory field will open.

SLEEP
Sleep is an altered state of consciousness necessary for the well-being of the organism. Humans
deprived of sleep for long periods of time become emotionally disturbed and may even manifest
psychotic behavior. It is estimated that humans spend approximately one-third of their lives
asleep.

Phases and Stages of Sleep

There are two recognized phases of sleep: (1) slow wave sleep and (2) rapid eye movement
(REM) or paradoxical sleep.

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A. SLOW WAVE SLEEP

Slow wave sleep is also known as synchronized sleep, light sleep, slow sleep, and non-REM
sleep. It constitutes 75% of the sleeping period in adults and is characterized by the following
somatic, behavioral, and EEG manifestations:

1. Reduced muscle tone.

2. Drop in blood pressure, heart rate, and respiratory rate.

3. Synchronized slow EEG activity of high voltage; hence the name slow wave sleep.

Slow wave sleep is divided into four stages:

Stage I (drowsiness). This stage lasts from one to seven minutes. The individual is
easily aroused in this stage.

Stage II (light sleep). Arousal in this stage needs more intense stimuli than in Stage I.

Stage III (moderately deep sleep). The EEG in this stage is characterized by the
appearance of slow, high voltage waves.

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Stage IV (deep sleep). Arousal from this stage requires strong stimuli. Slow activity in
the EEG in this stage comprises more than 50% of the EEG record. During this stage, blood
pressure, pulse rate, respiratory rate and oxygen consumption of the brain are very low.

Sleep walking, bed wetting, night terrors, and seizures are known to occur in slow wave sleep.

B. REM (PARADOXICAL) SLEEP

REM (paradoxical) sleep is also known as desynchronized sleep, active sleep, dreaming sleep,
fast wave sleep, and deep sleep. It constitutes 25% of sleeping time in adults and is
characterized by the following manifestations:

1. Marked hypotonia, especially in neck muscles, hence head drop in people entering this
state while sitting up in a chair.

2. Increase in blood pressure and heart rate; irregular and rapid respiration.

3. Erection in males.

4. Teeth grinding.

5. Dreaming, hence the name dreaming sleep.

6. Rapid eye movements (50 to 60 movements per min), hence the name REM sleep.

7. High voltage potentials in the pons, lateral geniculate nucleus, and occipital cortex (PGO
for pontogeniculooccipital spikes). PGO spikes are generated in the pons, propagate
rostrally through the lateral geniculate nucleus and other thalamic nuclei to reach the
cortex.

8. Rapid, low voltage, irregular electroencephalographic (EEG) activity resembling the waking
pattern (desynchronization pattern)

9. Increased threshold of arousal, hence deep sleep

It is easier to awaken a person from REM sleep than from stage IV slow wave (non-REM) sleep.
Anginal pain and cluster headache (type of vascular headache) are known to occur during REM
sleep.

The coexistence of rapid, low voltage cortical activity (active EEG state) and increased
autonomic activity (heart rate, blood pressure, respiration) in an otherwise motionless individual
in deep sleep justifies calling this stage the paradoxical stage of sleep.

During sleep, one alternates between slow wave sleep lasting 90 to 100 minutes and 10 to 30
minutes of REM sleep.

The various phases of sleep (stages I to IV of slow wave sleep and REM sleep) follow each other
with the same order throughout sleep. The first REM phase occurs about 90 minutes after sleep
onset and lasts about 10 to 15 minutes. Subsequent REM phases recur every 1 to 2 hours.

In general, there is more REM sleep toward the morning and more of the slow wave sleep early
at night. REM sleep constitutes almost all sleeping time in the fetus and about 50% of sleeping
time in the infant. As the brain matures, slow wave sleep increases, constituting 75% of
sleeping time in the adult.

Drugs affect the stages of sleep differentially. Barbiturates and alcohol suppress REM sleep but
have little effect on stage IV of non-REM (slow wave) sleep. On the other hand, benzodiazepines
(Valium, Librium) suppress stage IV non-REM sleep and have less effect on REM sleep.

Sleep and Arousal Mechanisms

Sleep is an active process triggered by known brain stem structures and through known
chemical transmitters.

The sleep-waking cycle follows a circadian rhythm and is controlled by a circadian rhythm
generator in the suprachiasmatic nucleus of the hypothalamus.

Over seventy years ago, a Viennese neurologist and neuropathologist, von Economo,
predicted, based on studies of patients suffering of encephalitis lethargica (a viral

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encephalitis that caused a profound and prolonged state of sleepiness), the existence of a sleep-
promoting region in the rostral midbrain and caudal hypothalamus, and a wake-promoting area
in the posterior hypothalamus.

In the years following the second World War, Moruzzi, in Italy, and Magoun (in the USA)
described the ascending reticular activating system (ARAS) that regulates wakefulness. The
basic neuronal circuitry of this system was, however, only defined in the 1980s and early 1990s.
Subsequent research on the mechanisms of sleep and wakefulness, especially in the last 5 to 7
years, has confirmed and elaborated on earlier observations made by von Economa and Moruzzi-
Magoun as follows:

1. It is now established that the ascending reticular activating system and cortical arousal are
mediated via two systems (Figure 32-2)

a. A cholinergic system from the pedunculopontine and laterodorsal tegmental reticular

nuclei to several thalam-ic nuclei (intralaminar, relay, reticular) and from there, via
thalamocortical projections, to the cerebral cortex. This system is active during
wakefulness and REM sleep.

b. An aminergic system from locus ceruleus (norepinephrine), raphe nuclei (serotonin),

tuberomammillary nucleus (histamine) directly (without passing through the
thalamus) to the cerebral cortex. This system is active during wakefulness but not
during REM sleep.

2. It has been shown that sleep is induced by activity in the ventrolateral preoptic nucleus (of
hypothalamus). GABAergic (inhibitory) connections have been demonstrated from this
hypothalamic nucleus to the arousal system (pedunculopontine, laterodorsal tegmental,
locus ceruleus, raphe, and tuberomammillary nuclei). It has also been demonstrated that
the ventrolateral preoptic nucleus receives reciprocal inhibitory input from aminergic
arousal system nuclei (tuberomammillary, locus ceruleus, raphe) (Figure 32-3).

3. Aminergic nuclei (tuberomammillary, locus ceruleus, raphe) can thus promote wakefulness
via direct excitation of cortex
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(1b above) and inhibition of sleep-promoting neurons in the ventrolateral preoptic nucleus
(Figure 32-4).

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Figure 32-2. Schematic diagram of the direct (aminergic) and indirect (cholinergic)
cortical arousal system.

4. REM and non-REM sleep are regulated by two different populations of neurons in the
ventrolateral preoptic nucleus. Core neurons within the nucleus regulate non-REM sleep via
inhibition of the tuberomammillary nucleus. Extended neurons of the ventrolateral preoptic
nucleus regulate REM sleep via inhibition of locus ceruleus, raphe, pedunculopontine and
laterodorsal tegmental nuclei (Figure 32-5).

5. In 1998, two groups of investigators identified a family of peptide neurotransmitters

in the lateral hypothalamus. These are now known as orexins or hypocretins. Neurons
containing orexins (hypocretins) were found to increase activity of aminergic neurons of
the ascending arousal system.
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Orexin (hypocretin) neurons are predominantly wake-active, although some fire also during
REM sleep. Destruction of orexin (hypocretin) neurons is associated with narcolepsy.

Figure 32-3. chematic diagram of the connections between the sleep promoting
ventrolateral preoptic nucleus and the nuclei (aminergic and cholinergic) of the ascending
arousal system. -, inhibition.

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Figure 32-4. Schematic diagram showing how aminergic brain stem nuclei promote
wakefulness via facilitation of the cerebral cortex and inhibition of sleep-promoting
neurons. +, facilitation; -, inhibition.

In retrospect, the hypersomnolence described by von Economo in encephalitis lethargica is now

believed to be due to lesion in the ascending arousal system at the midbrain-diencephalic
junction. The insomnia of von Economo is now believed to be due to lesion in the ventrolateral
preoptic nucleus. Von Economo's prediction that narcolepsy is caused by lesion of the posterior
diencephalon is now believed to be related to loss of orexin (hypocretin) neurons in that area.

Recent imaging studies have shed more light on sleep mechanisms. Positron emission
tomography (PET) scans have shown that during slow wave sleep, the most deactivated areas
are the upper brain stem, thalamic nuclei, basal forebrain, and the basal ganglia. In the cortex,
the least active areas are the association cortices of the frontal and parietal lobes. In REM
sleep, in comparison, there is significant activation of the ponto-mesencephalic area and
thalamic nuclei. The cortical areas activated are the limbic cortex (amygdala, hippocampus,
orbitofrontal cortex, and anterior cingulate cortex). These imaging studies confirm the existence
of different patterns of neuronal activities in slow wave and REM sleep.

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Figure 32-5. Schematic diagram of the two neuronal systems that regulate REM and non-
REM sleep.

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TERMINOLOGY
Alzheimer's disease.
A degenerative disease of the brain formerly known as senile dementia. Characterized by
memory loss, cortical atrophy, senile plaques, and neurofibrillary tangles. Described by Alois
Alzheimer, a German neuropsychiatrist, in 1907.

Cuneiform nucleus (Latin cuneus, “wedge”).

The cuneiform nucleus is wedge shaped.

Encephalitis lethargica (von Economo's disease).

An epidemic encephalitis that followed the influenza pandemic of 1915–1924. Although
described by Jean-Rene Cruchet two weeks before von Economo, the latter got credit because
he had defined the condition as a single disease which Cruchet had not.

Locus ceruleus (Latin, “place, dark blue”).

The pigmented noradrenergic nucleus in the rostral pons is dark blue in sections.

Meynert, Theodor Hermann (1833–1892).

Austrian psychiatrist and neurologist. Son of a historian father and an opera singer mother. He
studied the anatomy of the cortex and brain stem in detail. Among others, he described the
Meynert's decussation (dorsal tegmental decussation of midbrain) and Meynert's fasciculus
(habenulo-interpeduncular tract). He described the nucleus basalis in the 1872 book, Handbook
of Human and Animal Histology. The term nucleus basalis of Meynert was coined by Albert
Kölliker in 1896.

Narcolepsy (Greek, “numbness, seizure”).

A syndrome of excessive and irresistible urge of day sleeping. The condition was so named by
Gélineau, who gave the first modern account of the disorder in 1880. The American general
“Stonewall” Jackson is believed to have had narcolepsy.

Parabrachial nucleus (Greek para, “beside”).

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The parabrachial nucleus is beside the brachium conjunctivum (superior cerebellar peduncle).

Paradoxical sleep.
Rapid eye movement sleep. So named because electroencephalography shows a wakefulness
pattern when the person is asleep.

Parkinson's disease.
A degenerative disease of the brain characterized by postural tremor and rigidity from loss of
dopaminergic neurons in the substantia nigra. Described by James Parkinson, an English
physician, in 1817 under the name of shaking palsy.

Parvocellular nucleus (Latin parvus, “small”; cellula, “cell”).

So named because it is composed of small cells.

Raphe (Greek raphe, “a seam or suture”).

This word was used by Homer in the Odyssey in connection with the sewing of harnesses for
horses. The term is used in anatomy to refer to a seamlike formation that suggests that
adjacent structures have been sewn together. The midline reticular nuclei are called the raphe
nuclei.

von Bekhterev, Vladimir Mikhailovich (1857–1927).

Russian neuropathologist and psychiatrist. He published many papers on anatomy, the
vestibular system, cortical localization, nystagmus, and a number of neurological signs.

von Economo, Baron Konstantin (1876–1931).

Austrian neurologist and neuropathologist who, among other contributions, published on May
10, 1917, a paper about encephalitis lethargica. Jean-Rene Cruchet, French pathologist and
pediatrician had reported 13 days earlier (April 27, 1917) 40 cases of the same disease. Cruchet
claimed precedence but van Bogaert, Belgian neurologist, adjudicated in favor of von Economo
on the basis that he had defined the condition as a single disease which Cruchet had not.

SUGGESTED READINGS
Autret A et al: Sleep and brain lesions: A critical review of the literature and additional new
cases. Neurophysiol Clin 2001; 31:356–375.

Bystrzycka EK: Afferent projections to the dorsal and ventral respiratory nuclei in the
medulla oblongata of the cat studied by the horseradish peroxidase technique. Brain Res
1980; 185:59–66.

Corvaja N: The lateral reticular nucleus in the cat. I. An experimental anatomical study of its
spinal and supraspinal afferent connections. Neuroscience 1977; 2:537–553.

Evans BM: What does brain damage tell us about the mechanisms of sleep? J Roy Soc Med
2002; 95:591–597.

Gottesmann C: GABA mechanisms and sleep. Neuroscience 2002; 111:231–239.

Hobson JA, Scheibel AB: The brain stem core: Sensorimotor integration and behavioral state
control. Neurosci Res Program Bull 1980; 18, No. 1.

Hobson, JA, Pace-Schott EF: The cognitive neuroscience of sleep: Neuronal systems,
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Jessop EG: Sleep. J Public Health Med 2001; 23:89–90.

Kastin AJ et al: DSIP—More than a sleep peptide? Trends Neurosci 1980; 3:163–165.

Künzle M: Autoradiographic tracing of the cerebellar projections from the lateral reticular

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nucleus in the cat. Exp Brain Res 1975; 22:255–266.

LeBon E et al: Correlations using NREM-REM sleep cycle frequency support distinct
regulation mechanisms for REM and NREM sleep. J Appl Physiol 2002; 93:141–146.

Maquet P: Brain mechanisms of sleep: contribution of neuroimaging techniques. J

Psychopharmacol 1999; 13:S25–S28.

Mendelson WB: Neurotransmitters and sleep. J Clin Psychiatry 2001; 62 (Suppl 10):5–8.

Moore RY: The reticular formation: Monoamine neuron systems. In: Hobson JA, Brazier MAB
(eds): The reticular formation revisited: Specifying function for a nonspecific system.
International Brain Research Organization Monograph Series, Vol. 6, pp. 67–81, Raven
Press, 1980.

Salin-Pascual R et al: Hypothalamic regulation of sleep. Neuropsychopharmacology 2001; 25

(Suppl 5):S21–S27.

Saper CB et al: The sleep switch: Hypothalamic control of sleep and wakefulness. Trends
Neurosci 2001; 24:726–731.

Scheibel AB: Anatomical and physiological substrates of arousal: A view from the bridge. In:
Hobson JA, Brazier MAB (eds): The reticular formation revisited: Specifying function for a
nonspecific system. International Brain Research Organization Monograph Series, Vol. 6, pp.
55–66, Raven Press, 1980.

Zemlan FP, Pfaff DW: Topographical organization in medullary reticulospinal systems as

demonstrated by the horseradish peroxidase technique. Brain Res 1979; 174:161–166.

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Editors: Afifi, Adel K.; Bergman, Ronald A.

Title: Functional Neuroanatomy: Text and Atlas, 2nd Edition

Copyright ©2005 McGraw-Hill

> Table of Contents > Part I - Text > 33 - Reticular Formation, Wakefulness,
and Sleep: Clinical Correlates

33
Reticular Formation, Wakefulness,
and Sleep: Clinical Correlates

Parasomnias (Dyssomnias)
Sleep Walking (Somnambulism)
Night Terror (Pavor Nocturnus)
Nocturnal Groaning (Catathrenia)
REM Intrusion
Narcolepsy (Gélineau's Syndrome)
Kleine-Levin Syndrome (Kleine-Levin-Critchley
Syndrome, Hypersomnia-Bulimia)
Central Sleep Apnea
Ondine's Curse
Fatal Familial Insomnia
Coma
Akinetic Mutism (Cairn's Syndrome)
Locked-In Syndrome
Brain Death

KEY CONCEPTS

Parasomnias are a group of sleep disorders that include

sleep walking, night terror, nocturnal groaning, and REM
intrusions. The first three are slow wave (non-REM) sleep
disorders and the fourth (REM intrusions) is a REM sleep
disorder.

Narcolepsy is a sleep disorder characterized by recurrent

brief attacks of irresistible daytime sleep. It is due to loss of
orexin (hypocretin) neurons in the hypothalamus.

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Kleine-Levin syndrome is a sleep disorder characterized by

recurrent attacks of excessive somnolence alternating with
voracious appetite and sexual disinhibition when awake.

Central sleep apnea is a sleep disorder characterized by

apneic spells in sleep. The congenital form is evident during
the first few days of life, the acquired form is associated
usually with bilateral medullary infarcts.

Ondine's curse is a sleep disorder characterized by

cessation of respiration in sleep due to failure of automatic
respiration.

Fatal familial insomnia is an inherited fatal sleep disorder

due to point mutation in the prion protein gene.

Coma is a state of loss of consciousness in which motor

and sensory responses of the individual are impaired.

Akinetic mutism is an altered state of consciousness in

which the patient appears awake but is unable to
communicate.

Locked-in syndrome is an altered state of consciousness in

which consciousness is preserved but is inexpressible.
Patients communicate by eye blinking.

Brain death is a state of irreversible brain damage in

which normal cortical and brain stem functions are absent.

PARASOMNIAS (DYSSOMNIAS)
Parasomnias are a group of sleep disorders characterized by
unusual motor behaviors, autonomic behaviors, or both, occurring
in slow wave (non-REM) sleep. They include sleep walking, night terror,
and nocturnal groaning, among others. These disorders are thought to
be due to impaired ability to arouse fully from slow wave sleep. They
usually occur in the first third of the sleep cycle.

Sleep Walking (Somnambulism)

This parasomnia occurs in the first one to three hours after going to
sleep. The walking is not recalled. Patients may sit or stand in bed,
fumble with clothing without walking, or get up from bed and walk,
open doors, or descend stairs. They usually follow instructions to return

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to bed. Behaviors associated with sleep walking include eating, leaving

the house through a door or window, violent behavior, and homicide.
Sleep walking is more common
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in children than adults. In children, it may be associated with enuresis
or night terrors.

Night Terror (Pavor Nocturnus)

As in sleep walking, this parasomnia occurs in the first third of
nocturnal sleep [stages 3 to 4 of slow wave (non-REM) sleep], and is
more common in children. Episodes consist of agitation, apparent fear,
screaming, a number of autonomic behaviors (tachycardia, dilated
pupil, sweating), attempts to leave the bed or room, and
inconsolability. The episode lasts a few (2 to 10) minutes at the end of
which patients become quiet and return to deep sleep. The patient has
no recall for the episode.

Nocturnal Groaning (Catathrenia)

This is an uncommon parasomnia characterized by expiratory groaning
during slow wave (non-REM) sleep as well as REM sleep. Patients are
unaware of the behavior which causes concern to bed partners.

REM Intrusion
A more serious parasomnia in REM sleep in which the person will enact
a dream. Affected individuals can hurt their bed partner or themselves
as they are enacting the dream content.

NARCOLEPSY (GÉLINEAU'S SYNDROME)

The term narcolepsy was coined by Jean Baptiste Gélineau, a French
neuropsychiatrist, in 1880 to describe a condition characterized by
recurrent, brief attacks of irresistible daytime sleep. He recognized the
association of narcolepsy with loss of muscle tone subsequently called
cataplexy.

The combination of excessive daytime sleepiness (narcolepsy) and

spells of sudden loss of muscle tone (cataplexy) provoked by
emotional triggers (laughter, surprise, fright, excitement, and rage)
has puzzled neuroscientists for more than a century. In 1960, it was
recognized that narcolepsy was associated with premature onset of
REM sleep. In 1999, a major breakthrough occurred relating narcolepsy
to a decrease in a peptide, orexin (hypocretin), elaborated in the
perifornical area of the lateral hypothalamus. It is now believed that
the sleepiness of narcolepsy reflects lack of hypocretin excitatory
effects on histaminergic (tuberomamillary nucleus), dopaminergic
(ventral tegmental area and substantia nigra), and cholinergic

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(pedunculopontine and laterodorsal tegmental nuclei) components of

the ascending reticular activating system (ARAS) which promote
arousal. According to this hypothesis, cataplexy results from loss of
hypocretin excitation of serotonergic (raphe nuclei) and noradrenergic
(locus ceruleus) pathways responsible for REM sleep inhibition. In
addition to excessive daytime sleepiness and spells of loss of muscle
tone, narcoleptics characteristically show vivid perceptual (auditory or
visual) experiences at sleep onset (hypnagogic hallucinations) or upon
awakening from sleep (hypnopompic hallucinations), and transient
(few seconds), generalized inability to move or speak during transition
between sleep and wakefulness (sleep paralysis). Hypnagogic
hallucinations and sleep paralysis were added to the clinical picture of
narcolepsy-cataplexy by Yoss and Daly in 1957.

KLEINE-LEVIN SYNDROME(KLEINE-LEVIN-
CRITCHLEY SYNDROME, HYPERSOMNIA-
BULIMIA)
This is a rare syndrome that presents a fascinating complexity of
neurologic and psychiatric symptoms. Although a syndrome of
episodic hypersomnolence and morbid hunger was described by
Antimoff in 1898, credit for describing this syndrome is given to Willi
Kleine, a German psychiatrist who described the complete clinical
picture in 1925 and to Max Levin, an American psychiatrist who, in
1929, described a patient with extreme hunger and sleep attacks. The
syndrome, as currently defined, refers to a recurrent constellation of
symptoms, lasting days to weeks, which includes episodes of excessive
somnolence, voracious appetite, and sexual disinhibition. When awake,
affected patients may exhibit irritability, lack of energy, and apathy
and may appear confused or exhibit manic depressive symptoms.
Although adolescent males are more frequently affected, reports of the
syndrome in females are available. Etiology is uncertain, but is
believed to be due to a hypothalamic-pituitary dysfunction.

CENTRAL SLEEP APNEA

Central sleep apnea refers to dysfunction of central control of
breathing. Normal breathing requires the normal functioning of a
number of central and peripheral nervous system structures. Lesions in
any of these structures (chemoreceptors, sensory pathways, brain stem
centers, motor pathways, or effector muscles) may lead to respiratory
abnormality during sleep.

Central sleep apnea may be congenital or acquired. Congenital central

sleep apnea is usually seen in the first few days of life and is
manifested by apnea at onset of sleep. Acquired central sleep apnea is
usually associated with bilateral vascular lesions in the posterolateral
medulla.

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Sleep related apneic events have also been reported in encephalitis,

neuromuscular junction disorders (myasthenia gravis), primary muscle
disorders (muscular dystrophy), and in patients who undergo bilateral
cervical cordotomy for relief of intractable cancer pain.

ONDINE'S CURSE
This is a rare neurologic syndrome characterized by cessations of
respiration in sleep due to failure of the automatic respiratory
center in the medulla oblongata. Failure of automatic respiration
results from the loss of vagal and chemotactic inputs to the carbon
dioxide receptors in the medulla removing the drive to breathe. The
first distinct case was reported in 1955 by Ratto et al. in a patient with
a stroke. The syndrome was misnamed Ondine's curse by Severinghaus
and Mitchell in 1962 in reference to a water nymph in a 1939 novel
(Ondine) by the French playwright Jean Giraudoux who introduced the
loss of all automatic functions (not just breathing) as the manner of
the nymph's human lover's death. The word “ondine” is the French
word for mermaid and not the name of any specific person. The legend
that gave rise to the name “Ondine's curse” is an old Germanic myth of
a water nymph (“undine” in German) that falls in love with and marries
a human and makes a pact with the mermaid king that if her lover
were ever unfaithful, he would forfeit his life and she would return to
the sea. The term Ondine's curse is thus a misnomer. Mermaids
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loved their human lovers; there was never a curse. The prevalent
narrative of a nymph punishing her unfaithful mortal husband by
depriving him of the ability to breathe while asleep is unlikely.

FATAL FAMILIAL INSOMNIA

This is a rare disorder, inherited as an autosomal dominant trait
genetically linked to a point mutation at codon 178 of the prion
protein gene. Affected patients display intractable insomnia, alterations
in the sleep-wake cycle, attention deficit, sympathetic hyperactivity
and gait abnormality. Non-REM sleep is characteristically absent. The
disease progresses rapidly to stupor, coma, and death within two
years. Impairment of sleep and autonomic functions has been
attributed to damage of the dorsomedial and anterior thalamic nuclei,
cingulate gyrus, and orbitofrontal gyrus leading to interruption of
thalamocortical limbic circuits involved in the sleep-wake cycle.
Enhanced serotonergic neurotransmission has been implicated in some
symptoms of this disorder.

COMA
Coma is a state of loss of consciousness characterized by
impairment in the motor and sensory responses of the individual.

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A patient in coma cannot vocalize, has no spontaneous eye

movements, and responds reflexly or not at all to painful stimuli. The
electroencephalogram is characterized by slow activity in the delta
range (about 3 cycles per second).

There are grades of loss of consciousness. These vary from a state of

lethargy (also called obtundation) in which wakefulness is barely
maintained (drowsiness), responses to stimuli are sluggish or delayed,
and vocalization is slow, slurred, and spontaneous, to a state of stupor
(semicoma) in which there are some spontaneous eye movements,
motor responses only to painful stimuli, and no spontaneous
vocalization.

Coma can result from different causes. These include diseases of the
central nervous system (infection, tumor, trauma, hemorrhage,
thrombosis, etc.), metabolic disorders (acidosis, hypoglycemia, etc.),
and drug overdosage (barbiturates, tranquilizers, etc.).

In coma secondary to central nervous system affection, involvement of

the brain stem reticular formation (ascending reticular activating
system) is pivotal in the genesis of coma. Coma, however, can result
from extensive cortical disease without significant involvement of the
brain stem reticular formation.

AKINETIC MUTISM (CAIRN'S SYNDROME)

This is an altered state of consciousness, first described by Cairns
in 1941, in which the patient appears awake and maintains a
sleep-wake cycle, but does not react to environmental stimuli and is
unable to communicate in any way. Synonyms include persistent
vegetative state and coma vigil. The condition is characterized by
hypersomnolence or coma, some retention of eye movements, and loss
of REM sleep and of arousal mechanisms. Lesions producing akinetic
mutism have been reported in the pons, basal ganglia, thalamus,
anterior cingulate gyrus, and septal area.

LOCKED-IN SYNDROME
This term was introduced by Plum and Posner to describe patients
who are completely immobile, unable to speak, and incapable of
facial movements. Consciousness is preserved though inexpressible.
Patients are able to communicate by eye blinking signifying yes or no.
The patients are otherwise mute and akinetic. Only eye opening,
vertical eye movements and convergence remain. The syndrome was
first described by Darelles in 1875 in a patient with occlusion of the
basilar artery. The syndrome has been described most frequently with
bilateral infarcts in the basis pontis but also in infarcts in both cerebral
peduncles. Structures usually involved when the lesion is in the basis
pontis include corticospinal tracts (immobility) corticobulbar fibers

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(loss of facial movements and speech articulation) and abducens nerve

(loss of horizontal eye movements). Synonyms include pseudocoma,
de-efferented state, ventral pontine syndrome, Monte Cristo syndrome
(Alexandre Dumas' novel, The Count of Monte Cristo, in which M.
Noirtier communicated only by eye blinks), ponto-pseudo-coma, and
pontine disconnection syndrome.

BRAIN DEATH
Brain death is a state of irreversible brain damage so severe that
normal respiration and cardiovascular function can no longer be
maintained. Such patients are in deep coma, remain unresponsive to
external stimuli, and their respiration and cardiovascular functions are
maintained by external means (respirators, pressor drugs, etc.). In
modern clinical medicine, cessation of life is equated with brain death
rather than with cessation of heart beat.

Several criteria have to be present before a state of brain death is

declared. These criteria include the following.

1. Unresponsiveness to external stimuli

2. Absence of spontaneous breathing

3. Dilated fixed pupils

4. Absence of brain stem reflexes (corneal, gag, vestibuloocular)

5. No recognizable reversible cause for the coma

6. Flat electroencephalogram (absence of electrical activity)

7. Nonfilling of cerebral vessels in arteriography or radioisotope

imaging

Comatose patients who fulfill the above criteria are considered dead;
heroic measures to save life are futile.

TERMINOLOGY
Cairns, Sir Hugh William Bell (1896–1952).
Australian neurosurgeon who described the persistent vegetative state
(akinetic mutism) in 1941. Cairns suggested that the syndrome reflects
cortical dysfunction secondary to a diencephalic lesion.

Cataplexy (Greek, “to strike down”).

A REM sleep disorder in which the patient loses muscle power suddenly
in response to emotional triggers. The term was first applied by
Henneberg in 1916.

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Gélineau, Jean-Baptiste-Edouard (1828–1906).

French surgeon and neuropsychiatrist who described narcolepsy
(Gélineau syndrome) in 1880. He invented and marketed his own pills
for epilepsy.

Kleine, Willi.
German neuropsychiatrist who, in 1925, published a series of cases of
periodic somnolence and morbid hunger, the Kleine-Levin syndrome.

Levin, Max.
American neurologist who, in 1929, reported one case of periodic
somnolence and extreme hunger, and in 1936 described the features of
the Kleine-Levin syndrome.

Ondine.
French for mermaid or water nymph. The title of a novel written in
1939 by the French playwright Jean Giraudoux.
P.410

SUGGESTED READINGS
Aldrich MS: Narcolepsy. Neurology 1992; 42 (suppl 6):34–43.

Aldrich MS: Sleep-related spells associated with parasomnias and

narcolepsy. Sem Neurol 1995; 15:194–202.

D'Cruz OF, Vaughn BV: Parasomnias—an update. Sem Pediat Neurol

2001; 8:251–157.

Guilleminault C et al: Sleep-related obstructive and nonobstructive

apneas and neurologic disorders. Neurology 1992; 42 (suppl 6):53–
60.

Guilleminault C: Disorders of arousal in children: Somnambulism

and night terrors. In Guilleminault C (ed): Sleep and Its Disorders
in Children, Raven Press, 1987, pp 243–252.

Krahn LE et al: Narcolepsy: New understanding of irresistible sleep.

Mayo Clin Proc 2001; 76:185–194.

Orlosky MJ: The Kleine-Levin Syndrome: A review. Psychosomatics

1982; 23:609–621.

Pryse-Phillips W: Companion to Clinical Neurology, Boston, Little-

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Ovid: Functional Neuroanatomy: Text and Atlas Página 9 de 9

Brown, 1995.

Ratto O et al: Anoxemia secondary to polycythemia and

polycythemia secondary to anoxemia. Am J Med 1955; 19:958–965.

Reder AT et al: Clinical and genetic studies of fatal familial

insomnia. Neurology 1995; 45:1068–1075.

Scammell TE: The neurobiology, diagnosis, and treatment of

narcolepsy. Ann Neurol 2003; 53:154–166.

Severinghaus JW, Mitchll RA: Ondine's curse—failure of respiratory

center automaticity while awake. Clin Res 1962; 10:122.

Silber MH et al: Solving the mysteries of narcolepsy. The

hypocretin story. Neurology 2001; 56:1616–1618.

Taheri S et al: The role of hypocretins (orexins) in sleep regulation

and narcolepsy. Ann Rev Neurosci 2002; 25:283–313.

Vetrugno R et al: Catathrenia (nocturnal groaning): A new type of

parasomnia. Neurology 2001; 56:681–683.

Wanschitz J et al: Alteration of the serotonergic nervous system in

fatal familial insomnia. Ann Neurol 2000; 48:788–791.

Wise MS, Lynch J: Narcolepsy in children. Sem Pediat Neurol 2001;

8:198–206.

Yoss RE, Daly D: Criteria for the diagnosis of the narcoleptic

syndrome. Proc Staff Meet Mayo Clinic 1957; 32:320–328.

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Editors: Afifi, Adel K.; Bergman, Ronald A.

Title: Functional Neuroanatomy: Text and Atlas, 2nd Edition

Copyright ©2005 McGraw-Hill

> Table of Contents > Part I - Text > 34 - Control of Posture and Movement

34
Control of Posture and Movement

Major Players in Control of Posture and Movement

Sequence of Events in Control of Posture and Movement
Functional Anatomy of Motor Control
Segmental Motor Control
Stretch (Myotatic) Reflex
Segmental Motor Disorders
Lower Motor Neuron Syndrome
Peripheral Nerve Syndrome
Neuromuscular Junction (Motor End Plate) Syndrome
Primary Muscle Disorders
Suprasegmental Motor Control
Brain Stem
Cerebellum
Basal Ganglia
Cerebral Cortex
Locomotion
Overview of Control of Posture and Movement

KEY CONCEPTS

Neural control of posture and movement is the result of an orderly

sequence of events involving the cerebral cortex, basal ganglia,
cerebellum, brain stem, spinal cord, peripheral nerves, neuromuscular
junction, and skeletal muscle.

Segmental control of movement and posture is based on a number of

spinal reflexes, the myotatic (stretch) reflex being one of them.

Disorders of segmental motor control include: (1) the lower motor

neuron syndrome exemplified by motor neuron disease (Werdnig-
Hoffmann, amyotrophic lateral sclerosis) and poliomyelitis; (2)
peripheral nerve disorders (acquired and inherited peripheral
neuropathies); (3) neuromuscular junction disorders (myasthenia
gravis); and (4) primary muscle disorders (muscular dystrophy and
various myopathies).

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Decerebrate states in human are associated with lesions in the

midbrain caudal to the red nucleus.

Decorticate states are associated with lesions rostral to the midbrain

that disconnect the whole brain stem from the cerebral cortex.

Disorders of the cerebellum are associated with volitional tremor,

ataxia, dyssynergia, dysmetria, and difficulty performing alternate
motion rate.

Disorders of basal ganglia are associated with hyperkinetic (e.g.,

chorea) and hypokinetic (e.g., Parkinson's disease) syndromes.

Lesions in the cerebral cortex or in its output (corticospinal tract)

are associated with the upper motor neuron syndrome characterized by
paresis or paralysis, spasticity, hyperactive reflexes, Babinski sign, and
clonus.

Locomotion is the outcome of a series of events involving segmental

and suprasegmental areas.

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The story of the neural control of posture and movement is one of the most
fascinating chapters in the study of the nervous system. A proper understanding
of neural control is essential not only to the comprehension of the mechanisms
underlying normal posture and movement but also to an appreciation of functional
disturbances in those who have developed a disease of the system of control and
who therefore have lost the ability either to execute or to coordinate movement.

MAJOR PLAYERS IN CONTROL OF POSTURE AND

MOVEMENT
Several areas in the central and peripheral nervous systems participate in
the planning and execution of posture and movement. These are:

1. The frontal association cortex

2. Primary motor cortex (precentral gyrus)

3. Premotor cortex

4. Basal ganglia

5. Cerebellum

6. Thalamus (primarily ventrolateral and ventral anterior nuclei)

7. Red nucleus

8. Reticular formation

9. Vestibular nuclei

10. Alpha and gamma spinal motor neurons

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11. Peripheral nerves

12. Neuromuscular junction

13. Skeletal muscle

Lesions in one or more of these areas result in characteristic clinical syndromes.

SEQUENCE OF EVENTS IN CONTROL OF POSTURE

AND MOVEMENT (Figure 34-1)
The process of control of posture and movement is initiated in the sensory
association cortices of the parietal, temporal, and occipital lobes. These areas
project to the frontal association cortex by means of the long association fiber
bundles (1 in Figure 34-1). The frontal association cortex [areas of the frontal
lobe rostral to the premotor cortex (Brodmann area 6) and frontal eye field
(Brodmann area 8)] is the seat of thought processes and internal commands that
culminate in a motor act. The command to move is transmitted from the frontal
association cortex to the cerebellum via the corticopontocerebellar pathway (2 in
Figure 34-1) and to the basal ganglia via corticostriate pathways (3 in Figure 34-
1). The cerebellum and basal ganglia exert a modulating effect on the motor
command. The cerebellum and basal ganglia project to the thalamus. Cerebellar
output to the thalamus (4 in Figure 34-1) targets primarily the ventrolateral tha-
lamic nucleus and reaches there via the dentatothalamic pathway, in the
brachium conjunctivum. Basal ganglia output to the thalamus (5 in Figure 34-1)
targets primarily the ventral anterior thalamic nucleus and reaches there via the
ansa lenticularis, the lenticular fasciculus, and the thalamic fasciculus. The
internal
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command to movement generated in the frontal association cortex—now
modulated by input from the cerebellum, basal ganglia, and thalamus—finally
reaches the primary motor cortex (area 4 of Brodmann) and premotor cortex
(area 6 of Brodmann) via thalamocortical projections (6 in Figure 34-1) in the
internal capsule. The command for movement is now transmitted to the spinal
cord motor neurons (alpha and gamma), indirectly via brain stem motor centers
(7 and 9 in Figure 34-1) or directly via the corticospinal (pyramidal) system (8 in
Figure 34-1). Motor signals from the spinal cord reach skeletal muscles via
peripheral nerves (10 in Figure 34-1) and the neuromuscular junction to effect
the command to move.

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Figure 34-1. Schematic diagram showing the sequence of events in the

control of posture and movement.

Positron emission tomography scans in humans have shown that the dorsolateral
prefrontal cortex (frontal association cortex), as well as the caudate nucleus and
anterior putamen, is activated during learning of new movement. During the
selection of movement, activation is noted in the premotor cortex (area 6 of
Brodmann), and midputamen. During automatic (overlearned) movement,
activation is noted in the sensory motor cortex and posterior putamen. Movement
under sensory guidance activates the cerebellum. These activations suggest that
the basal ganglia are concerned with selection of movement or the selection of
the appropriate muscles to perform a movement selected by cortical areas,
whereas the cerebellum (neocerebellum) is involved in monitoring and optimizing
movement using sensory feedback.

FUNCTIONAL ANATOMY OF MOTOR CONTROL

In studying the motor system, one is inclined to overemphasize the role of one
component of the system, the corticospinal tract. Although no one denies the
importance of this tract, one should not understate the roles of less voluminous
but otherwise important tracts, such as the reticulospinal, vestibulospinal, and
rubrospinal. In the same vein, one should not underestimate the role of
modifying inputs from the cerebellum and basal ganglia. Last but not least, one
should add to the schema the input into this system from peripheral organs, the
muscle fibers without which movement could not be executed (Figure 34-2).

It is obvious from the above that neural control of posture and movement is
multifaceted. In the final analysis, all levels of control work in unison to produce
coordinated and integrated movement. For didactic purposes, however, the

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individual contributions of each of the different levels of control of posture and

movement will be dealt with separately.

SEGMENTAL MOTOR CONTROL

The spinal cord contains, in its anterior horn, motor neurons with axons that
supply somatic body musculature. Activation of groups of motor neurons
gives rise to contraction of groups of skeletal muscle and hence movement. Motor
neurons of the spinal cord are activated by (1) impulses from the periphery as
part of reflex mechanisms and (2) impulses from higher levels (suprasegmental),
with descending fibers that exert a modifying influence on reflex mechanisms.

To study the role of spinal reflex mechanisms in posture and movement,

experimentalists resorted to artificial preparations in which the spinal cord was
disconnected from higher levels by transection. Such an animal preparation is
known as a spinal animal.

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Figure 34-2. Schematic diagram showing the segmental reflex arc at the
spinal cord level and suprasegmental structures that are involved in posture
and movement.

The reflexes elicited in a spinal animal include the following:

1. Stretch (myotatic) reflex

2. Inverse myotatic reflex

3. Flexor reflex

4. Crossed extension reflex

Stretch (Myotatic) Reflex (see Figure 3-25)

Stretching a muscle (by tapping its tendon) activates the muscle spindle of the
intrafusal muscle fiber (primary annulospiral endings). Impulses from the
activated muscle spindle activate monosynaptically via Ia fibers the homonymous
(corresponding, ipsilateral) alpha motor neurons in the anterior horn of the spinal
cord. This type of excitation is known as autogenic. Impulses traveling via the
axons of such alpha motor neurons then reach the stretched skeletal muscle and
result in contraction of the muscle. Ia afferents also make direct monosynaptic
excitatory connections with alpha motor neurons, which innervate muscles that
are synergistic in action to the muscle from which the Ia fiber originated. In
addition, the activity in the Ia fibers disynaptically inhibits the motor neurons
that supply the antagonistic
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muscle (reciprocal inhibition). This obviously facilitates contraction of the
homonymous muscle.

In humans, myotatic stretch reflexes can be elicited in the following sites and are
part of a neurologic examination.

Biceps jerk: This reflex is elicited by tapping the tendon of the biceps
muscle. The biceps muscle will contract, resulting in flexion at the elbow.

Triceps jerk: This reflex is elicited by tapping the tendon of the triceps
muscle. As a result, the triceps will contract and extend the elbow joint.

Radial jerk: Tapping the tendon of the brachioradialis muscle at the wrist
will contract the brachioradialis muscle and flex the wrist joint.

Knee jerk (quadriceps myotatic reflex): This reflex is elicited by tapping

the tendon of the quadriceps femoris muscle at the patella. The quadriceps
muscle contraction will extend the knee joint.

Ankle jerk: Tapping the tendon of the gastrocnemius muscle at the Achilles
tendon will contract the gastrocnemius and plantar flex the ankle.

Pathology anywhere in the path of the reflex arc from the receptor to the effector
site will interfere with these reflexes. Reduction or absence of myotatic reflexes

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reflects pathology in the receptor site (the muscle spindle), the afferent or
efferent nerve fibers (peripheral neuropathy), or the central neurons (anterior
horn cells), as in poliomyelitis.

Myotatic reflexes may be exaggerated (hyperactive) in diseases that interfere

with the descending modifying influences. Such a condition occurs in upper motor
neuron disorders (e.g., stroke, multiple sclerosis, spinal cord tumors).

The described technique of eliciting a muscle contraction, namely stretching the

muscle by tapping its tendon, is the clinical method. There is, however, another
way by which a muscle can be made to contract; this is by eliciting a contraction
of the muscle spindle without stretching the muscle. Activity in gamma neurons
within the anterior horn of the spinal cord sends impulses via the gamma efferent
fibers to both poles of the muscle spindle. Contraction of the poles of the muscle
spindle activates the primary (annulospiral) endings. Consequently, impulses
travel via the Ia nerve fibers to activate monosynaptically alpha motor neurons,
resulting in contraction of the extrafusal muscle fibers. This type of muscle
contraction is elicited through activity in the gamma loop system (Figure 34-3).

Thus, under normal conditions, the cerebral cortex can trigger muscle contraction
and initiate postural changes and movement through two mechanisms: by
activating the alpha motor neuron directly or by activating the alpha motor
neuron indirectly via the gamma system loop.

Voluntary, precise, and sensitive movements are executed by the simultaneous

activation of both systems. In general, activation of the alpha system
predominates when a quick response is desired, whereas activation of the gamma
system predominates when a smooth and precise movement is desired. The two
systems are complementary.

The importance of, and rationale for, the described role of the gamma loop can
be illustrated in the mechanism of standing posture. When one stands, the
stretch of the quadriceps tendon activates the muscle spindle and the alpha
motor neuron, thus producing muscle contraction. As soon as muscle contraction
occurs, tension on the muscle spindle ceases, the rate of discharge on the alpha
motor neuron diminishes, and subsequently the muscle relaxes. The gamma
system corrects this, however, and maintains the tension of the spindle
necessary for posture. The gamma neuron is activated by descending influences
from the cortex, cerebellum, etc. This maintains activity in the muscle spindle
and secures constant firing of Ia nerve fibers and the alpha motor neuron. As a
result, the muscle contraction necessary for standing posture is maintained.

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Figure 34-3. Schematic diagram of the components of the gamma loop.

Activation of gamma motor neurons (1) results in contraction of the poles of
the muscle spindle and activation of the annulospiral ending. Impulses travel
via the Ia afferents (2) and activate alpha motor neurons. Axons (3) of the
alpha motor neurons contract the skeletal muscle fiber.

The inverse myotatic reflex, the flexor reflex, and the crossed extension reflexes
are discussed in Chapter 3.

SEGMENTAL MOTOR DISORDERS

Lower Motor Neuron Syndrome

This syndrome is characterized by loss or diminution of muscle movement
(paralysis or paresis of muscle), absence or marked decrease in myotatic
(stretch) reflexes (areflexia or hyporeflexia), decrease in muscle tone
(hypotonia), muscle atrophy, and spontaneous muscle activity at rest
(fibrillations, fasciculations). The conglomerate of these signs constitutes the
lower motor neuron syndrome and is the result of loss of spinal and cranial nerve
motor neurons. The lower motor neuron syndrome is seen in motor neuron
disease (Werdnig-Hoffmann disease, amyotrophic lateral sclerosis, Lou Gehrig
disease) and in poliomyelitis.

Peripheral Nerve Syndrome

Peripheral nerve disorders may be acquired (inflammatory demyelinating
polyneuropathy, Guillain-Barré-Strohl syndrome) or inherited (hereditary sensory
motor neuropathies). The classical syndrome consists of muscle paresis or
paralysis (more marked in distal muscles), hyporeflexia or areflexia, muscle
hypotonia, and muscle atrophy—all signs of lower motor neuron syndrome. In
contrast to the lower motor neuron syndrome, peripheral nerve syndrome is
associated with sensory deficit.

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Neuromuscular Junction (Motor End Plate)

Syndrome
Neuromuscular junction syndromes are characterized by fluctuating muscle
weakness. Muscle weakness usually appears with use of muscle and disappears
with rest. The fluctuating muscle weakness may be regional (extraocular or facial
muscles) or generalized. Muscle tone and myotatic reflexes are usually normal.
There is no muscle atrophy or sensory deficit. Neuromuscular junction syndrome
is seen in myasthenia gravis, a disorder due to abnormalities in the acetylcholine
receptor on the muscle membrane.

Primary Muscle Disorders

Primary muscle disorders are characterized by muscle weakness and hypotonia.
Muscle weakness is more marked in proximal muscles (shoulder and hip girdles)
than distal muscles. Myotatic reflexes remain intact until late in the disease,
when there is muscle atrophy. There is no sensory deficit. Primary muscle
disorders may be acquired (myositis) or hereditary (muscular dystrophy,
congenital myopathy).

SUPRASEGMENTAL MOTOR CONTROL

Brain Stem
Several descending tracts from the brain stem contribute to posture and
movement. The most important of these are the rubro-spinal, vestibulospinal,
and reticulospinal tracts. Collectively, they contribute to the recovery of
stereotyped movements in proximal muscle groups and to the spasticity noted
following a cerebral stroke.

The contribution of brain stem structures to posture and movement can be

studied in two types of experimental preparations, the decerebrate state and the
midbrain animal. These two experimental states resemble those in humans with
similar lesions.

A. DECEREBRATE STATE
In the decerebrate state, the disconnection between lower and upper levels
for control of posture and movement is made at the midcollicular level,
between the superior and inferior colliculi. In addition to the spinal cord, the
medulla oblongata and pons are intact. The facilitatory part of the reticular
formation at the level of the pons is released from the inhibitory effect of the
caudate nucleus and cerebral cortex. The reticular formation thus released
tonically activates gamma motor neurons in the spinal cord (Figure 34-4). The
activated gamma motor neurons stimulate the annulospiral endings of the
intrafusal muscle fibers through the gamma loop. Activation of the latter
generates impulses via the Ia nerve fibers, which discharge the alpha motor
neurons monosynaptically (myotatic reflex). As a result, skeletal muscles are
tonically activated and rigidity sets in. Decerebrate rigidity involves
predominantly antigravity (extensor) muscles. Animals in which the extensor
muscles are the antigravity muscles maintain a rigid posture, holding all four
extremities in the extended position while the head and tail are maximally
extended backward. Although the reticulospinal system plays the major role in
decerebrate rigidity, the vestibulospinal system is also important. The lateral
vestibular nucleus has a powerful descending excitatory influence on alpha and

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gamma extensor motor neurons. Ablation of the lateral vestibular nucleus in a

decerebrate preparation greatly reduces the rigidity. In humans, lesions in the
midbrain caudal to the red nucleus result in a decerebrate state in which the
patient assumes an extensor posture of the neck, trunk, and limbs, with
hyperpronation of the arms. The decerebrate state was first described in 1898 by
Sherrington.

Figure 34-4. Schematic diagram showing the mechanism of decerebrate

rigidity.

B. DECORTICATE STATE
In decorticate states, the lesion is rostral to the midbrain, thus
disconnecting the whole brain stem from the cerebral cortex, basal ganglia,
and the diencephalon (Figure 34-5). In the decorticate state, the head, trunk and
lower extremities are extended while the upper extremities are flexed at the
elbow. The lesion in decorticate states leaves the rubrospinal tract intact. The
rubrospinal tract primarily facilitates flexor muscles, mostly in the upper
extremities, hence the flexion of the upper extremities. The extensor hypertonus
in the lower extremities is explained on the same basis as that in the decerebrate

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state.

Cerebellum
The cerebellum is intimately related to all regions involved in motor activity.
Thus, it is related to the peripheral organ (muscle) as well as to all the central
levels concerned with movement (spinal cord, brain stem, thalamus, cerebral
cortex). It is perfectly suited, therefore, to play the role of coordinator and
integrator of motor activity. The cerebellum plays this role in both voluntary and
involuntary motor activities. Although it is generally acknowledged that the
cerebellum exerts its effect on movement that has already been initiated
elsewhere (i.e., cerebral cortex), evidence suggests that the cerebellum is also
involved in the planning and initiation of movement as well as in the moment-to-
moment control of movement. Electrophysiologic recordings from the cerebellum
have shown that the Purkinje neurons discharge prior to the start of movement.
It is generally agreed that
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the cerebellum plays a role in regulating the following parameters of voluntary
movement: rate, range, force, and direction.

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Figure 34-5. Schematic diagram showing the site of lesions in the

decerebrate (1) and decorticate (2) states.

The cerebellum is able to execute this role via the multitude of feedback
mechanisms that exist between it and the various motor centers (Figure 34-
6). Through these feedback circuits, the cerebellum can detect errors in
movement and institute corrective measures. If a moving limb appears to be
moving too fast (rate), to the degree of overshooting the intended target, the
cerebellum will detect this and institute inhibitory impulses through the cerebral
cortex to slow down the movement and prevent the overshoot (range). In
cerebellar disease, this ability to control the rate and range of movement is

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defective. As a result, the patient tends to move the limb farther than intended.
This is referred to as dysmetria. In clinical practice, this phenomenon can be
shown by asking the patient to touch a fingertip to the tip of the nose. A patient
with cerebellar disease tends to overshoot the nose and reach the cheek or ear
(“past pointing”).

In the smooth execution of movement, proper timing of the initiation and

termination of sequential steps in movement is extremely important. A delay in
the initiation of each successive movement will lead to a failure of proper
progression. In clinical medicine, this is demonstrated by asking the patient to
perform repetitive movements with the hand or tongue. Failure to do this in
orderly succession is referred to as dysdiadochokinesia.

Also important in the smooth execution of movement is the force of movement.

In diseases of the cerebellum, the normal steady increase and decrease in the
force of movement are affected. Such patients, therefore, execute movement in a
jerky, irregular manner. This phenomenon is known as dyssynergia. In clinical
situations, dyssynergia can be manifested in the irregular, jerky movements of
the patient's finger as it is moving toward the finger of the examiner.

The defective feedback mechanisms for the control of the force and timing of
movement in cerebellar disease are responsible for volitional tremor. This type of
tremor is characteristically absent when the limb is at rest but becomes manifest
when the patient attempts to move the limb.

In addition to its role in control of movement, the cerebellum plays an equally

important role in maintenance of body equilibrium. Lesions in the flocculonodular
lobe of the cerebellum (archicerebellum) are associated with disturbances in body
equilibrium. Such patients manifest unsteadiness of gait (ataxia). This
unsteadiness results from the inability of the diseased cerebellum to detect
changes in direction of motion as signaled by the semicircular canals and to
institute corrective action to maintain a steady gait.

Basal Ganglia
Although the key role of the basal ganglia in motor control is undisputed, the
exact mechanism by which the basal ganglia exert this control remains
incompletely explored despite the voluminous experimental work and published
literature on the subject.

Like the cerebellum, the basal ganglia exert a modifying and coordinating effect
on already initiated movement. As for the cerebellum, evidence suggests that the
basal ganglia may play a role in the initiation of motor activity. Recordings of
unit activity
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in the globus pallidus and putamen have revealed activity in their neurons prior
to the onset of movement.

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Figure 34-6. Schematic diagram showing the feedback mechanisms between

the cerebellum and other motor centers.

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Figure 34-7. Schematic diagram showing the feedback mechanisms between

the basal ganglia and other motor centers.

Both anatomic and physiologic data suggest that the basal ganglia exert their
modifying effect on movement through two systems (Figure 34-7):

1. A feedback circuit from the motor cortex to the basal ganglia, thalamus, and
back to the motor cortex and spinal cord

2. A descending pathway from the basal ganglia to motor centers of the brain
stem and from there to the spinal cord

It is evident that the basal ganglia do not exert direct influence on motor activity
in the spinal cord.

The thalamus is the central meeting place for inputs from the cerebellum and
basal ganglia. The significance of this in the coordination of cerebellar and basal
ganglia roles in motor activity is obvious. The relief of basal ganglia and
cerebellar involuntary movement by lesions in the thalamus attests to this
important focal role of the thalamus.

Most knowledge about the role of basal ganglia in motor control has been derived
from clinical material. Unfortunately, most of the clinical syndromes of basal
ganglia diseases cannot be reproduced in experimental animals, a fact that is at
the core of the scarcity of information about the exact pathophysiologic

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mechanisms.

In humans, disturbances in basal ganglia function are manifested as disturbances

in muscle tone and involuntary movements.

Different nuclei of the basal ganglia may have varying effects on muscle tone,
whereas the sum total effect of the basal ganglia is inhibitory on muscle tone.
This effect is mediated via the reticular formation of the brain stem. Thus, in
lesions of basal ganglia, the tone of muscle is increased, leading to a state of
rigidity, as in Parkinson's disease.

Disorders of movement in basal ganglia dysfunction are generally of two

types, hyperkinetic and hypokinetic. The hyperkinetic variety includes such
involuntary movements as chorea, athetosis, hemiballismus, and the rhythmic
tremor of Parkinson's disease. The hypokinetic variety is exemplified by the
akinesia of Parkinson's disease. The description of each of these involuntary
movements is detailed Chapter 13. In contrast to cerebellar tremor, the
involuntary movements of basal ganglia disorders are manifest in repose or in the
absence of motion; hence, they are known as rest tremor or postural tremor.

Although complete correlation of the type of involuntary movement with a

specific nucleus of the basal ganglia has not been achieved, it is generally
accepted that hemiballism is associated with lesions in the subthalamic nucleus,
parkinsonism with lesions of the nigrostriatal axis, and chorea with caudate
nucleus lesions.

Cerebral Cortex
The role of the cerebral cortex in control of movement assumes more importance
as one ascends in the phylogenetic tree. The areas of the cerebral cortex that are
involved in the control of movement and posture have been described previously
in this chapter and in the chapter on the cerebral cortex. They include the
primary motor cortex, the premotor area, the supplementary motor cortex, the
frontal association cortex, and part of the primary sensory cortex.

The cerebral cortex exerts its effects on movement and posture by two pathways
(Figure 34-8): (1) the direct, oligosynaptic pathway (direct corticospinal), and
(2) the indirect, multisynaptic pathway (indirect corticospinal).

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Figure 34-8. Schematic diagram showing the direct and indirect

corticospinal pathways.

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The role of the direct pathway is mainly in the control of rapid, voluntary, and
fine skilled movements. The role of the indirect pathway is in the control of slow
postural type movements. The two pathways have been referred to as the
pyramidal and extrapyramidal pathways, respectively. The pyramidal pathway
exerts a facilitatory effect on motor neurons, whereas the sum total effect of the
extrapyramidal pathway is inhibitory.

In the execution of voluntary motor activity, the descending influences from the
cortex and subcortical structures via these two pathways most likely act
simultaneously on alpha and gamma motor neurons of the spinal cord. Alpha
activation predominates in the case of rapid movements, however, whereas
gamma activation predominates in the case of slow, graduated movements.

Selective lesions in the two pathways in humans are difficult to produce, and

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both pathways are usually affected together to varying degrees. Lesions of the
motor areas of the cortex or of their axons along the neuraxis give rise generally
to a clinical picture known collectively as upper motor neuron syndrome. It is
usually seen in stroke patients and is characterized by the following signs:

1. Paresis (weakness) or paralysis (loss of movement), particularly affecting

distal muscles controlling fine skilled movements

2. Hyperactive deep tendon reflexes (hyperreflexia)

3. Babinski sign

4. Spasticity

5. Clonus

Careful observation and analysis of these different signs, however, allow their
division into two groups.

Immediately after onset of the lesion, there is paresis or paralysis, hypotonia,

and reduction or absence of deep tendon reflexes (hyporeflexia or areflexia).
These early signs are attributable to the affection of the pyramidal pathway.

Later on the following signs appear: (1) spasticity, (2) hyperactive deep tendon
reflexes (hyperreflexia), (3) Babinski sign, and (4) clonus. These later signs are
attributed to the affection of the extrapyramidal pathway. The mechanism of the
Babinski sign, however, remains uncertain. It is believed to be due to
involvement of the supplementary motor area or its outflow fibers.

The further course of this clinical picture is characterized by the reappearance of

gross postural movements, usually in proximal muscles. This return of postural
function is attributed to the part of the extrapyramidal areas or pathways not
involved in the lesion.

The cerebral cortex has long been recognized as the initiator and planner of
movement. Electrophysiologic studies confirm this concept and show that the
motor neurons in the cerebral cortex begin to discharge prior to the onset of
movement. The cerebral cortex also plays a central role in the execution of
appropriate movement. It can accomplish this by virtue of the feedback it
receives from the cerebellum and basal ganglia, which supply the cerebral cortex
with continuous information about the progress of movement so that corrective
action can be taken. In turn, the cerebral cortex, by virtue of collaterals to the
cerebellum and basal ganglia, keeps these two structures informed of ongoing
activity (Figure 34-9).

LOCOMOTION
The older concept of locomotion as a set of chain reflexes in which the sensory
input from a given part of a step cycle triggers the next part of the cycle by
reflex action has been challenged.

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Figure 34-9. Schematic diagram showing the feedback circuits between the
cortex, cerebellum, and basal ganglia.

The present concept suggests that locomotion is not reflexive in nature but
is generated by neurons located exclusively in the spinal cord. Although,
according to this concept, afferent inputs are not essential, they are nevertheless
important in grading the individual component movements.

The spinal cord neurons concerned with programming locomotion not only
produce alternate flexor and extensor activation, they also correctly time the
contraction of appropriate muscles for normal locomotion. Such neurons have
been termed pattern generators or neural oscillators. It has been shown that
there are individual pattern generators for each limb; when all limbs are active,
however, as in normal walking, the pattern generators of the different limbs are
coupled to one another.

As in posture and movement, spinal mechanisms for locomotion are under the
influence of modulatory descending inputs from supraspinal centers. Rubrospinal,
vestibulospinal, and reticulospinal tracts are rhythmically active in phase with
locomotor movements. In addition, locomotion can be triggered by stimulation of
the pedunculopontine nucleus in rostral pons and caudal mesencephalon
(locomotor center). The pedunculopontine nucleus receives facilitatory input from
the cerebral cortex and inhibitory input from the basal ganglia. It projects to the
medullary reticular formation concerned with locomotion. It is believed that the
pedunculopontine nucleus serves a relay function between the cerebral cortex
and spinal cord for interlimb coordination in locomotion.

Both dorsal and ventral spinocerebellar tract neurons in the spinal cord are active
during locomotion. The two tracts convey different information to the cerebellum:
the dorsal tract ordinarily informs the cerebellum about the state of muscle
activity in the periphery, whereas the ventral tract conveys information about the

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active processes within the spinal cord and pattern generation for locomotion.

OVERVIEW OF CONTROL OF POSTURE AND

MOVEMENT
Clearly, normal posture and movement are the products of interaction among a
number of neural structures. In the final analysis, spinal motor neurons have to
be activated to move the muscles.
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The spinal motor neurons are in turn controlled by suprasegmental influences
that originate from cortical and subcortical motor centers. The latter are also
under cortical control. Superimposed on this vertical axis (represented by the
direct and indirect corticospinal pathways) are modifying influences from the
basal ganglia and the cerebellum (Figure 34-10).

Lesions along the vertical axis (whether in the cerebral cortex, corticospinal
tract, or spinal cord) will produce a partial or total loss of movement. Lesions of
the modifying motor centers (basal ganglia, cerebellum), on the other hand, will
result in disorganized, abnormal movement. The disorganized movement of
cerebellar lesions is manifest on volition, whereas that of basal ganglia lesions is
manifest in repose.

Figure 34-10 is a simplified schematic diagram showing the loci of pathology

commonly encountered in clinical practice and listing the major motor deficits
accruing from such lesions.

1. Lesions of the corticospinal tract anywhere along its path—from its origin in
the cerebral cortex to its termination in the spinal cord (as in stroke,
hemorrhage, tumor, trauma)—produce the upper motor neuron syndrome
characterized by paresis, spasticity, hyperactive myotatic reflexes, abnormal
reflexes (Babinski reflex), and clonus.

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Figure 34-10. Simplified diagram showing the motor deficits that

result from lesions in different loci concerned with movement and
posture.

2. Lesions of the cerebellum produce a disorganized and erratic type of

movement characterized by volitional tremor on movement, ataxia of gait,
dysmetria, disturbances in alternate motion rate (dysdiadochokinesia), and
dyssynergia.

3. Lesions of the basal ganglia produce involuntary movements in repose, as

seen in the tremor of Parkinson's disease, chorea, athetosis, and

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hemiballismus. Such lesions also produce rigidity of muscles and, in some

cases, reduction in movement (hypokinesia).

4. Lesions of the motor neurons in the spinal cord (as in poliomyelitis and
motor neuron disease) produce paresis or paralysis of all muscles supplied
by the affected spinal cord segments. Because of the interruption of the
reflex arc, the muscles are hypotonic and myotatic reflexes are either
reduced or lost. Loss of the trophic influence of motor neurons on the
muscle fibers leads to atrophy of these fibers, which also exhibit
spontaneous movements at rest (fibrillation) attributed to denervation
hypersensitivity at the motor end plate.

5. Lesions interrupting the axons of motor neurons to the muscle (as in

peripheral neuropathy) produce weakness (paresis) or paralysis in the group
of muscles supplied by the affected nerve or nerves. Because such a lesion
will interrupt the reflex arc of myotatic reflexes, such reflexes will be
depressed (hyporeflexia) or lost (areflexia) and the muscles will be
hypotonic. Because most peripheral nerves are mixed (containing both
motor and sensory fibers), such lesions will also be manifested by sensory
loss.

6. Lesions in the neuromuscular junction, as in myasthenia gravis, result in

fluctuating muscle weakness precipitated by use of muscle and reversed by
rest.

7. Lesions in the muscle, as occur in muscular dystrophy, result in muscle

weakness and hypotonia.

TERMINOLOGY
Barré, J. A. (1880–1967).
French physician who, with George Guillain and Andre Strohl, described the
Guillain-Barré-Strohl syndrome.

Gehrig, Lou.
Renowned first base player for the New York Yankees from 1923–1939. Had a
lifetime batting average of .340 with a record 23 grand slams. Died of
amyotrophic lateral sclerosis. Other famous personalities afflicted with the
disease include actor David Niven, senator Jacob Javits, heavyweight boxer
Ezzard Charles, physicist Stephen Hawking, photographer Eliot Porter, and
composer Dmitri Shostakovich.

Guillain, George (1876–1961).

French physician who, in collaboration with J. A. Barré and Andre Strohl,
described acute inflammatory demyelinating polyneuropathy (the Guillain-Barré-
Strohl syndrome, later called Guillain-Barré syndrome) in World War I soldiers.

Hoffmann, Johann (1857–1919).

German neurologist who described Werdnig-Hoffmann disease in articles
published in 1893, 1897, and 1900 and acknowledged the previous description of
the disease.

Sherrington, Sir Charles (1857–1952).

English physician and physiologist. Nobel laureate for medicine in 1932. Coined
the

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term synapse in 1897 and introduced the terms exteroception, interoception, and
nociception. He described the decerebrate state and contributed significantly to
knowledge of neurophysiology.

Strohl, Andre (b. 1887).

French physician who contributed to the original description of Guillain-Barré-
Strohl syndrome but whose name was dropped from subsequent publications.

Werdnig, Guido (1844–1919).

Austrian neurologist who described motor neuron disease (Werdnig-Hoffmann) in
a series of articles between 1891 and 1894.

SUGGESTED READINGS
Arshavsky YI et al: Recordings of neurons of the dorsal spinocerebellar tract
during evoked locomotion. Brain Res 1972; 43:272–275.

Asanuma H: Cerebral cortical control of movement. Physiologist 1973;

16:143–166.

Evarts EV et al: Central control of movements. Neurosci Res Progr Bull 1971;
9:1–170.

Grillner S, Shik ML: On the descending control of the lumbosacral spinal cord
from the “mesencephalic locomotor region.” Acta Physiol Scand 1973;
87:320–333.

Henneman E: Motor functions of the brain stem and basal ganglia. In

Mountcastle VB (ed): Medical Physiology, 14th ed, vol 1. Mosby, 1980:787–
812.

Henneman E: Organization of the spinal cord and its reflexes. In Mountcastle

VB (ed): Medical Physiology, 14th ed, vol 1. Mosby, 1980:762–786.

Jueptner M, Weiller C: A review of differences between basal ganglia and

cerebellar control of movements as revealed by functional imaging studies.
Brain 1998; 121:1437–1449.

Lance JW: The control of muscle tone, reflexes, and movement. Robert
Wartenberg Lecture. Neurology 1980; 30:1303–1313.

Mettler FA et al: The extrapyramidal system: An experimental demonstration

of function. Arch Neurol Psychiatry 1939; 41:984–995.

Nutt JG et al: Human walking and higher-level gait disorders, particularly in

the elderly. Neurology 1993; 43:268–279.

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Pryse-Phillips W: Companion to Clinical Neurology. Oxford University Press,

2003.

Reeves AG: The initiation, elaborations and maintenance of movement: An

overview. In Mosenthal WT (ed): Textbook of Neuroanatomy. Parthenon,
1995:329–334.

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Editors: Afifi, Adel K.; Bergman, Ronald A.

Title: Functional Neuroanatomy: Text and Atlas, 2nd Edition

Copyright ©2005 McGraw-Hill

> Table of Contents > Part I - Text > 35 - Approach to a Patient with a
Neurologic Disorder

35
Approach to a Patient with a
Neurologic Disorder

The Where and What

The Art and Challenges of History Taking
The Neurologic Examination
The Equipment
The Examination
Neurologic Examination of Infants and Small Children
Developmental Reflexes
The Neurologic Diagnosis, The First Impression
Considerations That Influence Diagnosis
Age
Gender
Ethnicity
Socioeconomic Status
Tempo of Disease
Duration of Symptoms
Past Medical History
Identification of Site of Disorder
Cerebral Cortex
Brain Stem
Cerebellum
Basal Ganglia
Spinal Cord
Peripheral Nerve
Neuromuscular Junction
Muscle

KEY CONCEPTS

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The approach to a patient with a neurologic disorder aims

to define the site (where) and the type (what) of the lesion.

History taking in neurology is both an art and a challenge;

90% of diagnosis relies on accurate history taking.

Neurologic examination should be comprehensive with

tests for cortical function, cranial nerves, motor function,
coordination, sensory function and reflexes.

Neurologic examination of infants and small children

requires patience, persistence, and familiarity with
developmental milestones.

Certain developmental reflexes are elicited only in

infancy.

Careful observation of the behavior of the patient in the

waiting room, of his/her gait and facial features may yield
important information for the diagnosis.

In making a diagnosis, consideration should be given to

the age, gender, ethnicity, socioeconomic status, tempo of the
disease, duration of symptoms, and medical history.

Familiarity with symptoms and signs associated with

specific regions of the central and peripheral nervous system
are useful at defining the site of the lesion.

A major objective in learning functional neuroanatomy is the

localization of neurological disorders. Among the different medical
subspecialties, neurology lends itself best to correlation of symptoms
and signs with structure and function.

The approach to a patient with a neurological problem varies from one

healthcare professional to the other. With experience, each healthcare
professional develops his or her own personal approach. All, however,
adhere to a standard format by which all essential information is
obtained to arrive at the proper diagnosis.

THE WHERE AND WHAT

Whatever approach the healthcare professional uses should answer two
questions:

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1. Where is the lesion?

2. What is the lesion?

Neurological disorders may be localized to one or more of the following

sites: cerebral hemisphere, cerebellum, basal ganglia,
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brain stem, spinal cord, peripheral nerve, neuromuscular junction, or
skeletal muscle. Each of these sites has characteristic symptoms and
signs that help answer the question of “where is the lesion?”

In attempting to answer the question of “what is the lesion?”,

consideration is given to the following etiologies of disease: congenital,
traumatic, infectious, metabolic, toxic, vascular, neoplastic,
degenerative, and idiopathic.

In addressing the questions of “where is the lesion?” and “what is the

lesion?” the “where,” in general, precedes the “what.” In some
instances, however, the sequence is reversed as occurs in a patient
presenting with sudden onset of loss of speech (aphasia) and
hemiplegia. In such a patient, the diagnosis of stroke (the what) is
presumed. The location (the where) is then induced from findings on
the neurologic examination.

THE ART AND CHALLENGES OF HISTORY

TAKING
History taking in medicine in general, and in neurology in
particular, is extremely important. It is estimated that 90% of
neurologic diagnosis depends on the patient's medical history. The
remaining 10% is derived from the neurologic examination and
laboratory tests. A doctor who does not know how to take a history,
and a patient who cannot give one are in danger of giving and
receiving bad treatment.

The use of modern technology is no substitute for a good history.

History taking is a dynamic process in which the seasoned health
professional frequently alters the direction and depth of questioning to
elicit specific information useful in arriving at the proper diagnosis.

History taking is an art and a challenge. Seasoned historians master

the art of subtle direction of a conversation with the patient, and
succeed in the challenging task of eliciting history from a poor
observer, an uneducated person, or from a person who enjoys twisting
the meaning of things.

In attempting to obtain a history, the healthcare professional follows a

plan of inquiry about symptoms that includes the following features:

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1. Date of onset

2. Character and severity

3. Location and extension

4. Time relationship

5. Associated complaints

6. Aggravating and alleviating factors

7. Previous treatments and their effect

8. Progress, remissions, and exacerbations

In eliciting a history, it is important for the healthcare professionals to

exclude irrelevant information, and to arrive at their own opinion.
Some patients delight in providing inaccurate information about
hospitals they have been to, doctors they have seen, and treatment
ordered.

In eliciting a history, it is important to clarify the intended meaning of

terms used by the patient. The term “giddiness” or “dizziness” used by
a patient may refer to lightheadedness, vertigo, postural instability,
ataxia, disturbance of vision, nausea, or epileptic convulsion. Similarly,
the term “blackout” may refer to loss of consciousness, loss of vision,
loss of memory, or loss of confidence.

Interviewing patient's relatives is a desirable exercise and becomes

obligatory when the patient is a child, when the patient suffers from
episodes of loss of consciousness, in patients with memory defect or
mental change, and when there is a need to obtain information about
other family members.

As important as eliciting a reliable history is the accurate recording of

the history. The record should be clear, complete, and reflect the
patient's own narrative.

THE NEUROLOGIC EXAMINATION

The Equipment
Besides the patient, the following items are needed for a thorough
neurological examination:

1. Examination couch

2. Stethoscope

3. Penlight

4. Tuning fork

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5. Safety pin

6. Soft tissue paper

7. Test tubes with hot and cold water for thermal testing

8. Test tube with coffee for testing of smell

9. Two point discriminator

10. Percussion hammer

11. Ophthalmoscope

12. Visual acuity card

13. Tongue blades

14. Measuring tape

The Examination
The purpose of the neurologic examination is to test the structure
and function of different regions of the nervous system. It
includes assessment of the level of consciousness, examination of
higher cortical functions, cranial nerves, motor function, coordination,
sensory function, and reflexes. There are as many ways of performing
a neurologic examination as there are physicians performing it.

A. CORTICAL FUNCTION

1. Level of consciousness. The level of alertness of the patient (alert

and oriented, hyperalert, sleepy, lethargic, stuporous, comatose,
etc.) should be assessed.

2. Higher cortical function. Examination of higher brain function

should include assessment of the following:

a. General information. This refers to general knowledge

possessed by most people such as the name of the
President, famous people, capitals of countries, current
events, etc.

b. Orientation to time (day, month, year), place, and person.

c. Memory for recent and remote events such as birth and

wedding dates, names and ages of children and close
relatives, and details of recent events.

d. Language. This includes assessment of expression,

comprehension, fluency, and prosody of spoken language,
repetition, ability to read, write, recognize, and name
familiar objects.

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e. Calculation. This is assessed by ability of the patient to

count from 1–20 forward and backward, serial sevens
(counting from 100 backwards in increments of seven),
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multiplication and division of single numbers. The extent of
these tests varies with the educational level of the patient.

f. Retention and repetition of digits in natural or reverse order

(usually seven forward and five backward).

g. Judgment. This is tested by asking the patient to interpret

the meaning of simple proverbs or the meaning of a story.

h. Mood. The degree of anxiety, apathy, elation, depression,

etc.

i. Sensory interpretation. Stereognosis, spatial orientation,

graphesthesia.

B. CRANIAL NERVES
A thorough examination of cranial nerve function should include
evaluation of the following functions. The order of testing of these
functions varies between examiners.

1. Smell (CN I). Tested by using nonirritating familiar odors such as

coffee, peppermint, menthol, etc.

2. Visual acuity (CN II). Tested by use of Snellen chart or visual

acuity card.

3. Visual Field (CN II). Tested by the confrontation technique or

perimetry.

4. Pupillary response to light and accommodation (CN II, III). Tested

by flashing light on one pupil and observing the response of both
pupils (light response); and by looking at a near object
(accommodation response).

5. Extraocular movements in the horizontal and vertical planes (CN

III, IV, VI). The patient is asked to move his eyes laterally,
upward and downward.

6. Facial sensations (sensory root CN V). Tested by using a pin or a

piece of cotton on the face and anterior scalp.

7. Corneal reflex (CN V, VII). Tested by gently touching the cornea

with a wisp of cotton.

8. Forceful jaw deviation to one side (motor root CN V), pterygoid

muscle.

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9. Teeth clenching (motor root, CN V), masseter muscle.

10. Facial symmetry (CN VII). Tested by asking the patient to smile,
whistle, pucker lips, show teeth, close eyes, and wrinkle forehead.

11. Taste (CN VII, IX, X). Tested by applying solutions of sugar,
vinegar, saline, and quinine to tongue.

12. Hearing (CN VIII). Tested by use of vibrating tuning fork in front
and on a bony prominence behind the ear.

13. Palatal elevation (CN IX, X).

14. Gag reflex (CN IX, X). Tested by touching the pharynx by a
tongue blade.

15. Shoulder shrug against resistance (CN XI).

16. Head and neck turning against resistance (CN XI).

17. Tongue mass and movement (CN XII)

Common symptoms and signs noted in lesions of each of the cranial

nerves are listed in Table 35-1.

C. MOTOR FUNCTION
Examination of motor function should include evaluation of the
following:

1. Gait and stance (posture, balance, arm swing, and leg

movement).

Table 35-1. Symptoms and Signs of Cranial Nerve Lesions

Cranial nerve Symptoms and signs

I.Olfactory Anosmia

II.Optic Decreased visual acuity

Abnormal pupillary light
response

III.Oculomotor Diplopia
Dilated, unresponsive pupil
Ptosis

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Eye deviation down and out

IV.Trochlear Diplopia

V.Trigeminal Decreased facial sensations

Decreased corneal reflex
Weak masseter muscle

VI.Abducens Diplopia
Decreased eye abduction

VII.Facial Decrease strength in muscles

of facial expression
Decrease in taste sensation

VIII.Auditory- Deafness
vestibular Vertigo

IX.Glossopharyngeal Dysarthria
Dysphagia
Decreased gag reflex

X.Vagus Dysarthria
Dysphagia
Decreased gag reflex
Decreased palatal elevation

XI.Accessory Decreased strength in neck

turning and shoulder shrug

XII.Hypoglossal Dysarthria
Dysphagia
Tongue atrophy
Decreased tongue movement
Deviation of protruded tongue

2. Muscle tone. Resistance of the limb to passive movement.

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3. Muscle bulk.

4. Muscle strength (hopping, squatting, walking on heels and

tiptoes, testing of individual muscle groups). Muscle strength is
graded on a scale of 0 to 5 where 5 denotes normal strength; 4,
movement against gravity and resistance; 3, movement against
gravity but not resistance; 2, movement only with gravity
eliminated; 1, flicker or trace of contraction; and 0, no
contraction.

D. MOTOR COORDINATION
Examination of motor coordination consists primarily of evaluation of
cerebellar and basal ganglia functions. It includes:

1. Steadiness of gait and posture.

2. Tandem gait. Walking heel-to-toe down a line on the floor.

3. Rapid alternate movement.

4. Finger to nose to finger test. Patient to rapidly touch nose with

the point of forefinger and then the examiner's finger.

5. Heel to knee to shin test. Running the heel carefully up and down
the opposite shin.

6. Finger tapping. Approximating the pulp of the thumb to the pad of

each finger in succession rapidly and accurately.

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E. SENSORY FUNCTION
Examination of sensory function is the most subjective and requires
patience, determination, and a thorough knowledge of sensory patterns
to perform adequately. It requires utmost cooperation from the
patient, and hence is least reliable in children. It should include
evaluation of the following sensory modalities:

1. Vibration sense, by placing the vibrating tuning fork over bony

prominences in the upper and lower extremities.

2. Joint position sense, by asking the patient to determine the

position of toes and fingers when moved passively by the
examiner.

3. Pain, by applying the tip of a pin to the tested body part.

4. Temperature, by applying tubes containing cold and warm water

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to the tested body parts.

5. Light touch, by touching the tested part of the body by a piece of

cotton.

6. Two point discrimination, by the ability of the patient to recognize

two stimuli applied simultaneously to the tested body parts. The
distance between the two stimuli varies in different body parts
(0.3 to 0.6 cm over finger tips, 1.5 to 2 cm over the soles of feet
and palms of hands.

The Romberg test is particularly useful in evaluating posterior column

disorders but not cerebellar disorders. The test assesses the ability of
the patient to maintain upright posture while standing on a narrow
base with eyes closed. A patient with posterior column disease will
sway and may fall.

F. REFLEXES

1. Deep tendon (myotatic) reflexes. These include the following deep

tendon (myotatic) reflexes:

a. Biceps (C-5 and C-6).

b. Triceps (C-7 and C-8).

c. Brachioradialis (C-5 and C-6).

d. Quadriceps (knee, patellar reflex) (L-3 and L-4).

e. Achilles (ankle) (S-1 and S-2).

All are elicited by tapping the appropriate tendon.

2. Superficial reflexes. These include the following reflexes:

a. Plantar (S-1). Firmly stroking the outer border of the sole of

the foot will result in flexion of toes.

b. Abdominal (T-8 and T-12). Gentle stroking of abdomen in

each quadrant will pull the umbilicus in that direction.

c. Cremasteric (L-1 and L-2). Stroking of inner aspect of thigh

lightly results in retraction of ipsilateral testis.

3. Pathological reflexes appear with upper motor neuron disorders.

These include the following reflexes:

a. Babinski.

b. Clonus.

c. Frontal release.

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d. Crossed adductor.

e. Finger flexor.

f. Trommer.

g. Jaw jerk.

In the Babinski reflex, stroking the lateral aspect of the sole results in
dorsiflexion of the big toe and fanning out of the other toes. The reflex
was described in 1896 by Josef-François-Felix Babinski as the
“phenomenon of the toes.”

Thirteen different methods of eliciting the Babinski sign have been

described with varying degrees of positive response:

1. Gonda-Allen sign, elicited by forceful downward stretching or

snapping of the distal phalanx of the second or fourth toe.

2. Allen-Cleckley sign, elicited by sharp upward flick and sudden

release of the second toe or pressure over the ball of that toe.

3. Chaddock reflex (lateral malleolar sign) elicited by scratching the

skin below the lateral malleolus from behind forward. Described in
1911 by Charles Gilbert Chaddock who claimed that it has greater
sensitivity than the original Babinski sign. The reversed Chaddock
sign is elicited by scratching the skin from the front backward.

4. Cornell sign, elicited by scratching the inner side of the dorsum of

foot.

5. Oppenheim reflex, elicited by heavy pressure with thumb and

index finger to the anterior surface of the tibia, over the shin,
from knee to ankle.

6. Bing sign, elicited by pricking the dorsum of foot with a pin.

7. Schaffer sign, elicited by pinching the Achilles tendon. This

method was described by Babinski one year before Schaffer's
report of 1899.

8. Moniz sign, elicited by passive plantar flexion of the ankle.

9. Strümpell sign, elicited by forceful pressure by the finger and

thumb down the anterior tibial spine.

10. Throckmorton sign, elicited by tapping over the dorsum of the

first metatarsophalangeal joint just medial to the extensor
hallucis longus tendon.

11. Gordon sign, elicited by squeezing the calf muscles.

12. Thomas reflex, elicited by rubbing the sole of the foot with the

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back of the knuckles two or three times.

13. Stransky sign, elicited by pulling the little toe laterally and
suddenly releasing it.

The comparative yield of twelve methods used to elicit the extensor

plantar reflex (Babinski sign) in eighty-one children with spastic
cerebral palsy is shown in Table 35-2.

Clonus is the repetitive, rhythmic, involuntary contraction of agonist

and antagonist muscles induced by sudden passive dorsiflexion of the
ankle.

Frontal release, encountered with frontal lobe damage, consists of

grasping or curling of fingers in response to stimulation of the palmar
surface of the hand and finger tips.

Table 35-2. Extensor Plantar Reflex

Method of elicitation of reflex Yield

Classic Babinski 75%

Gonda-Allen 90%

Allen-Cleckley 82%

Chaddock 74%

Cornell 54%

Oppenheim 30%

Bing 28%

Schaffer 22%

Moniz 20%

Strümpell 18%

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Throckmorton 14%

Gordon 8%

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Crossed adductor reflex consists of adduction of both thighs in
response to tapping or striking (with a reflex hammer) the tendon of
the adductor tendon of one thigh.

Finger flexor reflex consists of adduction and flexion of the thumb and
exaggerated flexion of fingers in response to snapping the nail of the
middle finger.

Trommer reflex, a variant of the finger flexor reflex, consists of flexion

of fingers in response to a tap on the volar surface of the tip of the
patient's second or third fingers.

Jaw jerk reflex consists of exaggerated contraction of the masseter

muscle in response to tapping the relaxed chin.

NEUROLOGIC EXAMINATION OF INFANTS

AND SMALL CHILDREN
Neurologic examination of small children can be a challenging
task, especially for the beginner. The orderly sequence of
neurologic examination described earlier is not possible in infants and
young children. Much information can be gained by the principle of
“watch before you touch.” Observing the infant or young child, while
asleep, for posture, spontaneous movement, symmetry of limb
movement, facial symmetry or asymmetry, and birth marks will yield
valuable information. The full-term infant assumes, when asleep, a
posture of semiflexion of all four limbs with the thighs tucked under
the lower abdomen. Muscle tone can be assessed by passive
movements of limbs and by vertical suspension. Pulling the forearms
toward the opposite shoulder can provide information about muscle
tone. In motor neuron disease (Werdnig-Hoffman disease), it is
possible to wrap the arm around the neck, as if it were a scarf (scarf
sign). Observation of the awake child provides information about the

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degree of alertness and interest and the status of extraocular eye

movements. The infant at birth blinks to bright light and conjugate eye
movements develop rapidly after birth. The eyes may not follow
objects, however, for a few weeks after birth. Attention should be paid
to the vigor of the infant's cry, and the ability and vigor of sucking.
Those aspects of the examination that require restraint or discomfort
should be done last. Specifics about developmental milestones are
found in pediatric and child neurology texts.

The neurologic examination is incomplete without evaluating the

skeletal structures enclosing the central nervous system, the
extracranial blood vessels, and the skin. The shape and size of the
skull (especially in infants and young children) should be observed. The
skull should be palpated for bony defects or lumps. Auscultation of the
head and both eyes for bruits should be done. The carotid artery in the
neck should be palpated and auscultated for bruits or murmurs. The
head and neck should be flexed for signs of meningismus. If a spinal
cord lesion is suspected, the spine should be examined for local
tenderness or deformity such as spina bifida. The skin should be
observed for vascular malformations, neurofibromas, nevi, café-au-lait
spots, or other stigmata of neurocutaneous syndromes.

DEVELOPMENTAL REFLEXES
These are a group of reflexes that are present at birth or in the early
neonatal period and disappear later. They include:

Rooting reflex (search reflex, points cardineaux).

Exploration of the mother's skin by the newborn mouth in
search for the nipple. It can be elicited also by gently rubbing the
infant's cheek. As a result, the head turns toward the stimulus,
the mouth opens, and sucking begins. The reflex is present at
birth and usually disappears by two to three or four months of
age. Integrity of the trigeminal system (CN V) is important for the
reflex. Persistence of the reflex beyond four months suggests
abnormal brain function.

Sucking reflex. Stimulation of the circumoral area results in

involuntary tongue and lip movement (sucking). The reflex is
present at birth and disappears by ten to twelve months.

Moro reflex (startle reflex, embrace reflex). This reflex is

elicited by holding the infant supine at 45 degrees and allowing
the head to gently but abruptly drop. In response, the arms
briskly abduct, circumduct, and extend, with extension of the
fingers except the thumb and index finger which flex to form a
“C.” The legs either flex or extend slightly, and the hips abduct to
a lesser degree than the arms. This is followed by adduction of

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the arms. The reflex is present at birth and disappears between

four and six months of age. The reflex was described by E. Moro
in 1918.

Tonic neck (fencing) reflex. The reflex is elicited by rotating to

one side the head of the infant who is in supine position. In
response, the extremities on the side to which the head has been
turned extend. The extremities of the other side flex. The reflex
appears one month after birth or in the first month of life and
disappears by six months of life.

Palmar grasp reflex. In response to gentle stroking of the

palmar surface of the hand toward the fingers, the infant will
forcefully grip the examiner's fingers. The reflex is present at
birth and disappears by three to six months.

Plantar grasp reflex. In response to pressing a thumb against

the sole just behind the toes in the foot, or stroking the outer
surface of the sole from the heel to the toes, the toes will flex.
The reflex is present at birth and persists for six to twelve
months.

Crossed adductor reflex. Contraction of contralateral adductor

muscles in response to a tap on the quadriceps tendon. It is
basically a spread of the quadriceps reflex (knee jerk) to the
contralateral side. The reflex is present at birth and persists for
seven to eight months.

Parachute reflex. This reflex consists of extension of the arms of

an infant suspended prone and dropped while still in the
examiner's hand. The reflex appears between eight and nine
months and persists.

Galant reflex (truncal incurvation reflex). In response to

scratching the skin of the infant back from the shoulder
downward, 2 to 3 cm lateral to the spine, there will be incurvation
of the trunk with the concavity on the stimulated side. The reflex
is present at birth and persists for two to four months.

Landau (ventral suspension) reflex. When held prone in a

horizontal position, the body of the infant forms a convex arc
upward with head, neck, and hips extended, with shoulders drawn
back, and legs slightly flexed. The reflex appears at about three
months and persists to the age of two years.

Finger extension reflex. The reflex is elicited by gentle but firm

pressure applied to the ulnar surface of the small finger, starting
at the second phalanx and proceeding to the lateral surface of the
hypothenar eminence. This results in extension of the fingers
starting from the small finger and continuing to the index finger.

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Glabellar reflex. When the glabellar area (space between the

brows) is tapped, the infant blinks. The reflex is present at birth
and usually persists.

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Stepping (automatic walk, dance) reflex. When the infant is
held under the arms in a vertical position, and the feet contact a
smooth surface, the neonate simulates walking by a reciprocal
flexion and extension of the legs. The reflex is present at birth
and disappears by four months.

Placing reflex. When the infant is held vertically and the dorsum
of the foot is placed under the edge of a table, the infant
responds by raising the foot and placing it on the table top. The
reflex is present at birth and disappears between ten months and
one year of age.

Crossed extension reflex. With the infant in supine position,

one leg is firmly held with the knee pressed down. The sole of the
fixed foot is stimulated and the free leg will flex, adduct, and
extend. The reflex is present at birth and disappears by one
month of age.

THE NEUROLOGIC DIAGNOSIS, THE FIRST

IMPRESSION
Arriving at the correct neurologic diagnosis is a time-consuming task
that begins by careful observation of the patient in the waiting room or
as the patient enters the clinic.

The loud but relaxed conversation of a patient in the waiting room

reflects a patient very familiar with doctors' waiting rooms. In
contrast, the loud but labored conversation of a patient reflects a
nervous patient not accustomed to the milieu of doctors' waiting
rooms.

Observing the gait of the approaching patient can clinch the diagnosis.
Certain gaits are characteristic of the underlying neurological
conditions. Examples include the hemiplegic gait of stroke; the
shuffling short-stepped gait of Parkinsonism; the spastic paraplegic
(scissoring) gait of multiple sclerosis; the steppage and scraping toe
gait of foot drop; the wide-based ataxic gait of cerebellar disease; the
waddling gait of hip girdle weakness (as in muscular dystrophy); and
the dancing gait of chorea.

Similar to characteristic gaits, there are characteristic facial features

that suggest the underlying diagnosis. These include the plethoric and
hairy facies of Cushing syndrome; the exophthalmus and lid retraction
of hyperthyroidism; the baldness, ptosis, and myopathic facies of

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myotonic dystrophy; and the ptotic lids of myasthenia gravis and

ocular dystrophy.

CONSIDERATIONS THAT INFLUENCE

DIAGNOSIS
In arriving at the diagnosis of a neurological problem,
consideration should be given to the following factors: age,
gender, ethnicity, socioeconomic status, tempo of disease, duration of
symptoms, and past medical history.

Age
Age of the patient is an important determinant in the etiology of a
neurological condition.

The etiology of strokes in adults and children is different. In adults,

atherosclerosis, hypertension, and aneurysm rupture are common
etiologies for stroke. In contrast, etiologies for stroke in children
commonly include cyanotic heart disease, arteriovenous malformation,
moyamoya, fibromuscular dysplasia, coagulopathies, congenital
vascular hypoplasia, and developmental brain anomalies.

The etiology of progressive paraparesis in adults is commonly multiple

sclerosis, whereas in children it is commonly spinal cord tumor.

Gender
Certain neurological disorders are gender prevalent or specific. X-
linked Duchenne muscular dystrophy occurs in males. Autoimmune
disorders such as myasthenia gravis and lupus erythematosus are more
common in females.

Ethnicity
Certain disorders are more prevalent or are specific to certain ethnic
groups. Sickle cell disease and sarcoidosis are more prevalent in
blacks; Tay-Sachs disease is more prevalent in Ashkenazi Jews;
moyamoya disease and thyrotoxic periodic paralysis are more prevalent
in the Japanese; and the Marchiafava-Bignami disease is more
prevalent among Italians.

Socioeconomic Status
Certain disorders are more prevalent among those of low
socioeconomic status. Such disorders include alcoholism, drug
addiction, trauma, malnutrition, and infections.

Tempo of Disease
The tempo of the disease process is characteristic of certain etiologies.

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An abrupt onset is characteristic of seizures, syncope, and stroke.

Onset over hours is characteristic of infection, intoxication, and
subdural hematoma. Protracted onset is characteristic of brain and
cord tumors. Very slow onset is characteristic of Parkinson's and
Alzheimer's disease. Remissions and exacerbations are characteristic of
myasthenia gravis and multiple sclerosis. Diurnal variations and
fluctuation in symptoms is characteristic of myasthenia gravis and
dystonia. Episodic occurrence of symptoms is characteristic of periodic
paralysis and migraine.

Duration of Symptoms
Long lasting (years) daily headache is characteristic of tension
headache. Recent onset headache associated with change in
personality, on the other hand, is consistent with brain tumor.

Past Medical History

Elements in the past medical history are useful in arriving at the
correct diagnosis. Past medical history of hypertension and/or diabetes
are usual preludes to stroke. History of carcinoma is a prelude to
metastatic brain disease or the remote effects of cancer. History of
drug intake is a prelude to intoxication.

IDENTIFICATION OF SITE OF DISORDER

In identifying the site of the neurological disorder (where is the
lesion?), the following neurological signs are helpful:

Cerebral Cortex
Disorders of the cerebral cortex are usually associated with one or
more of the following symptoms and signs: seizures; focal cerebral
signs such as aphasia, hemianopia, hemiplegia; non-focal cerebral
signs such as dementia, headache, and delirium.

Brain Stem
Disorders of the brain stem are commonly associated with cranial nerve
palsies which are localizing, ocular signs (gaze palsies),
P.427
involuntary movements, and crossed syndromes (cranial nerve palsy on
one side and hemiparesis on the contralateral side).

Cerebellum
Cerebellar disorders characteristically present with ataxia and
volitional tremor. Ataxia is primarily truncal in midline cerebellar
(vermis) disorders, and appendicular or generalized in cerebellar
hemisphere disorders. Nystagmus is also characteristic of midline

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cerebellar disorders.

Basal Ganglia
Basal ganglia disorders manifest with dyskinesia. Two types of basal
ganglia disorder are the hyperkinetic (chorea, ballism, athetosis) and
the hypokinetic (Parkinson's disease).

Spinal Cord
Spinal cord disorders usually manifest with spastic gait, bladder and
bowel symptoms, sensory level and possible sacral sparing.

Peripheral Nerve
Peripheral nerve disorders (neuropathies) manifest characteristically
with both motor and sensory deficits. Distal (“glove and sock”)
distribution of sensory deficit, distal more than proximal muscle
weakness, and early loss of myotatic reflexes are characteristic
features.

Neuromuscular Junction
Neuromuscular junction disorders manifest with purely motor deficits
that characteristically fluctuate during the day, are triggered by use of
muscle and relieved with rest, with predominance of weakness in facial
and ocular muscles.

Muscle
Primary disorders of muscle (myopathies, dystrophies) are also purely
motor and involve primarily proximal muscles. There are no associated
sensory deficits. Myotatic reflexes are normal early and are decreased
or lost late in the disease.

TERMINOLOGY
Bing, Robert Paul (1878–1956).
Swiss neurologist who described an alternative method to elicit the
Babinski sign in 1939.

Chaddock, Charles Gilbert (1861–1936).

American neurologist who trained with Babinski and who introduced an
alternative method (the malleolar way) to elicit the Babinski sign. The
same method had been described five years earlier, in 1906, by the
Japanese physician Kisaku Yoshimura.

Gordon, A.M. (1874–1953).

French-American neurologist and psychiatrist whose main interest was

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the study of reflexes. He described an alternative method to elicit the

Babinski reflex in 1904.

Moniz, Antonio Caetano de Egas (1874–1955).

Portuguese neurosurgeon who introduced prefrontal leucotomy in 1936
and cerebral angiography in 1927. Also known for the less significant
description of an alternative method to elicit the Babinski reflex. He
received the Nobel prize for his prefrontal leucotomy work.

Moro, E. (1874–1951).
Austrian pediatrician. Described the Moro reflex in 1918.

Oppenheim, Hermann (1859–1919).

German neuropsychiatrist. Described an alternative method to elicit the
Babinski reflex in 1902.

Romberg, Moritz Heinrich (1795–1873).

German physician who described the Romberg sign between 1840 and
1846 as a diagnostic sign of tabes dorsalis.

Schaffer, Karoly (1864–1939).

Austrian neurologist and neuropathologist who was a pioneer in the
study of hereditary diseases of the nervous system. Also, in 1899,
described an alternative method to elicit the Babinski reflex, although
Babinski had mentioned the method one year earlier.

Strümpell, Ernst Adolf Gustav Gottfried von (1853–1925).

Russian physician. Published extensively on many topics in neurology.
Described an alternative method to elicit the Babinski reflex.

Throckmorton, T.B. (b. 1885).

American neurologist who described an alternative method to elicit the
Babinski sign.

SUGGESTED READINGS
DeMyer WE: Technique of the Neurologic Examination. A
Programmed Text, 5th ed. New York, McGraw-Hill, 2004.

Futagi Y et al: Asymmetry in plantar grasp response during infancy.

Pediatr Neurol 1995; 12:54–57.

Ghosh D, Pradhan S: “Extensor toe sign” by various methods in

spastic children with cerebral palsy. J Child Neurol 1998; 13:216–
220.

Greenberg DA et al: Clinical Neurology, 5th ed, New York, Lange

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Medical Books/McGraw-Hill, 2002.

Hoekelman RA: The Physical Examination of Infants and Children.

In: Bates B, ed. Guide to Physical Examination, Philadelphia, J.B.
Lippincott Co., 1983.

Jaffe M et al: The parachute reaction in normal and late walkers.

Pediatr Neurol 1996; 14:46–48.

Marcus JC: Flexor plantar responses in children with upper motor

neuron disease. Arch Neurol 1992; 49:1198–1199.

Mondanlou HD: Extension reflex of fingers in the newborn. Pediatr

Neurol 1988; 4:66–67.

Myers GJ et al: Clinical neurologic examination of the preterm and

term neonate. Sem Neurol 1993; 13:1–9.

Pryse-Phillips W: Companion to Clinical Neurology, 2d ed. Oxford,

Oxford University Press, 2003.

Rodnitzky RL: Van Allen's Pictorial Manual of Neurologic Tests, 3d

ed. Chicago, Year Book Medical Publishers, 1988.

Rowland LP: Signs and Symptoms in Neurologic Diagnosis. In:

Rowland LP, ed. Merritt's Textbook of Neurology, 8th ed.
Philadelphia, Lea & Febiger, 1989, pp 58–60.

Zafeiriou DI et al: Prospective follow-up of primitive reflex profiles

in high-risk infants: Clues to an early diagnosis of cerebral palsy.
Pediatr Neurol 1995; 13:148–152.

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Editors: Afifi, Adel K.; Bergman, Ronald A.

Title: Functional Neuroanatomy: Text and Atlas, 2nd Edition

Copyright ©2005 McGraw-Hill

> Table of Contents > Part II - Atlas > Section 1 - Sectional Anatomy

Section 1
Sectional Anatomy

Figure A1-1. Superficial axial section through the pre- and postcentral gyri.

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Figure A1-2. Axial section through the body of the lateral ventricles and the
forceps minor and major.

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Figure A1-3. Axial section through the thalamus and basal ganglia.

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Figure A1-4. Axial section through the basal ganglia, midbrain, and
cerebellum.

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Figure A1-5. Axial section through the pons and cerebellum.

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Figure A1-6. Axial section through the middle cerebellar peduncle

(brachium pontis).

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Figure A1-7. Axial section through the temporal lobe, medulla oblongata,
and cerebellum.

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Figure A1-8. Axial section through the temporal lobe, medulla oblongata,
and cerebellum.

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Editors: Afifi, Adel K.; Bergman, Ronald A.

Title: Functional Neuroanatomy: Text and Atlas, 2nd Edition

Copyright ©2005 McGraw-Hill

> Table of Contents > Part II - Atlas > Section 2 - Sagittal Yakovlev

Section 2
Sagittal Yakovlev

Figure A2-1. Parasagittal brain section just superficial to the insula.

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Figure A2-2. Parasagittal brain section through the insula.

Figure A2-3. Parasagittal brain section through the lenticular nucleus.

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Figure A2-4. Parasagittal brain section through the lateral geniculate

nucleus, amygdala, and hippocampus.

Figure A2-5. Parasagittal brain section through the corpus striatum.

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Figure A2-6. Parasagittal brain section through the centromedian nucleus of

the thalamus.

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Figure A2-7. Parasagittal brain section through the centromedian nucleus of

thalamus and subthalamic nucleus.

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Figure A2-8. Parasagittal brain section through the medial thalamus.

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Figure A2-9. Parasagittal brain section through the red nucleus and optic
chiasma.

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Editors: Afifi, Adel K.; Bergman, Ronald A.

Title: Functional Neuroanatomy: Text and Atlas, 2nd Edition

Copyright ©2005 McGraw-Hill

> Table of Contents > Part II - Atlas > Section 3 - Axial Yakovlev

Section 3
Axial Yakovlev

Figure A3-1. Axial section of the brain through the centrum semiovale.

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Figure A3-2. Axial section of the brain through the body of the corpus
callosum.

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Figure A3-3. Axial section of the brain through the genu and splenium of
the corpus callosum.

Figure A3-4. Axial section of the brain through the crus of the fornix and
dorsal thalamus.

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Figure A3-5. Axial section of the brain through the frontal and occipital
horns of the lateral ventricle.

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Figure A3-6. Axial section of the brain through the trigone of the lateral
ventricle.

Figure A3-7. Axial section of the brain through the anterior commissure and

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habenular nucleus.

Figure A3-8. Axial section of the brain through the habenular and posterior
commissures.

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Figure A3-9. Axial section of the brain through the dorsal midbrain.

Figure A3-10. Axial section of the brain through the mamillary body and
optic chiasma.

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Figure A3-11. Axial section of the brain through the pons.

Figure A3-12. Axial section of the brain stem through the middle cerebellar
peduncle.

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Figure A3-13. Axial section of the brain through the pontomedullary

junction.

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Editors: Afifi, Adel K.; Bergman, Ronald A.

Title: Functional Neuroanatomy: Text and Atlas, 2nd Edition

Copyright ©2005 McGraw-Hill

> Table of Contents > Part II - Atlas > Section 4 - Coronal Yakovlev

Section 4
Coronal Yakovlev

Figure A4-1. Coronal section of the frontal lobe rostral to the genu of the
corpus callosum.

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Figure A4-2. Coronal section of the brain through the genu and rostrum of
the corpus callosum.

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Figure A4-3. Coronal section of the brain through the rostral striatum
(neostriatum).

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Figure A4-4. Coronal section of the brain through the corpus striatum.

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Figure A4-5. Coronal section of the brain through the anterior commissure.

Figure A4-6. Coronal section of the brain through the rostral thalamus.

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Figure A4-7. Coronal section of the brain through the fields of Forel.

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Figure A4-8. Coronal section of the brain through the mamillary body and
subthalamus.

Figure A4-9. Coronal section of the brain through the subthalamic region.

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Figure A4-10. Coronal section of the brain through the habenula and lateral
geniculate nucleus.

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Figure A4-11. Coronal section of the brain through the pretectal area.

Figure A4-12. Coronal section of the brain through the dentate nucleus of
the cerebellum.

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Editors: Afifi, Adel K.; Bergman, Ronald A.

Title: Functional Neuroanatomy: Text and Atlas, 2nd Edition

Copyright ©2005 McGraw-Hill

> Table of Contents > Part II - Atlas > Section 5 - Brain Stem

Section 5
Brain Stem

Figure A5-1. Coronal section of the brain stem through the medulla
oblongata at the level of the motor (pyramidal) decussation.

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Figure A5-2. Coronal section of the brain stem through the medulla
oblongata at the level of the sensory (lemniscal) decussation.

Figure A5-3. Coronal section of the brain stem through the medulla

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oblongata at the level of the obex.

Figure A5-4. Coronal section of the brain stem through the medulla
oblongata at the level of the middle inferior olivary complex.

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Figure A5-5. Coronal section of the brain stem through the medulla
oblongata at the level of the cochlear nuclei and the glossopharyngeal nerve.

Figure A5-6. Coronal section of the brain stem through the pontomedullary
junction.

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Figure A5-7. Coronal section of the brain stem through the pons at the level
of the abducens and facial nerves.

Figure A5-8. Coronal section of the brain stem through the midpons at the
level of sensory and motor nuclei of the trigeminal nerve.

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Figure A5-9. Coronal section of the brain stem through the rostral pons at
the level of the isthmus.

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Figure A5-10. Coronal section of the brain stem through the rostral pons at
the level of the trochlear nerve.

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Figure A5-11. Coronal section of the brain stem through the midbrain at the
level of the caudal inferior colliculus and trochlear nucleus.

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Figure A5-12. Coronal section of the brain stem through the midbrain at the
level of the inferior colliculus.

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Figure A5-13. Coronal section of the brain stem through the midbrain at the
level of the superior colliculus.

Figure A5-14. Coronal section of the brain stem through the midbrain at the
level of the rostral superior colliculus.

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Figure A5-15. Coronal section of the brain stem through the midbrain-
diencephalic junction.

Figure A5-16. Coronal section of the brain stem through the caudal
diencephalon at the level of the habenular nuclei and mamillary bodies.

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Figure A5-17. Coronal section of the brain stem through the mid-
diencephalon at the level of the ventral lateral nucleus of the thalamus.

Figure A5-18. Coronal section of the brain stem through the rostral
diencephalon at the level of the ventral anterior thalamic nucleus.

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Figure A5-19. Coronal section of the brain stem through the basal ganglia
at the level of the head of the caudate nucleus and the putamen.

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Editors: Afifi, Adel K.; Bergman, Ronald A.

Title: Functional Neuroanatomy: Text and Atlas, 2nd Edition

Copyright ©2005 McGraw-Hill

> Table of Contents > Part II - Atlas > Section 6 - Spinal Cord

Section 6
Spinal Cord

Figure A6-1. Composite coronal sections of spinal cord at different levels.

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Figure A6-2. Coronal section of the spinal cord at the upper cervical (C1–
C2) level.

Figure A6-3. Coronal section of the spinal cord at the lower cervical (C8)
level.

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Figure A6-4. Coronal section of the spinal cord at the upper thoracic level.

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Figure A6-5. Coronal section of the spinal cord at the lower thoracic level.

Figure A6-6. Coronal section of the spinal cord at the lower lumbar level.

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Figure A6-7. Coronal section of the spinal cord at the level of the third
sacral segment.

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Figure A6-8. Coronal section of the spinal cord of a term stillborn infant at
the lower lumbar level showing variation in degree of myelination of different
tracts.

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Editors: Afifi, Adel K.; Bergman, Ronald A.

Title: Functional Neuroanatomy: Text and Atlas, 2nd Edition

Copyright ©2005 McGraw-Hill

> Table of Contents > Part II - Atlas > Section 7 - Sagittal MRI

Section 7
Sagittal MRI

Figure A7-1. T2-weighted parasagittal section of the brain through the

insular cortex.

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Figure A7-2. T2-weighted parasagittal section of the brain through the

basal ganglia.

Figure A7-3. T2-weighted parasagittal section of the brain close to the

midline through the brain stem.

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Figure A7-4. T2-weighted midsagittal section of the brain through the

corpus callosum and brain stem.

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Figure A7-5. T2-weighted midsagittal section of the brain through the

corpus callosum and brain stem.

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Editors: Afifi, Adel K.; Bergman, Ronald A.

Title: Functional Neuroanatomy: Text and Atlas, 2nd Edition

Copyright ©2005 McGraw-Hill

> Table of Contents > Part II - Atlas > Section 8 - Axial MRI

Section 8
Axial MRI

Figure A8-1. T2-weighted axial section of the upper part of the brain
through the centrum semiovale of the frontal and parietal lobes.

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Figure A8-2. T2-weighted axial section of the brain through the body of the
lateral ventricle.

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Figure A8-3. T2-weighted axial section of the brain through the thalamus.

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Figure A8-4. T2-weighted axial section of the brain through the rostral
midbrain.

Figure A8-5. T2-weighted axial section of the brain through the pons and
cerebellum.

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Figure A8-6. T2-weighted axial section of the brain through the middle
cerebellar peduncle and cerebellum.

Figure A8-7. T2-weighted axial section of the brain through the medulla
oblongata and cerebellum.

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Editors: Afifi, Adel K.; Bergman, Ronald A.

Title: Functional Neuroanatomy: Text and Atlas, 2nd Edition

Copyright ©2005 McGraw-Hill

> Table of Contents > Part II - Atlas > Section 9 - Coronal MRI

Section 9
Coronal MRI

Figure A9-1. T2-weighted coronal section of the brain at the level of the
neostriatum.

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Figure A9-2. T2-weighted coronal section of the brain at the level of the
amygdaloid nucleus and corpus striatum.

Figure A9-3. T2-weighted coronal section of the brain at the level of the
thalamus and third ventricle.

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Figure A9-4. T2-weighted coronal section of the brain at the level of the
caudal thalamus.

Figure A9-5. T2-weighted coronal section of the brain through the cerebral

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hemispheres and brain stem.

Figure A9-6. T2-weighted coronal section of the brain through the cerebral
hemispheres and brain stem.

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Figure A9-7. T2-weighted coronal section of the brain at the level of the
occipital horn of the lateral ventricle.

Figure A9-8. T2-weighted coronal section of the brain at the level of the
occipital lobe and cerebellum.

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Editors: Afifi, Adel K.; Bergman, Ronald A.

Title: Functional Neuroanatomy: Text and Atlas, 2nd Edition

Copyright ©2005 McGraw-Hill

> Back of Book > Bibliography

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