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Neurobiology of Posttraumatic Stress Disorder
By Christine Heim, PhD, and Charles B. Nemeroff, MD, PhD
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
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: firstname.lastname@example.org.
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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. and suggest strategies for future research. and developmental exposures to stress influence neurobiological systems and moderate responses to trauma likely contributing to individual vulnerability versus resilience against developing PTSD. personality.C. and abused persons with PTSD. and devise targets for the prevention or treatment of PTSD can be derived. NEUROBIOLOGY OF PTSD: STATE OF SCIENCE Hypothalamic-Pituitary-Adrenal Axis The HPA axis. has been closely scrutinized in patients with PTSD. Sustained glucocorticoid exposure has adverse effects on hippocampal neurons.7 Studies using low-dose dexamethasone Januar y 2009 .6 Differences in type and timing of the psychological trauma. or helplessness.3-5 Although acute stressors activate the HPA axis. it soon became evident that only a minority of individuals who experience a traumatic event will develop the disorder. such as altered mechanisms of learning and extinction. sex differences. and brainstem nuclei. we summarize core neurobiological findings in PTSD. in which the peptide is transported to the anterior pituitary where it stimulates the production and release of adrenocorticotropin (ACTH). 14 important hypotheses for developing novel strategies to identify subjects at risk. an organism’s major neuroendocrine stress response system.1 Although initial theorists proposed that PTSD represents a normative response to exposure to extreme stressors. including reduction in dendritic branching. Glucocorticoids exert negative feedback control of the HPA axis by regulating hippocampal and hypothalamic PVN neurons. 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. among other factors. defined as this. much research has been focused on elucidating alterations in stress-regulating neurobiological systems in patients with PTSD. accompanied by intense fear. symptom patterns. hippocampus.B. rape. is required for the diagnosis of posttraumatic stress disorder (PTSD). 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. initial studies in combat veterans with PTSD revealed paradoxical decreases in cortisol concentrations. More recently. Nemeroff childhood abuse. Several brain pathways modulate HPA axis activity. may contribute to this inconsistency. In the following. and genetic dispositions. although findings are not uniformly consistent across studies. The hippocampus and prefrontal cortex (PFC) inhibit the HPA axis. amygdala. Accordingly. neurons in the hypothalamic paraventricular nucleus (PVN) secrete corticotropin-releasing factor (CRF) from the median eminence into the hypothalamo-hypophyseal portal circulation. horror. assault. measured in urine or blood. On the basis of such neurobiological findings. sensitization to stress. though the latter is controversial. whereas the amygdala and monoaminergic input from the brainstem stimulate the activity of PVN CRF neurons. compared to healthy controls and other diagnostic groups. there have been attempts to link the identified neurobiological changes to the specific features that constitute PTSD. there is increasing consideration of factors that affect outcome after trauma. discuss unresolved issues in the field. comorbidity. refugees. promote resilience. Genetic variability. adjusting physiological functions and behavior to the stressor. A traumatic event is defined as an experience that is threatening to oneself or a close person. and a wide variety of other severe psychological traumas. accidents. loss of dendritic spines. ACTH. Consequently. C. Experience of any such trauma may be associated with potentially lasting effects on the individual.6 This counterintuitive finding has been replicated in Holocaust survivors. making PTSD a psychiatric disorder that by definition is related to and occurs as a consequence of a stressful or traumatic event. as well as various neurotransmitters and neuropeptides that comprise a network of brain regions that regulate fear and stress responses. Neurobiological systems that have been implicated in the pathophysiology of PTSD include the hypothalamic-pituitary-adrenal (HPA) axis. Upon exposure to stress. immune function.1 Exposure to a traumatic event. through binding to glucocorticoid receptors (GR) and mineralocorticoid receptors.2 Thus. stimulates the release of glucocorticoids from the adrenal cortex. describe current developments. Furthermore. CNS Spectr 14:1 (Suppl 1) ©MBL Communications. Heim. while most individuals are able to cope with the stressor and maintain or regain homeostasis. Glucocorticoids exert effects on metabolism. as well as ACTH secretion. and arousal. Inc. and impairment of neurogenesis. and the brain. in turn. including the prefrontal cortex.
There is evidence for a feedforward circuit connecting the amygdala and the hypothalamus with the LC. an enzyme that converts tyrosine into DOPA.6 Interestingly.19 In the periphery. both in single lumbar puncture and serial sampling CNS Spectr 14:1 (Suppl 1) ©MBL Communications.6 At the central nervous system (CNS) level. sensitization to exposure to stressors. In noradrenergic neurons.15 Indeed.6 This neuroendocrine pattern distinguishes PTSD from major depression.17 studies. is a cardinal feature of PTSD. and the latter were negatively correlated with PTSD symptoms. and integrate endocrine and autonomic responses to stress. prospective studies have shown that low cortisol levels at the time of exposure to psychological trauma predict the development of PTSD. sympathoadrenal activation during exposure to stressors results in the release of NE and epinephrine from the adrenal medulla. decreased availability of cortisol. a frequently comorbid but distinct disorder. reduced volume of the hippocampus. including the CRF and norepinephrine (NE) systems. it was recently demonstrated that hydrocortisone treatment. increased CNS CRF activity may promote certain of the cardinal features of PTSD. ie. Because of its multiple roles in regulating arousal and autonomic stress responses. Inc. may have permissive effects towards the sustained activation of neural systems involved in stress reactivity and fear processing.14 In addition. as well as promoting the encoding of emotional memories. In view of the CNS effects of CRF as described in vari. two pharmacologic agents that alter the availability of stress hormones exerting feedback on the HPA axis. hypothalamus. administration of hydrocortisone directly after exposure to psychological trauma has been shown to effectively prevent PTSD in humans in several studies.11.9 Although the precise neuroanatomical source of CRF in CSF remains obscure. 15 Catecholamines: Norepinephrine and Dopamine The catecholamines comprise a family of neurotransmitters derived from the amino acid tyrosine. periaqueductal grey. The rate-limiting factor in the synthesis of catecholamines is tyrosine hydroxylase. Consequently. the α2 receptor. the major brain region inhibiting the HPA axis. serves as a presynaptic autoreceptor inhibiting NE release. The effects of NE are mediated via postsynaptic α1. reflecting an alarm reaction that mobilizes the body to allow for optimal coping. and changes in blood flow to a variety of organs. increased startle reactivity. and thalamus. dopamine β hydroxylase converts DA into NE. including the PFC. which subsequently is converted into dopamine (DA) by the action of DOPA decarboxylase. Glucocorticoids inhibit this cascade.8. conditioned fear responses. whereas another NE-activated receptor. in which CRF and NE interact to increase fear conditioning and encoding of emotional memories.Neurobiology of Posttraumatic Stress Disorder suppression and metyrapone testing. and hyperarousal. increased CSF concentrations of CRF have been measured in patients with PTSD.9 Sustained elevations in CRF concentrations were observed despite comparably low cortisol concentrations.14. The majority of CNS NE is derived from neurons of the LC that project to various brain regions involved in the stress response. β1 and β2 receptors. revealed that hypocortisolism in PTSD occurs in the context of increased sensitivity of the HPA axis to negative glucocorticoid feedback. amygdala. NEUROTRANSMITTERS AND NEUROPEPTIDES Corticotropin-Releasing Factor As noted above. marked and sustained increases of CRF concentrations have been measured in the cerebrospinal fluid (CSF) of patients with PTSD.8.12 suggesting that hypocortisolism might be a preexisting risk factor that is associated with maladaptive stress responses such as PTSD. the specific constellation of neuroendocrine findings in PTSD reflects sensitization of the HPA axis to exposure to stressors. These results suggest that CRF1 receptor antagonists may well represent a novel therapeutic approach for the treatment of PTSD.6 Findings of increased GR binding and function support the assumption of increased negative feedback sensitivity of the HPA axis in PTSD. and hence lack of regulatory effects in the CNS.10 Taken together.6. increased release of NE from sympathetic nerve endings. hippocampus. NE is one of the principal mediators of the CNS and autonomic stress responses.13. simulating normal circadian cortisol rhythm. NE has been a central candiJanuar y 2009 . CSF CRF concentrations are believed to reflect CRF activity at extra-hypothalamic sites.16 Glucocorticoids further interfere with the retrieval of traumatic memories and thereby may prevent or reduce symptoms of PTSD. enhance arousal and vigilance.6 In addition. is effective in the treatment of PTSD. ous animal models.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.
which in turn may impact on HPA axis responses. Accordingly. also known as 5-hydroxytryptamine (5-HT). Other evidence for altered 5-HT neurotransmission in PTSD includes decreased serum concentrations of 5-HT. This indoleamine has roles in regulating sleep.B. and their metabolites. At the CNS level. patients with PTSD exhibit increased heart rate. and neuroendocrine control. though genetic variations in the DA system have been implicated in moderating risk for PTSD. aggression. blood pressure. skin conductance level. and suppress encoding of learned associations via 5-HT1A receptors. impulsivity. including symptoms of impulsivity. CNS Spectr 14:1 (Suppl 1) ©MBL Communications.27 and therefore may reduce the severity or chronicity of PTSD. increased CNS NE (re)activity plausibly contributes to features of PTSD.20-21 There is also evidence for a role of altered CNS NE function in PTSD. A cardinal feature of patients with PTSD is sustained hyperactivity of the sympathetic branch of the autonomic nervous system. Heim. sexual behavior. and PFC. analgesia.28 Indirect evidence suggests a role of 5-HT in the pathophysiology of PTSD.20.C. It is believed that 5-HT neurons of the dorsal raphé projecting to the amygdala and hippocampus mediate anxiogenic (stress-increasing) effects via 5-HT2 receptors. In addition. GABA exerts anxiolytic effects and dampens behavioral and physiological responses to stressors. aggression/impulsivity. motor function. it may have blocked traumatic memory consolidation. Serotonergic neurons originate in the dorsal and medial nuclei raphé in the brainstem and project to multiple forebrain regions. and NE responses to challenge. depression. blood pressure.21 Interestingly. and children with PTSD. It also has been implicated in the pathophysiology of mood and anxiety disorders and in the modulation of affective and stress responses. including the amygdala. Inc.21 It should be noted that increased urinary excretion of DA and its metabolite has been reported for patients with PTSD. Nemeroff date in studying the pathophysiology of PTSD. and altered responsiveness to CNS serotonergic challenge. including hyperarousal. which increases NE release. though there is a paucity of controlled trials. increased urinary excretion of NE and epinephrine.25 Remarkably. is a monoamine neurotransmitter synthesized from the amino acid tryptophan. Decreased platelet α2 receptor binding further suggests NE hyperactivity in PTSD. C. such as traumatic reminders. Various anti-adrenergic agents have been tested for their therapeutic efficiency in the treatment of PTSD in open label trials. Whether or not the CNS DA system is altered in PTSD remains unclear. mesolimbic DA plays a critical role in the processing of rewards. increased startle. and receptor type.28 However. brain region.26 Although this did not prevent the development of PTSD. There is evidence in humans that exposure to stressors induces mesolimbic DA release. facilitate extinction. as evidenced by heart rate. whereas 5-HT neurons from the median raphé exert anxiolytic effects. Administration of the α2 receptor antagonist yohimbine. no differences in CNS 5-HT1A receptor binding were detected in patients with PTSD compared to controls using positron emission tomography (PET) imaging. The direction of the modulatory effects of 5-HT on affective and stress responses depends on stressor intensity. DA has also been implicated in fear conditioning. appetite. in animal models. respectively.22 Serial sampling revealed sustained increases in CSF NE concentrations and increased CSF NE responses to psychological stressors in PTSD. and other psychophysiological measures. 16 Serotonin Serotonin. GABA/Benzodiazepine Receptor System Gamma-aminobutyric acid (GABA) is the principal inhibitory neurotransmitter in the CNS. hippocampus. induces symptoms of flashbacks and increased autonomic responses in patients with PTSD.23-24 Taken together. 5-HT1A receptor knockout mice exhibit increased stress responses. and suicidality. Chronic exposure to stressors induces upregulation of 5-HT2 and downregulation of 5-HT1A receptors. 12. and intrusive memories. altered 5-HT transmission may contribute to symptoms of PTSD such as hypervigilance. bed nucleus of the stria terminalis. Most important concerning a role of 5-HT circuits in PTSD is the demonstrated efficacy of the selective serotonin reuptake inhibitors (SSRI). in part by Januar y 2009 . hostility. administration of the centrally acting β 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. abused women. increased startle. and encoded fear memories.20.29 Taken together. prospective studies have shown that increased heart rate and peripheral epinephrine excretion at the time of exposure to trauma predict subsequent development of PTSD. decreased density of platelet 5-HT uptake sites. The 5-HT system interacts with the CRF and NE systems in coordinating affective and stress responses. has been documented in combat veterans.
are endogenous neuropeptides that act upon opiate receptors also activated by synthetic or naturally occurring opiates (such as morphine or heroin). CNS Spectr 14:1 (Suppl 1) ©MBL Communications. Changes in brain structure and function have been identified in patients with PTSD Januar y 2009 . Treatment with BZ. Patients with PTSD exhibit decreased platelet BZ binding sites. patients with PTSD have been reported to exhibit decreased plasma NPY concentrations and blunted NPY responses to yohimbine challenge compared to controls. and dissociation in PTSD. Alterations in endogenous opioids have been postulated to be involved in symptoms of numbing.21 Glutamate/NMDA Receptor System Glutamate is the primary excitatory neurotransmitter in the CNS. This process is believed in part to underlie the process of conditioning and memory consolidation. the opiate receptor antagonist.33 Although there are multiple studies implicating the GABA/BZ receptor system in anxiety disorders. has been reported to be effective in treating symptoms of dissociation and flashbacks in traumatized patients. and memory. LTP plausibly contributes to consolidation of trauma memories in PTSD. learning. elevated glucocorticoids increase the expression and/or sensitivity of NMDA receptors. a μ opiate receptor antagonist.32 However. Inc. increases HPA axis activity by blocking an inhibitory opioidergic influence on hypothalamic CRF secretion. Of note.Neurobiology of Posttraumatic Stress Disorder Neuropeptide Y Neuropeptide Y (NPY) is a neuropeptide with anxiolytic and stress-buffering properties. Uncontrollable stress has been shown to lead to alterations in the GABAA/ BZ receptor complex. stress-induced analgesia. GABA acts on GABAA receptors. including the well studied phenomenon of longterm potentiation (LTP). and patients with PTSD have been reported to exhibit an exaggerated HPA axis response to naloxone. part of the GABA A /benzodiazepine (BZ) receptor complex.34 In addition to its role in learning and memory. The glutamate/NMDA receptor system has been implicated in synaptic plasticity. and plausibly could contribute to a loss of neurons in the hippocampus and PFC in PTSD. Indeed.37 Administration of morphine has been shown to prevent the development of PTSD. Of note. Interestingly. PTSD patients exhibit increased CSF β-endorphin levels. Naloxone. one of which is the N-methyl D-aspartate (NMDA) N receptor.30 Single photon emission computed tomography and PET imaging studies revealed decreased BZ receptor binding in the cortex. 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. Finally. Glutamate binds to several so-called excitatory aminoacid receptors. Interestingly. 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. naltrexone.38 inhibiting the CRF/NE circuits involved in mediating fear and stress responses. overexposure to glutamate is associated with excitotoxicity. suggesting increased activation of the endogenous opioid system. A relative lack of NPY may promote maladaptive stress responses and contribute to the development of PTSD. suggesting that decreased NPY activity may contribute to noradrenergic hyperactivity in PTSD. which may sensitize the brain to excitotoxic insults. 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.35 However. treatment with BZs after exposure to psychological trauma does not prevent PTSD. Endogenous opioids further exert inhibitory influences on the HPA axis.21. such as the endorphins or enkephalins. or GABA reuptake inhibitors decreases symptoms of anxiety in PTSD. GABA agonists. hippocampus and thalamus of patients with PTSD. Exposure to stressors and the release or administration of glucocorticoids increase glutamate release in the brain. leading to long-lasting enhancement in communication between neurons.36 Endogenous Opioids Endogenous opioids. studies in PTSD are relatively sparse. These results suggest that decreased density or affinity of the BZ receptor may play a role in PTSD. 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. the extended excitation of neural circuits.31. suggesting that the GABA/BZ system may be involved in the pathophysiology of PTSD. Whether or not DCS is effective in enhancing the outcome of exposure therapy in PTSD remains to be studied. naloxone also has been shown to reverse the analgesia of PTSD patients after exposure to traumatic reminders.
5355 Increased amygdala activation has also been reported for PTSD patients during fear acquisition in a conditioning experiment. prolonged exposure to stress and high glucocorticoid levels damages the hippocampus.50 Both hippocampal atrophy and functional deficits reverse after successful treatment with SSRIs. functional imaging studies have revealed hyperresponsivity of the amygdala in PTSD during the presentation of traumatic scripts.C. Connections between the PFC and the amygdala modulate stress responsiveness and mediate extinction of fear memory. Prefrontal Cortex The medial prefrontal cortex (mPFC) comprises the anterior cingulate cortex (ACC).48 Moreover. 18 Amygdala In addition to the hippocampus.40 Of note. These findings were generally replicated in subsequent studies. cues.47 Hippocampal volume reduction in PTSD may reflect toxic effects over time of repeatedly increased glucocorticoid exposure or increased glucocorticoid sensitivity. and behavioral responses to danger. amygdala.51 which have been demonstrated to increase neurotrophic factors and neurogenesis in preclinical studies. and prefrontal cortical regions. loss of dendritic spines.49 Indeed. declarative memory and contextual aspects of fear conditioning. Connections between the amygdala and the hippocampus are implicated in context conditioning. the amygdala also seems to be sensitized to subliminally presented threatening cues in PTSD. Although there is no clear evidence for structural alterations of the amygdala in PTSD.B. The central nucleus projects to the midbrain and brainstem nuclei to coordinate rapid autonomic. subcallosal Januar y 2009 .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. NAA reductions were correlated with serum cortisol concentrations. C.58 increased amygdala reactivity may represent a biological risk factor for the development of PTSD. though recent evidence also suggests that a small hippocampus might represent a preexisting vulnerability factor for developing PTSD. Inc.5 Hippocampus The most reproducible finding in structural imaging studies of PTSD is reduced volume of the hippocampus.39-41 Brain regions that are altered in patients with PTSD include the hippocampus. and may contribute to impaired extinction of conditioned fear as well as deficits in discriminating between safe and unsafe contexts.46 Interestingly. Heim.57 which moderate risk for PTSD.10. inasmuch as the PFC exerts inhibitory control over the amygdala. early life trauma in the form of childhood abuse is associated with reduced hippocampal volume. The amygdala is a critical limbic structure involved in emotional processing and in the acquisition of fear responses. As noted above. endocrine. The amygdala is connected to both cortical and subcortical regions. Nemeroff using brain imaging methods. including anterior cingulate and orbitofrontal cortex. leading to reduction in dendritic branching. Studies using proton magnetic resonance spectroscopy (MRS) observed reduced levels of N-acetyl aspartate (NAA).4 Initial magnetic resonance imaging studies demonstrated smaller hippocampal volumes in Vietnam veterans with PTSD and patients with abuse-related PTSD compared to controls.39 Of note. 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. reduced hippocampal volume was not observed in children with PTSD.41 PTSD patients further show increased amygdala responses to general emotional stimuli that are not associated with the trauma. such as emotional faces. The central nucleus also receives visceral information from brainstem regions.56 Given that increased amygdala reactivity has been linked to genetic traits. hippocampal deficits may promote activation of and failure to shut down stress responses. in the hippocampus of adult patients with PTSD.40. The hippocampus is implicated in the control of stress responses.39 tive memory task. and is known as one of the most plastic regions in the brain. a marker of neuronal integrity. The basolateral complex is innervated by neocortical and subcortical sensory regions and sends information to the central nucleus of the amygdala. and changes in this circuit are proposed to be directly linked to the development of PTSD. These brain regions interact and form a connected neurocircuit that mediates adaptation to stress and fear conditioning. other brain structures implicated in a neural circuitry of stress include the amygdala and the prefrontal cortex. our group reported that in patients with major depression. and impairment of neurogenesis. and other reminders.42-45 Small hippocampal volumes were associated with the severity of trauma and memory impairments in these studies.
and the medial frontal gyrus.40 Of note. Impaired prefrontal cortical function may underlie deficits in suppressing stress responses and fear associations and interferes with extinction.60.14. The mPFC is connected with the amygdala.65. These neurotransmitter systems comprise a connected network of brain regions that is involved in the regulation and integration of stress and fear responses.40 Patients with PTSD exhibit decreased volumes of the frontal cortex. A hallmark feature of PTSD is reduced volume of the hippocampus. promote the activation of stress responses and acquisition of fear associations. such as declarative memory deficits.56 extinction of conditioned fear was associated with decreased activation of the ACC. thereby promoting the development of PTSD. A recent twin study suggests that volume loss in the ACC is an acquired correlate of having PTSD.70 and others. potentially resulting in enhanced and prolonged stress responses. 68 fearful faces. These hypotheses Januar y 2009 cortex. interactions in activation patterns between these regions have been reported in PTSD. though there are also discordant findings. as seen in patients with PTSD. rather than a preexisting risk factor. Altered shape of the ACC62 and decreased NAA concentrations in the ACC63 have also been reported in PTSD patients. An impaired hippocampus in PTSD patients may contribute to increased neuroendocrine stress reactivity. 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. several of the altered neurochemical systems are critically involved in processes of learning and extinction. the constellation of elevated noradrenergic activity and relative hypocortisolism may lead to enhanced encoding of traumatic memories and lack of inhibition of memory retrieval.16 Lack of regulatory effects of GABA. 69 emotional Stroop. In addition to mediating stress responses.67 trauma unrelated negative narratives. A relative lack of cortisol at the time of the trauma may facilitate the activation of the central CRF-NE cascade. The mPFC further mediates extinction of conditioned fear through active inhibition of acquired fear responses. Finally. Other brain changes involved in PTSD include exaggerated amygdala responsiveness and impaired mPFC function. Exaggerated amygdala responses. including the hippocampus. and NPY may further accentuate stress responsiveness. Thus. such as traumatic scripts.6.59 including reduced volumes of the ACC. and mPFC that regulate and integrate stress and fear responses. together with increased glucocorticoid receptor sensitivity. which could plausibly underlie intrusive memories in PTSD.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. increased cortisol responses to stress. Inc.66 combat pictures and sounds. thereby impacting conditioned fear responses and the consolidation or retrieval of traumatic memories. CNS Spectr 14:1 (Suppl 1) ©MBL Communications. in the above cited conditioning experiment. hippocampal damage may underlie some of the cognitive symptoms of PTSD. Given the connectivity between the amygdala and mPFC. NPY. glutamatergic. amygdala. Glucocorticoids block the retrieval of emotional memories. may further promote hippocampal damage.40 SUMMARY OF NEUROBIOLOGICAL FINDINGS AND CURRENT DEVELOPMENTS In summary.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.64 Functional imaging studies have found decreased activation of the mPFC in PTSD patients in response to stimuli. and opioid systems. Additional neurochemical changes include alterations in serotonergic. serotonin. providing a biological basis for imprinted traumatic memories in PTSD. Moreover. In turn. GABA-ergic. a damaged hippocampus may facilitate generalization of learned fear to other contexts and may impair the ability to discriminate between safe and unsafe contexts. where it exerts inhibitory control over stress responses and emotional reactivity.61 The reduction in ACC volume was correlated with PTSD symptom severity in some of these studies.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. Norepinephrine enhances the encoding of fear memories. because the hippocampus is critical for context conditioning. though the direction of the relationship is inconsistent across studies. 19 .
B. In addition. We discuss below the role of genetic factors. and early developmental stress experiences in moderating risk for developing PTSD in response to trauma. it is crucial to identify vulnerability and resilience factors. Moreover. Similarly. after the experience of stress or trauma. 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. Finally. 34 The partial NMDAreceptor antagonist DCS improves extinction of fear in rodents and in phobic patients undergoing exposure therapy. potentially genetic. Why some individuals develop PTSD following trauma while others do not is an important unexplored area.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. a novel strategy based on insights into the mechanisms of learning is the use of “cognitive enhancers” to facilitate extinction learning during exposure therapy. as well as other trauma spectrum disorders. it is equally unclear why some patients develop PTSD after trauma exposure. 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. Inc. Gilbertson and colleagues71 studied 40 pairs of monozygotic twins. hydrocortisone treatment simulating a normal circadian cortisol rhythm appears to be beneficial in the treatment of PTSD. In contrast. including Vietnam veterans who were exposed to combat trauma and their cotwins who did not go to Vietnam. because NE promotes encoding of traumatic memories. Studies in twins discordant for trauma exposure provide an excellent opportunity to discern the contributions of predisposition. In most cases. trauma exposure. the manifestation of a trauma spectrum disorder will be influenced by a complex interplay of preexisting vulnerabilities. For example. As expected. 14. low cortisol concentrations may disinhibit CRF/NE neurocircuits and thereby promote autonomic stress responses. rather than markers of PTSD itself. represent markers of neural risk to develop PTSD upon exposure to extreme stress. including genetic disposition.38 Although propranolol did not prevent the development of PTSD. low cortisol levels and elevated heart rates at the time of a trauma predict subsequent development of PTSD. this brain region was also smaller in the co-twins of the men with PTSD. and prior experiences. whereas others develop depression or another Axis I disorder. Nemeroff have yet to be fully tested and integrated in a neurocircuitry model of PTSD. 20 directly target the above-described neurobiological mechanisms that appear to be implicated in the development of PTSD. and measured the size of the hippocampus in all the twins. As noted above. vulnerability factor that predisposes a person to PTSD. though it is presently unknown whether the drug enhances the outcome of exposure therapy in PTSD patients.71 This suggests that a smaller hippocampus is a preexisting. 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. this intervention reduced symptom severity and reactivity to reminders of the traumatic event.C. or whether a small hippocampus is a risk factor for the development of PTSD. personality styles. the reduced size of the hippocampus in PTSD has been a “chicken-or-egg” question for many years. and PTSD to neurobiological findings in PTSD. Glucocorticoid substitution is hypothesized to exert inhibitory effects on sustained stress responses and blocks traumatic memory retrieval. potentially reflecting blockade of traumatic memory consolidation. Heim. in fact. hypocortisolism might represent a preexisting risk factor that promotes the manifestation of PTSD. Therefore. OUTCOME VARIATION IN THE RESPONSE TO TRAUMA: RISK VERSUS RESILIENCE Not all individuals who undergo a trauma develop PTSD. as well as fear conditioning and traumatic memory consolidation. Administration of hydrocortisone shortly after a traumatic experience has been reported to be effective in preventing the development of PTSD. sex differences. C. administration of the centrally acting β adrenergic antagonist propranolol after exposure to psychological trauma has been tested for its potential to prevent the development of PTSD. the hippocampus was smaller in those had PTSD as compared to those who did not develop the disorder. Januar y 2009 .17 Similarly. However. among Vietnam veterans. 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.
2009. risk versus resilience to develop PTSD. though results have been inconsistent. Vol. there is evidence for heritable contributions to some of the neurobiological endophenotypes of PTSD.Neurobiology of Posttraumatic Stress Disorder GENETIC RISK FACTORS OF PTSD Studies on the genetics of PTSD. An excess of the SLC6A3 9 repeat allele was present in those with PTSD. will not develop PTSD). a similar phenotype likely develops from different risk genotypes) and incomplete penetrance of the phenotype (eg. particularly in the presence of low social support.73 Several studies have investigated polymorphisms in the D2 receptor to PTSD risk. In addition. one study has linked a polymorphism in the DA transporter gene to PTSD risk. 21 21 Januar y 2009 . there is increasing evidence that risk for PTSD is influenced by genetic factors.72 Finally. Ressler K. have been hampered by a variety of factors. Nemeroff CB. consequently. literature emerging on genetic variations in neurobiological systems that determine responses to trauma and. who is not exposed to trauma. like those of other complex disorders that are characterized by both genetic and environmental risk factors. Despite these difficulties.72 For example.57 Although it is beyond the scope of this chapter to comprehensively discuss the genetics of PTSD. a person with a genetic risk for PTSD. The same variant has now been associated with risk for developing PTSD. Spectr CNS Spectr 14:1 (Suppl 1) ©MBL Communications. Heim C. to stress responsiveness and risk for developing depression in relation to life stress. including genetic heterogeneity (eg.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 C 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 D 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. This finding suggests that genetically determined changes in DA reactivity may contribute to PTSD among trauma survivors. Inc. CNS Spectr. it should be noted that there is an exciting FIGURE. No 1 (Suppl 1). Evidence from family and twin studies has long suggested a heritable contribution in the development of PTSD. Bradely R. the so-called “s” allele of the serotonin-transporter-linked polymorphic region (5-HTTLPR). 14. there is considerable evidence linking a low expression variant of the serotonin transporter. such as decreased hippocampal volume71 or exaggerated amygdala reactivity.
86-88 For example. Januar y 2009 .77 though findings in humans are not entirely consistent. the serotonin system. sex differences in HPA axis responses to stress have also been observed independent of acute gonadal steroid effects. or developmentally programmed effects of gonadal steroids. SEX DIFFERENCES AND RISK FOR PTSD Women more frequently suffer from PTSD than men. Nemeroff associated with increased amygdala reactivity57 as well as the trait of neuroticism. In the following section. 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). In addition. there might be sex differences in the neurobiological response to trauma.78 Sex differences in neuroendocrine stress responses have been attributed to direct effects of circulating estrogen on CRF neurons. Meta-anlayses of existing studies might be a fruitful approach to reconcile inconsistent results. time elapsed since the trauma.81 However. different types or timing of the trauma. Particularly exciting are recent results that genetic variation of the glucocorticoid receptor cochaperone. is a vast area of future research. FKBP5 genotype was further linked to enhanced glucocorticoid receptor sensitivity. maternal separation interacted with female gender and the 5-HTTLPR polymorphism of the serotonin transporter gene in determining adult sensitization to acute stress. sex) and developmental factors in determining neurobiological vulnerability to PTSD.C. 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. ie. FKBP5 polymophisms significantly interacted with child abuse to predict adult PTSD symptoms. and to scrutinize interactions between dispositional (genes.89 In another non-human primate study.85 There is a burgeoning literature documenting that early adverse experience. A multitude of candidate genes as well as genome-wide associations have yet to be tested. produce an adult phenotype with sensitization to fear cues. sex steroids play a role in lifelong structural plasticity of several brain regions. moderates risk to develop PTSD in relation to childhood abuse. Heim. and dispositional factors among others. including prenatal stress and stress throughout childhood. symptom constellations. including areas involved in stress responsiveness. Inc. Thus. CRF neuronal hyperactivity. non-human primates exposed to a variable foraging demand condition. childhood adversity is associated with increased risk to develop PTSD in response to combat exposure in Vietnam veterans.76 Rodent studies suggest that females generally exhibit a greater magnitude and duration of HPA axis responses to stress than males. 82 Functional imaging studies identified sex differences in the brain’s response to fear stimuli.79 Sex steroids also interact with other neurotransmitter systems involved in the stress response. FKBP5. and hypocortisolism similar to features of PTSD. has profound and long-lasting effects on the development of neurobiological systems. organizational differences in brain structures. 22 FUTURE RESEARCH NEEDS We have provided an overview of the state of science and current developments concerning the neurobiology of PTSD. as well as illness course and treatment response. 78. selected unmet needs are described together with future research recommendations: 1. perhaps in part due to sex differences in the exposure to different types of trauma. and genetic polymorphisms in the FKBP5 gene in 900 non-psychiatric clinic patients. the hippocampus and amygdala. adulthood trauma. as reflected by dexamethasone hypersuppression.80 Progesterone has also been implicated in modulating these systems.91 Studies are needed to identify sensitive periods for the effects of early stress and their reversal. a hallmark feature of PTSD (Figure).82 Other factors that might determine sex differences in the stress response include genomic differences. ie.83 Of note.75 The study tested interactions of child abuse. thereby “programming” subsequent stress reactivity and vulnerability to develop PTSD.82.74 the latter another risk factor for PTSD. Childhood abuse and adulthood trauma each predicted PTSD symptoms.84 Such CNS Spectr 14:1 (Suppl 1) ©MBL Communications.75 Identifying interactions between genetic disposition and trauma exposure in determining PTSD risk and the underlying neurobiological phenotypes. which causes unpredictable maternal care infants. C.B.7 The field must address and explain such inconsistencies by considering potential effects of disease stages.90 Adult women with childhood trauma histories exhibit sensitization of neuroendocrine and autonomic stress responses.
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