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Supplement

Neurobiology of
Posttraumatic Stress Disorder
By Christine Heim, PhD, and Charles B. Nemeroff, MD, PhD

ABSTRACT Needs Assessment
Exposure to a traumatic event is required for This article provides an update on the state of the research regarding the
neurobiology of posttraumatic stress disorder (PTSD). There have been
the diagnosis of posttraumatic stress disorder several important recent developments in the field, including linking neuro-
biological changes to specific features of PTSD, identifying neurobiological
(PTSD). The symptoms of PTSD are believed to markers of PTSD risk, deriving new intervention strategies based on neuro-
biological findings, and providing insight into gene-environment interactions
reflect stress-induced changes in neurobiological in determining PTSD risk versus resilience. Current needs and open issues
are discussed based on the literature overview.
systems and/or an inadequate adaptation of neu- Learning Objectives
At the end of this activity, the participant should be able to:
robiological systems to exposure to severe stress- • Summarize current neurobiological findings in PTSD
ors. More recently, there have been attempts to • Link neurobiological findings to specific features of PTSD
• Explain the potential mechanism of a neurobiological marker of PTSD risk
link the identified neurobiological changes to the • Give an example of a novel treatment strategy derived from neurobio-
logical findings in PTSD
specific features that constitute PTSD, such as
Target Audience: Psychiatrists
altered mechanisms of learning and extinction,
sensitization to stress, and arousal. Furthermore, for developing novel strategies to identify subjects
there have been efforts to understand whether at risk, promote resilience, and devise targets for the
certain neurobiological changes in PTSD reflect prevention or treatment of PTSD can be derived.
preexisting vulnerability factors rather than con- CNS Spectr
Spectr. 2009;14:1(Suppl 1):13-24.
sequences of trauma exposure or correlates of
PTSD. Genetic variability, sex differences, and INTRODUCTION
In addition to the large numbers of soldiers
developmental exposures to stress influence neu-
deployed to combat around the world, civilians in
robiological systems and moderate PTSD risk. On modern societies face surprisingly high rates of expo-
the basis of these findings, important hypotheses sure to traumatic stressors, including war, terrorism,

Dr. Heim is associate professor in the Department of Psychiatry and Behavioral Sciences at the Emory University School of Medicine in Atlanta, GA. Dr. Nemeroff
is Reunette W. Harris Professor in the Department of Psychiatry and Behavioral Sciences at the Emory University School of Medicine in Atlanta, GA.
Disclosures: Dr. Heim receives research funding or support from the Anxiety Disorders Association of America, the Centers for Disease Control, NARSAD,
the National Institutes of Health, and Novartis. Dr. Nemeroff receives research grants from the National Institutes of Health; serves on the scientific advi-
sory boards for the American Foundation for Suicide Prevention (AFSP), AstraZeneca, Forest Laboratories, Quintiles, NARSAD, Janssen/Ortho-McNeil,
PharmaNeuroboost, and Mt. Cook Pharma Inc.; owns stock or equity in CeNeRx, Corcept, NovaDel Pharma, PharmaNeuroboost, and Reevax; serves
on the board of directors of the AFSP, NovaDel Pharmaceuticals, George West Mental Health Foundation, and Mt. Cook Pharma Inc.; and holds the fol-
lowing patents: method and devices for transdermal delivery of lithium (US 6,375,990 B1), method to estimate serotonin and norepinephrine transporter
occupancy after drug treatment using patient or animal serum (provisional filing April, 2001).
Submitted for publication: September 26, 2008; Accepted for publication: December 6, 2008.
Please direct all correspondence to: Christine Heim, PhD, Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, 101
Woodruff Circle, WMRB, Suite 4311, Atlanta, Georgia 30322; Tel: 404-727-5835; Fax: 404-727-3233; E-mail: cmheim@emory.edu.

CNS Spectr 14:1 (Suppl 1) ©MBL Communications, Inc. 13 Januar y 2009

as adrenocorticotropin (ACTH). it soon became evident that only a minor. measured in urine or blood. Accordingly. ACTH. and impairment of neurogenesis. Upon exposure to ity of individuals who experience a traumatic event stress. C. although findings are not uniformly con- differences. as well as lating hippocampal and hypothalamic PVN neu- various neurotransmitters and neuropeptides that rons. gies to identify subjects at risk. stress-induced changes in neurobiological sys. promote resilience. lates the release of glucocorticoids from the adrenal The symptoms of PTSD are believed to reflect cortex. negative feedback control of the HPA axis by regu- thalamic-pituitary-adrenal (HPA) axis. initial studies in combat veterans with PTSD have been efforts to understand whether certain revealed paradoxical decreases in cortisol concen- neurobiological changes in PTSD reflect preexisting trations. there have been attempts reduction in dendritic branching. as well as ACTH secretion. sistency. assault. and a important hypotheses for developing novel strate- wide variety of other severe psychological traumas. Furthermore. current developments. Although acute stressors activate the HPA sitization to stress. and genetic dispositions. hippocampus. 14 Januar y 2009 . accom. loss of dendritic to link the identified neurobiological changes to spines. iological functions and behavior to the stressor. Glucocorticoids exert in the pathophysiology of PTSD include the hypo. and arousal.3-5 altered mechanisms of learning and extinction. accidents. such as the latter is controversial. On the basis of such neurobiological findings.B. in turn. symptom patterns. including nuclei.2 Thus. stimu- manifested in the symptoms of PTSD. C. (CRF) from the median eminence into the hypo- tain or regain homeostasis. sex with PTSD. in which minority of persons fails to recover and exhibits the peptide is transported to the anterior pituitary prolonged and abnormal behavioral and physio. biological systems to exposure to severe stressors. though the specific features that constitute PTSD. Consequently. through binding to comprise a network of brain regions that regulate glucocorticoid receptors (GR) and mineralocorticoid fear and stress responses. Sustained glucocorticoid exposure has tal cortex. and the brain. an organism’s major neuroen- sents a normative response to exposure to extreme docrine stress response system. Nemeroff childhood abuse. receptors.6 Differences in type and tim- influence neurobiological systems and moderate ing of the psychological trauma. discuss unresolved issues in panied by intense fear. and abused persons affect outcome after trauma. and brainstem adverse effects on hippocampal neurons. and suggest strategies for future research. may contribute to this incon- PTSD.7 Studies using low-dose dexamethasone CNS Spectr 14:1 (Suppl 1) ©MBL Communications. This counterintuitive finding has been replicated in there is increasing consideration of factors that Holocaust survivors. whereas the amygdala and mono- neurobiological systems in patients with PTSD. defined as this. while most indi. In the following. compared vulnerability factors rather than consequences of to healthy controls and other diagnostic groups. Heim.6 trauma exposure or correlates of PTSD. A PTSD can be derived. sen. Several brain pathways modulate HPA axis activity.1 the field. vulnerability versus resilience against developing among other factors. responses to trauma likely contributing to individual comorbidity. aminergic input from the brainstem stimulate the Neurobiological systems that have been implicated activity of PVN CRF neurons. making PTSD a psychiatric dis. More recently. where it stimulates the production and release of logical responses to the traumatic experience. amygdala. refugees. including the prefron. neurons in the hypothalamic paraventricular will develop the disorder. describe threatening to oneself or a close person. nucleus (PVN) secrete corticotropin-releasing factor viduals are able to cope with the stressor and main. we summa- traumatic event is defined as an experience that is rize core neurobiological findings in PTSD. Experience of any such trauma may be associated and devise targets for the prevention or treatment of with potentially lasting effects on the individual. and developmental exposures to stress sistent across studies. horror.1 Hypothalamic-Pituitary-Adrenal Axis Although initial theorists proposed that PTSD repre. The HPA axis. there axis. Inc. STATE OF SCIENCE order that by definition is related to and occurs as a consequence of a stressful or traumatic event. a small but significant thalamo-hypophyseal portal circulation. personality. scrutinized in patients with PTSD. Exposure to a traumatic event. Glucocorticoids exert effects on metabolism. has been closely stressors. immune function. adjusting phys- tems and/or an inadequate adaptation of neuro. much research has been focused The hippocampus and prefrontal cortex (PFC) inhibit on elucidating alterations in stress-regulating the HPA axis. is required for the diagnosis of posttraumatic stress NEUROBIOLOGY OF PTSD: disorder (PTSD). Genetic variability. or helplessness. rape.

as described in vari- axis in PTSD. centrations have been measured in the cerebrospi. of NE and epinephrine from the adrenal medulla.15 Indeed. tions were observed despite comparably low cor- mones exerting feedback on the HPA axis. increased CNS CRF activity may level. including the PFC.8. prospective studies have shown the action of DOPA decarboxylase. Inc.6 At the central nervous system (CNS) ous animal models. Dopamine dinal feature of PTSD. Neurobiology of Posttraumatic Stress Disorder suppression and metyrapone testing. it was recently forward circuit connecting the amygdala and the demonstrated that hydrocortisone treatment. of catecholamines is tyrosine hydroxylase.8. and changes in blood flow to a variety of prevent or reduce symptoms of PTSD. β1 and β2 NEUROPEPTIDES receptors. in which CRF and NE lating normal circadian cortisol rhythm. a frequently enzyme that converts tyrosine into DOPA.11. and the latter were negatively that hypocortisolism in PTSD occurs in the context correlated with PTSD symptoms. conditioned fear responses. sympathoadrenal activation involved in stress reactivity and fear processing. ing down-regulating of pituitary CRF receptors.16 Glucocorticoids further interfere with the increased release of NE from sympathetic nerve retrieval of traumatic memories and thereby may endings. ie. LC that project to various brain regions involved Consequently. as well as promoting the encoding of both in single lumbar puncture and serial sampling emotional memories. Because of its multiple As noted above. amyg- directly after exposure to psychological trauma has dala. revealed tisol concentrations.19 In the periphery. marked and sustained increases of CRF con. responses. The effects NEUROTRANSMITTERS AND of NE are mediated via postsynaptic α1.6 This neuroendocrine pattern distin. In increased negative feedback sensitivity of the HPA view of the CNS effects of CRF. simu. the Catecholamines: Norepinephrine and major brain region inhibiting the HPA axis. the specific The catecholamines comprise a family of neu- constellation of neuroendocrine findings in PTSD rotransmitters derived from the amino acid tyro- reflects sensitization of the HPA axis to exposure sine.9 Sustained elevations in CRF concentra- cologic agents that alter the availability of stress hor. In noradren- that low cortisol levels at the time of exposure to ergic neurons. enhance arousal and availability of cortisol.10 Taken together. an guishes PTSD from major depression. hypothalamus with the LC. studies. is effec. dopamine β hydroxylase converts psychological trauma predict the development of DA into NE.6 Findings of increased GR obscure. during exposure to stressors results in the release including the CRF and norepinephrine (NE) sys. and thalamus. hypothalamus. sensitization to exposure to stressors. interact to increase fear conditioning and encod- tive in the treatment of PTSD. 15 Januar y 2009 . which comorbid but distinct disorder. the α2 receptor.17 organs. two pharma. tems. hippocampus. and hence lack of regulatory vigilance. whereas another NE-activated receptor. serves as a presynaptic autorecep- Corticotropin-Releasing Factor tor inhibiting NE release.12 suggesting that hypocortisolism might of the CNS and autonomic stress responses.13. reduced volume of the hippocampus. may have permissive effects responses to stress.6 subsequently is converted into dopamine (DA) by Interestingly.14. and integrate endocrine and autonomic effects in the CNS.9 Although the pre- of increased sensitivity of the HPA axis to negative cise neuroanatomical source of CRF in CSF remains glucocorticoid feedback. therapeutic approach for the treatment of PTSD. administration of hydrocortisone in the stress response.6. CSF CRF concentrations are believed to binding and function support the assumption of reflect CRF activity at extra-hypothalamic sites.14 In addition. promote certain of the cardinal features of PTSD. reflecting an alarm reaction that mobilizes the body to allow for optimal coping. NE is one of the principal mediators PTSD. is a car. Glucocorticoids inhibit this cas- towards the sustained activation of neural systems cade. There is evidence for a feed- in several studies.6 In addition. decreased ing of emotional memories. The rate-limiting factor in the synthesis to stressors. The be a preexisting risk factor that is associated with majority of CNS NE is derived from neurons of the maladaptive stress responses such as PTSD. increased startle nal fluid (CSF) of patients with PTSD. These results suggest that CRF1 supports the hypothesis that PTSD involves elevated receptor antagonists may well represent a novel levels of hypothalamic CRF activity and correspond. blunted ACTH responses to CRF stimulation in PTSD and hyperarousal. NE has been a central candi- CNS Spectr 14:1 (Suppl 1) ©MBL Communications. increased CSF concentrations roles in regulating arousal and autonomic stress of CRF have been measured in patients with PTSD. periaqueductal been shown to effectively prevent PTSD in humans grey.9 Evidence of reactivity.

tors. including hyperarousal. no differences in CNS 5-HT1A receptor It should be noted that increased urinary excre. There is evidence in humans that expo. 5-HT1A receptors. Chronic exposure to stressors increased startle. 16 Januar y 2009 .21 However. prospective studies have shown tion of 5-HT1A receptors. such as traumatic remind. Serotonin. analgesia. GABA in the DA system have been implicated in moder. ity. Most to reminders of the traumatic event. hostil- to reduce PTSD symptom severity and reactivity ity. Decreased platelet α2 receptor binding further of mood and anxiety disorders and in the modula- suggests NE hyperactivity in PTSD.21 induces upregulation of 5-HT2 and downregula- Interestingly. C. models. and neuroendocrine control. whereas 5-HT neurons from the median chological stressors in PTSD. This mented in combat veterans. It is believed symptoms of flashbacks and increased autonomic that 5-HT neurons of the dorsal raphé projecting responses in patients with PTSD. raphy (PET) imaging. including the amygdala. and NE function.25 acts with the CRF and NE systems in coordinating Remarkably. of the stria terminalis.28 there is a paucity of controlled trials. and PFC. Serotonin A cardinal feature of patients with PTSD is sus. which increases NE release. such as hypervigilance.23-24 Taken together. blood pressure. Administration of the α2 receptor antagonist and stress responses depends on stressor inten- yohimbine. and intrusive memories. as evidenced sized from the amino acid tryptophan. it is the demonstrated efficacy of the selective sero- may have blocked traumatic memory consolida. responses to challenge. meso. At the CNS level. and suicidality.B. sure to stressors induces mesolimbic DA release. The direc- evidence for a role of altered CNS NE function in tion of the modulatory effects of 5-HT on affective PTSD.29 Taken together. which in turn may impact on HPA axis responses. suggests a role of 5-HT in the pathophysiology of sure to psychological trauma has been reported PTSD. in part by CNS Spectr 14:1 (Suppl 1) ©MBL Communications. increased startle. The 5-HT system inter- predict subsequent development of PTSD. decreased have been tested for their therapeutic efficiency in density of platelet 5-HT uptake sites.27 and therefore may reduce the severity or altered 5-HT neurotransmission in PTSD includes chronicity of PTSD. has been docu. appe- children with PTSD. abused women. administration of the centrally acting β affective and stress responses. binding were detected in patients with PTSD com- tion of DA and its metabolite has been reported pared to controls using positron emission tomog- for patients with PTSD. patients with PTSD tite. Serotonergic by heart rate. impulsiv- ditioning. including symptoms of impulsivity. hippocampus. though responsiveness to CNS serotonergic challenge. depression. raphé exert anxiolytic effects. though genetic variations pal inhibitory neurotransmitter in the CNS. respectively. motor exhibit increased heart rate. is a monoamine neurotransmitter synthe- of the autonomic nervous system.20-21 There is also tion of affective and stress responses. iogenic (stress-increasing) effects via 5-HT2 recep- trations and increased CSF NE responses to psy.20. increased urinary excretion of NE and brain regions. Various anti-adrenergic agents decreased serum concentrations of 5-HT. In addition. and suppress encoding of learned associations via utes to features of PTSD. and receptor type. Inc. DA has also been implicated in fear con. raphé in the brainstem and project to multiple fore- Accordingly. and encoded fear memories. bed nucleus epinephrine. also known as 5-hydroxytryptamine tained hyperactivity of the sympathetic branch (5-HT). and indoleamine has roles in regulating sleep. altered 5-HT limbic DA plays a critical role in the processing of transmission may contribute to symptoms of PTSD rewards.22 Serial sampling to the amygdala and hippocampus mediate anx- revealed sustained increases in CSF NE concen. It also has been implicated in the pathophysiology ers. aggression/impulsivity.28 Indirect evidence adrenergic blocker propranolol shortly after expo. GABA/Benzodiazepine Receptor System Whether or not the CNS DA system is altered in Gamma-aminobutyric acid (GABA) is the princi- PTSD remains unclear. and physiological responses to stressors. induces sity. brain region. 5-HT1A receptor knockout mice exhibit rine excretion at the time of exposure to trauma increased stress responses. and other psychophysiological measures. Nemeroff date in studying the pathophysiology of PTSD. aggression. increased CNS NE (re)activity plausibly contrib.26 Although important concerning a role of 5-HT circuits in PTSD this did not prevent the development of PTSD. and their metabolites.20. 12. blood pressure. Heim. tonin reuptake inhibitors (SSRI). sexual behavior. exerts anxiolytic effects and dampens behavioral ating risk for PTSD. and altered the treatment of PTSD in open label trials. skin conductance neurons originate in the dorsal and medial nuclei level. in animal that increased heart rate and peripheral epineph. facilitate extinction. C. Other evidence for tion.

17 Januar y 2009 . it the cortex. and patients with memory.21 Endogenous opioids. sociation and flashbacks in traumatized patients. Endogenous opioids further exert one of which is the N-methyl N D-aspartate (NMDA) inhibitory influences on the HPA axis. which opment of PTSD. hippocampus and thalamus of patients has been suggested that NPY may be involved in with PTSD. GABA release of NE from sympathetic nerve cells. Indeed. Interestingly. the ries in PTSD. learning.36 PTSD. Uncontrollable stress has been shown to inhibit CRF/NE circuits involved been shown to lead to alterations in the GABAA/ in stress and fear responses and reduces the BZ receptor complex.38 of exposure therapy in PTSD remains to be stud- ied. PTSD patients exhibit increased CSF conditioning and memory consolidation. Neurobiology of Posttraumatic Stress Disorder inhibiting the CRF/NE circuits involved in mediating Neuropeptide Y fear and stress responses. Exposure to stressors and the phine or heroin). such as the endorphins or enkephalins. of PTSD. ciation in PTSD.33 Although there are multiple studies impli- cating the GABA/BZ receptor system in anxiety dis. has been antagonist D-cycloserine (DCS) has been shown to reported to be effective in treating symptoms of dis- improve the extinction of fear in rodents and in pho. Alterations in endogenous opioids release or administration of glucocorticoids increase have been postulated to be involved in symptoms glutamate release in the brain. brain regions that have been implicated in the devel- sion and/or sensitivity of NMDA receptors. and on hypothalamic CRF secretion. studies in PTSD are relatively sparse. PTSD patients after exposure to traumatic remind- cess is believed in part to underlie the process of ers.32 However.21. These results suggest that decreased promoting recovery from or resilience to PTSD density or affinity of the BZ receptor may play a because combat veterans without PTSD have been role in PTSD. part of the GABA A /benzodiazepine anxiolytic and stress-buffering properties. STRUCTURAL AND FUNCTIONAL overexposure to glutamate is associated with exci. A rela- agonists. elevated glucocorticoids increase the expres. a μ opiate receptor antagonist.35 However. increases HPA axis activ- receptor. Endogenous Opioids orders.30 Single photon bine challenge compared to controls. suggesting emission computed tomography and PET imaging that decreased NPY activity may contribute to nor- studies revealed decreased BZ receptor binding in adrenergic hyperactivity in PTSD. Interestingly. NPY has (BZ) receptor complex. of the endogenous opioid system. leading to long-lasting enhance. Inc. Finally. The glutamate/NMDA receptor system has ity by blocking an inhibitory opioidergic influence been implicated in synaptic plasticity.37 bic patients undergoing exposure therapy. Naloxone. the extended excitation HPA axis response to naloxone. the partial NMDA-receptor opiate receptor antagonist. naltrexone. treatment with BZs after demonstrated to exhibit elevated plasma NPY lev- exposure to psychological trauma does not prevent els compared to veterans with PTSD. Patients with PTSD exhibit centrations and blunted NPY responses to yohim- decreased platelet BZ binding sites. stress-induced analgesia. This pro. GABA acts on GABAA Neuropeptide Y (NPY) is a neuropeptide with receptors. patients with PTSD have been reported to exhibit decreased plasma NPY con- physiology of PTSD. and plausibly could contribute to a loss of The neurotransmitters discussed above serve as neurons in the hippocampus and PFC in PTSD. Changes in brain structure and may sensitize the brain to excitotoxic insults. nalox- of neural circuits. Of note. and disso- several so-called excitatory aminoacid receptors. NEUROANATOMY totoxicity. Whether Administration of morphine has been shown to pre- or not DCS is effective in enhancing the outcome vent the development of PTSD. Glutamate binds to of numbing. are endogenous neuropeptides that Glutamate/NMDA Receptor System act upon opiate receptors also activated by syn- Glutamate is the primary excitatory neurotrans. or GABA reuptake inhibitors decreases tive lack of NPY may promote maladaptive stress symptoms of anxiety in PTSD. suggesting that the responses and contribute to the development GABA/BZ system may be involved in the patho. suggesting increased activation sibly contributes to consolidation of trauma memo. Treatment with BZ.34 In addition to its role in learning and memory. one also has been shown to reverse the analgesia of ment in communication between neurons. LTP plau. including the well studied phenomenon of PTSD have been reported to exhibit an exaggerated longterm potentiation (LTP). function have been identified in patients with PTSD CNS Spectr 14:1 (Suppl 1) ©MBL Communications.31. β-endorphin levels. thetic or naturally occurring opiates (such as mor- mitter in the CNS. Of the chemical messengers of a connected network of note.

C.48 liminally presented threatening cues in PTSD. prolonged exposure central nucleus projects to the midbrain and brain- to stress and high glucocorticoid levels damages stem nuclei to coordinate rapid autonomic. The baso- the control of stress responses. ther show increased amygdala responses to gen- cocorticoid exposure or increased glucocorticoid eral emotional stimuli that are not associated with sensitivity.39 Of note. Connections between the ing studies demonstrated smaller hippocampal vol. Connections between the with abuse-related PTSD compared to controls. The branching. hippocampal deficits amygdala reactivity has been linked to genetic may promote activation of and failure to shut down traits.56 Given that increased pocampal volume. such as emotional faces. that a small hippocampus might represent a pre. and changes in this cir.40 Of note. leading to reduction in dendritic crine.10. C. discriminating between safe and unsafe contexts. Prefrontal Cortex ther revealed that PTSD patients exhibit deficits in The medial prefrontal cortex (mPFC) comprises hippocampal activation during a verbal declara.52 The functional role of the amyg- replicated in subsequent studies. to increase neurotrophic factors and neurogenesis tal cortex. and behavioral responses to danger. declarative mem. endo- the hippocampus. The hippocampus is implicated in both cortical and subcortical regions. from brainstem regions. As noted above. amygdala in PTSD. our group reported that in patients with 55 Increased amygdala activation has also been major depression. and may contribute to impaired amygdala reactivity may represent a biological risk extinction of conditioned fear as well as deficits in factor for the development of PTSD. Hippocampus The amygdala is a critical limbic structure involved The most reproducible finding in structural in emotional processing and in the acquisition imaging studies of PTSD is reduced volume of the of fear responses. the amygdala also seems to be sensitized to sub- existing vulnerability factor for developing PTSD. and other reminders. In addition to the hippocampus. though recent evidence also suggests the trauma. in the hippo. in a conditioning experiment. The amygdala is connected to hippocampus.50 Both hippocampal atrophy and that are altered in patients with PTSD include the functional deficits reverse after successful treat- hippocampus. amygdala.39 structures implicated in a neural circuitry of stress include the amygdala and the prefrontal cortex.42-45 PFC and the amygdala modulate stress respon- Small hippocampal volumes were associated with siveness and mediate extinction of fear memory.58 increased stress responses. Amygdala cuit are proposed to be directly linked to the devel. subcortical sensory regions and sends informa- and is known as one of the most plastic regions tion to the central nucleus of the amygdala.5 connected neurocircuit that mediates adaptation to stress and fear conditioning. functional imaging studies have centrations.47 PTSD during the presentation of traumatic scripts. and prefrontal cortical ment with SSRIs. lateral complex is innervated by neocortical and ory and contextual aspects of fear conditioning. Inc. Hippocampal volume reduction in PTSD may reflect cues. the anterior cingulate cortex (ACC). Although there is campus of adult patients with PTSD. and impairment central nucleus also receives visceral information of neurogenesis.B. other brain opment of PTSD.53- Moreover. The in the brain. early life trauma in the form of reported for PTSD patients during fear acquisition childhood abuse is associated with reduced hip. the severity of trauma and memory impairments inasmuch as the PFC exerts inhibitory control over in these studies. the pathophysiology of PTSD. loss of dendritic spines. These findings were generally the amygdala. subcallosal CNS Spectr 14:1 (Suppl 1) ©MBL Communications.4 Initial magnetic resonance imag. 18 Januar y 2009 .49 Indeed. Heim.39-41 Brain regions tive memory task. reduced hippocampal revealed hyperresponsivity of the amygdala in volume was not observed in children with PTSD. Nemeroff using brain imaging methods. NAA no clear evidence for structural alterations of the reductions were correlated with serum cortisol con.57 which moderate risk for PTSD.51 which have been demonstrated regions.40.46 Interestingly. amygdala and the hippocampus are implicated in umes in Vietnam veterans with PTSD and patients context conditioning. These brain regions interact and form a in preclinical studies. Studies using functional neuroimaging have fur. Studies using dala in mediating both stress responses and emo- proton magnetic resonance spectroscopy (MRS) tional learning suggests that changes in this region observed reduced levels of N-acetyl aspartate and its connected circuitry may be implicated in (NAA). including anterior cingulate and orbitofron.41 PTSD patients fur- toxic effects over time of repeatedly increased glu. a marker of neuronal integrity.

Inc. 69 of emotional memories. Impaired prefron- campus.70 and others. Norepinephrine enhances the encoding of scripts. GABA-ergic. including the hippo- activation patterns between these regions have campus. traumatic memories. Given the connectivity These neurotransmitter systems represent a between the amygdala and mPFC. such as traumatic ries. further promote conditioning and consolidation of providing a biological basis for imprinted trau.40 hippocampus in PTSD patients may contribute to increased neuroendocrine stress reactivity.17 The glutamate/ experiment. rather than a preexist- involved in processes of learning and extinction. serotonin. The mPFC Linking Neurobiological Findings with is connected with the amygdala.67 trauma fear memories. A hallmark promote the activation of stress responses and feature of PTSD is reduced volume of the hippo. 68 fearful faces.16 Lack of regu- ies.59 including reduced volumes of the ACC. Additional neurochemical changes include eralization of learned fear to other contexts and alterations in serotonergic. in the above cited conditioning intrusive memories in PTSD.66 combat pictures and sounds. 19 Januar y 2009 .40 Of note. Glucocorticoids block the retrieval unrelated negative narratives. of traumatic memories and lack of inhibition of ful SSRI treatment restored mPFC activation pat. memory retrieval. DEVELOPMENTS Moreover. as seen in patients with PTSD. In addi- reported in PTSD patients. The mPFC further mediates patients likely reflect sensitization of stress-medi- extinction of conditioned fear through active inhi. matic memories in PTSD. thereby promoting mitter systems comprise a connected network of the development of PTSD. hippocampal damage may underlie In summary. glutama. amygdala. and the medial frontal gyrus. Neurobiology of Posttraumatic Stress Disorder cortex. together SUMMARY OF NEUROBIOLOGICAL with increased glucocorticoid receptor sensitiv- FINDINGS AND CURRENT ity. These hypotheses CNS Spectr 14:1 (Suppl 1) ©MBL Communications.65. These neurotrans. A recent twin study sug. Exaggerated amyg- brain regions that is involved in the regulation and dala responses. though the direction of the integrate stress and fear responses. Altered shape of the ACC62 and decreased latory effects of GABA. acquisition of fear associations.40 Patients with stress responses in order to regain homeosta- PTSD exhibit decreased volumes of the frontal sis. core features of PTSD include low basal cortisol secretion and enhanced negative some of the cognitive symptoms of PTSD. which could plausibly underlie terns. the constellation emotional Stroop. In turn. though there are also discordant findings.64 Functional imaging studies have thereby impacting conditioned fear responses and found decreased activation of the mPFC in PTSD the consolidation or retrieval of traumatic memo- patients in response to stimuli. may impair the ability to discriminate between tergic. such feedback control of the HPA axis that occurs in the as declarative memory deficits. and NPY may NAA concentrations in the ACC63 have also been further accentuate stress responsiveness. NPY. Other brain changes involved in PTSD tal cortical function may underlie deficits in sup- include exaggerated amygdala responsiveness and pressing stress responses and fear associations impaired mPFC function. may further promote hippocampal damage. because context of increased autonomic responsiveness the hippocampus is critical for context condition- as well as increased CNS CRF and noradrenergic ing. and interferes with extinction. and prolonged stress responses.56 extinction of conditioned fear was NMDA receptor system mediates LTP and may associated with decreased activation of the ACC.40 Reduced activation of of elevated noradrenergic activity and relative the mPFC was associated with PTSD symptom hypocortisolism may lead to enhanced encoding severity in several of these studies and success. integration of stress and fear responses. ing risk factor. increased cortisol responses to stress. An impaired relationship is inconsistent across studies. several of gests that volume loss in the ACC is an acquired the altered neurochemical systems are critically correlate of having PTSD. a damaged hippocampus may facilitate gen- activity.61 trauma may facilitate the activation of the central The reduction in ACC volume was correlated with CRF-NE cascade.14. tion to mediating stress responses. and mPFC that regulate and been reported in PTSD. safe and unsafe contexts. potentially resulting in enhanced PTSD symptom severity in some of these stud. ating systems and/or decreased ability to restrain bition of acquired fear responses. and opioid systems. where it exerts Features of PTSD inhibitory control over stress responses and Neurotransmitter changes observed in PTSD emotional reactivity. Thus.60. A relative lack of cortisol at the time of the cortex.6. interactions in network of brain regions. Finally.

or whether during exposure therapy. and prior experiences. stress experiences in moderating risk for develop- ment of PTSD are currently being tested that ing PTSD in response to trauma. low cortisol concentrations may disinhibit development of PTSD. hypo. trauma whether the drug enhances the outcome of expo- exposure. administration cortisolism might represent a preexisting risk factor of the centrally acting β adrenergic antagonist pro- that promotes the manifestation of PTSD. Moreover. low cortisol levels and stress responses and blocks traumatic memory elevated heart rates at the time of a trauma predict retrieval. whereas others develop depres- hippocampus is a preexisting. Administration of hydro- Are Neurobiological Changes Preexisting cortisone shortly after a traumatic experience has Risk Factors of PTSD? been reported to be effective in preventing the A number of studies have raised the important development of PTSD. because NE promotes subsequent development of PTSD. In addition. Because the majority of trauma survivors will not develop a dis- Deriving New Strategies for the order.64 of and in the aftermath of the trauma.B. potentially genetic. treatment simulating a normal circadian cortisol cal changes in PTSD patients might. including genetic disposition. and measured VERSUS RESILIENCE the size of the hippocampus in all the twins. receptor antagonist DCS improves extinction of opment of PTSD. 34 The partial NMDA- a small hippocampus is a risk factor for the devel. PTSD.71 This suggests that a smaller trauma exposure. CNS Spectr 14:1 (Suppl 1) ©MBL Communications. 20 Januar y 2009 . it is equally this brain region was also smaller in the co-twins of unclear why some patients develop PTSD after the men with PTSD. Therefore. the vulnerability factor that predisposes a person to manifestation of a trauma spectrum disorder will PTSD. 14. and PTSD to neurobiological findings in sure therapy in PTSD patients. the hippocam- develop PTSD. Why some individuals develop pus was smaller in those had PTSD as compared to PTSD following trauma while others do not is an those who did not develop the disorder. Heim. important unexplored area. rhythm appears to be beneficial in the treatment sent markers of neural risk to develop PTSD upon of PTSD. In most cases. potentially reduced size of the hippocampus in PTSD has been reflecting blockade of traumatic memory consoli- a “chicken-or-egg” question for many years. ing vulnerabilities. C. in fact. There dation. as well as other trauma spectrum disorders. the to reminders of the traumatic event. Gilbertson and colleagues71 studied 40 pairs of monozygotic twins. directly target the above-described neurobiologi- rocircuitry model of PTSD. As Not all individuals who undergo a trauma expected. sex differences. among Vietnam veterans. For example. repre. more recent results from the same group suggest personality styles.17 Similarly. this inter- nomic stress responses. In contrast. However. cal mechanisms that appear to be implicated in the development of PTSD. rather than markers esized to exert inhibitory effects on sustained of PTSD itself. as psychological and situational factors at the time ture that occurs as a result of PTSD. be influenced by a complex interplay of preexist- after the experience of stress or trauma. Finally. it is crucial to identify vulnerability and resil- Prevention and Treatment of PTSD Based ience factors. a novel strategy based on insights was considerable debate on whether this brain into the mechanisms of learning is the use of “cog- region shrinks as a result of the trauma exposure nitive enhancers” to facilitate extinction learning or due to the presence of PTSD itself. sion or another Axis I disorder. Similarly. and early developmental New strategies for the prevention and treat. though it is presently unknown discern the contributions of predisposition. We discuss below the role of genetic on Neurobiological Findings factors. as well that grey matter loss in the ACC is an acquired fea. hydrocortisone question of whether the identified neurobiologi. as well as fear conditioning vention reduced symptom severity and reactivity and traumatic memory consolidation. C. Nemeroff have yet to be fully tested and integrated in a neu. Inc. Studies in twins discordant for fear in rodents and in phobic patients undergoing trauma exposure provide an excellent opportunity to exposure therapy. As noted pranolol after exposure to psychological trauma has been tested for its potential to prevent the above.38 Although propranolol did CRF/NE neurocircuits and thereby promote auto- not prevent the development of PTSD. Glucocorticoid substitution is hypoth- exposure to extreme stress. including Vietnam veterans OUTCOME VARIATION IN THE who were exposed to combat trauma and their co- RESPONSE TO TRAUMA: RISK twins who did not go to Vietnam. encoding of traumatic memories.

including a polymorphism in the DA transporter gene to genetic heterogeneity (eg. 2009. morphic region (5-HTTLPR). consequently. like those of robiological systems that determine responses to other complex disorders that are characterized by trauma and.72 Finally. have develop PTSD. Heim C. one study has linked been hampered by a variety of factors. No 1 (Suppl 1). 14. such as decreased ness and risk for developing depression in relation hippocampal volume71 or exaggerated amygdala to life stress. to stress responsive- ical endophenotypes of PTSD. though risk for PTSD is influenced by genetic factors.57 Although it is beyond the scope of this ciated with risk for developing PTSD. a gests that genetically determined changes in DA person with a genetic risk for PTSD. will not develop PTSD). In addition. the so-called ment of PTSD. there is evidence for “s” allele of the serotonin-transporter-linked poly- heritable contributions to some of the neurobiolog. This finding sug- incomplete penetrance of the phenotype (eg. there is Evidence from family and twin studies has long considerable evidence linking a low expression suggested a heritable contribution in the develop. Inc. An excess of the SLC6A3 9 repeat allele likely develops from different risk genotypes) and was present in those with PTSD. Bradely R. Neurobiology of Posttraumatic Stress Disorder GENETIC RISK FACTORS OF PTSD literature emerging on genetic variations in neu- Studies on the genetics of PTSD. it should be noted that there is an exciting is intriguing because the same polymorphism is FIGURE. variant of the serotonin transporter. 21 21 Januar y 2009 . Nemeroff CB.72 For example. The same variant has now been asso- reactivity. Despite survivors.58 This finding PTSD. Vol. FKBP5 Polymorphisms Moderate PTSD Risk After Child Abuse (Panels A and B) as well as Association between PTSD and Dexamethasone Suppression (Panels C and D)75 A C Probable PTSD 16 PTSD Symptom Score (PSS) 40 14 30 Serum Cortisol ng/ml 12 10 20 8 10 6 4 0 No Abuse 1 Type Child 2 Types Child 2 Abuse Abuse 0 B AA D No PTSD 110 N=11 40 PTSD Symptom Score (PSS) AG Probable PTSD % Cortisol Supression GG 90 30 N=15 70 N=44 N=7 20 50 10 30 10 0 No Abuse 1 Type Child 2 Types Child rs9296158 rs9296158 Abuse Abuse GG genotype A allele carrier Figure provided by and reproduced with permission from Binder E. CNS Spectr 14:1 (Suppl 1) ©MBL Communications.73 Several studies have investigated poly- these difficulties. results have been inconsistent. risk versus resilience to both genetic and environmental risk factors. a similar phenotype PTSD risk. there is increasing evidence that morphisms in the D2 receptor to PTSD risk. who is not reactivity may contribute to PTSD among trauma exposed to trauma. Ressler K. CNS Spectr Spectr. particularly in chapter to comprehensively discuss the genetics of the presence of low social support.

91 Studies are cal response to trauma. Thus.B. activity. ie. sex differences in HPA axis selected unmet needs are described together with responses to stress have also been observed inde.82. child- genetic polymorphisms in the FKBP5 gene in 900 hood adversity is associated with increased risk to non-psychiatric clinic patients. crine and autonomic stress responses.76 Rodent studies suggest needed to identify sensitive periods for the effects that females generally exhibit a greater magni.78 Sex differences in neuroen. Inc. In the following section. systems. ie.77 though findings in humans are not developmental factors in determining neurobiologi- entirely consistent. CNS Spectr 14:1 (Suppl 1) ©MBL Communications. Heim. which causes unpredictable response. Nemeroff associated with increased amygdala reactivity57 as processes may eventually converge into the basis well as the trait of neuroticism. 82 the trauma. Meta-anlayses of existing studies might be a fruitful ences in the brain’s response to fear stimuli. has profound and long-lasting effects on the coid receptor sensitivity.79 Sex steroids also interact with other FUTURE RESEARCH NEEDS neurotransmitter systems involved in the stress We have provided an overview of the state of response. trauma histories exhibit sensitization of neuroendo- there might be sex differences in the neurobiologi. PTSD risk and the underlying neurobiological phe. types or timing of the trauma. includ- child abuse to predict adult PTSD symptoms. as reflected by dexametha- development of neurobiological systems. FKBP5 ing prenatal stress and stress throughout child- genotype was further linked to enhanced glucocorti- hood. is a vast area of future research. Vietnam veterans. the hippocampus and amygdala. time elapsed since siveness. C. 78.85 There is a burgeoning literature FKBP5 polymophisms significantly interacted with documenting that early adverse experience. It must be stressed that neurobiological find- factors that might determine sex differences in ings in PTSD are not unequivocal (the finding of the stress response include genomic differences. CRF neuronal hyper- associations have yet to be tested. and to scrutinize tude and duration of HPA axis responses to stress interactions between dispositional (genes. symptom constellations. cal vulnerability to PTSD.86-88 For example. and developing PTSD in response to trauma. future research recommendations: pendent of acute gonadal steroid effects.90 Adult women with childhood exposure to different types of trauma. that translate into differential risk for PTSD.75 The study tested Previous experience clearly moderates risk for interactions of child abuse. produce an adult phenotype titude of candidate genes as well as genome-wide with sensitization to fear cues. and dispositional factors among others. perhaps in part due to sex differences in the tion to acute stress. the serotonin system. maternal care infants. and hypocortisolism similar to features of PTSD. sex) and than males. or ies and some studies even report hypercortisolism developmentally programmed effects of gonadal in PTSD). as well as illness course and treatment ing demand condition.82 Other 1. FKBP5. adulthood trauma. of early stress and their reversal. Childhood abuse and develop PTSD in response to combat exposure in adulthood trauma each predicted PTSD symptoms. different regions.81 However.83 Of note.89 In another non-human primate study. including areas involved in stress respon.80 Progesterone science and current developments concerning the has also been implicated in modulating these neurobiology of PTSD. maternal separation interacted with female gender SEX DIFFERENCES AND RISK FOR PTSD and the 5-HTTLPR polymorphism of the serotonin Women more frequently suffer from PTSD than transporter gene in determining adult sensitiza- men.7 The field must address and explain such steroids.74 the latter another of sex differences in the consequences of trauma risk factor for PTSD. Particularly exciting are recent results that genetic variation of the glucocorticoid receptor co- EARLY DEVELOPMENTAL FACTORS chaperone. 22 Januar y 2009 . C. a hallmark feature of PTSD “programming” subsequent stress reactivity and (Figure). hypocortisolism has not been replicated in all stud- organizational differences in brain structures. docrine stress responses have been attributed to direct effects of circulating estrogen on CRF neurons. Functional imaging studies identified sex differ. thereby sone hypersuppression. non-human primates exposed to a variable forag- notypes.84 Such approach to reconcile inconsistent results. A mul.75 Identifying interactions between genetic disposition and trauma exposure in determining vulnerability to develop PTSD. moderates risk to develop PTSD AND PTSD in relation to childhood abuse. In addition. sex steroids play a role inconsistencies by considering potential effects of in lifelong structural plasticity of several brain disease stages.

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