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Neurobiological Pathways Involved in Fear, Stress, and PTSD 

Neurobiological Pathways Involved in Fear, Stress, and PTSD
Neurobiological Pathways Involved in Fear, Stress, and PTSD

Christine Heim

, Katharina Schultebraucks

, Charles R. Marmar

, and Charles B. Nemeroff

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date: 20 May 2019


A traumatic event is defined as an experience that is threatening to oneself or to a person close to one, accompanied by intense fear, horror, or helplessness. Exposure to such a traumatic event is required for the diagnosis of post-traumatic stress disorder (PTSD), rendering 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 In fact, while it is estimated that 37%–92% of the U.S. population experience a severe traumatic event during their lifetime,3 the prevalence of PTSD in the population is 10%.4 Most individuals exposed to a severe trauma will develop transient acute stress symptoms, characterized by intrusion, avoidance behavior, and hyperarousal, that resolve after a short period of time. Thus, while most individuals are able to cope with the stressor and maintain or regain homeostasis, a small but significant minority of people fail to recover and exhibit 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 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 and the sympatho-adrenomedullary system, as well as various neurotransmitters and neuropeptides that comprise a neural circuitry that regulates fear and stress responses, including the prefrontal cortex (PFC), hippocampus, amygdala, and brainstem nuclei (see Section III of this volume). Changes in these neuroendocrine and neurobiological systems appear to reflect stress sensitization in PTSD. Of note, several of the neuroendocrine and neurochemical factors that mediate stress responses and that are altered in PTSD have potent effects on learning and synaptic plasticity in brain regions implicated in fear conditioning.5,6,7 Because increased fear conditioning, overgeneralization of fear cues, and failure to extinguish fear memories are cardinal mechanisms producing the clinical manifestations of PTSD, recent attempts have focused on efforts to integrate the neuroendocrine and neurobiological features of PTSD with modulation of mechanisms of fear learning and extinction.

Consequently, there has been an increasing understanding that the neurobiological state in which a person experiences a trauma determines the clinical outcomes of the exposure, including the development of PTSD symptoms over time. Indeed, it appears that certain neuroendocrine and neurobiological features of PTSD represent preexisting vulnerability factors, rather than consequences of a traumatic exposure or correlates of PTSD. Such insights have led to an increased consideration of factors that determine preexisting individual variability in pathways modulating stress and fear responses. These include developmental exposures to stress and/or genetic factors, as well as their interaction. In addition, sex appears to moderate these risk pathways. These results have opened the door for the development of novel hypotheses in translational research that attempt to identify pathophysiology-driven strategies for the prevention and treatment of PTSD that directly target the biological mechanisms that lead to stress sensitization, fear memories, and arousal. In this chapter, we summarize the core neurobiological findings in PTSD and discuss current developments in the field.

Neurobiological Findings in PTSD

Neurobiological stress response systems have been closely scrutinized in patients with PTSD, given the fact that stress-induced neurobiological changes and/or inadequate adaptation to severe stress is believed to contribute to the pathophysiology of PTSD. Available studies have focused on the major neuroendocrine stress response systems that are activated as a result of coordinated input from a neural network of brain regions implicated in the mediation and regulation of the stress and fear responses, including the PFC, hippocampus, amygdala, and brainstem nuclei. In these circuits, several neurochemical systems interact to integrate behavioral and physiological responses to stress and to modulate fear learning through effects on excitatory synapses and synaptic plasticity.

Neuroendocrine Findings in PTSD

Hypothalamic–Pituitary–Adrenal Axis

The HPA axis, the organism’s 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 nerve terminals in the median eminence into the hypothalamo-hypophyseal portal circulation. Here 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 potent effects on metabolism, immune function, and the brain. Several central nervous system (CNS) circuits modulate the HPA axis: the hippocampus and PFC inhibit HPA axis activity, whereas the amygdala and monoaminergic input from brainstem nuclei stimulate the activity of PVN CRF neurons. In addition, circulating glucocorticoids exert negative feedback control of the HPA axis at several sites, for example, by regulating hippocampal and hypothalamic PVN neurons as well as adenohypophyseal ACTH secretion, through binding to glucocorticoid receptors (GRs) and mineralocorticoid receptors (MRs). Altered expression of GR or its co-chaperones, such as FK506 binding protein (FKBP5), may interfere with adequate control of the HPA axis during stress.8 Sustained glucocorticoid exposure produces adverse effects on hippocampal and PFC neurons, including reduction in dendritic branching, loss of dendritic spines, and impairment of neurogenesis.9,10 Of note, because of the widespread distribution of GRs in the neural circuitry that mediates fear conditioning, glucocorticoids have a powerful impact on the consolidation of fear memories and on extinction learning.7,11

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, when compared to healthy controls and other diagnostic groups. This counterintuitive finding has been replicated in Holocaust survivors, refugees, and abused persons with PTSD, though findings are not uniformly consistent across studies.12 Meta-analyses have shown that differences in type and timing of the trauma, symptom patterns, comorbidity, and personality and genetic factors, among others, contribute to this inconsistency.13 Studies using low-dose dexamethasone and metyrapone testing, two pharmacological agents that alter the availability of glucocorticoids 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.12 Findings of increased GR binding and signal transduction in peripheral blood cells support the hypothesis of increased negative feedback sensitivity of the HPA axis in PTSD.12 At the CNS level, marked and sustained increases of CRF concentrations have been measured in cerebrospinal fluid (CSF) of patients with PTSD.14,15 Reduced volume of the hippocampus, the major brain region inhibiting the HPA axis, is a cardinal feature of PTSD, although it is unclear whether this is a preexisting risk factor for PTSD or a consequence of the trauma.16 Taken together, the specific constellation of neuroendocrine findings in PTSD reflects sensitization of the HPA axis to stress, which, in turn, may plausibly have an impact on fear learning and extinction.

A number of prospective studies have reported that low cortisol secretion around the time of exposure to the trauma predicts the development of PTSD symptoms over time.17,18,19 These results suggest that hypocortisolism might be a preexisting risk factor that is associated with maladaptive responses to stress, including PTSD. Consequently, in a relatively new field of research, administration of hydrocortisone is tested as a pharmacological strategy to prevent or treat PTSD. Indeed, administration of hydrocortisone directly after exposure to psychological trauma has been shown to effectively prevent the development of PTSD in humans in a number of studies.20,21,22 In addition, it has been demonstrated in case studies that hydrocortisone replacement is effective in the treatment of PTSD.23 Treatment with hydrocortisone was further shown to reduce symptomatic responses to a memory activation task in combat veterans with PTSD.24 Indeed, decreased availability of cortisol, and hence lack of regulatory effects in the CNS, may have permissive effects toward the sustained activation of neural systems involved in stress reactivity and fear conditioning, including the CRF and norepinephrine (NE) systems.12,25 As noted earlier, glucocorticoids also exert direct effects on aspects of fear conditioning, by facilitating the formation of extinction memories.11,26 Through these actions, glucocorticoid treatment may prevent or reduce symptoms of PTSD, although more replication studies are needed.

Because glucocorticoids facilitate the extinction of fear memories, hydrocortisone administration has been studied as a potential augmentation strategy to enhance the efficacy of exposure therapy in PTSD. A recent randomized controlled trial in 24 war veterans with PTSD confirmed that glucocorticoid augmentation of prolonged exposure therapy resulted in greater symptom reduction than prolonged exposure therapy paired with placebo. Remarkably, glucocorticoid sensitivity status as measured in vitro in peripheral blood cells predicted the beneficial effects of glucocorticoid augmentation of prolonged exposure therapy in the treatment of PTSD.27

The prospective effects of hydrocortisone on the development of intrusive memories have also been investigated recently. In a double-blind experimental trauma film paradigm, the repeated administration of low dosages of hydrocortisone (20 mg) for three consecutive days after “trauma exposure” showed no overall effect on the development of intrusive memories in 65 healthy female students.28 Further research is needed, and there are several ongoing studies investigating the effects of cortisol as a pharmacological intervention for preventing PTSD (e.g., NCT00855270, NCT00039715).

Studies examining the effects of dexamethasone in PTSD found mixed results. A double-blind, randomized controlled trial in 65 PTSD patients found that dexamethasone facilitated fear extinction and discrimination.29 However, in a longitudinal randomized controlled trial (n = 1,244), high dosages of intraoperatively administered dexamethasone showed no effect on PTSD in cardiac patients at 18 months follow-up.30 Subgroup analysis indicated beneficial effects of dexamethasone on PTSD only in female patients and may warrant further examination.30 There are some pending studies on dexamethasone as intervention for PTSD (e.g., NCT01965366, NCT02753166).


Other Neuroendocrine Findings


Neurochemical Findings in PTSD

Neurochemical studies in patients with PTSD have considered different classes of neurotransmitters, including catecholamines, serotonin, amino acids, peptides, neurotrophins, and lipids. These neurochemicals interact in a network of brain regions that is implicated in mediating and controlling behavioral and physiological responses to stress. More recently, neurochemical studies in PTSD have focused on mechanisms and systems implicated in learning and synaptic plasticity, particularly in the context of fear conditioning.


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 to dopamine (DA) by the action of DOPA decarboxylase. In noradrenergic neurons, dopamine β‎-hydroxylase converts DA into NE. Phenylethanolamine N-methyltransferase (PNMT) converts NE into EPI.

NE is one of the principal mediators of the central and autonomic stress responses. The majority of CNS NE is derived from neurons of the locus coeruleus (LC), located in the brainstem, that project to various brain regions involved in the stress response, including the PFC, amygdala, hippocampus, hypothalamus, periaqueductal gray, and thalamus. There is evidence for a feed-forward 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.34

Glucocorticoids inhibit this cascade,35 providing a mechanism by which glucocorticoids act as a “stress brake” to terminate behavioral and autonomic responses to stress. In the periphery, sympatho-adrenal activation during exposure to stressors is characterized by the release of NE and EPI from the adrenal medulla, as well as increased release of NE from sympathetic nerve endings, resulting in changes in blood flow to a variety of organs; increases in heart rate, blood pressure, and respiratory rate; and changes in gastrointestinal activity. These rapid responses reflect an alarm reaction that mobilizes the body to allow for optimal coping (fight or flight). The effects of NE are mediated via postsynaptic α‎1, β‎1, and β‎2 receptors, whereas another NE-activated receptor, the α‎2 receptor, serves as a presynaptic autoreceptor inhibiting NE release. Of note, in addition to profound effects on arousal, the LC-NE system accentuates the acquisition and consolidation of fear memories.36 More recently, it has been reported that NE signaling supports extinction learning, by increasing neuronal excitability in regions relevant to extinction, including the PFC.11 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 candidate in studying the pathophysiology of PTSD.

A prominent feature of patients with PTSD is sustained hyperactivity of the sympathetic nervous system, as evidenced by elevated heart rate, blood pressure, and skin conductance levels and by other psychophysiological measures, as well as increased psychophysiological reactivity to trauma reminders. In accordance with these psychophysiological studies, increased urinary excretion of NE and EPI and their metabolites has been documented in combat veterans, abused women, and children with PTSD. Decreased platelet α‎2 receptor binding further supports NE hyperactivity in PTSD.37 There is also evidence for a role of altered CNS NE function in PTSD. Administration of the α‎2 receptor antagonist yohimbine, which increases NE release, induces symptoms of flashbacks and increased autonomic responses in patients with PTSD.38 Serial sampling revealed sustained increases in CSF NE concentrations39 and increased CSF NE responses to psychological stressors in PTSD.40 Taken together, these findings suggest that increased CNS NE (re)activity plausibly contributes to features of PTSD, including hyperarousal, increased startle, and potentiated fear memories.

Prospective studies have shown that increased heart rate and peripheral EPI excretion at the time of exposure to trauma predicts subsequent development of PTSD.17,41 Of note, administration of the centrally acting α‎-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.21 Although this did not prevent the development of PTSD, it may have blocked traumatic memory consolidation,43 and therefore may have reduced the severity or chronicity of PTSD. In PTSD patients, weekly administration of propranolol after memory activation over 6 consecutive weeks was shown to stably reduce physiological reactivity to trauma reminders.44 Various anti-adrenergic agents have been tested for their therapeutic efficiency in the treatment of PTSD in open-label trials, although results from placebo-controlled trials are lacking.37 There are currently ongoing clinical studies examining propranolol effects in PTSD and trauma-related disorders (e.g., NCT03152175, NCT02789982).

It should be noted that increased urinary excretion of DA and its metabolite has been reported in patients with PTSD. At the CNS level, mesolimbic DA circuits play a critical role in the processing of rewards. There is evidence in humans that exposure to stressors induces mesolimbic DA release, which in turn may have an impact on HPA axis responses. There is also increasing evidence suggesting that DA signaling is critical for extinction learning.45 Via projections from the ventral tegmental area to limbic regions and the medial PFC, DA modulates circuits implicated in extinction. It has been shown that DA is released in the PFC during extinction training and that pharmacological increase in DA signaling in the PFC facilitates extinction learning.11 There are some ongoing clinical studies on brexpiprazole that are still in early research phases (NCT02934932, NCT03033069) and one study for levodopa that is already in phase IV (NCT02560389).

Interestingly, a small clinical trial in PTSD patients has shown that augmentation of cognitive-behavioral therapy (CBT) with the DA-enhancing drug 3,4-methylenedioxy-methamphetamine (MDMA, known as “ecstasy”) produced a profound effect on treatment response (83% response in augmented group vs. 25% response in the placebo group) that was preserved for up to 74 months.46,47 Beneficial effects of MDMA may also be due to its hypothesized effects on the CNS oxytocin system.48 Taken together, these results suggest that the DA system is implicated in fear pathways leading to PTSD. Further open-label studies on MDMA are currently ongoing (NCT03282123, NCT02876172). However, despite these interesting initial pilot findings, it is important to note that MDMA and related drugs have a strong potential for addiction.


Serotonin, or 5-hydroxytryptamine (5HT), is an indoleamine neurotransmitter synthesized from the precursor amino acid tryptophan. Serotonergic neurons originate in the dorsal and medial raphé nuclei in the brainstem and project to multiple forebrain regions, including the amygdala, bed nucleus of the stria terminalis, hippocampus, and PFC. Serotonin has roles in regulating sleep, appetite, sexual behavior, aggression/impulsivity, motor function, analgesia, and neuroendocrine control. The effects of 5HT on affective and stress responses depend on stressor intensity, brain region, and receptor type. It is believed that dorsal raphé 5HT neurons projecting to the amygdala and hippocampus mediate anxiogenic, stress-increasing effects via 5HT2 receptors, whereas 5HT neurons from the median raphé exert anxiolytic effects and facilitate extinction learning via 5HT1A receptors.49 In animal models, chronic stress induces up-regulation of 5HT2 and down-regulation of 5HT1A receptors, respectively, in animal models. 5HT1A receptor knockout mice exhibited increased stress responses (see Ressler and Nemeeroff.49). 5HT could plausibly contribute to several accompanying features of PTSD, such as impulsivity, hostility, aggression, depression, and suicidality. A role of 5HT circuits in PTSD is indirectly supported by the therapeutic efficacy of the selective serotonin reuptake inhibitors (SSRIs). Other evidence for altered 5HT neurotransmission in PTSD includes decreased serum concentrations of 5HT (although this is largely from enterochromaffin cells of the gastrointestinal tract), decreased density of platelet 5HT uptake sites, and altered neuroendocrine responses to increasing CNS serotonergic tone.49 Results of PET studies assessing 5HT1A receptor binding in patients with PTSD compared to controls are mixed.50,51 However, 5HT transporter levels and 5HT1B receptor binding appear to be reduced in PTSD.52,53 It should be noted that 5HT has facilitating effects on extinction learning through ascending projections to the amygdala, hippocampus, and PFC. Facilitation of extinction learning is mediated via 5HT2 and 5HT1A receptors in the medial PFC and the lateral amygdala. Both receptors modulate PFC and lateral amygdala excitability.11 One study with PTSD patients revealed that an SSRI, paroxetine, augmented the effects of exposure therapy on PTSD symptoms versus placebo.54 Taken together, these findings suggest that altered 5HT transmission may contribute to symptoms of PTSD such as hypervigilance, impulsivity, and intrusive memories.

Amino Acids

The amino acids consist of glutamate and α‎-aminobutyric acid (GABA). Glutamate is the principal excitatory neurotransmitter in the brain. Exposure to stress or administration of glucocorticoids has been found to increase glutamate release in the brain. Glutamate signaling has been extensively implicated in synaptic plasticity and in many forms of learning and memory, including fear conditioning. Glutamate exerts excitatory effects on neurons mediated by binding to ionotropic receptors, including the NMDA and the α‎-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, as well as metabotropic receptors. Glutamate’s effects include the well-studied phenomenon of long-term potentiation (LTP), the extended excitation of neural circuits, leading to long-lasting enhancement in communication between neurons, a process thought to underlie learning and memory. While all receptors have been implicated in fear or extinction learning, the glutamate–NMDA system has been most systematically studied in this context and has been found to be critically involved in the consolidation of fear memories as well as in extinction learning. Of note, blockade of NMDA receptors in the basolateral amygdala or medial PFC disrupts extinction (see Singewald et al.11). Based on such findings, the partial NMDA-receptor antagonist D-cycloserine (DCS) has been evaluated as an augmentation strategy to improve the extinction of fear in phobic patients undergoing exposure therapy.55 More recently, several studies have confirmed that DCS also augments extinction learning during exposure therapy in PTSD patients, including pediatric patients with PTSD.56,57,58,59 Furthermore, a meta-analysis found a small augmentation effect of DCS in addition to exposure-based therapy in patients with anxiety, obsessive-compulsive, and post-traumatic stress disorders.60 There are several ongoing studies examining the influence of D-cycloserine (e.g., NCT00371176, NCT03216356).

Since glutamatergic function and dysfunction in glutamate neurotransmission seem to been linked to PTSD,61 further glutamate-modulating components such as ketamine, an NMDA antagonist, recently received attention as potential new pharmacological targets for the treatment of PTSD. There are various ongoing clinical studies for ketamine (NCT02766192, NCT02655692, NCT02397889, NCT02727998, NCT02577250, NCT02734602, NCT03305055). Moreover, there is one ongoing clinical study for lanicemine (NCT03166501).

In addition to its role in learning and memory, overexposure to glutamate is associated with excitotoxicity and, plausibly, contributes to loss of neurons in the hippocampus and PFC in PTSD. Because glucocorticoids increase the expression and/or sensitivity of NMDA receptors, stress may promote excitoxic insults.

GABA is the major inhibitory neurotransmitter in the brain. GABA exerts potent anxiolytic effects and dampens behavioral and physiological responses to stressors. GABA acts on GABAA receptors, part of the GABAA–benzodiazepine (BZ) receptor complex. Benzodiazepines are potent anxiolytic and sedative-hypnotic drugs. GABAergic signaling has also been extensively implicated in fear learning, particularly in the formation of extinction memories. During extinction learning, there is a marked up-regulation of GABA/GABAA receptor-mediated signaling in the amygdala. Blockade of GABAergic signaling in the basolateral amygdala, medial PFC, and hippocampus disrupts extinction learning (see Singewald et al.11). Therefore, deficient GABAergic signaling may contribute to stress sensitivity, anxiety, and failure to extinguish fear memories in PTSD. In fact, in clinical studies, patients with PTSD exhibit decreased BZ receptor binding in platelets and in the CNS,62,63,64 as well as decreased concentrations of GABA in the cortical regions.65,66 However, global up-regulation of GABA seems to limit the efficacy of exposure therapy.59 Although BZs have not been found to be effective in the treatment of PTSD, the development of subunit-specific GABAA receptor agonists are under discussion as an augmentation strategy in its treatment (see Singewald et al.11).


Neuropeptide transmitters that have been discussed in the context of PTSD include CRF, neuropeptide Y (NPY), endogenous opioids, and oxytocin. In addition to its role as the main hypothalamic releasing factor activating the neuroendocrine stress response, CRF also acts as a neurotransmitter in a widespread circuitry throughout the brain, including the PFC, cingulate cortex, central nucleus of the amygdala, bed nucleus of the stria terminalis, nucleus accumbens, and periaqueductal gray, as well as the LC and the dorsal and median raphe nuclei. CRF in these circuits coordinates and integrates behavioral, endocrine, autonomic, and immune responses to stress. Behavioral effects of CRF include neophobia, enhanced startle reactivity, increased defensive withdrawal, and facilitated fear conditioning. These effects are mediated by the interaction of CRF and NE in a neural circuit connecting the amygdala with the LC. This circuit is inhibited by glucocorticoids and GABA, as noted earlier. The effects of CRF in promoting stress, anxiety, and fear responses are mediated through CRF1 receptors, whereas CRF2 receptors appear to be stress protective.34,67 As noted earlier, increased CSF concentrations of CRF have been reported for patients with PTSD, both in single lumbar puncture and serial sampling studies,14,15 likely reflecting CRF activity at extra-hypothalamic sites. In view of the CNS effects of CRF, increased CNS CRF activity may promote certain of the cardinal features of PTSD, including sensitization to stress, increased startle response, conditioned fear, and hyperarousal. These results would suggest that CRF1 receptor antagonists may well represent a novel therapeutic approach for the treatment of PTSD. However, a first clinical study examining the CRF1 receptor antagonist as a treatment agent for PTSD found no beneficial effects in female PTSD patients.68

Another hypothalamic releasing factor, ghrelin, has been shown to produce potent effects on fear memory when directly injected into the amygdala of rodents and therefore may also be implicated in the pathophysiology of PTSD.69 Oxytocin is another hypothalamic hormone that dampens amygdala responses.70 Recently, first studies examined the influence of intranasal oxytocin administration as treatment in PTSD. Oxytocin showed beneficial effects in participants with high acute clinician-rated PTSD symptom severity at baseline.71 Another study found that oxytocin administration had beneficial effects in female patients with PTSD.72 Currently, there are several ongoing clinical studies for oxytocin (e.g., NCT02336568, NCT03238924, NCT03211013, NCT02546570, NCT02505984, NCT03031405).



Finally, endogenous opioids, including the endorphins or enkephalins, are neuropeptides that act on opiate receptors, as do synthetic or naturally occurring opiates such as morphine or heroin. Alterations in endogenous opioids may contribute to numbing, stress-induced analgesia and to dissociation in PTSD. Endogenous opioids further dampen stress responses. Patients with PTSD exhibit increased CSF β‎-endorphin concentrations. The opiate receptor antagonist naltrexone has been reported to be effective in treating symptoms of dissociation and flashbacks in patients with PTSD (see Strawn and Geracioti37). In combat veterans with traumatic injuries, the degree of therapeutic use of morphine in acute medical care appears to predict reduced risk for PTSD.77


Neurotrophins are growth factors that are implicated in neuronal survival, differentiation, and function. These proteins are also critical for synaptic plasticity. Neurotrophins exert their effects via p75 neurotrophin receptors and the family of tyrosine kinase receptors (Trk). Among the neurotrophins, BDNF has been best studied in relation to stress and PTSD. There is evidence that effects of chronic stress on neuronal atrophy and cell death in the CA3 region of the hippocampus are mediated by inhibitory effects of glucocorticoids on brain-derived neurotrophic factor (BDNF) signaling pathways, leading to hippocampal damage and consequently stress sensitization.10 Hippocampal damage may also contribute to loss of contextual specificity and, hence, generalization of fear responses. Of note, while chronic stress decreases BDNF signaling in the CA3 region of the hippocampus, resulting in loss of dendritic spines, stress increases BDNF signaling in the basolateral amygdala, where fear memories are formed, resulting in increases in dendritic spines.78 Activation of the BDNF–Trk pathway in the amygdala has been shown to increase the acquisition of fear memories. Of note, inhibiting BDNF signaling in the amygdala interferes with the acquisition and consolidation of fear memories, whereas BDNF signaling in the hippocampus and PFC is required for extinction learning.79 There are few studies that have measured BDNF in patients with PTSD. Although blood levels of BDNF were reported to be decreased in patients with PTSD80,81, the only available lumbar puncture study found no differences in CSF BDNF concentrations between patients with PTSD and controls.82 It has been suggested that, in PTSD patients with more recent trauma, plasma BDNF levels are increased, whereas more distant trauma is associated with reduced plasma BDNF levels in PTSD.83 Because the BDNF–Trk pathway likely represents a final common pathway translating stress signals and fear associations into synaptic changes, this pathway is a promising target for novel therapeutic interventions.


Endocannabinoids are lipid neurotransmitters that have been implicated in the pathophysiology of PTSD. The endocannabinoids include anandamide and 2-arachidonolyglycerol, which exert their actions via two known receptors, CB1 and CB2. These receptors are abundantly expressed in neural circuits that mediate stress responses and fear conditioning. Endocannabinoid signaling has been shown to modulate neuronal excitability in these circuits. Of note, in animal models, chronic stress reduces endocannabinoid signaling. Extinction training increases levels of endocannabinoids in the basolateral amygdala. Pharmacological enhancement of CB1 receptor signaling facilitates the extinction of fear memories, whereas disruption of CB1 receptor signaling results in failure to extinguish fear memories (see Singewald et al.; Neumeister et al.11,84). Patients with PTSD show low circulating levels of endocannabinoids85 as well as up-regulation of CB1 receptor in the brain,86 potentially reflecting a compensatory response to decreased CNS availability of endocannabinoids.86 These results suggest that the endocannabinoid system may be critically involved in PTSD, by modulating mechanisms of extinction learning, and therefore may represent a target for augmentation of exposure therapy. Several ongoing clinical studies and first randomized controlled trials are examining cannabinoids, such as THC, CBD, and THC + CBD (e.g., NCT02759185, NCT02517424, NCT03008005).

In healthy volunteers, cannabinoid administration improves extinction learning. In addition to exogenous cannabinoids, other factors that modulate endocannabinoid fatty acid amide hydrolase inhibitors may be useful targets for intervention development.11

Integrating Neurobiological Findings into a Model of PTSD

It has been shown that PTSD is associated with changes in multiple neurobiological systems, as evidenced by neuroendocrine and neurochemical changes. These neurobiological factors interact in a network of brain regions, including the hippocampus, amygdala, and medial PFC, that regulate and integrate stress and fear responses. Patients with PTSD show marked abnormalities in structure and function of these brain regions, as evidenced in neuroimaging studies (see Chapter 18 in this volume).

Of note, neurobiological changes in PTSD can be integrated, together with neuroimaging results, in an attempt to conceptualize a neural circuit model of PTSD (see Figure 19.1). The core biological features of PTSD include sensitization of neuroendocrine stress responses systems as well as increased autonomic arousal that occurs in the context of hyperactive CRF-NE pathways that connect the amygdala and brainstem nuclei with the hypothalamus. These CRF-NE pathways appear to be disinhibited by deficient glucocorticoid signaling as well as by reduced activity in modulatory or inhibitory neurochemical systems, including the GABA, NPY, opioid, and endocannabinoid systems. In addition to sensitizing the stress responses, this constellation of neurobiological changes appears to facilitate the over-consolidation of traumatic memories, as well as the failure to extinct such memories, likely mediated through effects on transmitter systems involved in neuronal excitability and synaptic plasticity during learning. Such systems include the glutamate–NMDA and BDNF–TrkB systems. Hippocampal damage due to stress mediators may further accentuate stress responses and facilitates generalization of fear to other contexts. Exaggerated amygdala responses and impaired PFC function may represent a neurochemical constellation that shifts the balance from cognitive control toward automated emotional responses, contributing to deficits in suppressing stress responses and fear responses. These hypotheses have yet to be fully tested and integrated into a neurocircuitry model of PTSD. Epigenetic changes likely contribute to the neurocircuitry of PTSD and need to be integrated with neurobiological findings.

Figure 19.1 A simplified neural circuit model of PTSD. The core biological features of PTSD include sensitization of neuroendocrine and autonomic stress responses systems as well as altered mechanisms of fear learning (red circles). Initial decreases in cortisol secretion (1) at the time of a traumatic exposure may lead to glucocorticoid receptor (GR) up-regulation (2) as well as disinhibition of corticotropin-releasing factor–norepinephrine (CRF-NE) pathways (3) that connect the amygdala and brainstem nuclei with the hypothalamus. These CRF-NE pathways are further disinhibited by reduced activity in modulatory neurochemical systems, including the GABA, neuropeptide Y (NPY), opioid, and endocannabinoid systems (4). This constellation of neurobiological changes appears to facilitate stress responses and the over-consolidation of traumatic memories, as well as the failure to extinct such memories. Neurostructural and functional changes such as hippocampal and prefrontal damage in concert with exaggerated amygdala responses (5) further contribute to stress sensitization and fear responses.

Figure 19.1 A simplified neural circuit model of PTSD. The core biological features of PTSD include sensitization of neuroendocrine and autonomic stress responses systems as well as altered mechanisms of fear learning (red circles). Initial decreases in cortisol secretion (1) at the time of a traumatic exposure may lead to glucocorticoid receptor (GR) up-regulation (2) as well as disinhibition of corticotropin-releasing factor–norepinephrine (CRF-NE) pathways (3) that connect the amygdala and brainstem nuclei with the hypothalamus. These CRF-NE pathways are further disinhibited by reduced activity in modulatory neurochemical systems, including the GABA, neuropeptide Y (NPY), opioid, and endocannabinoid systems (4). This constellation of neurobiological changes appears to facilitate stress responses and the over-consolidation of traumatic memories, as well as the failure to extinct such memories. Neurostructural and functional changes such as hippocampal and prefrontal damage in concert with exaggerated amygdala responses (5) further contribute to stress sensitization and fear responses.

Vulnerability versus Resilience

One important insight from the extant neurobiological studies is the view that some of the identified neurobiological changes in patients with PTSD appear to represent preexisting vulnerability factors that determine risk to develop PTSD upon exposure to extreme stress, rather than reflecting consequences of trauma or correlates of PTSD. This represents an important paradigmatic shift in the conceptualization of PTSD that offers novel possibilities for the early detection of those at risk to develop PTSD if exposed to trauma. Understanding the mechanisms of variability in individual vulnerability in neurobiological systems may allow for the development of biomarkers to identify those in need of early interventions that reverse or counteract risk pathways and promote resilience, leading toward the prevention of PTSD. Therefore, it is important to understand sources of variability in neurobiological systems that are implicated in stress and fear responses. Such sources of variability include developmental programming by early life experiences, genetic factors, and the interaction between the two. Sex also moderates neurobiological risk pathways, as further outlined later.

Previous experience clearly moderates risk for developing PTSD in response to a given trauma. Thus, for example, childhood maltreatment and dysfunctional parenting have been associated with increased risk to develop adult PTSD in response to combat exposure in Vietnam veterans.87 Indeed, there is a burgeoning body of 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. In animal models and human clinical studies, it has been shown that early adverse experience leads to sensitization of the neuroendocrine and autonomic stress responses, as well as manifold changes in a connected neural network that is implicated in the mediation and regulation of stress and fear responses.88,89,90 In nonhuman primates, unpredictable maternal care in the infant produces an adult phenotype with sensitization to fear cues, CRF neuronal hyperactivity, and hypocortisolism, similar to features of PTSD.91 Adult women with childhood trauma histories exhibit sensitization of neuroendocrine and autonomic stress responses.92 Childhood adversity is also related to increased amygdala reactivity and heightened fear responses in adulthood.93,94 Such stable effects of early adversity in producing at-risk phenotypes are likely mediated by epigenetic programming of neural systems implicated in stress and fear response and are also moderated by genetic traits (see Meany and Szyf; Klengel et al.88,95 More studies are needed that identify biomarkers of risk associated with early-life stress in humans, and to identify methods to reverse or counteract such risk, in order to devise novel prevention strategies for PTSD.

As noted earlier, genetic factors interact with stress exposure to moderate risk for developing PTSD. To date, allele variations in candidate genes selected on the basis of their involvement in stress regulation, neural plasticity, and/or fear regulation have been scrutinized to understand variability in the risk of developing PTSD in response to a trauma (for detailed discussion of the genetics of PTSD, see Chapter 26 in this book). Generally, it is apparent in these studies that PTSD certainly is the product of interaction of multiple genes and multiple environments, and there are no single genes mediating these effects. It has also been shown that certain genes, such as the GR-regulating FKBP5 gene, interact only with childhood trauma, but not with adulthood trauma, to increase PTSD risk.96 Importantly, such gene × environment interactions also determine intermediate phenotypes, including epigenetic and neurobiological changes, that lead to the development of PTSD symptoms.95,96 Additional research should precisely map the molecular and biological mechanisms, as well as time windows for these effects across development, to understand how genetic risk and stress exposures are translated into the manifestation of PTSD symptoms. A multitude of candidate gene and genome-wide association studies have yet to be conducted.

Most recently, pro-inflammatory cytokines have been proposed to play a role in PTSD. Combat-exposed PTSD is associated with an increase in peripheral markers of inflammation that is not confounded by smoking, body mass index, medications, or somatic comorbidities.97 In addition, combat PTSD was reported to be associated with elevations in circulating white blood cells, red blood cells, and platelets.98 Given the correlation of circulating blood cells with inflammation, the clinical significance for PTSD was suggested.98 Further research is needed to corroborate whether “cytokine reactivity might represent a valuable addition to the list of potential biomarkers of resilience.”99 There are some drug-repurposing trials for anti-inflammatory effects of N-acetylcysteine in PTSD registered (e.g., NCT02499029, NCT02911285, NCT01664260).

Finally, sex is an important moderator of PTSD risk, with women being more vulnerable than men. Indeed, there appear to exist sex differences in the neurobiological response to trauma.100 Sex differences in neuroendocrine stress responses have been attributed to direct effects of circulating estrogen on CRF neurons.101 Sex steroids also interact with other neurotransmitter systems involved in stress and fear responses.102 Other factors that might determine sex differences in responses to stress include genomic differences, organizational differences in brain structures, or developmentally programmed effects of gonadal steroids.103 Indeed, variations in the PAC1 receptor moderate risk for developing PTSD in women only.104 Sex steroids have lifelong effects on neural plasticity and moderate fear extinction.105 Sex also moderates epigenetic processes, including DNA methylation changes in response to stress.106 Understanding the impact of sex on molecular and neurobiological pathways implicated in stress and fear will improve the understanding of sex differences in PTSD.


Taken together, the concatenation of findings reveals that substantial progress in recent years has occurred in identifying the neurobiological mechanisms implicated in the development of the clinical manifestations of PTSD, namely stress sensitization as well as consolidation of fear memory and failure to extinguish these memories. It has been increasingly recognized that several of the neurobiological changes that are characteristic of PTSD may be predisposing factors that influence neural responses to the trauma and lead toward the behavioral changes that are reflected in clinical symptoms such as intrusive memories, flashbacks, avoidance behavior, and increased arousal. Importantly, classic stress mediators, including the glucocorticoids and norepinephrine, have potent modulating effects on the formation and maintenance of traumatic memories. Therefore, translational research attempts to evaluate whether alteration of the neurobiological state directly after traumatic exposure (e.g., by substituting hydrocortisone) may prevent the development of PTSD. The effects of stress hormones on fear conditioning might be evolutionary adaptive, because a strong fear memory may enhance survival and enable a rapid, automated response to threatening situations, not requiring higher cognition. However, if these memories cannot be controlled or are overgeneralized to other contexts, owing to a neurobiological state that interferes with extinction and context-specificity of the memories, this adaptive fear learning may become pathological. Therefore, in addition to attempts to prevent the development of PTSD by modifying the neurobiological state shortly after trauma, current pharmacological intervention strategies are focused on using “cognitive enhancers” that influence synaptic plasticity and facilitate the learning and maintenance of extinction memories during classic exposure therapy.

A deeper understanding of the origins of variability in the neurobiological pathways that lead toward the manifestation of PTSD in response to a traumatic exposure, such as developmental stress stressors and genetic factors and their interactions, may aid in identifying diagnostic markers to determine individual risk versus resilience. Understanding temporal sequences in the manifestation of neurobiological mechanisms that lead to PTSD as well as the sources of variability in these mechanisms may further help to predict which treatment might be maximally effective in a given patient at a given time point and hence inform individualized treatment selection. It has recently been demonstrated that new biostatistical methods, such as machine learning, can be usefully applied to identify risk factors in spite of the heterogeneous genetic, neurobiological, and environmental factors that contribute to resilience and vulnerability for PTSD.107 Indeed, it might be possible to identify biological markers that help to decide which patient might benefit most from which specific type of pharmacotherapy in combination with prolonged exposure therapy or other evidence-based psychotherapy. Almost certainly, epigenetic mechanisms in neural pathways implicated in stress and fear processing play a role in these processes, and modifying epigenetic pathways that lead to stress sensitization and fear consolidation represents a promising target for novel treatments.

In conclusion, the rapid developments in the field of behavioral neuroscience, including novel insights into stress and fear pathways and their intersection, has boosted the understanding of the neurobiology of PTSD. The translation of these novel insights into mechanism-driven interventions for PTSD holds enormous promise to soon overcome current challenges in the prevention and treatment of this debilitating disorder.


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