Review TRENDS in Neurosciences Vol.29 No.

3 March 2006

Mapping brain maturation

Arthur W. Toga, Paul M. Thompson and Elizabeth R. Sowell
Laboratory of Neuro Imaging, Department of Neurology, UCLA School of Medicine, 635 Charles E. Young Drive South,
Suite 225, Los Angeles, CA 90095-7332, USA

Human brain maturation is a complex, lifelong process (MRI) was still in its infancy. His histological work in the
that can now be examined in detail using neuroimaging 1980s paved the way in showing that the time-course for
techniques. Ongoing projects scan subjects longitudin- synaptic blooming and pruning in the human brain varies
ally with structural magnetic resonance imaging (MRI), enormously by brain region. For example, in the visual
enabling the time-course and anatomical sequence of cortex, synaptic overproduction reaches a maximum at
development to be reconstructed. Here, we review about the fourth postnatal month. Then synapse elimin-
recent progress on imaging studies of development. ation starts, and this continues until preschool age, by
We focus on cortical and subcortical changes observed which time synaptic density has reached the adult level.
in healthy children, and contrast them with abnormal But in the medial prefrontal cortex, an area of the brain
developmental changes in early-onset schizophrenia, involved in executive, attentional and regulatory func-
fetal alcohol syndrome, attention-deficit–hyperactivity tions, the peak occurs at 3–4 years of age, and substantial
disorder (ADHD) and Williams syndrome. We relate decline does not occur until mid-to-late adolescence [1].
these structural changes to the cellular processes that Early work by Yakovlev and Lecours documented the
underlie them, and to cognitive and behavioral changes progression of myelination in the developing human brain
occurring throughout childhood and adolescence. [2]. More recent work by Benes et al. with much larger
samples showed similar results, with myelination con-
Introduction tinuing well into the third decade of life [3]. Interestingly,
The dynamic course of brain maturation is one of the most the spatial and temporal pattern of these cellular changes
fascinating aspects of the human condition. Although seemed to parallel developmental changes in synaptic
brain change and adaptation are part of a lifelong process, density. Simply put, myelination of the most dorsal
the earliest phases of maturation – during fetal develop- regions of the brain responsible for higher cognitive
ment and childhood – are perhaps the most dramatic and functions seemed to continue well into adolescence, and
important. Indeed, much of the potential and many of the more ventral and deep brain structures – some of which
vulnerabilities of the brain might, in part, depend on the are responsible for relatively more primitive functions –
first two decades of life. were myelinated earlier.
The cortex and subcortical gray-matter nuclei develop However, the sequence of myelination might be more
during fetal life in a carefully orchestrated sequence of cell complex than this. A problem with many interpretations
proliferation, migration and maturation. This leads to a of the work by Yakovlev and Lecours [2], and of similar
human brain with w100 billion neurons at birth. studies of myelogenesis, is that dorsal and ventral systems
However, the brain of a newborn child is only one-quarter do not ultimately myelinate to the same degree: on
to one-third of its adult volume, and it continues to grow average, dorsal cortex, at its most mature, is less
and specialize according to a precise genetic program, with myelinated than ventral cortex. Therefore, if myelination
modifications driven by environmental influences, both took the same time-course, then at any given time areas
positive and negative. With stimulation and experience, that myelinate more fully would appear more myelinated
the dendritic branching of neurons greatly increases, as do than those that myelinate less. Therefore, when the
the numbers of synaptic connections. As layers of degree of myelination is observed on histologically stained
insulating lipids are laid down on axons through the sections or in MRI scans of the brain, one must also
process of myelination, the conduction speed of fibers that consider the ultimate extent of myelination for each
interconnect different brain regions increases w100-fold. system. Recent research studying patterning molecules,
This exuberant increase in brain connections is followed and rates of proliferation and neuronal migration, show a
by an enigmatic process of dendritic ‘pruning’ and synapse much more complex pattern of cortical maturation,
elimination, which leads to a more efficient set of occurring primarily from a rostral-lateral-ventral pole
connections that are continuously remodeled toward a dorsal-medial-caudal pole (reviewed in [4]).
throughout life. This histological evidence suggested that brain
development is a dynamic process of progressive and
Synaptic changes and myelination regressive changes. But histology gave only very frag-
When Huttenlocher began to demonstrate this succession mented evidence for late brain maturation, given the
of events in the human brain, magnetic resonance imaging dearth of post-mortem data from childhood and adolescent
Corresponding author: Toga, A.W. ([email protected]). years. By contrast, MRI can non-invasively document
these large-scale processes of brain development, can
www.sciencedirect.com 0166-2236/$ - see front matter Q 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.tins.2006.01.007
 Review TRENDS in Neurosciences Vol.29 No.3 March 2006 149

provide insight into the sequence and timing of these visual detail and group statistics regarding the rates of
developmental processes in longitudinal experiments, and change and their regional variation. Time-lapse anima-
can document how they occur in living subjects. tions also can be computed to illustrate the changes.
Many of the basic functions of the brain, such as vision,
Initial brain-imaging studies hearing, speech, planning and emotional control are
The first quantitative structural brain-imaging studies in primarily handled in the cortex, so much of the work
normal children using MRI were conducted in the late mapping brain development has focused on the cortex,
1980s and early 1990s. Terry Jernigan and colleagues although some groups have studied subcortical gray
showed that young adults actually had less cortical gray matter. The goal of cortical mapping is to create group
matter than children, despite the fact that adults had average maps of cortical features of interest such as gray-
somewhat larger overall total brain volumes [5]. They matter thickness, gray-matter density, cortical shape,
found that gray-matter volumes generally declined after average sulcal patterning and hemispheric asymmetries,
age 7, perhaps because the advancement of white matter all of which change during development (for methods, see
(i.e. myelination) throughout childhood began to overtake [13]). Next, statistics are defined that help localize age
the overall rate of brain volume expansion, causing a net effects on these measurements, such as localized
decrement in the amount of tissue appearing gray (or reductions or increases in gray-matter density or thick-
unmyelinated) on MRI. They then determined that the ness, and brain growth.
timing of gray-matter loss was different for different brain
regions: loss was first observed in the deep motor nuclei in
early childhood, then in the parietal and frontal lobes at Changes in gray and white matter
around puberty [6]. Although MRI did not assess synaptic The earliest cross-sectional pediatric brain MRI studies of
density per se, this was the first in vivo evidence to support normal developmental changes showed that gray-matter
the post-mortem findings of Huttenlocher and of Yakovlev volumes generally declined after 6–7 years of age and
and Lecours. continued to decrease during adolescence, whereas white-
matter volumes increased linearly over time. However, in
Anatomical parcellation and mapping one of the first studies to compile growth curves for the
The aforementioned studies used a method called volu- volumes of different lobes of the brain as subjects aged (i.e.
metric parcellation. In this approach, the brain is studies that were longitudinal rather than cross-sectional)
subdivided into several, separate anatomical regions [14], there was a clear linear increase in white matter up
with different functions (e.g. the frontal lobe, the deep to age 20, whereas there were non-linear changes in
motor nuclei or the hippocampus), and their volumes are cortical gray matter. Giedd et al. demonstrated a pre-
measured (Figure 1). Parcellation enables the compilation adolescent increase, with developmental curves peaking
of growth curves that document how regional volumes at w12 years for the frontal and parietal lobe, and at w16
vary with age. Results are typically illustrated using years for the temporal lobe. After that, gray-matter
scatterplots but regional measurements are limited by loss occurs.
anatomical structures (i.e. sulcal landmarks) and can also More recently, another developmental study quantified
be reliably visualized and defined using MRI. human cortical development by measuring gray-matter
In the late 1990s, a few teams began to make composite density in each lobe, point by point [4]. This map was
3D maps of developing brain structures [4,7–12] showing, constructed from serial brain MRI scans of 13 children
for example, the average pattern of age-related change in followed over a ten year period. Children were scanned
gray-matter thickness between childhood and young every two years for eight years from the time they were
adulthood. More recently, these mapping techniques recruited, and were given a structured diagnostic inter-
have become more popular because they provide more view at each visit to confirm lack of a psychiatric disorder.

(a) (b) (c)

MRI scan Tissue classification Parcellation into lobes

Figure 1. Typical processing steps in an analysis of MRI brain scans. (a) A typical coronal section from a T1-weighted MRI scan of the brain. (b) The result of applying a tissue-
classification approach to classify image voxels as gray matter (green), white matter (blue) or cerebrospinal fluid (CSF; red). Non-brain tissues such as scalp and meninges
surrounding the brain have been digitally edited from the image. (c) Parcellation of the brain into the frontal lobe (blue), parietal lobe (green), occipital lobe (red) and temporal
lobe (yellow). This subdivision of anatomy is performed with the aid of a cortical surface model on which sulcal landmarks separating the lobes can be reliably identified.
Once partitioned in this way, the volumes of each tissue type in the major lobes can be computed and growth curves established for each major lobe. The quantity of gray and
white matter in the brain and of CSF in the ventricles and cortical sulci can be computed and compared across subjects and over time. Maps of these tissue types (b) can be
used to calculate shape, size and other statistics, and can also be subdivided into smaller regions to determine the amount of each tissue type in each lobe (c).

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150 Review TRENDS in Neurosciences Vol.29 No.3 March 2006

This study measured which brain regions change

(a) 5.5
between 4 and 21 years of age and illustrated these
statistics as a time-lapse movie. This revealed a shifting 5.0
pattern of gray-matter loss, appearing first (at w4–8 years
4.5
of age) in dorsal parietal and primary sensorimotor
regions near the interhemispheric margin, and spreading 4.0
laterally and caudally into temporal cortices and ante-
riorly into dorsolateral prefrontal areas. The first areas to 3.5
mature were those with the most basic functions, such as 3.0
those processing the senses and movement. Areas
involved in spatial orientation and language (parietal 2.5
lobes) followed, around the age of puberty (11–13 years). 2.0
Areas with more advanced functions – integrating
information from the senses, reasoning and other ‘execu- 1.5
tive’ functions (e.g. prefrontal cortex) – matured last, in 1.0
late adolescence. This sequence also provided evidence
that phylogenetically older cortical areas mature earlier (b)
than the more recently evolved higher-order association
cortices, which integrate information from earlier
maturing cortex.

Cortical thickness
In another longitudinal study, changes in cortical thick-
ness were measured (in millimeters) in a group of 45
normally developing children studied between 5 and 11
years of age [12]. Each child was studied twice with a two-
year scanning interval. Maps of cortical thickness were < 2 mm
2.0–2.5 mm
created for each child, and the average cortical-thickness 2.5–3.0 mm
maps were remarkably similar to maps created from post- 3.0–3.5 mm
3.5–4.0 mm
mortem data by von Economo [15]. The average cortical
thickness for the normally developing children and from Figure 2. Cortical thickness maps. (a) An in vivo average cortical-thickness map
the post-mortem data are shown in Figure 2. As can be created from 45 normally developing children at their first scan [12]. The brain
seen on the medial brain surface, the cortex is thickest in surface is color coded according to the bar on the right, where thickness is shown in
millimeters. The average thickness map can be compared to an adapted version of
the most dorsal aspects of the frontal and parietal lobes the 1929 cortical thickness map of von Economo [15] (b). Color coding has been
(w4–5 mm), and thinnest in the visual cortices of the applied over his original stippling pattern, respecting the boundaries of his original
work, to highlight the similarities between the two maps. Reproduced, with
occipital lobes surrounding the calcarine sulcus (2.0–
permission, from [12].
2.5 mm). These data revealed cortical thinning of w0.15–
0.30 mm per year in normally developing children, most mature. In the same 45 normally developing children
prominently in right dorsal frontal and bilateral parietal already described, cortical thinning in the left dorsal
regions. Cortical thickening was also observed with frontal and parietal lobes correlated with improved
increases of w0.10–0.15 mm per year in the classical performance on a test of general verbal intellectual
language regions of the temporal and frontal lobes functioning [12,17]. Greater left hemisphere gray-matter
(Figure 3). The brain grew at a rate of w0.4–1.5 mm per thinning was associated with improved performance on
year in many regions, most prominently in the frontal and the vocabulary subtest of a standardized IQ measure [17]
occipital regions. This pattern of results is similar to those (Figure 4). When permutation analyses were conducted to
observed in cross-sectional and longitudinal data of correct for multiple comparisons in the brain–behavior
normal brain maturation [4,16], but the new methods analyses, change in cortical thickness was correlated with
enabled changes in cortical thickness to be assessed in change in the behavioral measure only in dorsal frontal
millimeters for the first time. Additionally, this study and parietal cortex of the left hemisphere. Cortex in these
confirmed that dynamic but distinct changes occur in regions tends to thin with increased age. Thus, the results
posterior temporal and frontal language regions, where of negative relationships between cortical thickness and
gray matter continues to increase in thickness. We vocabulary improvements are consistent with what would
speculate that cortical changes in these regions could be be expected. Considering these data, it seems reasonable
related to changing language abilities that continue after to speculate that the brain changes are related to cognitive
5 years of age (e.g. changes in reading ability) [12]; changes during development, although few studies have
functional and structural imaging studies are underway addressed this issue.
to test these hypotheses.

Cognitive correlates Cortical changes throughout life

Changes in cortical thickness during normal development The brain-mapping studies of normal brain maturation
relate to cognitive changes as children and adolescents described here have been limited by the age ranges of the
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 Review TRENDS in Neurosciences Vol.29 No.3 March 2006 151

Left Right

0.30
0.25
0.20
0.15
0.10
0.05
0.00
–0.05
–0.10
–0.15
–0.20
–0.25
–0.30

Figure 3. Annualized rate of change in cortical thickness. The average rate of change in cortical thickness is shown in millimeters according to the color bar on the right
(maximum gray-matter loss is shown in shades of red and maximum gray-matter gain is shown in shades of blue). Forty-five children were studied twice (two-year scan
interval) between 5 and 11 years of age. Reproduced, with permission, from [12].

subjects studied. They have clearly shown regional and and parietal regions. Notably, the most lateral aspects of
temporal patterns of dynamic maturational change the brain in the posterior temporal and inferior parietal
continuing through childhood and adolescence. However, lobes bilaterally showed a distinct pattern of gray-matter
they could not enable conclusions to be made about the change, one in which the non-linear age effects were
endpoint in cortical sculpting (which probably results inverted relative to the age effects in more dorsal cortices.
from increased myelination and synaptic pruning) A subtle increase in gray-matter density was observed
because they did not assess individuals O30 years of until w30 years of age, and it then remained stable until a
age. This issue was addressed in a study of a large sample precipitous decline in later decades. As these data
of normal individuals (nZ176) across the span of life (7–87 illustrate, the trajectory of maturational changes might
years of age) [11]. Significant, non-linear age effects were continue beyond adolescence and into young adulthood,
observed over large areas of the most dorsal aspects of the and can be assessed only using an extended age range.
frontal and parietal regions on both the lateral and The question of when brain maturational changes
interhemispheric surfaces and in the orbitofrontal cortex. traverse into the more degenerative changes of aging
Scatterplots of these effects revealed a dramatic decline in becomes even more poignant when considering these data
gray-matter density between 7 and 60 years of age, with (for a detailed discussion, see [18]). The last systems to
little or no decline thereafter. A sample scatterplot of the mature are also among the first to degenerate in disorders
quadratic effect of age on gray-matter density at one such as Alzheimer’s disease; their high degree of plasticity
brain-surface point on the superior frontal sulcus is shown throughout life might make them more vulnerable to
in Figure 5, and is similar to plots from the dorsal frontal neurodegeneration [19–21].

P = 0.10–0.05

P = 0.05–0.01

P <0.01

Figure 4. Brain-behavior maps for vocabulary and cortical thickness. P values are for negative correlations between change in cortical thickness (time 2 minus time 1, as
shown in figure 2 of [12]) and change in vocabulary raw scores (time 2 minus time 1). Negative P values (i.e. regions where greater thinning was associated with greater
vocabulary improvement) are color-coded, and regions in white showed no significant association. Positive correlations were not significant in the permutation analyses for
any of the regions of interest, and are not shown here. Reproduced, with permission, from [12].

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152 Review TRENDS in Neurosciences Vol.29 No.3 March 2006

(a) Superior frontal sulcus

0.70

Gray-matter density
0.55

0.40 0.00010
0.00008
0.00006
0.00004
0.00002
0.25 0.00000
–0.00002
–0.00004
–0.00006
0.10 –0.00008
–0.00010
0 10 20 30 40 50 60 70 80 90
Nonlinear
Age (years) regression
coefficient
Superior temporal sulcus
0.70
Gray-matter density

0.55 P <0.01 (inverted U curve)

P <0.0000008 (U curve)

0.40

0.25

0.10
0 10 20 30 40 50 60 70 80 90
Age (years) (c)

(b)

(d)

5y
ear
s

Ag
e

20
yea
rs

Gray-
matter
volume

Figure 5. Mapping brain change over time. Brain changes in development can be identified by fitting time-dependent statistical models to data collected from subjects cross-
sectionally (i.e. across a group of subjects at a particular time), longitudinally (i.e. following individual subjects as they aged), or both. Measurements such as cortical
thickness are then plotted onto the cortex using a color code. (a,b) Trajectory of gray-matter loss over the human lifespan, based on a cohort of 176 subjects aged 7–87 years
[11]. Plots superimposed on the brain in (b) show how gray-matter density decreases for particular regions; (a) highlights example regions in which the gray-matter density
decreases rapidly during adolescence (the superior frontal sulcus) or follows a more steadily declining time-course during lifespan (the superior temporal sulcus). (c,d)

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 Review TRENDS in Neurosciences Vol.29 No.3 March 2006 153

(a) Tensor maps of growth (b) Tensor-based morphometry

80 0.1
Healthy
children 0.0
60
(n = 20)
–0.1
40
–0.2
20 Autistic
children –0.3
0 (n = 20)
–0.4
3–6 years Log (Jacobian)
–20 1
Local Areas thinner
growth (%) 0 in autism
–1
–2
R
–3 S

–4
t statistic

Figure 6. Tensor maps of growth and tensor-based morphometry. (a) The corpus callosum (indicated by a green box) of a healthy three-year-old girl in a sagittal section from
a 3D MRI scan. Using a follow-up scan thee years later, an elastic deformation field is computed that digitally aligns, or warps, the anatomy of the earlier time-point to match
its shape at the later time point. The amount of local stretching of the anatomy is color-coded, indicating fastest growth rates (red) in the anterior corpus callosum. In a related
approach (b), maps can be compiled to represent the average expansion factor required to deform an average corpus callosum shape elastically onto each subject in a set of
healthy children and matched autistic children. This identifies areas of the corpus callosum that are thinner in autistic children, pinpointing where abnormal white-matter
growth might lead to the disorder in early childhood. The letters ‘S’ and ‘R’ denote the splenium and rostrum of the corpus callosum, respectively. Data in (a) is adapted, with
permission, from [22]; (b) is adapted, with permission, from [53].

Subcortical changes during development Fetal and neonatal MRI

Most brain-mapping studies of development have focused Mapping fetal and neonatal brains presents another set of
on the cortex, but developmental changes in subcortical practical and technical challenges. Aside from the obvious
structures have also been characterized. For example, one difficulty in obtaining motion-artifact-free images, at
study mapped a front-to-back wave of growth through the these ages the degree of myelination produces consider-
corpus callosum at 3–15 years of age [22] (Figure 6). The ably less contrast in images obtained using the most
continuous myelination of interhemispheric fibers results commonly applied T1 and T2 weighted pulse sequences.
in increased axonal conduction speed and transmission of Nevertheless, considerable insight into the earliest
information between the brain hemispheres. Perhaps the myelination and differentiation of the telencephalon and
main surprise from the subcortical studies is the diencephalon can be seen by imaging from fetal stages in
progressive volume loss in the deep gray-matter nuclei – utero through the first six months after birth [23]. These
especially the caudate – at around puberty. In contrast to imaging results are consistent with post-mortem
the basal ganglia, temporal lobe gray-matter structures measures of increased myelination before birth [24–26].
(the amygdala and hippocampus) seem to increase in A general caudal-to-rostral progression can be appreciated
volume during childhood and adolescence. in this age group. Furthermore, morphological differen-
tiation of several structures such as the internal capsule
(a fan-like structure of white matter separating the
lentiform nucleus from the caudate and dorsal thalamus)
Relationship to cellular changes
precedes changes in white-matter, often by many months.
We cannot conclude directly what cellular changes are
Utilizing specific magnetic resonance pulse sequences to
involved in the dynamic maturational processes described
identify white matter, in an approach called diffusion
here. MRI measures changes in the volume and density of
tensor imaging (DTI), can also help characterize the
brain structures, but lacks the resolution to characterize
changes associated with myelination. Neil et al. [27]
the cellular mechanism (e.g. dendritic remodeling, cell
found dramatic and generalized changes in water
death, synaptic pruning or myelination) of such changes.
apparent diffusion coefficients and diffusion anisotropy.
Moreover, gray-matter volume and thickness reflect not These diffusion parameters, measurable using DTI, are
only the dendritic and synaptic processes that occur in locally sensitive to the degree of myelination (which
neurons but also the complex architecture of neurons, glia provides resistance to water diffusion) and to fiber
(i.e. myelin) and vasculature. However, we can say that orientation (which constrains the principal directions of
the gray-matter changes described in this review correlate water diffusion to be aligned with axons). Gilmore et al.
well with the post-mortem sequence of regionally variable [28] found significant increases in fractional anisotropy in
increased synaptic pruning and myelination during the anterior and posterior regions (genu and splenium) of
adolescence and early adulthood. the corpus callosum during development that reflect

Trajectory of cortical gray-matter density in 13 children scanned longitudinally every two years for eight years [4]. The units used in (a) and (d) are gray-matter density, which
is defined as the proportion of tissue segmenting as gray matter within a 15-mm-diameter sphere centered at each point on the cortical surface. This widely-used measure
ranges from 0 to 1, and is highly correlated with cortical thickness [52].

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154 Review TRENDS in Neurosciences Vol.29 No.3 March 2006

underlying changes to water content and cytoarchitecture schizophrenia [31]. Even so, they might represent a
during maturation. separate process entirely that begins in adolescence –
twins studies have hinted that the earliest deficits,
Developmental disorders occurring in the parietal cortex, might have a non-genetic
Statistical maps can also be created to assess group effects trigger [32]. Some histological studies suggest that there
such as brain structure differences between healthy is decreased neuropil in schizophrenia, but autopsy
children and those with neuropsychiatric disorders such material is scarce and findings are inconsistent. As in
as schizophrenia, bipolar illness or attention-deficit– normal development, the observed cortical changes might
hyperactivity disorder (ADHD), those with genetic dis- also be glial or vascular in origin, rather than purely
orders of brain development such as Williams syndrome neuronal [33]. Intracortical contrast might also be affected
(WS; a mental retardation disorder), and those exposed to by changes in myelination [34], and by changes in lipid
teratogens during brain development, such as children metabolism during the use of atypical antipsychotic
with fetal alcohol syndrome (FAS). The resulting maps can agents. It is possible that in schizophrenia, changes in
reveal where in the brain differences are located, how gray-matter density also reflect, at least in part, increas-
significant they are, and – depending on the study design – ing intracortical myelination. Still, four dimensional maps
whether they are stable or progressive [29]. such as these offer a biological marker of disease
Statistically significant reductions or increases in progression for drug trials, where brain mapping can
measured gray- or white-matter structures are commonly assess how well antipsychotic medications oppose
found in children with developmental disorders, and advancement of the disease [35].
different brain abnormalities have been observed in
different disorders. However, most of the abnormalities Williams syndrome
observed in the quantitative MRI studies of children with Brain imaging has also helped to identify circumscribed
developmental disorders have been relatively subtle. That alterations in brain structure that are associated with
is, the brain structural abnormalities could not typically developmental disorders that have genetic causes. Wil-
be observed within individual children, but rather only liams syndrome (WS), for example, is a developmental
when studied in groups of children with a particular disorder associated with a deletion of w20 genes in the
disorder compared with non-affected or medication- 7q11.23 region of chromosome 7. WS subjects have mild to
matched controls. moderate mental retardation, but have remarkable
proficiencies in language skills, social drive and musical
Childhood-onset schizophrenia ability. Figure 7 shows a range of brain regions affected by
Beginning in 1992, scientists led by Judith Rapoport at this genetic deletion: in general, the cortex is thinner,
the National Institute of Mental Health employed MRI except in perisylvian language regions, where it is thicker
technology to scan a group of w50 teenagers repeatedly as by 5–10%; cortical complexity is also significantly
their schizophrenia developed and a group of O500 increased [36]. In post-mortem data from WS subjects,
healthy children as controls. The collected data were Holinger et al. [37] observed larger cells in Heschl’s gyrus
analyzed using brain-mapping methods developed to in the primary auditory area – a finding congruent with
detect subtle changes in the cortex [30]. Healthy subjects the cortical thickening seen here. WS subjects also have
lost gray matter at a subtle rate of 1–2% per year in the disproportionately reduced white matter, so cortical cells
parietal cortices, with very little detectable change in the fitting over a smaller white-matter area can ‘pile up’, and
other lobes of the brain. By contrast, the childhood-onset the cortex can thicken owing to a crowding effect. Some
schizophrenia patients showed a rapid progressive loss of Wnt signaling genes, which direct early cell differentiation
gray matter in superior frontal and temporal cortices, and segmentation, are in the deleted 7q11.23 chromo-
reaching 3–4% per year in some regions. This pattern was somal region, suggesting a genetic basis for the cortical
seen in both boys and girls. Early deficits in parietal brain dysmorphology observed on MRI. Other genes deleted in
regions that support language and associative thinking WS might normally contribute to fissure formation in the
spread forwards into the temporal lobes, supplementary human cortex, and their absence might account for the
motor cortices and frontal eye fields. The deficits spread abnormal cortical thickening. Ongoing work is examining
anatomically over a period of 5 years, consistent with the the changes in folding complexity in the same regions that
characteristic neuromotor, sensory and visual search show thickened cortex, to ensure that this thickening is
impairments in the disease. In temporal cortices, includ- not simply a consequence of increased gyrus formation
ing primary auditory regions, severe gray-matter loss was (e.g. microgyria often appears as thickened cortex, when
absent at disease onset but later became pervasive. in fact it is thinner, four-layered cortex). If cortical
Patients with the worst brain tissue loss also had the thickness and complexity were positively correlated in
worst symptoms, which included hallucinations, delu- general, the frontal and parietal regions of greater
sions, bizarre and psychotic thoughts, hearing voices gyrification found in studies of WS (e.g. [38]) would be
and depression. expected to show greater cortical thickness, but this was
The notion of schizophrenia as a dynamically emerging not found. There is, therefore, no simple relationship
disease of neurodevelopment is still controversial. The between thickness and complexity, and careful study of
spreading patterns of deficits corroborate the idea that the these measures in larger samples is warranted. Alter-
normal developmental process of dendritic and synaptic natively, the cortical thickening might represent an
pruning might be abnormally accelerated or derailed in adaptive response to the genetic deletion, perhaps even
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 Review TRENDS in Neurosciences Vol.29 No.3 March 2006 155

(a) WS versus controls

(b) ADHD versus controls

(c) FAS versus controls

Figure 7. Differences in gray-matter density between subjects with three neurodevelopmental disorders. The percentage differences in gray-matter density between subjects
with Williams syndrome (WS) (a), attention-deficit–hyperactivity disorder (ADHD) (b), fetal alcohol syndrome (FAS) (c) and their respective normally developing control
groups are color-coded. In all maps, warmer colors represent positive differences, indicating an increase in the patient group (arbitrarily coded as 1) relative to the control
group (arbitrarily coded as 0), with red representing the largest group difference. Note that the maximum value varies on the three color bars, depending on the maximum
group difference from each comparison. Adapted, with permission, from [36,41,46].

from increased use or overuse of specific cortical networks. regionally reduced brain size are not yet understood, but
Identification of such neuroanatomical characteristics of these regions of the brain are known to be part of an
WS is important for better understanding of the scope and action–attention network probably involved in the symp-
timing of the cortical anomaly in WS. tomatology of ADHD (discussed in [41]).

Attention-deficit–hyperactivity disorder Fetal alcohol syndrome

ADHD is a much more common, and less debilitating, Brain mapping has also identified anomalies in develop-
disorder of childhood than childhood-onset schizophrenia mental disorders with known environmental causes. Fetal
and WS. Nonetheless, volumetric structural brain-ima- alcohol syndrome (FAS) is a severe neurodevelopmental
ging studies of ADHD patients have demonstrated subtle disorder observed in children whose mothers abused
reductions in total brain volume, and in volumes of the alcohol during pregnancy [42,43]. Not all women who
right frontal lobe and caudate nucleus [39,40]. To further abuse alcohol during pregnancy have children with FAS,
understanding of brain abnormalities in ADHD, brain but it is quickly becoming more evident from animal and
mapping studies were conducted in 27 children and both post-mortem and in vivo human studies that the
adolescents with ADHD and in 46 age-matched and brain is especially vulnerable to the teratogenic effects of
gender-matched control subjects [41]. As predicted, alcohol. Children with FAS display prenatal growth
abnormal morphology was observed in the frontal cortices deficiency, developmental delay, craniofacial anomalies
of ADHD subjects, with reduced regional brain size (i.e. microcephaly, epicanthal folds and short palpebral
localized primarily to inferior portions of dorsal prefrontal fissures) and limb defects. Cognitive deficits in these
cortices bilaterally. Brain size was also reduced in anterior children are significant and mental retardation is fre-
temporal cortices bilaterally. Gray-matter density was quently observed, but a clear neuropsychological profile
prominently increased in large portions of the posterior has yet to be discovered [44].
temporal and inferior parietal cortices bilaterally In vivo quantitative MRI studies have confirmed brain
(Figure 7). The etiology and cognitive and behavioral morphological abnormalities in children prenatally
sequelae of this increased gray-matter density and exposed to alcohol. In addition to the microcephaly
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156 Review TRENDS in Neurosciences Vol.29 No.3 March 2006

frequently observed in these children, volumetric MRI factors, because the children were assessed on different
studies have shown that within the cortex, only the scanners at different imaging centers.
parietal lobes were significantly reduced in volume above
and beyond the generalized brain size reduction. White- Genetic influences on the developing brain
matter hypoplasia (i.e. incomplete development) was more In the quest to understand what factors contribute to the
significant than gray-matter hypoplasia, and hippocampal trajectory of brain development in normally developing
volume was relatively intact [45]. These volumetric children and those with neurodevelopmental disorders,
findings prompted use of cortical mapping techniques to genetic and imaging methods can be combined to answer
assess brain abnormalities on a more local level. Localized questions about the influence of genes and environment on
abnormalities in brain size and gray-matter density were brain structure – the so-called nature–nurture debate.
identified in a group of 21 children, adolescents and young With this in mind, twins or family members with different
adults with severe prenatal alcohol exposure compared degrees of genetic affinity can be compared. Of course,
with 21 age-matched and gender-matched non-exposed influences of nature and nurture in the determination of
subjects [46]. The resulting brain maps confirmed parietal individual brain structure are not independent. None-
lobe size reductions observed in the volumetric studies, theless, twin designs can reveal the degree to which
and revealed frontal lobe size reductions that had not been heredity is involved.
previously observed. In fact, frontal lobe abnormalities
were predicted given these children’s deficits on neurop- Twin studies
sychological tests of executive functioning [47]. Further- Probably the best known twin database is the Finnish
more, gray-matter density increases were observed twin registry, which covers information on twin births in
bilaterally in the inferior parietal and posterior temporal Finland from 1940 and has been a resource to many
lobes (Figure 7). These mapping studies suggest that brain epidemiological studies recognized worldwide. These data
growth continues to be adversely affected long after the enabled investigation of which brain regions develop
prenatal insult of alcohol exposure to the developing under tight genetic control and which are more influenced
brain, and the regions most prominently affected are by the environment. Before that, twins had been studied
consistent with the behavioral and neuropsychological using MRI and some similarities in the volumes of brain
deficits in these children. structures had been noted in identical twins, with weaker
resemblance in fraternal twins. In 2001, utilizing this
Similarities among the developmental disorders database, the first study of twins using brain mapping
It is interesting to note the regional correspondence of revealed aspects of brain structure that are largely
gray-matter density abnormalities observed in three of the inherited [50].
four neurodevelopmental disorders reviewed here. As Forty healthy adult subjects, consisting of ten mono-
shown in Figure 7, gray-matter density increases were zygotic and ten dizygotic twin pairs (five male pairs and
observed in perisylvian (language) cortices in ADHD [41], five female pairs in each group) were drawn from a twin
WS [36] and FAS [46]. The magnitude of increase in gray cohort consisting of all the same-sex twins born in Finland
matter relative to their respective control groups varies between 1940 and 1957 for which both members of each
across the disorders, with maxima of w30% in ADHD, pair were alive and still residing in Finland. All the
10% in WS and 50% in FAS. The spatial extent of these subjects were scanned and 3D maps of gray matter and
gray-matter density increases also varies across the models of cortical surface anatomy were derived. Mono-
disorders, and is bilateral in ADHD and FAS, but more zygotic pairs were then matched with the dizygotic pairs.
prominent in the right hemisphere in WS. These disorders Gray-matter volumes in the frontal parts of the brain were
are distinct in terms of their etiologies and neurocognitive more closely matched in the identical twins than in twins
deficit profiles, although various levels of language who were less similar genetically. One interpretation of
impairment are observed in all three disorders. Facial the findings is that areas of the brain involved in process
dysmorphology is present in both FAS and WS. Of and rule learning (e.g. frontal lobe structures) are under
particular relevance might be that ADHD diagnoses are more tight genetic control, at least in terms of gross
common among children with FAS [48] and WS [49]. structural development, than areas of the brain that map
Perhaps the similar profile of gray-matter density life experience and content (the temporal and parietal
abnormalities observed in these three groups are related lobes).
to the common symptoms of ADHD. Functional and The finding that the gross anatomy of the frontal cortex
structural imaging studies evaluating children that have develops under such strong genetic control is also of
ADHD, WS with ADHD, WS without ADHD, FAS with practical use for genetic studies of disease. These
ADHD, and FAS without ADHD might yield interesting genetically mediated structural differences have even
results, although they would be difficult given the relative been linked, using genetic brain-mapping methods, with
rarity of WS in particular. These examples are illustrative known genetic markers that are overrepresented in
only and summarize visualizations derived from different patients with frontal lobe deficits [51].
studies (e.g. case-control studies of FAS, WS and ADHD).
Further studies are required in which the magnitudes and Limitations of brain-imaging studies
spatial patterns of the effects in the different patient As we have shown, MRI used in both cross-sectional and
groups are directly compared. Such direct comparisons longitudinal studies gives precious data on normal and
would have to take into account possible confounding pathological brain development. Key information is now
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 Review TRENDS in Neurosciences Vol.29 No.3 March 2006 157

coming from the large-scale analysis of data from children gray-matter density). As gray matter becomes more
scanned longitudinally using MRI. Moreover, advances in myelinated, the border between gray and white changes,
MRI techniques other than anatomical MRI are now and can be displaced toward the pia. One factor in the
offering additional perspectives on the functional develop- cortical thinning seen in adolescence is not absolute
ment of the brain. Functional MRI studies are now diminution of the cortical gray matter, but rather a change
emerging as a tool to study brain development, as are in the gray–white segmentation boundary because of
fiber-mapping studies using DTI to track connections and increasing intracortical myelin with age, which might
how they develop during maturation. shift the gray–white junction further into the cortical
However, several limitations need to be acknowledged. mantle. Other anatomical features might also affect the
Some are technical. For example, because it requires accurate segmentation of gray and white matter on
considerable statistical power to detect systematic differ- magnetic resonance images. The inner band of Baillarger,
ences in brain structure, sample size is a major issue, for instance, is so richly myelinated that in brain sections
especially when rare disorders are considered. MRI data it is visible with the naked eye, close to the gray–white
can be heterogeneous. Scan databases are only now interface in layer 5b; this might affect the ability to define
becoming large enough to stratify images of brain an accurate cortical boundary in conventional magnetic
development by symptom profiles, therapeutic response resonance images. Further studies with improved tissue
and currently identified risk factors. classification algorithms, tissue relaxometry and high-
MRI has some limits in resolving distinctions between field imaging (providing increased resolution and con-
gray and white matter that are relevant when assessing trast-to-noise ratio) are likely to resolve some of
maturational changes. Recent algorithms for measuring these limitations.
cortical thickness [13] rely on definition of a boundary Other issues concern the interpretation given to some
between gray and white matter, or at least on a proportion data. The key question is: what does a change in the
of tissue identified as gray matter (in the case of volume of a brain region mean, especially when one

(a) Hemispheric asymmetry (b) Gray-matter correlation between twins Perfectly

correlated (%)
16
100
Child Adolescent Adult 14 Identical twins (MZ) Fraternal twins (DZ)
90
r2
12 W 80
10 70
60
8
50
6 40
4 30
2 20
0 10
0
(c) Schizophrenia (d) Alzheimer’s disease

Healthy Schizophrenia Early deficit

adolescents subjects

Boys
Average
Loss rate deficit
(%/year)
0
0
T
–1 –5
1.5 years later (same subjects)
–2
Girls –10
–3
–4 –15
–5

Figure 8. Statistical maps of cortical structure. Various maps can be made that describe different aspects of cortical anatomy. These include maps of gyrus-pattern asymmetry
(a) and how strongly genes and environmental influence brain structure (b). Panel (a) shows the increasing gyrus-pattern asymmetry in groups of children, adolescents and
adults [55]. In these maps, the differences in asymmetry in the three age groups can be evaluated as the angle of the left relative to the right Sylvian fissure in each age group.
Note the angle is larger in the adults than in the children. The color coding enables the displacement in millimeters between the left and right hemisphere within each age
group to be visualized. Asymmetry measures can also be extended to rest of the cortical surface and expressed in millimeters. Panel (b) shows correlations in gray matter for
groups of identical (monozygotic, MZ) and fraternal (dizygotic, DZ) twins. Some brain regions develop under tight genetic control, and these include many frontal and
temporal lobe regions, such as the dorsolateral prefrontal cortex and temporal poles (red). Other regions are more strongly influenced by the environment as they develop
(i.e. a greater proportion of the inter-subject variance is explained by non-genetic factors). (c) Average maps of gray-matter loss rates for healthy boys and girls, scanned
longitudinally over five years. Also shown are maps of the considerably faster loss rates in age-matched and gender-matched subjects with childhood-onset schizophrenia
scanned at the same ages and intervals. The frontal cortex underwent a selective rapid loss of gray matter (up to 3–4% per year faster in patients than controls). These changes
might be, in some respects, an exaggeration of changes that normally occur in adolescence [10,54]. By contrast, deficits occurring as Alzheimer’s disease progresses are
shown (d) by comparing average profiles of gray-matter density between 12 Alzheimer’s disease patients (mean age 68.4G1.9 years) and 14 age-matched controls (mean age
71.4G0.9 years). In Alzheimer’s disease, gray-matter loss sweeps forward in the brain from limbic to frontal cortices in concert with cognitive decline, but in the schizophrenia
patients (c), the frontal cortices lose gray matter the fastest. The letters ‘W’ and ‘T’ denote Wernicke’s area and the temporal cortex, respectively.

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158 Review TRENDS in Neurosciences Vol.29 No.3 March 2006

considers pathology (Figure 8)? Even if the volume and 21 Toga, A.W. and Thompson, P.M. (2003) Temporal dynamics of brain
shape of brain structures are determined, to identify the anatomy. Annu. Rev. Biomed. Eng. 5, 119–145
22 Thompson, P.M. et al. (2000) Growth patterns in the developing brain
underlying cellular cause of these differences one must detected by using continuum-mechanical tensor maps. Nature 404,
rely on using additional sources of information, such as 190–193
post-mortem tissue. Nevertheless, these MRI studies are 23 Martin, E. et al. (1988) Developmental stages of human brain: an MR
likely to help us better understand the links between study. J Comp Assist Tomogr. 12, 917–922
changes in the brain and cognitive development, in 24 Grodd, W. (1993) Normal and abnormal patterns of myelin develop-
ment of the fetal and infantile human brain using magnetic resonance
addition to the clinical course of development and imaging. Curr. Opin. Neurol. Neurosurg 6, 393–397
treatment of illnesses. 25 Hansen, P.E. et al. (1993) MR imaging of the developing human brain,
part 1. Radiographics 13, 21–36
Acknowledgements 26 Wang, Z. et al. (1998) The research of myelinization of normal fetal
This work was funded by grants from the National Institute for brain with magnetic resonance imaging. Chin. Med. J. (Engl.) 111,
Biomedical Imaging and Bioengineering, the National Center for 71–74
Research Resources, and the National Institutes on Aging, Neuro- 27 Neil, J. et al. (2002) Diffusion tensor imaging of normal and injured
degenerative Diseases and Mental Health (grant numbers PO1 developing human brain – a technical review. NMR Biomed. 15,
EB001955, U54 RR021813, MO1 RR000865 and P41 RR13642 to 543–552
A.W.T., and R21 EB01651, R21 RR019771 and P50 AG016570 to 28 Gilmore, J.H. et al. (2004) 3 Tesla magnetic resonance imaging of the
P.M.T.), and from the National Institute of Mental Health, the National brain in newborns. Psychiatry Res. 132, 81–85
Institute of Drug Abuse and the March of Dimes (K01 MH01733, R21 29 Toga, A.W. et al. (2001) Probabilistic approaches for atlasing normal
DA15878, R01 DA017831 and MOD 5FY03-12 to E.R.S.). and disease-specific brain variability. Anat. Embryol. (Berl.) 204,
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30 Thompson, P.M. et al. (2001) Mapping adolescent brain change reveals
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