Dialogues in Clinical Neuroscience

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Post-traumatic stress disorder: the neurobiological

impact of psychological trauma

Jonathan E. Sherin & Charles B. Nemeroff

To cite this article: Jonathan E. Sherin & Charles B. Nemeroff (2011) Post-traumatic
stress disorder: the neurobiological impact of psychological trauma, Dialogues in Clinical
Neuroscience, 13:3, 263-278, DOI: 10.31887/DCNS.2011.13.2/jsherin

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State of the art

Post-traumatic stress disorder:
the neurobiological impact of
psychological trauma
Jonathan E. Sherin, MD, PhD; Charles B. Nemeroff, MD, PhD

Overview of psychological trauma,

post-traumatic stress disorder,
and biological markers

P sychological trauma can result from witnessing

an event that is perceived to be life-threatening or to
pose the potential of serious bodily injury to self or oth-
ers. Such experiences, which are often accompanied by
The classic fight-or-flight response to perceived threat intense fear, horror, and helplessness, can lead to the
is a reflexive nervous phenomenon that has obvious development of, and are required for the diagnosis of,
survival advantages in evolutionary terms. However, post-traumatic stress disorder (PTSD).1 It was originally
the systems that organize the constellation of reflex- thought that PTSD represented a normative response,
ive survival behaviors following exposure to perceived at the extreme end of a response continuum, the sever-
threat can under some circumstances become dysreg- ity of which related primarily to trauma/stressor inten-
ulated in the process. Chronic dysregulation of these sity. However, it has become clear over time that the
systems can lead to functional impairment in certain response of an individual to trauma depends not only on
individuals who become “psychologically traumatized” stressor characteristics, but also on factors specific to the
and suffer from post-traumatic stress disorder (PTSD). individual.2 For the vast majority of the population, the
A body of data accumulated over several decades has psychological trauma brought about by the experience
demonstrated neurobiological abnormalities in PTSD of profound threat is limited to an acute, transient dis-
patients. Some of these findings offer insight into the turbance. Though transient, such reactions can be quite
pathophysiology of PTSD as well as the biological vul- unpleasant and are typically characterized by phenom-
nerability of certain populations to develop PTSD. ena that can be grouped for the most part into three pri-
Several pathological features found in PTSD patients mary domains: (i) reminders of the exposure (including
overlap with features found in patients with traumatic
Author affiliations: Department of Psychiatry and Behavioral Sciences,
brain injury, paralleling the shared signs and symptoms University of Miami, Leonard M. Miller School of Medicine, Miami, Florida, USA
of these clinical syndromes. (Jonathan E. Sherin, Charles B. Nemeroff); Department of Mental Health and
© 2011, LLS SAS Dialogues Clin Neurosci. 2011;13:263-278. Behavioral Sciences, Miami VA Healthcare System, Miami, Florida, USA
(Jonathan E. Sherin)
Keywords: stress; psychological trauma; traumatic brain injury; PTSD; biological
markers; psychopathology; pathophysiology Address for correspondence: Jonathan E. Sherin, Department of Psychiatry and
Behavioral Sciences, University of Miami Leonard M. Miller School of Medicine,
Miami, Florida 33136, USA
(e-mail: [email protected])

Copyright © 2011 LLS SAS. All rights reserved 263 www.dialogues-cns.org

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Selected abbreviations and acronyms could be, however, that certain abnormalities in the
5HT serotonin patient with PTSD simply represent pre-existing or
CRH corticotropin-releasing hormone “upstream” pathology that is functionally dormant until
DA dopamine released by trauma exposure and detected thereafter
GABA 웂-aminobutyric acid upon investigation. Along these lines, recent interest has
HPA hypothalamic-pituitary-adrenal focused on factors that seem to modulate outcome vari-
NE norepinephrine ation in neurobiological systems following trauma expo-
NPY neuropeptide Y sure including genetic susceptibility factors, female gen-
PTSD post-traumatic stress disorder der, prior trauma, early developmental stage at the time
of traumatic exposure, and physical injury (including
flashbacks, intrusive thoughts, nightmares); (ii) activa- traumatic brain injury—TBI) at the time of psychologi-
tion (including hyperarousal, insomnia, agitation, irri- cal trauma; these parameters likely contribute to vulner-
tability, impulsivity and anger); and (iii) deactivation ability for, versus resilience against, developing PTSD.
(including numbing, avoidance, withdrawal, confusion, Although the biological, psychological, and social ram-
derealization, dissociation, and depression). As these ifications of PTSD have been under scientific scrutiny
reactions are self-limiting by definition, in general they for some time now, and treatment has improved dra-
provoke minimal functional impairment over time. On matically, much remains unknown about this condition
the other hand, for a significant minority of the popu- and controversy persists in both the neuroscientific as
lation, the psychological trauma brought about by the well as the clinical/treatment literature. In this text, we
experience of profound threat leads to a longer-term review the neurobiological impact of psychological
syndrome that has been defined, validated, and termed trauma from the perspective that genetic, developmen-
PTSD in the clinical literature. PTSD is often accompa- tal, and experiential factors predispose certain individ-
nied by devastating functional impairment. uals to the development of PTSD. More specifically, we
PTSD is characterized by the presence of signs and review the current database as pertains to biological
symptoms in the three primary domains described above markers of PTSD and the possibility that some biologi-
for a period extending beyond 1 month (such periods can cal markers may not be acquired but, rather, may in fact
in some cases occur long after the original, precipitating predate trauma until functionally “unmasked” by stress.
traumatic exposure). The signs and symptoms of PTSD, Where relevant, we also make note of similarities
therefore, appear to reflect a persistent, abnormal adap- between PTSD and TBI, which extend beyond well-
tation of neurobiological systems to the stress of wit- known signs and symptoms (such as irritability and
nessed trauma. The neurobiological systems that regulate social withdrawal) to include abnormalities in the same
stress responses include certain endocrine and neuro- neurobiological systems. Lastly, the article includes a
transmitter pathways as well as a network of brain short section on basic considerations for future direction.
regions known to regulate fear behavior at both con- Ideas put forth in this communication are done so in the
scious and unconscious levels. Not surprisingly, much interest of developing a consistent model for conceptual
research has consequently focused on exploring these purposes. It is recognized at the outset that numerous
systems in more detail as well as attempting to elucidate inconsistencies can be found in the literature that high-
the pathological changes that occur in patients who light the multifactorial and complex nature of this field.
develop PTSD. More specifically, there have been and
continue to be ongoing efforts to link neurobiological The biology of PTSD
changes identified in patients who suffer from PTSD to
the specific clinical features that constitute PTSD, includ- There are a number of factors that must be considered
ing altered learning/extinction, heightened arousal, and in contemplating the interplay between adverse envi-
intermittent dissociative behavior as examples relevant ronmental stimulation, stress responses/reactions, and
to each of the three primary domains. Efforts to identify pathology. In this section, basic findings are reviewed
neurobiological markers for PTSD originally presumed from endocrinology, neurochemistry, and brain circuitry
that abnormalities were acquired “downstream” from an research conducted on patients with a diagnosis of
exposure, as a consequence of traumatic experience. It PTSD (Table I).

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Endocrine factors nucleus (PVN) secrete corticotropin-releasing hormone

(CRH) from nerve terminals in the median eminence
Core endocrine features of PTSD include abnormal reg- into the hypothalamo-hypophyseal portal circulation,
ulation of cortisol and thyroid hormones, though there which stimulates the production and release of adreno-
is some disagreement about these findings in the litera- corticotropin (ACTH) from the anterior pituitary. ACTH
ture. Of note, endocrine dysregulation is also found in in turn stimulates the release of glucocorticoids from the
patients diagnosed with TBI as a result of damage to the adrenal cortex. Glucocorticoids modulate metabolism as
pituitary stalk. well as immune and brain function, thereby orchestrat-
ing physiological and organismal behavior to manage
The hypothalamic-pituitary-adrenal axis stressors. At the same time, several brain pathways mod-
ulate HPA axis activity. In particular, the hippocampus
The hypothalamic-pituitary-adrenal (HPA) axis is the and prefrontal cortex (PFC) inhibit, whereas the amyg-
central coordinator of the mammalian neuroendocrine dala and aminergic brain stem neurons stimulate, CRH
stress response systems, and as such, it has been a major neurons in the PVN. In addition, glucocorticoids exert
focus of scrutiny in patients with PTSD (Figure 1). In negative feedback control of the HPA axis by regulating
short, the HPA axis is made up of endocrine hypothala- hippocampal and PVN neurons. Sustained glucocorticoid
mic components, including the anterior pituitary, as well exposure has adverse effects on hippocampal neurons,
as an effector organ, the adrenal glands. Upon exposure including reduction in dendritic branching, loss of den-
to stress, neurons in the hypothalamic paraventricular dritic spines, and impairment of neurogenesis.3-5

Feature Change Effect

A. Neuroendocrine
Hypothalamic-pituitary-adrenal axis Hypocortisolism Disinhibits CRH/NE and upregulates response to stress
Drives abnormal stress encoding and fear processing
Sustained, increased level of CRH Blunts ACTH response to CRH stimulation
Promotes hippocampal atrophy
Hypothalamic-pituitary-thyroid axis Abnormal T3:T4 ratio Increases subjective anxiety
B. Neurochemical
Catecholamines Increased dopamine levels Interferes with fear conditioning by mesolimbic system
Increased norepinephrine levels/activity Increases arousal, startle response, encoding of fear memories
Increases pulse, blood pressure, and response to memories
Serotonin Decreased concentrations of 5HT in:
Dorsal raphé Disturbs dynamic between amygdala and hippocampus
Median raphé Compromises anxiolytic effects
Dorsal/median raphé Increases vigilance, startle, impulsivity, and memory intrusions
Amino acids Decreased GABA activity Compromises anxiolytic effects
Increased glutamate Fosters derealization and dissociation
Peptides Decreased plasma NPY concentrations Leaves CRH/NE unopposed and upregulates response to stress
Increased CSF β-endorphin levels Fosters numbing, stress-induced analgesia, and dissociation
C. Neuroanatomic
Hippocampus Reduced volume and activity Alters stress responses and extinction
Amygdala Increased activity Promotes hypervigilance and impairs discrimination of threat
Cortex Reduced prefrontal volume Dysregulates executive functions
Reduced anterior cingulate volume Impairs the extinction of fear responses
Decreased medial prefrontal activation Unclear

Table I. Summary of neurobiological features with identified abnormalities and functional implications in patients with post-traumatic stress disorder.
CRH, corticotropin-releasing hormone; 5HT, serotonin; GABA, γ-aminobutyric acid; NPY, neuropeptide Y; ACTH, adrenocorticotropin; NE, nor-
epinephrine; CSF, cerebrospinal fluid

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Although stressors as a general rule activate the HPA parator groups. This surprising finding, though replicated
axis, studies in combat veterans with PTSD demonstrate in PTSD patients from other populations including
decreases in cortisol concentrations, as detected in urine Holocaust survivors, refugees, and abused persons, is not
or blood, compared with healthy controls and other com- consistent across all studies.6 It has been suggested that

Figure 1. The hypothalamic-pituitary-adrenal axis is the body’s major response system for stress. The hypothalamus secretes CRH, which binds to recep-
tors on pituitary cells, which produce/release ACTH, which is transported to the adrenal gland where adrenal hormones such as cortisol are
produced/released. The release of cortisol activates sympathetic nervous pathways and generates negative feedback to both the hypothala-
mus and the anterior pituitary. This negative feedback system appears to be compromised in patients with post-traumatic stress disorder. CRH,
corticotropin-releasing hormone; ACTH, adrenocorticotropin

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inconsistent findings may result from differences in the ever, there has not been a significant research effort tar-
severity and timing of psychological trauma, the patterns geting the relationship between the HPT axis and PTSD.
of signs/symptoms, comorbid conditions, personality, and Studies have been conducted, however, on Vietnam
genetic makeup.7 Studies using low-dose dexamethasone Veterans with PTSD who were found to have elevated
suppression testing suggest that hypocortisolism in PTSD baseline levels of both tri-iodothyronine (T3) and thy-
occurs due to increased negative feedback sensitivity of roxine (T4). Of note, the level of T3 in these subjects was
the HPA axis. Sensitized negative feedback inhibition is disproportionately elevated relative to T4, implicating
supported by findings of increased glucocorticoid recep- an increase in the peripheral deiodinization process.15,16
tor binding and function in patients with PTSD.6 Further, These findings were replicated for the most part in a
sustained increases of CRH concentrations have been study of WWII Veterans with more longstanding PTSD
measured in cerebrospinal fluid (CSF) of patients with diagnoses. In these individuals, isolated T3 levels were
PTSD. As such, blunted ACTH responses to CRH stim- elevated whereas T4 levels were normal.17 Taken
ulation implicate a role for the downregulation of pitu- together, these studies suggest that over time the impact
itary CRH receptors in patients with PTSD.6 In addition, of trauma on T4 levels may abate. The authors suggest
reduced volume of the hippocampus, the major brain that elevated T3 may relate to subjective anxiety in these
region inhibiting the HPA axis, is a cardinal feature of individuals with PTSD.
PTSD.8 Taken as a whole, these neuroendocrine findings
in PTSD reflect dysregulation of the HPA axis to stres- Neurochemical factors
sors.6
In the context of the above discussion, prospective stud- Core neurochemical features of PTSD include abnormal
ies suggest that low cortisol levels at the time of expo- regulation of catecholamine, serotonin, amino acid, pep-
sure to psychological trauma may predict the develop- tide, and opioid neurotransmitters, each of which is
ment of PTSD.9,10 Therefore, hypocortisolism might be a found in brain circuits that regulate/integrate stress and
risk factor for maladaptive stress responses and predis- fear responses. Of note, catecholamine and serotonin (as
pose to future PTSD. This hypothesis is supported in well as acetylcholine) dysregulation is also found in
principle by the finding that exogenously administered patients diagnosed with TBI, presumably as a result of
hydrocortisone shortly after exposure to psychological diffuse axonal injury.
trauma can prevent PTSD.11,12 In addition, it has been
shown that simulation of a normal circadian cortisol The catecholamines
rhythm using exogenously introduced hydrocortisone is
effective in the treatment of PTSD.13 In sum, it may be The catecholamine family of neurotransmitters, includ-
that decreased availability of cortisol, as a result of or in ing dopamine (DA) and norepinephrine (NE), derive
combination with abnormal regulation of the HPA axis, from the amino acid tyrosine. Increased urinary excre-
may promote abnormal stress reactivity and perhaps tion of DA and its metabolite has been reported in
fear processing in general. That said, it should be noted patients with PTSD. Further, mesolimbic DA has been
that glucocorticoids interfere with the retrieval of trau- implicated in fear conditioning. There is evidence in
matic memories, an effect that may independently pre- humans that exposure to stressors induces mesolimbic
vent or reduce symptoms of PTSD.14 DA release, which in turn could modulate HPA axis
responses. Whether or not DA metabolism is altered in
The hypothalamic-pituitary-thyroid axis PTSD remains unclear, though genetic variations in the
DA system have been implicated in moderating risk for
The hypothalamic-pituitary-thyroid (HPT) axis is PTSD (see below). NE, on the other hand, is one of the
involved in regulating metabolic versus anabolic states principal mediators of autonomic stress responses
and other homeostatic functions, which it does by con- through both central and peripheral mechanisms. The
trolling the blood level of thyroid hormones. A possible majority of CNS NE is derived from neurons of the
role for the HPT axis in stress-related syndromes has locus ceruleus (LC) that project to various brain
been suspected for some time because it is known that regions involved in the stress response, including the
trauma can trigger thyroid abnormalities. To date, how- prefrontal cortex, amygdala, hippocampus, hypothala-

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mus, periaqueductal grey, and thalamus. In addition, of the centrally acting β-adrenergic receptor antagonist
there is evidence for a feed-forward circuit connecting propranolol shortly after exposure to psychological
the amygdala and hypothalamus with the LC, in which trauma has been reported to reduce PTSD symptom
CRH and NE interact to increase fear conditioning and severity and reactivity to trauma cues.24 Although pro-
encoding of emotional memories, enhance arousal and pranolol administration in this study did not prevent the
vigilance, and integrate endocrine and autonomic development of PTSD, it may have blocked traumatic
responses to stress. Like other stress pathways, this cas- memory consolidation,25 and therefore may reduce the
cade is inhibited by glucocorticoids,18 which serve as a severity and/or chronicity of PTSD. It is important to
“brake” for the system. In the periphery, stress-induced note, however, that this finding contradicts those from
sympathetic nervous system activation results in the an earlier study.26 Various antiadrenergic agents have
release of NE and epinephrine from the adrenal been tested for their therapeutic efficacy in the treat-
medulla, increased release of NE from sympathetic ment of PTSD in open-label trials; there is a paucity of
nerve endings, and changes in blood flow to a variety controlled trials.20
of organs as needed for fight-or-flight behavior. The NE
effects are mediated via postsynaptic α1, β1, and β2 Serotonin
receptors, whereas another NE-activated receptor, the
α2 receptor, serves as a presynaptic autoreceptor Serotonin (5HT), is a monoamine neurotransmitter syn-
inhibiting NE release. Because of its multiple roles in thesized from the amino acid tryptophan. Neurons con-
regulating arousal and autonomic stress responses, as taining 5HT originate in the dorsal and median raphé
well as promoting the encoding of emotional memories, nuclei in the brain stem and project to multiple forebrain
NE has been a central focus of many studies investi- regions, including the amygdala, bed nucleus of the stria
gating the pathophysiology of PTSD. terminalis, hippocampus, hypothalamus, and prefrontal
A cardinal feature of patients with PTSD is sustained cortex. 5HT has roles in regulating sleep, appetite, sex-
hyperactivity of the autonomic sympathetic branch of ual behavior, aggression/impulsivity, motor function,
the autonomic nervous system, as evidenced by eleva- analgesia, and neuroendocrine funtion. Not surprisingly,
tions in heart rate, blood pressure, skin conductance, and given its connectivity and broad homeostatic role, 5HT
other psychophysiological measures. Accordingly, has been implicated in the modulation of affective and
increased urinary excretion of catecholamines, and their stress responses, as well as a role in PTSD. Although the
metabolites, has been documented in combat veterans, mechanisms are not entirely clear, the effects of 5HT on
abused women, and children with PTSD. In addition, affective and stress responses vary according to stressor
patients with PTSD exhibit increased heart rate, blood intensity, brain region, and receptor type. It is believed
pressure, and NE responses to traumatic reminders. that 5HT neurons of the dorsal raphé mediate anxio-
Decreased platelet α2 receptor binding further suggests genic effects via 5HT2 receptors through projections to
NE hyperactivity in PTSD.19,20 Administration of the α2 the amygdala and hippocampus. In contrast, 5HT neu-
receptor antagonist yohimbine, which increases NE rons from the median raphé are thought to mediate anx-
release, induces flashbacks and increased autonomic iolytic effects, facilitate extinction and suppress encod-
responses in patients with PTSD.21 Serial sampling ing of learned associations via 5HT1A receptors. Chronic
revealed sustained increases in CSF NE concentrations exposure to stressors induces upregulation of 5HT2 and
and increased CSF NE responses to psychological stres- downregulation of 5HT1A receptors in animal models.
sors in PTSD.22,23 Taken together, there is an abundance Further, 5HT1A knockouts exhibit increased stress
of evidence that NE accounts for certain classic aspects responses.
of PTSD symptomatology, including hyperarousal, The 5HT system interacts with the CRH and NE sys-
heightened startle, and increased encoding of fear mem- tems in coordinating affective and stress responses.19,27
ories.20 Indirect evidence suggests a role for 5HT in PTSD-
Interestingly, prospective studies have shown that related behaviors including impulsivity, hostility, aggres-
increased heart rate and peripheral epinephrine excre- sion, depression, and suicidality. In addition, 5HT pre-
tion at the time of exposure to trauma predict subse- sumably mediates the therapeutic effects of the selective
quent development of PTSD.10 Further, administration serotonin reuptake inhibitors (SSRIs). A recent small

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and controversial study suggests that the street drug PTSD are relatively sparse and conclusive statements
3, 4-Methylenedioxymethamphetamine (also known as would be premature.19
MDMA or “ecstasy”), which alters central serotonin Glutamate is the primary excitatory neurotransmitter in
transmission, has therapeutic potential in the treatment the brain. Exposure to stressors and the release of, or
of PTSD.28 Other evidence for altered 5HT neurotrans- administration of, glucocorticoids activates glutamate
mission in PTSD includes decreased serum concentra- release in the brain. Among a number of receptor sub-
tions of 5HT, decreased density of platelet 5HT uptake types, glutamate binds to N-methyl D-aspartate
sites, and altered responsiveness to CNS serotonergic (NMDA) receptors that are localized throughout the
challenge in patients diagnosed with PTSD.19,27 However, brain. The NMDA receptor system has been implicated
no differences in CNS 5HT1A receptor binding were in synaptic plasticity, as well as learning and memory,
detected in patients with PTSD compared with controls thereby contributing in all likelihood to consolidation of
using PET imaging.28 Taken together, altered 5HT trans- trauma memories in PTSD. The NMDA receptor system
mission may contribute to symptoms of PTSD including is also believed to play a central role in the derealization
hypervigilance, increased startle, impulsivity, and intru- phenomena and dissocation associated with illicit and
sive memories, though the exact roles and mechanisms medical uses of the anesthetic ketamine. In addition to
remain uncertain. its role in learning and memory, overexposure of neu-
rons to glutamate is known to be excitotoxic, and may
Amino acids contribute to the loss of neurons and/or neuronal
integrity in the hippocampus and prefrontal cortex of
γ-Aminobutyric acid (GABA) is the principal inhibitory patients with PTSD. Of additional note, elevated gluco-
neurotransmitter in the brain. GABA has profound corticoids increase the expression and/or sensitivity of
anxiolytic effects and dampens behavioral and physio- NMDA receptors, which may render the brain generally
logical responses to stressors, in part by inhibiting the more vulnerable to excitoxic insults at times of stress.
CRH/NE circuits involved in mediating fear and stress
responses. GABA’s effects are mediated by GABAA Peptides
receptors, which are colocalized with benzodiazepine
receptors that potentiate the inhibitory effects of CRH neurons in the hypothalamic PVN integrate infor-
GABA on postsynaptic elements. Uncontrollable stress mation relevant to stress and thereby serve as a major
leads to alterations of the GABAA/benzodiazepine component of the HPA axis. CRH neurons are also
receptor complex such that patients with PTSD exhibit found in widespread circuitry throughout the brain,
decreased peripheral benzodiazepine binding sites.29 including the prefrontal and cingulate cortices, central
Further, SPECT and PET imaging studies have nucleus of the amygdala, the bed nucleus of the stria ter-
revealed decreased binding of radiolabeled benzodi- minalis, hippocampus, nucleus accumbens, periaqueduc-
azepine receptor ligands in the cortex, hippocampus, tal gray, and locus coeruleus (LC) as well as both dorsal
and thalamus of patients with PTSD, suggesting that and median raphé. Direct injection of CRH into the
decreased density or receptor affinity may play a role in brain of laboratory animals produces physiological stress
PTSD.30,31 However, treatment with benzodiazepines responses and anxiety-like behavior, including neopho-
after exposure to psychological trauma does not pre- bia (fear of new things or experiences), enhanced star-
vent PTSD.32,33 Further, a recent study suggests that trau- tle, and facilitated fear conditioning. Anxiety-like behav-
matic exposure at times of intoxication actually facili- iors have been specifically linked with increased activity
tates the development of PTSD.34 Although perhaps of amygdalar CRH-containing neurons that project to
counterintuitive, the authors suggest that the contextual the LC. Of note, glucocorticoids inhibit CRH-induced
misperceptions which commonly accompany alcohol activation of LC noradrenergic neurons, providing a
intoxication may serve to make stressful experiences potential mechanism by which low cortisol may facilitate
more difficult to incorporate intellectually, thereby sustained central stress and fear responses.
exacerbating fear. Taken together, while there are mul- The effects of CRH are mediated primarily through two
tiple studies strongly implicating the GABA/benzodi- CRH receptor subtypes, CRH1 and CRH2. In animal
azepine receptor system in anxiety disorders, studies in experiments, both exogenous administration of a CRH1

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receptor antagonist, and experimental knockout of the stress-induced analgesia, and dissociation. Of additional
CRH1 receptor, produce attenuated stress responses and interest, the nonselective opioid receptor antagonist, nal-
reduced anxiety. A recent experiment demonstrated that trexone, appears to be effective in treating symptoms of
CRH1 receptor blockade impacted not only gastroin- dissociation and flashbacks in traumatized persons.19,37
testinal measures of chronic stress, but also prevented Further, the administration of morphine has been
stress-induced hair loss in rodents.35 Thus, CRH1 recep- reported to prevent PTSD.38 Of note, an experiment
tor stimulation may be involved in facilitating stress investigating the hypothesis that PTSD may play an eti-
responses and anxiety. By contrast, CRH2 knockout ologic role in fostering opioid addiction in an opioid-
mice demonstrate stress sensitization and increased anx- dependent group of subjects rendered negative results.39
iety, suggesting a role for CRH2 receptor activation in
reducing stress reactivity.3 Given the central effects of Brain circuitry
CRH, as described in animal models, increased CNS
CRH activity may promote certain of the cardinal fea- Characteristic changes in brain structure and function
tures of PTSD, such as conditioned fear responses, have been identified in patients with PTSD using brain-
increased startle reactivity, sensitization to stressor expo- imaging methods.40-42 Brain regions that are altered in
sure, and hyperarousal. These results suggest that CRH1 patients with PTSD include the hippocampus and amyg-
receptor antagonists and/or CRH2 agonists might have dala as well as cortical regions including the anterior cin-
important therapeutic potential in the treatment of gulate, insula, and orbitofrontal region. These areas
PTSD. interconnect to form a neural circuit that mediates,
Neuropeptide Y (NPY) may well be protective against among other functions, adaptation to stress and fear con-
the development of PTSD in that it has anxiolytic and ditioning. Changes in these circuits have been proposed
stress-buffering properties. NPY has been shown to to have a direct link to the development of PTSD.40
inhibit CRH/NE circuits involved in stress and fear Recent work raises the question as to which CNS ele-
responses and to reduce the release of NE from sympa- ments are involved in circuit changes resulting from
thetic neurons. As such, a lack of NPY may promote stress, and suggests a critical role for myelin.43 Similar to
maladaptive stress responses and contribute to the PTSD, brain areas most impacted by TBI include infe-
development of PTSD. Indeed, patients with PTSD have rior frontal and temporal lobes, and it is likely that
been reported to exhibit decreased plasma NPY con- myelinated circuits are subject to damage broadly as a
centrations and blunted NPY responses to yohimbine result of shear forces.
challenge, compared with controls. Together, these find-
ings suggest that decreased NPY activity may contribute Hippocampus
to noradrenergic hyperactivity in PTSD.36 Moreover, it
has been suggested that NPY may be involved in pro- A hallmark feature of PTSD is reduced hippocampal
moting recovery from, or perhaps resilience to PTSD, volume. The hippocampus is implicated in the control of
given that combat veterans without PTSD have been stress responses, declarative memory, and contextual
shown to exhibit elevated NPY levels compared with aspects of fear conditioning. Not surprisingly, the hip-
veterans with PTSD.6 pocampus is one of the most plastic regions in the brain.
Endogenous opioid peptides including the endorphins As mentioned above, prolonged exposure to stress and
and enkephalins act upon the same CNS receptors acti- high levels of glucocorticoids in laboratory animals dam-
vated by exogenous opioid molecules such as morphine ages the hippocampus, leading to reduction in dendritic
or heroin. Endogenous opioids exert inhibitory influ- branching, loss of dendritic spines, and impairment of
ences on the HPA axis. Naloxone, an opioid receptor neurogenesis.4 Initial magnetic resonance imaging
antagonist, increases HPA axis activation as evidenced (MRI) studies demonstrated smaller hippocampal vol-
by exaggerated HPA axis response to naloxone. PTSD umes in Vietnam Veterans with PTSD and patients with
patients exhibit increased CSF β-endorphin levels, sug- abuse-related PTSD compared with controls.44-47 Small
gesting increased activation of the endogenous opioid hippocampal volumes were associated with the severity
system. Alterations in endogenous opioids may be of trauma and memory impairments in these studies.
involved in certain PTSD symptoms such as numbing, These findings were generally replicated in most but not

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all subsequent work. Studies using proton magnetic res- moderate risk for PTSD,58,59 increased amygdala reactiv-
onance spectroscopy further observed reduced levels of ity may represent a biological risk factor for developing
N-acetyl aspartate (NAA), a marker of neuronal PTSD.
integrity, in the hippocampus of adult patients with
PTSD.40 Of note, NAA reductions were correlated with Cortex
cortisol levels.48 Interestingly, reduced hippocampal vol-
ume has been observed in depressed women with a his- The medial prefrontal cortex (PFC) comprises the ante-
tory of early life trauma49 but not in children with rior cingulate cortex (ACC), subcallosal cortex, and the
PTSD.50 medial frontal gyrus. The medial PFC exerts inhibitory
Hippocampal volume reduction in PTSD may reflect the control over stress responses and emotional reactivity in
accumulated toxic effects of repeated exposure to part by its connections with the amygdala. It further
increased glucocorticoid levels or increased glucocorti- mediates extinction of conditioned fear through active
coid sensitivity, though recent evidence also suggests that inhibition of acquired fear responses.41 Patients with
decreased hippocampal volumes might be a pre-existing PTSD exhibit decreased volumes of the frontal cortex,60
vulnerability factor for developing PTSD.24 Indeed, hip- including reduced ACC volumes.61,62 This reduction in
pocampal deficits may promote activation of and failure ACC volume has been correlated with PTSD symptom
to terminate stress responses, and may also contribute to severity in some studies. In addition, an abnormal shape
impaired extinction of conditioned fear as well as deficits of the ACC,63 as well as a decrease of NAA levels in the
in discriminating between safe and unsafe environmen- ACC,64 has been reported for PTSD patients. A recent
tal contexts. Studies using functional neuroimaging have twin study suggests that, unlike the hippocampus, vol-
further shown that PTSD patients have deficits in hip- ume loss in the ACC is secondary to the development of
pocampal activation during a verbal declarative mem- PTSD rather than a pre-existing risk factor.65 Functional
ory task.51 Both hippocampal atrophy and functional imaging studies have found decreased activation of the
deficits reverse to a considerable extent after treatment medial PFC in PTSD patients in response to stimuli,
with SSRIs,52 which have been demonstrated to increase such as trauma scripts,66,67 combat pictures and sounds,68
neurotrophic factors and neurogenesis in some preclin- trauma-unrelated negative narratives,69 fearful faces,70
ical studies,5 but not others.53 emotional stroop,71 and others, though there are also dis-
cordant findings.41 Reduced activation of the medial PFC
Amygdala was associated with PTSD symptom severity in several
studies and successful SSRI treatment has been shown
The amygdala is a limbic structure involved in emotional to restore medial prefrontal cortical activation patterns.41
processing and is critical for the acquisition of fear Of note, in the abovementioned conditioning experi-
responses. The functional role of the amygdala in medi- ment,57 extinction of conditioned fear was associated
ating both stress responses and emotional learning impli- with decreased activation of the ACC, providing a bio-
cate its role in the pathophysiology of PTSD. Although logical correlate for imprinted traumatic memories in
there is no clear evidence for structural alterations of the PTSD. Not surprisingly, given the connectivity between
amygdala in PTSD, functional imaging studies have the amygdala and medial PFC, interactions in activation
revealed hyper-responsiveness in PTSD during the pre- patterns between these regions have been reported in
sentation of stressful scripts, cues, and/or trauma PTSD, though the direction of the relationship is incon-
reminders.41 PTSD patients further show increased amyg- sistent across studies.41
dala responses to general emotional stimuli that are not
trauma-associated, such as emotional faces.41 The amyg- The origin of neurobiological
dala also seems to be sensitized to the presentation of abnormalities in PTSD
subliminally threatening cues in patients with PTSD,54-56
and increased activation of the amygdala has been A number of studies have investigated the fundamental
reported in PTSD patients during fear acquisition in a question as to whether the neurobiological changes iden-
conditioning experiment.57 Given that increased amyg- tified in patients with PTSD represent markers of neural
dala reactivity has been linked to genetic traits which risk to develop PTSD upon exposure to extreme stress

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as opposed to abnormalities acquired through traumatic PTSD. Why some individuals will develop PTSD fol-
exposure or, most likely, a combination of both. As an lowing trauma, whereas others do not, is of paramount
example, low cortisol levels at the time of a trauma pre- importance. Because the majority of trauma survivors
dict subsequent development of PTSD. Thus, low levels do not go on to develop PTSD, it is crucial going forward
of cortisol might be a pre-existing risk factor that engen- to understand vulnerability and resiliency factors. In this
ders the development of PTSD; low levels of cortisol section, the role of genetic factors, gender differences,
could disinhibit CRH/NE circuits and thereby promote and early developmental stress experiences in moderat-
unopposed autonomic and neuroendocrine responses to ing risk for developing PTSD in response to psycholog-
stress, as well as augmented fear conditioning and trau- ical trauma are discussed as is the increased risk for
matic memory consolidation. Similarly, the reduced size developing PTSD in the context of co-occurring physi-
of the hippocampus in PTSD has remained an unre- cal traumas (including TBI).
solved question for many years. There has been consid-
erable debate as to whether this brain region shrinks as Genetic risk factors for PTSD
a result of trauma exposure, or whether the hippocam-
pus of PTSD patients might be smaller prior to trauma Studies on the genetics of PTSD have been hampered
exposure. Studies in twins discordant for trauma expo- by a variety of factors, such as genetic heterogeneity
sure have provided a means to address this question, (similar phenotypes develop from different genotypes)
though without complete resolution. Gilbertson and col- and incomplete phenotypic penetrance (a person with
leagues72 studied 40 pairs of identical twins, including genetic risk for PTSD, who is not exposed to trauma, will
Vietnam Veterans who were exposed to combat trauma not develop PTSD). Despite these confounds, there is
and their twins who did not serve in Vietnam, and mea- accumulating evidence that risk for PTSD is heavily
sured hippocampal volumes in all subjects. As expected, influenced by genetic factors. Evidence from family and
among Vietnam Veterans, the hippocampus was smaller twin studies has long suggested a heritable contribution
in those diagnosed with PTSD as compared with those to the development of PTSD. In addition, there is evi-
without a diagnosis. However, this brain region was dence for heritable contributions to some of the neuro-
abnormally smaller in non-PTSD twins as well, despite biological endophenotypes of PTSD as discussed above,
the absence of trauma exposure and diagnosis. These such as decreased hippocampal volume72 or exaggerated
findings suggest that a smaller hippocampus could be a amygdala reactivity.58 Although it is beyond the scope of
pre-existing, potentially genetic, neurodevelopmental, this review to comprehensively discuss the genetics of
and almost surely multifactorial vulnerability factor that PTSD, it should be noted that there is an emerging lit-
predisposes to the development of PTSD (and perhaps erature on genetic variations in those neurobiological
other stress-spectrum disorders). Recent results from the systems that drive responses to trauma and, conse-
same study group indicate, as above, that gray matter quently, risk versus resilience to develop PTSD.73
loss in the ACC seems on the contrary to be an acquired One study has linked a polymorphism in the DA trans-
feature.65 Studies are needed to identify the timing porter gene to PTSD risk. In this study, PTSD patients
and/or etiology of other hallmark neurobiological fea- were found to have an excess of the SLC6A39 repeat
tures of PTSD. allele. This finding suggests that genetically determined
features of DA transmission may contribute to the
Risk and resilience for developing PTSD development of PTSD among trauma survivors.74 Several
studies have suggested polymorphisms in the D2 recep-
Individuals exposed to an event that either threatens tor as possible elements of PTSD risk, though results
serious injury/death, or is perceived as such, respond in have not been consistent.73 In addition, there is evidence
different ways. Most will experience minimal (seconds) linking a low expression variant of the serotonin trans-
to brief (hours) to short-term (days/weeks) abnormali- porter to stress responsiveness and risk for developing
ties while a smaller number will suffer from significant depression in relation to life stress, particularly in the
psychopathology over longer-term (months) and chronic presence of low social support.59 This finding is intrigu-
(lifetime) time frames. In short, not all individuals who ing as the same polymorphism is associated with
face potentially catastrophic trauma go on to develop increased amygdala reactivity58 as well as the trait of

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PTSD: neurobiological impact of psychological trauma - Sherin and Nemeroff Dialogues in Clinical Neuroscience - Vol 13 . No. 3 . 2011

neuroticism,75 which is another risk factor for PTSD. It implicated in modulating these systems as well.84
must be noted, however, that these findings of genetic However, gender differences in HPA responses to stress
risk with regard to the serotonin transporter have have also been observed independent of acute gonadal
recently been questioned.76 steroid effects.85
Particularly exciting are findings that a genetic variation Factors that might determine gender differences in the
of the glucocorticoid receptor cochaperone protein, stress response include genomic differences (as above)
FKBP5, moderates risk of developing PTSD in relation and/or developmentally programmed effects of gonadal
to childhood abuse.77 This study tested interactions of steroids.81,85,86 Of note, a very recent study of female
childhood abuse, adulthood trauma, and genetic poly- Veterans demonstrated that pregnancy raises the risk of
morphisms in the FKBP5 gene in 900 nonpsychiatric, PTSD above that for nonpregnant females.87 In addition,
general internal medicine clinic patients. Childhood sex steroids play a role in structural plasticity across the
abuse and adulthood trauma each predicted PTSD lifespan of several brain regions, including areas involved
symptoms and FKBP5 polymorphisms significantly in stress responsiveness such as the hippocampus and
interacted with childhood abuse to predict adult PTSD amygdala.86 Functional imaging studies have identified
symptoms. The FKBP5 genotype was further linked to gender differences in the brain’s response to fear stim-
enhanced glucocorticoid receptor sensitivity, as reflected uli.88 Over time our understanding of this constellation
by dexamethasone hypersuppression, a hallmark feature of processes may eventually converge to allow for a bet-
of PTSD.77 Most recently, Ressler and colleagues have ter description of the basis for gender differences and,
demonstrated that a female-specific elevation of pitu- specifically, how the consequences of trauma translate
itary adenylate cyclase-activating peptide (PACAP) cor- into differential risk for PTSD.
related not only with fear physiology and the diagnosis
of PTSD78 but also a specific single nucleotide repeat on Early developmental factors and PTSD
an estrogen response element in the same subjects.
These findings and this type of work may shed new light Previous experience moderates risk for developing
not only on the well-known differences in PTSD risk PTSD in response to trauma, particularly when exposure
between men and women that are discussed in the next to stress occurs early in life. Thus, childhood adversity is
section, but on our mechanistic understanding of PTSD associated with increased risk to develop PTSD in
in general. response to combat exposure in Vietnam Veterans.51
There is a burgeoning literature documenting that early
Gender differences and risk for PTSD adverse experience, including prenatal stress and stress
throughout childhood, has profound and long-lasting
Women more frequently suffer from PTSD than men for effects on the development of neurobiological systems,
reasons that are not entirely clear. Women and men are, thereby “programming” subsequent stress reactivity and
in general, subjected to different types of trauma, though vulnerability to develop PTSD.89-91 As an example, chil-
the differences in PTSD frequency (reportedly 2:1) are dren with a history of date violence have recently been
unlikely to be explained solely on the basis of exposure shown at risk of developing future PTSD.92 Further, a
type and/or severity alone. In addition to those findings study of child survivors from the Hurricane Katrina dis-
by Ressler described above, a number of gender-related aster indicates significantly increased risk of PTSD.93
differences in the neurobiological response to trauma Along these lines, nonhuman primates exposed to a vari-
have been documented.79 Rodent studies suggest that able foraging demand condition, which causes unpre-
females generally exhibit greater magnitude and dura- dictable maternal care in the infant, leads to an adult
tion of HPA axis responses to stress than males,80 though phenotype with sensitization to fear cues, CRH hyper-
findings in humans are not entirely consistent.81 Sex dif- activity and low cortisol levels, a pattern of the classic
ferences in neuroendocrine stress responses have been features found in PTSD.94 Consistent with these findings,
attributed to direct effects of circulating estrogen on adult women with childhood trauma histories exhibit
CRH neurons.82 Sex steroids also interact with other sensitization of both neuroendocrine, and autonomic
neurotransmitter systems involved in the stress response, stress responses.95 Studies are needed that identify par-
such as the serotonin system.83 Progesterone has been ticular sensitive periods for the effects of early stress,

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determine parameters for their reversal, and scrutinize these changes signify an indelible sensory imprint of a mal-
the interactions of dispositional factors (genes, gender) adaptively processed experience that co-opts an imbal-
with developmental features in determining neurobio- anced degree of emotional importance and thereafter
logical vulnerability to PTSD. releases (or restrains) behavioral reactions that focus on
defending against future trauma via activation (or deac-
The influence of physical trauma (and TBI) on the tivation) in a losing effort to secure homeostasis.
development of PTSD Considering neurobiological findings in PTSD patients
with this overview in mind, a relative lack of baseline
It has been known for some time that physical injury con- cortisol at the time of a psychological trauma may facil-
comitant with psychological trauma increases risk for the itate overactivation of the central CRH-NE cascade,
development of PTSD. In studies of Vietnam Veterans,96,97 resulting in enhanced and prolonged stress responses.6,95
and more recently in a study of Iraq and Afghanistan This increased stress responsiveness may be further
Veterans,98 it was found that physical injury increased the accentuated by inadequate regulatory effects of GABA,
risk of PTSD at least twofold. Similarly, a literature serotonin, and NPY. Additionally, altered norpinephrine
review of patients with documented TBI and program and stress hormone activity may be critically involved in
evaluation data from surveys of US Marines following processes of learning and extinction, both of which are
blast exposures in Iraq99 demonstrate that TBI presents abnormal in PTSD; for example, norepinephrine
an increased risk for the development of PTSD. Though enhances the encoding of fear memories and glucoco-
differentiating the risk of developing PTSD in patients corticoids block the retrieval of emotional memories.
with TBI is complicated by the subjective and objective The constellation of elevated noradrenergic activity and
abnormalities common to both clinical entities, it is strik- relative hypocortisolism may lead to the enhanced
ing that each shares common endocrine, neurochemical, encoding of traumatic memories and the lack of inhibi-
and circuit abnormalities (see above, The biology of tion of memory retrieval both of which presumably trig-
PTSD). As such, it would follow that the existence of ger re-experiencing phenomena in PTSD.12
both diagnoses in an individual patient might be additive Further, an abnormally functioning hippocampus may
if not multiplicative from a clinical standpoint. For exam- account for some of the cognitive symptoms of PTSD,
ple, in the context of TBI (with frontal lobe damage and such as declarative memory deficits. In addition, because
behavioral disinhibition) it would be reasonable to the hippocampus is critical for context conditioning, an
expect a very high violence risk profile for a patient suf- impaired hippocampus may facilitate generalization of
fering from the irritability and anger characteristic of learned fear in contexts unrelated to a previous trau-
comorbid PTSD. Of additional note, the helplessness that matic exposure and impair the ability to discriminate
accompanies certain physical injuries (perhaps most between safe and unsafe stimuli. In combination with
notably TBI) is certain to compound issues of limited exaggerated amygdalar responses seen in patients with
self-efficacy (and the overall lost sense of agency) that PTSD, a limited capacity for discerning threat due to
characterize PTSD. The psychological challenges of TBI hippocampal and amygdalar dysfunction may promote
may thereby introduce an additional chronic risk for the paranoia, hypervigilance, behavioral activation, exag-
victimization that fosters PTSD in those patients with a gerated stress responses, and further acquisition of fear
tendency to become increasingly dependent over time. associations. Disrupted prefrontal cortical function may
then serve to facilitate PTSD pathology further as a
A basic model of PTSD neurobiology result of deficient suppression of stress responses, fear
associations, and extinction.
The biological perturbations observed in patients suffer-
ing from PTSD are numerous, and likely reflect an endur- Future directions
ing dysregulation of multiple stress-mediating systems that
occurs as a result of a psychological “shock.” These patho- In this article, we have selected findings from a broad
physiological perturbations presumably occur in patients range of the PTSD literature to consider the impact of
with genetic, epigenetic, and experiential predispositions psychological trauma on neurobiological systems. As
when exposed to certain extreme conditions. Presumably described, some neurobiological findings in patients with

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PTSD: neurobiological impact of psychological trauma - Sherin and Nemeroff Dialogues in Clinical Neuroscience - Vol 13 . No. 3 . 2011

PTSD are controversial and need to be further examined. and gene expression need to be assessed in detail across
In addition, there are a number of understudied yet illness duration. Though difficult, such studies will neces-
important topics in the field such as factors that impact sitate accessing, assaying and following populations at
resiliency and vulnerability. For example, stress-protec- risk for exposure to trauma before any exposure occurs
tive neurobiological factors such as activity in oxytocin (ideally, predeployment soldiers). Where possible, the dis-
and NPY-containing circuits could, in principle, be manip- tinction between PTSD and TBI must also be better
ulated to promote resilience. In addition, there is a gen- understood. Though the presumed mechanism of injury
eral need to explore further the molecular biology of from psychological trauma as opposed to brain trauma is
PTSD; identifying interactions between dispositional fac- overtly different, the etiologic abnormalities seem to
tors (genetic and epigenetic) and trauma exposure is crit- involve similar neurobiological systems and produce
ical to understand PTSD risk, gauge illness course, and overlapping clinical syndromes. ❏
predict treatment response. The effects of trauma on neu-
Acknowledgements: The authors would like to thank Ms Cynthia Crider-
rotrophic factors (in the hippocampus), neural plasticity Vega, Ms Magaly Gomez, and Ms Carmen Alsina for their outstanding
(CNS-wide), circuit remodeling (myelination patterns) administrative assistance.

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Trastorno por estrés postraumático: État de stress post-traumatique :
el impacto neurobiológico del trauma impact neurobiologique du traumatisme
psíquico psychologique

La clásica respuesta de ataque o huída ante la per- La réponse classique de lutte ou de fuite à une
cepción de una amenaza es un fenómeno nervioso menace perçue est un phénomène nerveux réflexe
reflejo que, obviamente en términos evolutivos, dont les avantages pour la survie sont évidents en
tiene ventajas para la supervivencia. Sin embargo, los termes d’évolution. Cependant, les systèmes orga-
sistemas que organizan la constelación de conductas nisés en constellation de comportements réflexes
reflejas de supervivencia que siguen a la exposición de survie après exposition à une menace perçue
a la amenaza percibida en algunas circunstancias peuvent se déréguler dans certaines circonstances.
pueden constituirse en procesos mal regulados. La Une dysrégulation chronique de ces systèmes peut
mala regulación crónica de estos sistemas puede lle- entraîner un déficit fonctionnel chez certains sujets
var a un deterioro funcional en ciertos individuos qui deviennent « psychologiquement traumatisés »
quienes pueden convertirse en “traumatizados psi- et souffrent de l’état de stress post-traumatique
cológicamente” y presentar un trastorno por estrés (ESPT). Des données recueillies pendant des dizai-
postraumático (TEPT). Una gran cantidad de infor- nes d’années montrent des anomalies neurobiolo-
mación acumulada en varias décadas ha demostrado giques chez les patients souffrant d’ESPT, ce qui per-
alteraciones neurobiológicas en los pacientes con met de mieux comprendre la physiopathologie de
TEPT. Algunos de estos hallazgos permiten aden- l’ESPT ainsi que la vulnérabilité biologique de cer-
trarse en la fisiopatología así como en la vulnerabili- taines populations à développer un ESPT. Certaines
dad biológica de ciertas poblaciones que van a desa- caractéristiques pathologiques de l’ESPT se super-
rrollar un TEPT. Algunas características patológicas posent à celles trouvées chez des patients atteints
encontradas en pacientes con TEPT se sobreponen de lésion cérébrale traumatique, en parallèle avec
con características de pacientes con daño cerebral les signes et les symptômes partagés par ces deux
traumático, estableciendo un paralelo de signos y syndromes.
síntomas compartidos entre estos síndromes clínicos.

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