Supplement

Neurobiology of Posttraumatic Stress Disorder

By Christine Heim, PhD, and Charles B. Nemeroff, MD, PhD

ABSTRACT
Exposure to a traumatic event is required for the diagnosis of posttraumatic stress disorder (PTSD). The symptoms of PTSD are believed to reflect stress-induced changes in neurobiological systems and/or an inadequate adaptation of neurobiological systems to exposure to severe stressors. More recently, there have been attempts to link the identified neurobiological changes to the specific features that constitute PTSD, such as altered mechanisms of learning and extinction, sensitization to stress, and arousal. Furthermore, there have been efforts to understand whether certain neurobiological changes in PTSD reflect preexisting vulnerability factors rather than consequences of trauma exposure or correlates of PTSD. Genetic variability, sex differences, and developmental exposures to stress influence neurobiological systems and moderate PTSD risk. On the basis of these findings, important hypotheses

Needs Assessment This article provides an update on the state of the research regarding the neurobiology of posttraumatic stress disorder (PTSD). There have been several important recent developments in the field, including linking neurobiological changes to specific features of PTSD, identifying neurobiological markers of PTSD risk, deriving new intervention strategies based on neurobiological findings, and providing insight into gene-environment interactions in determining PTSD risk versus resilience. Current needs and open issues are discussed based on the literature overview. Learning Objectives At the end of this activity, the participant should be able to: Summarize current neurobiological findings in PTSD Link neurobiological findings to specific features of PTSD Explain the potential mechanism of a neurobiological marker of PTSD risk Give an example of a novel treatment strategy derived from neurobiological findings in PTSD Target Audience: Psychiatrists

for developing novel strategies to identify subjects at risk, promote resilience, and devise targets for the prevention or treatment of PTSD can be derived. CNS Spectr. 2009;14:1(Suppl 1):13-24. Spectr

INTRODUCTION
In addition to the large numbers of soldiers deployed to combat around the world, civilians in modern societies face surprisingly high rates of exposure 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 advisory 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 following 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

C. Heim, C.B. Nemeroff

childhood abuse, rape, assault, accidents, and a wide variety of other severe psychological traumas. Experience of any such trauma may be associated with potentially lasting effects on the individual. A traumatic event is defined as an experience that is threatening to oneself or a close person, accompanied by intense fear, horror, or helplessness.1 Exposure to a traumatic event, defined as this, is required for the diagnosis of posttraumatic stress disorder (PTSD), making PTSD a psychiatric disorder that by definition is related to and occurs as a consequence of a stressful or traumatic event.1 Although initial theorists proposed that PTSD represents a normative response to exposure to extreme stressors, it soon became evident that only a minority of individuals who experience a traumatic event will develop the disorder.2 Thus, while most individuals are able to cope with the stressor and maintain or regain homeostasis, a small but significant minority of persons fails to recover and exhibits prolonged and abnormal behavioral and physiological responses to the traumatic experience, as manifested in the symptoms of PTSD. The symptoms of PTSD are believed to reflect stress-induced changes in neurobiological systems and/or an inadequate adaptation of neurobiological systems to exposure to severe stressors. Consequently, much research has been focused on elucidating alterations in stress-regulating neurobiological systems in patients with PTSD. Neurobiological systems that have been implicated in the pathophysiology of PTSD include the hypothalamic-pituitary-adrenal (HPA) axis, as well as various neurotransmitters and neuropeptides that comprise a network of brain regions that regulate fear and stress responses, including the prefrontal cortex, hippocampus, amygdala, and brainstem nuclei. More recently, there have been attempts to link the identified neurobiological changes to the specific features that constitute PTSD, such as altered mechanisms of learning and extinction, sensitization to stress, and arousal. Furthermore, there have been efforts to understand whether certain neurobiological changes in PTSD reflect preexisting vulnerability factors rather than consequences of trauma exposure or correlates of PTSD. Accordingly, there is increasing consideration of factors that affect outcome after trauma. Genetic variability, sex differences, and developmental exposures to stress influence neurobiological systems and moderate responses to trauma likely contributing to individual vulnerability versus resilience against developing PTSD. On the basis of such neurobiological findings,
CNS Spectr 14:1 (Suppl 1) MBL Communications, Inc. 14

important hypotheses for developing novel strategies to identify subjects at risk, promote resilience, and devise targets for the prevention or treatment of PTSD can be derived. In the following, we summarize core neurobiological findings in PTSD, describe current developments, discuss unresolved issues in the field, and suggest strategies for future research.

NEUROBIOLOGY OF PTSD: STATE OF SCIENCE

Hypothalamic-Pituitary-Adrenal Axis The HPA axis, an organisms major neuroendocrine stress response system, has been closely scrutinized in patients with PTSD. Upon exposure to stress, neurons in the hypothalamic paraventricular nucleus (PVN) secrete corticotropin-releasing factor (CRF) from the median eminence into the hypothalamo-hypophyseal portal circulation, in which the peptide is transported to the anterior pituitary where it stimulates the production and release of adrenocorticotropin (ACTH). ACTH, in turn, stimulates the release of glucocorticoids from the adrenal cortex. Glucocorticoids exert effects on metabolism, immune function, and the brain, adjusting physiological functions and behavior to the stressor. Several brain pathways modulate HPA axis activity. The hippocampus and prefrontal cortex (PFC) inhibit the HPA axis, whereas the amygdala and monoaminergic input from the brainstem stimulate the activity of PVN CRF neurons. Glucocorticoids exert negative feedback control of the HPA axis by regulating hippocampal and hypothalamic PVN neurons, as well as ACTH secretion, through binding to glucocorticoid receptors (GR) and mineralocorticoid receptors. Sustained glucocorticoid exposure has adverse effects on hippocampal neurons, including reduction in dendritic branching, loss of dendritic spines, and impairment of neurogenesis, though the latter is controversial.3-5 Although acute stressors activate the HPA axis, initial studies in combat veterans with PTSD revealed paradoxical decreases in cortisol concentrations, measured in urine or blood, compared to healthy controls and other diagnostic groups.6 This counterintuitive finding has been replicated in Holocaust survivors, refugees, and abused persons with PTSD, although findings are not uniformly consistent across studies.6 Differences in type and timing of the psychological trauma, symptom patterns, comorbidity, personality, and genetic dispositions, among other factors, may contribute to this inconsistency.7 Studies using low-dose dexamethasone
Januar y 2009

Neurobiology of Posttraumatic Stress Disorder

suppression and metyrapone testing, two pharmacologic agents that alter the availability of stress hormones exerting feedback on the HPA axis, revealed that hypocortisolism in PTSD occurs in the context of increased sensitivity of the HPA axis to negative glucocorticoid feedback.6 Findings of increased GR binding and function support the assumption of increased negative feedback sensitivity of the HPA axis in PTSD.6 At the central nervous system (CNS) level, marked and sustained increases of CRF concentrations have been measured in the cerebrospinal fluid (CSF) of patients with PTSD.8,9 Evidence of blunted ACTH responses to CRF stimulation in PTSD supports the hypothesis that PTSD involves elevated levels of hypothalamic CRF activity and corresponding down-regulating of pituitary CRF receptors.6 In addition, reduced volume of the hippocampus, the major brain region inhibiting the HPA axis, is a cardinal feature of PTSD.10 Taken together, the specific constellation of neuroendocrine findings in PTSD reflects sensitization of the HPA axis to exposure to stressors.6 This neuroendocrine pattern distinguishes PTSD from major depression, a frequently comorbid but distinct disorder.6 Interestingly, prospective studies have shown that low cortisol levels at the time of exposure to psychological trauma predict the development of PTSD,11,12 suggesting that hypocortisolism might be a preexisting risk factor that is associated with maladaptive stress responses such as PTSD. Consequently, administration of hydrocortisone directly after exposure to psychological trauma has been shown to effectively prevent PTSD in humans in several studies.13,14 In addition, it was recently demonstrated that hydrocortisone treatment, simulating normal circadian cortisol rhythm, is effective in the treatment of PTSD.15 Indeed, decreased availability of cortisol, and hence lack of regulatory effects in the CNS, may have permissive effects towards the sustained activation of neural systems involved in stress reactivity and fear processing, including the CRF and norepinephrine (NE) systems.6,16 Glucocorticoids further interfere with the retrieval of traumatic memories and thereby may prevent or reduce symptoms of PTSD.14,17

studies.8,9 Sustained elevations in CRF concentrations were observed despite comparably low cortisol concentrations, and the latter were negatively correlated with PTSD symptoms.9 Although the precise neuroanatomical source of CRF in CSF remains obscure, CSF CRF concentrations are believed to reflect CRF activity at extra-hypothalamic sites. In view of the CNS effects of CRF as described in vari, ous animal models, increased CNS CRF activity may promote certain of the cardinal features of PTSD, ie, conditioned fear responses, increased startle reactivity, sensitization to exposure to stressors, and hyperarousal. These results suggest that CRF1 receptor antagonists may well represent a novel therapeutic approach for the treatment of PTSD.

NEUROTRANSMITTERS AND NEUROPEPTIDES

Corticotropin-Releasing Factor As noted above, increased CSF concentrations of CRF have been measured in patients with PTSD, both in single lumbar puncture and serial sampling
CNS Spectr 14:1 (Suppl 1) MBL Communications, Inc. 15

Catecholamines: Norepinephrine and Dopamine The catecholamines comprise a family of neurotransmitters derived from the amino acid tyrosine. The rate-limiting factor in the synthesis of catecholamines is tyrosine hydroxylase, an enzyme that converts tyrosine into DOPA, which subsequently is converted into dopamine (DA) by the action of DOPA decarboxylase. In noradrenergic neurons, dopamine hydroxylase converts DA into NE. NE is one of the principal mediators of the CNS and autonomic stress responses. The majority of CNS NE is derived from neurons of the LC that project to various brain regions involved in the stress response, including the PFC, amygdala, hippocampus, hypothalamus, periaqueductal grey, and thalamus. There is evidence for a feedforward circuit connecting the amygdala and the hypothalamus with the LC, in which CRF and NE interact to increase fear conditioning and encoding of emotional memories, enhance arousal and vigilance, and integrate endocrine and autonomic responses to stress. Glucocorticoids inhibit this cascade.19 In the periphery, sympathoadrenal activation during exposure to stressors results in the release of NE and epinephrine from the adrenal medulla, increased release of NE from sympathetic nerve endings, and changes in blood flow to a variety of organs, reflecting an alarm reaction that mobilizes the body to allow for optimal coping. The effects of NE are mediated via postsynaptic 1, 1 and 2 receptors, whereas another NE-activated receptor, the 2 receptor, serves as a presynaptic autoreceptor inhibiting NE release. Because of its multiple roles in regulating arousal and autonomic stress responses, as well as promoting the encoding of emotional memories, NE has been a central candiJanuar y 2009

C. Heim, C.B. Nemeroff

date in studying the pathophysiology of PTSD. A cardinal feature of patients with PTSD is sustained hyperactivity of the sympathetic branch of the autonomic nervous system, as evidenced by heart rate, blood pressure, skin conductance level, and other psychophysiological measures. Accordingly, increased urinary excretion of NE and epinephrine, and their metabolites, has been documented in combat veterans, abused women, and children with PTSD. In addition, patients with PTSD exhibit increased heart rate, blood pressure, and NE responses to challenge, such as traumatic reminders. Decreased platelet 2 receptor binding further suggests NE hyperactivity in PTSD.20-21 There is also evidence for a role of altered CNS NE function in PTSD. Administration of the 2 receptor antagonist yohimbine, which increases NE release, induces symptoms of flashbacks and increased autonomic responses in patients with PTSD.22 Serial sampling revealed sustained increases in CSF NE concentrations and increased CSF NE responses to psychological stressors in PTSD.23-24 Taken together, increased CNS NE (re)activity plausibly contributes to features of PTSD, including hyperarousal, increased startle, and encoded fear memories.21 Interestingly, prospective studies have shown that increased heart rate and peripheral epinephrine excretion at the time of exposure to trauma predict subsequent development of PTSD. 12,25 Remarkably, administration of the centrally acting adrenergic blocker propranolol shortly after exposure to psychological trauma has been reported to reduce PTSD symptom severity and reactivity to reminders of the traumatic event.26 Although this did not prevent the development of PTSD, it may have blocked traumatic memory consolidation,27 and therefore may reduce the severity or chronicity of PTSD. Various anti-adrenergic agents have been tested for their therapeutic efficiency in the treatment of PTSD in open label trials, though there is a paucity of controlled trials.21 It should be noted that increased urinary excretion of DA and its metabolite has been reported for patients with PTSD. At the CNS level, mesolimbic DA plays a critical role in the processing of rewards. DA has also been implicated in fear conditioning. There is evidence in humans that exposure to stressors induces mesolimbic DA release, which in turn may impact on HPA axis responses. Whether or not the CNS DA system is altered in PTSD remains unclear, though genetic variations in the DA system have been implicated in moderating risk for PTSD.
CNS Spectr 14:1 (Suppl 1) MBL Communications, Inc. 16

Serotonin Serotonin, also known as 5-hydroxytryptamine (5-HT), is a monoamine neurotransmitter synthesized from the amino acid tryptophan. Serotonergic neurons originate in the dorsal and medial nuclei raph in the brainstem and project to multiple forebrain regions, including the amygdala, bed nucleus of the stria terminalis, hippocampus, and PFC. This indoleamine has roles in regulating sleep, appetite, sexual behavior, aggression/impulsivity, motor function, analgesia, and neuroendocrine control. It also has been implicated in the pathophysiology of mood and anxiety disorders and in the modulation of affective and stress responses. The direction of the modulatory effects of 5-HT on affective and stress responses depends on stressor intensity, brain region, and receptor type. It is believed that 5-HT neurons of the dorsal raph projecting to the amygdala and hippocampus mediate anxiogenic (stress-increasing) effects via 5-HT2 receptors, whereas 5-HT neurons from the median raph exert anxiolytic effects, facilitate extinction, and suppress encoding of learned associations via 5-HT1A receptors. Chronic exposure to stressors induces upregulation of 5-HT2 and downregulation of 5-HT1A receptors, respectively, in animal models. 5-HT1A receptor knockout mice exhibit increased stress responses. The 5-HT system interacts with the CRF and NE systems in coordinating affective and stress responses.20,28 Indirect evidence suggests a role of 5-HT in the pathophysiology of PTSD, including symptoms of impulsivity, hostility, aggression, depression, and suicidality. Most important concerning a role of 5-HT circuits in PTSD is the demonstrated efficacy of the selective serotonin reuptake inhibitors (SSRI). Other evidence for altered 5-HT neurotransmission in PTSD includes decreased serum concentrations of 5-HT, decreased density of platelet 5-HT uptake sites, and altered responsiveness to CNS serotonergic challenge.20,28 However, no differences in CNS 5-HT1A receptor binding were detected in patients with PTSD compared to controls using positron emission tomography (PET) imaging.29 Taken together, altered 5-HT transmission may contribute to symptoms of PTSD such as hypervigilance, increased startle, impulsivity, and intrusive memories. GABA/Benzodiazepine Receptor System Gamma-aminobutyric acid (GABA) is the principal inhibitory neurotransmitter in the CNS. GABA exerts anxiolytic effects and dampens behavioral and physiological responses to stressors, in part by
Januar y 2009

Neurobiology of Posttraumatic Stress Disorder

Neuropeptide Y Neuropeptide Y (NPY) is a neuropeptide with anxiolytic and stress-buffering properties. NPY has been shown to inhibit CRF/NE circuits involved in stress and fear responses and reduces the release of NE from sympathetic nerve cells. A relative lack of NPY may promote maladaptive stress responses and contribute to the development of PTSD. Indeed, patients with PTSD have been reported to exhibit decreased plasma NPY concentrations and blunted NPY responses to yohimbine challenge compared to controls, suggesting that decreased NPY activity may contribute to noradrenergic hyperactivity in PTSD.35 However, it has been suggested that NPY may be involved in promoting recovery from or resilience to PTSD because combat veterans without PTSD have been demonstrated to exhibit elevated plasma NPY levels compared to veterans with PTSD.36 Endogenous Opioids Endogenous opioids, such as the endorphins or enkephalins, are endogenous neuropeptides that act upon opiate receptors also activated by synthetic or naturally occurring opiates (such as morphine or heroin). Alterations in endogenous opioids have been postulated to be involved in symptoms of numbing, stress-induced analgesia, and dissociation in PTSD. Endogenous opioids further exert inhibitory influences on the HPA axis. Naloxone, a opiate receptor antagonist, increases HPA axis activity by blocking an inhibitory opioidergic influence on hypothalamic CRF secretion, and patients with PTSD have been reported to exhibit an exaggerated HPA axis response to naloxone. Interestingly, naloxone also has been shown to reverse the analgesia of PTSD patients after exposure to traumatic reminders. Finally, PTSD patients exhibit increased CSF -endorphin levels, suggesting increased activation of the endogenous opioid system. Interestingly, the opiate receptor antagonist, naltrexone, has been reported to be effective in treating symptoms of dissociation and flashbacks in traumatized patients.21,37 Administration of morphine has been shown to prevent the development of PTSD.38

inhibiting the CRF/NE circuits involved in mediating fear and stress responses. GABA acts on GABAA receptors, part of the GABA A /benzodiazepine (BZ) receptor complex. Uncontrollable stress has been shown to lead to alterations in the GABAA/ BZ receptor complex. Treatment with BZ, GABA agonists, or GABA reuptake inhibitors decreases symptoms of anxiety in PTSD, suggesting that the GABA/BZ system may be involved in the pathophysiology of PTSD. Patients with PTSD exhibit decreased platelet BZ binding sites.30 Single photon emission computed tomography and PET imaging studies revealed decreased BZ receptor binding in the cortex, hippocampus and thalamus of patients with PTSD. These results suggest that decreased density or affinity of the BZ receptor may play a role in PTSD.31,32 However, treatment with BZs after exposure to psychological trauma does not prevent PTSD.33 Although there are multiple studies implicating the GABA/BZ receptor system in anxiety disorders, studies in PTSD are relatively sparse.21

Glutamate/NMDA Receptor System Glutamate is the primary excitatory neurotransmitter in the CNS. Exposure to stressors and the release or administration of glucocorticoids increase glutamate release in the brain. Glutamate binds to several so-called excitatory aminoacid receptors, one of which is the N-methyl D-aspartate (NMDA) N receptor. The glutamate/NMDA receptor system has been implicated in synaptic plasticity, learning, and memory, including the well studied phenomenon of longterm potentiation (LTP), the extended excitation of neural circuits, leading to long-lasting enhancement in communication between neurons. This process is believed in part to underlie the process of conditioning and memory consolidation. LTP plausibly contributes to consolidation of trauma memories in PTSD. Of note, the partial NMDA-receptor antagonist D-cycloserine (DCS) has been shown to improve the extinction of fear in rodents and in phobic patients undergoing exposure therapy. Whether or not DCS is effective in enhancing the outcome of exposure therapy in PTSD remains to be studied.34 In addition to its role in learning and memory, overexposure to glutamate is associated with excitotoxicity, and plausibly could contribute to a loss of neurons in the hippocampus and PFC in PTSD. Of note, elevated glucocorticoids increase the expression and/or sensitivity of NMDA receptors, which may sensitize the brain to excitotoxic insults.
CNS Spectr 14:1 (Suppl 1) MBL Communications, Inc. 17

STRUCTURAL AND FUNCTIONAL NEUROANATOMY

The neurotransmitters discussed above serve as the chemical messengers of a connected network of brain regions that have been implicated in the development of PTSD. Changes in brain structure and function have been identified in patients with PTSD
Januar y 2009

C. Heim, C.B. Nemeroff

using brain imaging methods.10,39-41 Brain regions that are altered in patients with PTSD include the hippocampus, amygdala, and prefrontal cortical regions, including anterior cingulate and orbitofrontal cortex. These brain regions interact and form a connected neurocircuit that mediates adaptation to stress and fear conditioning, and changes in this circuit are proposed to be directly linked to the development of PTSD.39

tive memory task.50 Both hippocampal atrophy and functional deficits reverse after successful treatment with SSRIs,51 which have been demonstrated to increase neurotrophic factors and neurogenesis in preclinical studies.5

Hippocampus The most reproducible finding in structural imaging studies of PTSD is reduced volume of the hippocampus. The hippocampus is implicated in the control of stress responses, declarative memory and contextual aspects of fear conditioning, and is known as one of the most plastic regions in the brain. As noted above, prolonged exposure to stress and high glucocorticoid levels damages the hippocampus, leading to reduction in dendritic branching, loss of dendritic spines, and impairment of neurogenesis.4 Initial magnetic resonance imaging studies demonstrated smaller hippocampal volumes in Vietnam veterans with PTSD and patients with abuse-related PTSD compared to controls.42-45 Small hippocampal volumes were associated with the severity of trauma and memory impairments in these studies. These findings were generally replicated in subsequent studies. Studies using proton magnetic resonance spectroscopy (MRS) observed reduced levels of N-acetyl aspartate (NAA), a marker of neuronal integrity, in the hippocampus of adult patients with PTSD.39 Of note, NAA reductions were correlated with serum cortisol concentrations.46 Interestingly, reduced hippocampal volume was not observed in children with PTSD.47 Hippocampal volume reduction in PTSD may reflect toxic effects over time of repeatedly increased glucocorticoid exposure or increased glucocorticoid sensitivity, though recent evidence also suggests that a small hippocampus might represent a preexisting vulnerability factor for developing PTSD.48 Moreover, our group reported that in patients with major depression, early life trauma in the form of childhood abuse is associated with reduced hippocampal volume.49 Indeed, hippocampal deficits may promote activation of and failure to shut down stress responses, and may contribute to impaired extinction of conditioned fear as well as deficits in discriminating between safe and unsafe contexts. Studies using functional neuroimaging have further revealed that PTSD patients exhibit deficits in hippocampal activation during a verbal declaraCNS Spectr 14:1 (Suppl 1) MBL Communications, Inc. 18

Amygdala In addition to the hippocampus, other brain structures implicated in a neural circuitry of stress include the amygdala and the prefrontal cortex. The amygdala is a critical limbic structure involved in emotional processing and in the acquisition of fear responses. The amygdala is connected to both cortical and subcortical regions. The basolateral complex is innervated by neocortical and subcortical sensory regions and sends information to the central nucleus of the amygdala. The central nucleus projects to the midbrain and brainstem nuclei to coordinate rapid autonomic, endocrine, and behavioral responses to danger. The central nucleus also receives visceral information from brainstem regions. Connections between the amygdala and the hippocampus are implicated in context conditioning. Connections between the PFC and the amygdala modulate stress responsiveness and mediate extinction of fear memory, inasmuch as the PFC exerts inhibitory control over the amygdala.52 The functional role of the amygdala in mediating both stress responses and emotional learning suggests that changes in this region and its connected circuitry may be implicated in the pathophysiology of PTSD. Although there is no clear evidence for structural alterations of the amygdala in PTSD, functional imaging studies have revealed hyperresponsivity of the amygdala in PTSD during the presentation of traumatic scripts, cues, and other reminders.40,41 PTSD patients further show increased amygdala responses to general emotional stimuli that are not associated with the trauma, such as emotional faces.40 Of note, the amygdala also seems to be sensitized to subliminally presented threatening cues in PTSD.5355 Increased amygdala activation has also been reported for PTSD patients during fear acquisition in a conditioning experiment.56 Given that increased amygdala reactivity has been linked to genetic traits,57 which moderate risk for PTSD,58 increased amygdala reactivity may represent a biological risk factor for the development of PTSD. Prefrontal Cortex The medial prefrontal cortex (mPFC) comprises the anterior cingulate cortex (ACC), subcallosal
Januar y 2009

Neurobiology of Posttraumatic Stress Disorder

Linking Neurobiological Findings with Features of PTSD Neurotransmitter changes observed in PTSD patients likely reflect sensitization of stress-mediating systems and/or decreased ability to restrain stress responses in order to regain homeostasis. A relative lack of cortisol at the time of the trauma may facilitate the activation of the central CRF-NE cascade, potentially resulting in enhanced and prolonged stress responses.6,16 Lack of regulatory effects of GABA, serotonin, and NPY may further accentuate stress responsiveness. In addition to mediating stress responses, several of the altered neurochemical systems are critically involved in processes of learning and extinction, thereby impacting conditioned fear responses and the consolidation or retrieval of traumatic memories. Norepinephrine enhances the encoding of fear memories. Glucocorticoids block the retrieval of emotional memories. Thus, the constellation of elevated noradrenergic activity and relative hypocortisolism may lead to enhanced encoding of traumatic memories and lack of inhibition of memory retrieval, which could plausibly underlie intrusive memories in PTSD.14,17 The glutamate/ NMDA receptor system mediates LTP and may further promote conditioning and consolidation of traumatic memories. These neurotransmitter systems represent a network of brain regions, including the hippocampus, amygdala, and mPFC that regulate and integrate stress and fear responses. An impaired hippocampus in PTSD patients may contribute to increased neuroendocrine stress reactivity. In turn, increased cortisol responses to stress, together with increased glucocorticoid receptor sensitivity, may further promote hippocampal damage. Moreover, hippocampal damage may underlie some of the cognitive symptoms of PTSD, such as declarative memory deficits. Finally, because the hippocampus is critical for context conditioning, a damaged hippocampus may facilitate generalization of learned fear to other contexts and may impair the ability to discriminate between safe and unsafe contexts, thereby promoting the development of PTSD. Exaggerated amygdala responses, as seen in patients with PTSD, promote the activation of stress responses and acquisition of fear associations. Impaired prefrontal cortical function may underlie deficits in suppressing stress responses and fear associations and interferes with extinction. These hypotheses
Januar y 2009

cortex, and the medial frontal gyrus. The mPFC is connected with the amygdala, where it exerts inhibitory control over stress responses and emotional reactivity. The mPFC further mediates extinction of conditioned fear through active inhibition of acquired fear responses.40 Patients with PTSD exhibit decreased volumes of the frontal cortex,59 including reduced volumes of the ACC.60,61 The reduction in ACC volume was correlated with PTSD symptom severity in some of these studies. Altered shape of the ACC62 and decreased NAA concentrations in the ACC63 have also been reported in PTSD patients. A recent twin study suggests that volume loss in the ACC is an acquired correlate of having PTSD, rather than a preexisting risk factor.64 Functional imaging studies have found decreased activation of the mPFC in PTSD patients in response to stimuli, such as traumatic scripts,65,66 combat pictures and sounds,67 trauma unrelated negative narratives, 68 fearful faces, 69 emotional Stroop,70 and others, though there are also discordant findings.40 Reduced activation of the mPFC was associated with PTSD symptom severity in several of these studies and successful SSRI treatment restored mPFC activation patterns.40 Of note, in the above cited conditioning experiment,56 extinction of conditioned fear was associated with decreased activation of the ACC, providing a biological basis for imprinted traumatic memories in PTSD. Given the connectivity between the amygdala and mPFC, interactions in activation patterns between these regions have been reported in PTSD, though the direction of the relationship is inconsistent across studies.40

SUMMARY OF NEUROBIOLOGICAL FINDINGS AND CURRENT DEVELOPMENTS

In summary, core features of PTSD include low basal cortisol secretion and enhanced negative feedback control of the HPA axis that occurs in the context of increased autonomic responsiveness as well as increased CNS CRF and noradrenergic activity. Additional neurochemical changes include alterations in serotonergic, GABA-ergic, glutamatergic, NPY, and opioid systems. These neurotransmitter systems comprise a connected network of brain regions that is involved in the regulation and integration of stress and fear responses. A hallmark feature of PTSD is reduced volume of the hippocampus. Other brain changes involved in PTSD include exaggerated amygdala responsiveness and impaired mPFC function.
CNS Spectr 14:1 (Suppl 1) MBL Communications, Inc. 19

C. Heim, C.B. Nemeroff

have yet to be fully tested and integrated in a neurocircuitry model of PTSD.

Are Neurobiological Changes Preexisting Risk Factors of PTSD? A number of studies have raised the important question of whether the identified neurobiological changes in PTSD patients might, in fact, represent markers of neural risk to develop PTSD upon exposure to extreme stress, rather than markers of PTSD itself. For example, low cortisol levels and elevated heart rates at the time of a trauma predict subsequent development of PTSD. Therefore, hypocortisolism might represent a preexisting risk factor that promotes the manifestation of PTSD. As noted above, low cortisol concentrations may disinhibit CRF/NE neurocircuits and thereby promote autonomic stress responses, as well as fear conditioning and traumatic memory consolidation. Similarly, the reduced size of the hippocampus in PTSD has been a chicken-or-egg question for many years. There was considerable debate on whether this brain region shrinks as a result of the trauma exposure or due to the presence of PTSD itself, or whether a small hippocampus is a risk factor for the development of PTSD. Studies in twins discordant for trauma exposure provide an excellent opportunity to discern the contributions of predisposition, trauma exposure, and PTSD to neurobiological findings in PTSD. Gilbertson and colleagues71 studied 40 pairs of monozygotic twins, including Vietnam veterans who were exposed to combat trauma and their cotwins who did not go to Vietnam, and measured the size of the hippocampus in all the twins. As expected, among Vietnam veterans, the hippocampus was smaller in those had PTSD as compared to those who did not develop the disorder. However, this brain region was also smaller in the co-twins of the men with PTSD.71 This suggests that a smaller hippocampus is a preexisting, potentially genetic, vulnerability factor that predisposes a person to PTSD, as well as other trauma spectrum disorders, after the experience of stress or trauma. In contrast, more recent results from the same group suggest that grey matter loss in the ACC is an acquired feature that occurs as a result of PTSD.64 Deriving New Strategies for the Prevention and Treatment of PTSD Based on Neurobiological Findings New strategies for the prevention and treatment of PTSD are currently being tested that
CNS Spectr 14:1 (Suppl 1) MBL Communications, Inc. 20

directly target the above-described neurobiological mechanisms that appear to be implicated in the development of PTSD. Administration of hydrocortisone shortly after a traumatic experience has been reported to be effective in preventing the development of PTSD. In addition, hydrocortisone treatment simulating a normal circadian cortisol rhythm appears to be beneficial in the treatment of PTSD. Glucocorticoid substitution is hypothesized to exert inhibitory effects on sustained stress responses and blocks traumatic memory retrieval. 14,17 Similarly, because NE promotes encoding of traumatic memories, administration of the centrally acting adrenergic antagonist propranolol after exposure to psychological trauma has been tested for its potential to prevent the development of PTSD.38 Although propranolol did not prevent the development of PTSD, this intervention reduced symptom severity and reactivity to reminders of the traumatic event, potentially reflecting blockade of traumatic memory consolidation. Finally, a novel strategy based on insights into the mechanisms of learning is the use of cognitive enhancers to facilitate extinction learning during exposure therapy. 34 The partial NMDAreceptor antagonist DCS improves extinction of fear in rodents and in phobic patients undergoing exposure therapy, though it is presently unknown whether the drug enhances the outcome of exposure therapy in PTSD patients.

OUTCOME VARIATION IN THE RESPONSE TO TRAUMA: RISK VERSUS RESILIENCE

Not all individuals who undergo a trauma develop PTSD. Why some individuals develop PTSD following trauma while others do not is an important unexplored area. Moreover, it is equally unclear why some patients develop PTSD after trauma exposure, whereas others develop depression or another Axis I disorder. In most cases, the manifestation of a trauma spectrum disorder will be influenced by a complex interplay of preexisting vulnerabilities, including genetic disposition, personality styles, and prior experiences, as well as psychological and situational factors at the time of and in the aftermath of the trauma. Because the majority of trauma survivors will not develop a disorder, it is crucial to identify vulnerability and resilience factors. We discuss below the role of genetic factors, sex differences, and early developmental stress experiences in moderating risk for developing PTSD in response to trauma.
Januar y 2009

Neurobiology of Posttraumatic Stress Disorder

GENETIC RISK FACTORS OF PTSD
Studies on the genetics of PTSD, like those of other complex disorders that are characterized by both genetic and environmental risk factors, have been hampered by a variety of factors, including genetic heterogeneity (eg, a similar phenotype likely develops from different risk genotypes) and incomplete penetrance of the phenotype (eg, a person with a genetic risk for PTSD, who is not exposed to trauma, will not develop PTSD). Despite these difficulties, there is increasing evidence that risk for PTSD is influenced by genetic factors. Evidence from family and twin studies has long suggested a heritable contribution in the development of PTSD. In addition, there is evidence for heritable contributions to some of the neurobiological endophenotypes of PTSD, such as decreased hippocampal volume71 or exaggerated amygdala reactivity.57 Although it is beyond the scope of this chapter to comprehensively discuss the genetics of PTSD, it should be noted that there is an exciting
FIGURE.

literature emerging on genetic variations in neurobiological systems that determine responses to trauma and, consequently, risk versus resilience to develop PTSD.72 For example, one study has linked a polymorphism in the DA transporter gene to PTSD risk. An excess of the SLC6A3 9 repeat allele was present in those with PTSD. This finding suggests that genetically determined changes in DA reactivity may contribute to PTSD among trauma survivors.73 Several studies have investigated polymorphisms in the D2 receptor to PTSD risk, though results have been inconsistent.72 Finally, there is considerable evidence linking a low expression variant of the serotonin transporter, the so-called s allele of the serotonin-transporter-linked polymorphic region (5-HTTLPR), to stress responsiveness and risk for developing depression in relation to life stress. The same variant has now been associated with risk for developing PTSD, particularly in the presence of low social support.58 This finding is intriguing because the same polymorphism is

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
PTSD Symptom Score (PSS) 40 30 20 10 0 No Abuse 1 Type Child 2 Types Child Abuse Abuse AA AG GG

16 14 Serum Cortisol ng/ml 12 10 8 6 4 2 0 110 90 70 50 30 10 N=11

Probable PTSD

B
PTSD Symptom Score (PSS) 40 30 20 10 0

No PTSD Probable PTSD N=15 N=44

% Cortisol Supression

N=7

No Abuse

1 Type Child 2 Types Child Abuse Abuse

rs9296158 GG genotype

rs9296158 A allele carrier

Figure provided by and reproduced with permission from Binder E, Bradely R, Ressler K. Heim C, Nemeroff CB. CNS Spectr. Vol. 14, No 1 (Suppl 1). 2009. Spectr

CNS Spectr 14:1 (Suppl 1) MBL Communications, Inc. 21 21

Januar y 2009

C. Heim, C.B. Nemeroff

associated with increased amygdala reactivity57 as well as the trait of neuroticism,74 the latter another risk factor for PTSD. Particularly exciting are recent results that genetic variation of the glucocorticoid receptor cochaperone, FKBP5, moderates risk to develop PTSD in relation to childhood abuse.75 The study tested interactions of child abuse, adulthood trauma, and genetic polymorphisms in the FKBP5 gene in 900 non-psychiatric clinic patients. Childhood abuse and adulthood trauma each predicted PTSD symptoms. FKBP5 polymophisms significantly interacted with child abuse to predict adult PTSD symptoms. FKBP5 genotype was further linked to enhanced glucocorticoid receptor sensitivity, as reflected by dexamethasone hypersuppression, a hallmark feature of PTSD (Figure).75 Identifying interactions between genetic disposition and trauma exposure in determining PTSD risk and the underlying neurobiological phenotypes, as well as illness course and treatment response, is a vast area of future research. A multitude of candidate genes as well as genome-wide associations have yet to be tested.

processes may eventually converge into the basis of sex differences in the consequences of trauma that translate into differential risk for PTSD.

EARLY DEVELOPMENTAL FACTORS AND PTSD

Previous experience clearly moderates risk for developing PTSD in response to trauma. Thus, childhood adversity is associated with increased risk to develop PTSD in response to combat exposure in Vietnam veterans.85 There is a burgeoning literature documenting that early adverse experience, including prenatal stress and stress throughout childhood, has profound and long-lasting effects on the development of neurobiological systems, thereby programming subsequent stress reactivity and vulnerability to develop PTSD.86-88 For example, non-human primates exposed to a variable foraging demand condition, which causes unpredictable maternal care infants, produce an adult phenotype with sensitization to fear cues, CRF neuronal hyperactivity, and hypocortisolism similar to features of PTSD.89 In another non-human primate study, maternal separation interacted with female gender and the 5-HTTLPR polymorphism of the serotonin transporter gene in determining adult sensitization to acute stress.90 Adult women with childhood trauma histories exhibit sensitization of neuroendocrine and autonomic stress responses.91 Studies are needed to identify sensitive periods for the effects of early stress and their reversal, and to scrutinize interactions between dispositional (genes, sex) and developmental factors in determining neurobiological vulnerability to PTSD.

SEX DIFFERENCES AND RISK FOR PTSD

Women more frequently suffer from PTSD than men, perhaps in part due to sex differences in the exposure to different types of trauma. In addition, there might be sex differences in the neurobiological response to trauma.76 Rodent studies suggest that females generally exhibit a greater magnitude and duration of HPA axis responses to stress than males,77 though findings in humans are not entirely consistent.78 Sex differences in neuroendocrine stress responses have been attributed to direct effects of circulating estrogen on CRF neurons.79 Sex steroids also interact with other neurotransmitter systems involved in the stress response, ie, the serotonin system.80 Progesterone has also been implicated in modulating these systems.81 However, sex differences in HPA axis responses to stress have also been observed independent of acute gonadal steroid effects.82 Other factors that might determine sex differences in the stress response include genomic differences, organizational differences in brain structures, or developmentally programmed effects of gonadal steroids. 78,82,83 Of note, sex steroids play a role in lifelong structural plasticity of several brain regions, including areas involved in stress responsiveness, ie, the hippocampus and amygdala. 82 Functional imaging studies identified sex differences in the brains response to fear stimuli.84 Such
CNS Spectr 14:1 (Suppl 1) MBL Communications, Inc. 22

FUTURE RESEARCH NEEDS

We have provided an overview of the state of science and current developments concerning the neurobiology of PTSD. In the following section, selected unmet needs are described together with future research recommendations: 1. It must be stressed that neurobiological findings in PTSD are not unequivocal (the finding of hypocortisolism has not been replicated in all studies and some studies even report hypercortisolism in PTSD).7 The field must address and explain such inconsistencies by considering potential effects of disease stages, symptom constellations, different types or timing of the trauma, time elapsed since the trauma, and dispositional factors among others. Meta-anlayses of existing studies might be a fruitful approach to reconcile inconsistent results.
Januar y 2009

Neurobiology of Posttraumatic Stress Disorder

2. Related to the above topic, trajectories of neurobiological changes (pre-trauma, immediately following trauma, longer-term changes related to illness manifestation/chronicity versus changes related to compensatory regulation associated with resilience/remission) must be identified in longitudinal studies, accessing populations before exposure to trauma (eg, deployed soldiers). 3. Further research is needed to fully understand the mechanisms of PTSD. For example, molecular mechanisms contributing to the neurobiological phenotypes and pathophysiology of PTSD have not been sufficiently studied. It will be critical to consider neurotrophic factors and neural plasticity/ remodeling, gene expression changes, proteomics, and effects of trauma on DNA methylation. A specific animal model of PTSD as well as human postmortem brain studies will be helpful to address some of these research needs. 4. Brain imaging research must further scrutinize the neural circuitry of PTSD. Studies in depression92 might be used as a framework to conceptualize a neural network model of failed adaptation to stress/trauma in PTSD. Such a model could be useful in identifying neural markers of PTSD risk, disease state, compensatory regulation, and treatment response. 5. One major unmet need is integrating findings from different neurobiological domains in PTSD. For example, effects of neuroendocrine dysregulation on brain function and fear responses can be experimentally tested by combining neuroendocrine challenges with functional imaging paradigms. Contributions of genetic and developmental factors to neuroendocrine-neural interactions must be considered. 6. Insights from the above studies will serve to identify subjects at risk based on genetic, developmental, and neurobiological features. Prospective follow-up studies are needed that characterize subjects pre-trauma and identify pre-trauma predictors of pathological response versus resilience. 7 Based on insights into resilience markers, new . strategies to promote resilience could be derived. Future studies should consider the role stressprotective neurobiological systems, such as the oxytocin and NPY systems, as potential targets for prevention. Prospective studies could implement and test the efficacy of such pharmacological or cognitive-behavioral interventions before trauma (ie, stress inoculation, stress management trainings, relaxation methods, and CRF antagonists) to enhance resilience.
CNS Spectr 14:1 (Suppl 1) MBL Communications, Inc. 23 23

8. Novel treatments should further be developed based on new insights into the neurobiology of PTSD. Insights from depression research may be translated to PTSD (ie, in depression research, there are efforts to predict differential responsiveness to different types of treatment based on neural patterns92 and developmental/genetic factors93). Similarly, individual features of PTSD patients may be used in the future to select the optimal treatment approach for a given patient. CNS

REFERENCES

1. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association; 1997. 2. Yehuda R, LeDoux J. Response variation following trauma: a translational neuroscience approach to understanding PTSD. Neuron. 2007;56:19-32. 3. Arborelius L, Owens MJ, Plotsky PM, Nemeroff CB. The role of corticotropin-releasing factor in depression and anxiety disorders. J Endocrinol. 1999;160:1-12. Endocrinol 4. Fuchs E, Gould E. Mini-review: in vivo neurogenesis in the adult brain: regulation and functional implications. Eur J Neurosci. 2000;12:2211-2214. 5. Nestler EJ, Barrot M, DiLeone RJ, Eisch AJ, Gold SJ, Monteggia LM. Neurobiology of depression. Neuron. 2002;34:13-25. 6. Yehuda R. Advances in understanding neuroendocrine alterations in PTSD and their therapeutic implications. Ann N Y Acad Sci. 2006;1071:137-166. Sci 7. Meewisse ML, Reitsma JB, de Vries GJ, Gersons BP, Olff M. Cortisol and post-traumatic stress disorder in adults: systematic review and meta-analysis. Br J Psychiatry. 2007;191:387-392. 8. Bremner JD, Licinio J, Darnell A, et al. Elevated CSF corticotropin-releasing factor concentrations in posttraumatic stress disorder. Am J Psychiatry. 1997; 154:624-629. 9. Baker DG, West SA, Nicholson WE, et al. Serial CSF corticotropin-releasing hormone levels and adrenocortical activity in combat veterans with posttraumatic stress disorder. Am J Psychiatry. 1999;156:585-588. Psychiatry 10. Bremner JD, Elzinga B, Schmahl C, Vermetten E. Structural and functional plasticity of the human brain in posttraumatic stress disorder. Prog Brain Res. 2008;167:171-186. 11. Resnick HS, Yehuda R, Pitman RK, Foy DW. Effect of previous trauma on acute plasma cortisol level following rape. Am J Psychiatry. 1995;152:1675-1677. 12. Yehuda R, McFarlane AC, Shalev AY. Predicting the development of posttraumatic stress disorder from the acute response to a traumatic event. Biol Psychiatry. 1998;44:1305-1313. 13. Schelling G, Kilger E, Roozendaal B, et al. Stress doses of hydrocortisone, traumatic memories, and symptoms of posttraumatic stress disorder in patients after cardiac surgery: a randomized study. Biol Psychiatry Psychiatry. 2004;55:627-633. 14. De Quervain DJ. Glucocorticoid-induced reduction of traumatic memories: implications for the treatment of PTSD. Prog Brain Res. 2008;167:239-247. 15. Aerni A, Traber R, Hock C, et al. Low-dose cortisol for symptoms of posttraumatic stress disorder. Am J Psychiatry. 2004;161:1488-1490. 16. Heim C, Ehlert U, Hellhammer DH. The potential role of hypocortisolism in the pathophysiology of stressrelated bodily disorders. Psychoneuroendocrinology. 2000;25:1-35. Psychoneuroendocrinology 17. De Quervain DJ, Margraf J. Glucocorticoids for the treatment of post-traumatic stress disorder and phobias: A novel therapeutic approach. Eur J Pharmacol. 2008;583:365-371. 18. Koob GF. Corticotropin-releasing factor, norepinephrine, and stress. Biol Psychiatry. 1999;46:1167-1180. 19. Pavcovich LA, Valentino RJ. Regulation of a putative neurotransmitter effect of corticotropin-releasing factor: effects of adrenalectomy. J Neurosci. 1997;17:401-408. 20. Vermetten E, Bremner JD. Circuits and systems in stress. II. Applications to neurobiology and treatment in posttraumatic stress disorder. Depress Anxiety. 2002;16:14-38. 21. Strawn JR, Geracioti TD. Noradrenergic dysfunction and the psychopharmacology of posttraumatic stress disorder. Depress Anxiety. 2008;25:260-271. 22. Southwick SM, Bremner JD, Rasmusson A, Morgan CA 3rd, Arnsten A, Charney DS. Role of norepinephrine in the pathophysiology and treatment of posttraumatic stress disorder. Biol Psychiatry. Psychiatry 1999;46:1192-1204. 23. Geracioti TD Jr, Baker DG, Ekhator NN, et al. CSF norepinephrine concentrations in posttraumatic stress disorder. Am J Psychiatry. 2001;158:1227-1230. Psychiatry 24. Geracioti TD Jr, Baker DG, Kasckow JW, et al. Effects of trauma-related audiovisual stimulation on cerebrospinal fluid norepinephrine and corticotropin-releasing hormone concentrations in post-traumatic stress disorder. Psychoneuroendocrinology. 2008;33:416-424. Psychoneuroendocrinology 25. Delahanty DL, Nugent NR. Predicting PTSD prospectively based on prior trauma history and immediate biological responses. Ann N Y Acad Sci. 2006;1071:27-40. 26. Pitman RK, Sanders KM, Zusman RM, et al. Pilot study of secondary prevention of posttraumatic stress disorder with propranolol. Biol Psychiatry. 2002;51:189-192. 27. Brunet A, Orr SP, Tremblay J, Robertson K, Nader K, Pitman RK. Effect of post-retrieval propranolol on psychophysiologic responding during subsequent script-driven traumatic imagery in post-traumatic stress disorder. J Psychiatr Res. 2008;42:503-506. 28. Ressler KJ, Nemeroff CB. Role of serotonergic and noradrenergic systems in the pathophysiology of depression and anxiety disorders. Depr Anxiety. 2000;12:2-19. Anxiety 29. Bonne O, Bain E, Neumeister A, et al. No change in srotonin type 1A receptor binding in patients with posttraumatic stress disorder. Am J Psychiatry. 2005;162:383-385. 30. Gavish M, Laor N, Bidder M, et al. Altered platelet peripheral-type benzodiazepine receptor in posttraumatic stress disorder. Neuropsychopharmacology. 1996;14:181-186. Neuropsychopharmacology 31. Bremner JD, Innis RB, Southwick SM, Staib L, Zoghbi S, Charney DS. Decreased benzodiazepine receptor binding in prefrontal cortex in combat-related posttraumatic stress disorder. Am J Psychiatry. Psychiatry 2000;157:1120-1126. 32. Geuze E, van Berckel BN, Lammertsma AA, et al. Reduced GABAA benzodiazepine receptor binding in veterans with post-traumatic stress disorder. Mol Psychiatry. 2008;13:74-83. 33. Gelpin E, Bonne O, Peri T, Brandes D, Shalev AY. Treatment of recent trauma survivors with benzodiazepines: a prospective study. J Clin Psychiatry. 1996;57:390-394. 34. Davis M, Ressler K, Rothbaum BO, Richardson R. Effects of D-cycloserine on extinction: translation from preclinical to clinical work. Biol Psychiatry. 2006;60:369-375. Psychiatry 35. Rasmusson AM, Hauger RL, Morgan CA, Bremner JD, Charney DS, Southwick SM. Low baseline and yohimbine-stimulated plasma neuropeptide Y (NPY) levels in combat-related PTSD. Biol Psychiatry. Psychiatry 2000;47:526-539. 36. Yehuda R, Brand S, Yang RK. Plasma neuropeptide Y concentrations in combat exposed veterans: relationship to trauma exposure, recovery from PTSD, and coping. Biol Psychiatry. 2006;59:660-663.

Januar y 2009

C. Heim, C.B. Nemeroff

37. Newport DJ, Nemeroff CB. Neurobiology of posttraumatic stress disorder. Curr Opin Neurobiology. 2000;10:211-218. 38. Pitman RK, Delahanty DL. Conceptually driven pharmacologic approaches to acute trauma. CNS Spectr. Spectr 2005;10:99-106. 39. Rauch SL, Shin LM, Phelps EA. Neurocircuitry models of posttraumatic stress disorder and extinction: human neuroimaging research--past, present, and future. Biol Psychiatry. 2006;60:376-382. 40. Shin LM, Rauch SL, Pitman RK. Amygdala, medial prefrontal cortex, and hippocampal function in PTSD. Ann N Y Acad Sci. 2006;1071:67-79. 41. Liberzon I, Sripada CS. The functional neuroanatomy of PTSD: a critical review. Prog Brain Res. 2008;167:151-169. 42. Bremner JD, Randall P, Scott TM, et al. MRI-based measurement of hippocampal volume in patients with combat-related posttraumatic stress disorder. Am J Psychiatry. 1995;152:973-981. Psychiatry 43. Bremner JD, Randall P, Vermetten E, et al. Magnetic resonance imaging-based measurement of hippocampal volume in posttraumatic stress disorder related to childhood physical and sexual abuse--a preliminary report. Biol Psychiatry. 1997;41:23-32. 44. Gurvits TV, Shenton ME, Hokama H, et al. Magnetic resonance imaging study of hippocampal volume in chronic, combat-related posttraumatic stress disorder. Biol Psychiatry. 1996;40:1091-1099. Psychiatry 45. Stein MB, Koverola C, Hanna C, Torchia MG, McClarty B. Hippocampal volume in women victimized by childhood sexual abuse. Psychol Med. 1997;27:951-959. Med 46. Neylan TC, Schuff N, Lenoci M, Yehuda R, Weiner MW, Marmar CR. Cortisol levels are positively correlated with hippocampal N-acetylaspartate. Biol Psychiatry. 2003;54:1118-1121. Psychiatry 47. De Bellis MD, Keshavan MS, Clark DB, et al. A.E. Bennett Research Award. Developmental traumatology. Part II: Brain development. Biol Psychiatry. 1999;45:1271-1284. Psychiatry 48. Pitman RK, Gilbertson MW, Gurvits TV, et al. Clarifying the origin of biological abnormalities in PTSD through the study of identical twins discordant for combat exposure. Ann N Y Acad Sci. 2006;1071:242-254. Sci 49. Vythilingam M, Heim C, Newport J, et al. Childhood trauma associated with smaller hippocampal volume in women with major depression. Am J Psychiatry. 2002;159:2072-2080. 50. Bremner JD, Vythilingam M, Vermetten E, et al. Neural correlates of declarative memory for emotionally valenced words in women with posttraumatic stress disorder related to early childhood sexual abuse. Biol Psychiatry. 2003;53:879-889. 51. Bremner JD, Vermetten E. Neuroanatomical changes associated with pharmacotherapy in posttraumatic stress disorder. Ann N Y Acad Sci. 2004;1032:154-7. 52. Schulkin J. Angst and the amygdala. Dialogues Clin Neurosci. 2006;8:407-416. 53. Hendler T, Rotshtein P, Yeshurun Y, et al. Sensing the invisible: differential sensitivity of visual cortex and amygdala to traumatic context. Neuroimage. 2003;19:587-600. 54. Rauch SL, Whalen PJ, Shin LM, et al. Exaggerated amygdala response to masked facial stimuli in posttraumatic stress disorder: a functional MRI study. Biol Psychiatry. 2000;47:769-776. 55. Bryant RA, Kemp AH, Felmingham KL, et al. Enhanced amygdala and medial prefrontal activation during nonconscious processing of fear in posttraumatic stress disorder: an fMRI study. Hum Brain Mapp. 2008;29:517-523. 56. Bremner JD, Vermetten E, Schmahl C, et al. Positron emission tomographic imaging of neural correlates of a fear acquisition and extinction paradigm in women with childhood sexual-abuse-related post-traumatic stress disorder. Psychol Med. 2005;35:791-806. 57. Hariri AR, Mattay VS, Tessitore A, et al. Serotonin transporter genetic variation and the response of the human amygdala. Science. 2002;297:400-403. 58. Kilpatrick DG, Koenen KC, Ruggiero KJ, et al. The serotonin transporter genotype and social support and moderation of posttraumatic stress disorder and depression in hurricane-exposed adults. Am J Psychiatry. 2007;164:1693-1699. 59. Rauch SL, Shin LM, Segal E, et al. Selectively reduced regional cortical volumes in post-traumatic stress disorder. Neuroreport. 2003;14:913-916. Neuroreport 60. Yamasue H, Kasai K, Iwanami A, et al. Voxel-based analysis of MRI reveals anterior cingulate graymatter volume reduction in posttraumatic stress disorder due to terrorism. Proc Natl Acad Sci U S A. 2003;100:9039-9043. 61. Woodward SH, Kaloupek DG, Streeter CC, Martinez C, Schaer M, Eliez S. Decreased anterior cingulate volume in combat-related PTSD. Biol Psychiatry. 2006;59:582-587. Psychiatry 62. Corbo V, Clment MH, Armony JL, Pruessner JC, Brunet A. Size versus shape differences: contrasting voxel-based and volumetric analyses of the anterior cingulate cortex in individuals with acute posttraumatic stress disorder. Biol Psychiatry. 2005;58:119-124. 63. De Bellis MD, Keshavan MS, Spencer S, Hall J. N-Acetylaspartate concentration in the anterior cingulate of maltreated children and adolescents with PTSD. Am J Psychiatry. 2000;157:1175-1177. Psychiatry 64. Kasai K, Yamasue H, Gilbertson MW, Shenton ME, Rauch SL, Pitman RK. Evidence for acquired pregenual anterior cingulate gray matter loss from a twin study of combat-related posttraumatic stress disorder. Biol Psychiatry. 2008;63:550-556.

65. Shin LM, Orr SP, Carson MA, et al. Regional cerebral blood flow in the amygdala and medial prefrontal cortex during traumatic imagery in male and female Vietnam veterans with PTSD. Arch Gen Psychiatry. Psychiatry 2004;61:168-176. 66. Britton JC, Phan KL, Taylor SF, Fig LM, Liberzon I. Corticolimbic blood flow in posttraumatic stress disorder during script-driven imagery. Biol Psychiatry. 2005;57:832-840. 67. Bremner JD, Narayan M, Staib LH, Southwick SM, McGlashan T, Charney DS. Neural correlates of memories of childhood sexual abuse in women with and without posttraumatic stress disorder. Am J Psychiatry. 1999;156:1787-1795. 68. Lanius RA, Williamson PC, Hopper J, et al. Recall of emotional states in posttraumatic stress disorder: an fMRI investigation. Biol Psychiatry. 2003;53:204-210. 69. Shin LM, Wright CI, Cannistraro PA, et al. A functional magnetic resonance imaging study of amygdala and medial prefrontal cortex responses to overtly presented fearful faces in posttraumatic stress disorder. Arch Gen Psychiatry. 2005;62:273-281. 70. Bremner JD, Vermetten E, Vythilingam M, et al. Neural correlates of the classic color and emotional stroop in women with abuse-related posttraumatic stress disorder. Biol Psychiatry. 2004;55:612-620. 71. Gilbertson MW, Shenton ME, Ciszewski A, et al. Smaller hippocampal volume predicts pathologic vulnerability to psychological trauma. Nat Neurosci. 2002;5:1242-1247. Neurosci 72. Broekman BF, Olff M, Boer F. The genetic background to PTSD. Neurosci Biobehav Rev. 2007;31:348-62. Rev 73. Segman RH, Cooper-Kazaz R, Macciardi F, et al. Association between the dopamine transporter gene and posttraumatic stress disorder. Mol Psychiatry. 2002;7:903-907. Psychiatry 74. Lesch KP, Bengel D, Heils A, et al. Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science. 1996;274:1527-1531. 75. Binder EB, Bradley RG, Liu W, et al. Association of FKBP5 polymorphisms and childhood abuse with risk of posttraumatic stress disorder symptoms in adults. JAMA. 2008;299:1291-1305. 76. Becker JB, Monteggia LM, Perrot-Sinal TS, et al. Stress and disease: is being female a predisposing factor? J Neurosci. 2007;27:11851-11855. 77. Rhodes ME, Rubin RT. Functional sex differences (sexual diergism) of central nervous system cholinergic systems, vasopressin, and hypothalamic-pituitary-adrenal axis activity in mammals: a selective review. Brain Res Brain Res Rev. 1999;30:135-152. Rev 78. Kudielka BM, Kirschbaum C. Sex differences in HPA axis responses to stress: a review. Biol Psychol. Psychol 2005;69:113-132. 79. Vamvakopoulos NC, Chrousos GP. Evidence of direct estrogenic regulation of human corticotropinreleasing hormone gene expression. J Clin Invest. 1993;92:1896-1902. Invest 80. Bethea CL, Mirkes SJ, Su A, Michelson D. Effects of oral estrogen, raloxifene and arzoxifene on gene expression in serotonin neurons of macaques. Psychoneuroendocrinology. 2002;27:431-445. Psychoneuroendocrinology 81. Centeno ML, Reddy AP, Smith LJ, et al. Serotonin in microdialysate from the mediobasal hypothalamus increases after progesterone administration to estrogen primed macaques. Eur J Pharmacol. 2007;555:67-75. Pharmacol 82. McEwen BS. Invited review: Estrogens effects on the brain: multiple sites and molecular mechanisms. J Appl Physiol. 2001;91:2785-2801. 83. Roca CA, Schmidt PJ, Deuster PA, et al. Sex-related differences in stimulated hypothalamic-pituitaryadrenal axis during induced gonadal suppression. J Clin Endo Metab. 2005;90:4224-4231. 84. Schienle A, Schafer A, Stark R, Walter B, Vaitl D. Gender differences in the processing of disgust- and fear-inducing pictures: an fMRI study. Neuroreport. 2005;16:277-280. Neuroreport 85. Bremner JD, Southwick SM, Johnson DR, Yehuda R, Charney DS. Childhood physical abuse and combatrelated posttraumatic stress disorder in Vietnam veterans. Am J Psychiatry. 1993;150:235-239. Psychiatry 86. Seckl JR, Meaney MJ. Glucocorticoid programming and PTSD risk. Ann N Y Acad Sci. 2006;1071: Sci 351-378. 87. Meaney MJ, Szyf M. Environmental programming of stress responses through DNA methylation: life at the interface between a dynamic environment and a fixed genome. Dialogues Clin Neurosci. 2005;7:103-123. Neurosci 88. Nemeroff CB. Neurobiological consequences of childhood trauma. J Clin Psychiatry. 2004;65:18-28. Psychiatry 89. Coplan JD, Andrews MW, Rosenblum LA, et al. Persistent elevations of cerebrospinal fluid concentrations of corticotropin-releasing factor in adult nonhuman primates exposed to early-life stressors: implications for the pathophysiology of mood and anxiety disorders. Proc Natl Acad Sci U S A. 1996;93:1619-1623. 90. Barr CS, Newman, TK, Schwandt M, et al. Sexual dichotomy of an interaction between early adversity and the serotonin transporter gene promoter variant in rhesus macaques. Proc Natl Acad Sci U S A. 2004;101:12358-12363. 91. Heim C, Newport DJ, Heit S, et al. Pituitary-adrenal and autonomic responses to stress in women after sexual and physical abuse in childhood. JAMA. 2000;284:592-597. 92. Mayberg HS. Modulating dysfunctional limbic-cortical circuits in depression: towards development of brain-based algorithms for diagnosis and optimised treatment. Br Med Bull. 2003;65:193-207. Bull 93. Nemeroff CB, Heim CM, Thase ME, et al. Differential responses to psychotherapy versus pharmacotherapy in patients with chronic forms of major depression and childhood trauma. Proc Natl Acad Sci U S A. 2003;100:14293-14296.

CNS Spectr 14:1 (Suppl 1) MBL Communications, Inc. 24 24

Januar y 2009