The development of in vivo neuroimaging methodologies and emergence of affective neuroscience have shifted the focus of contemporary neuropsychiatric inquiry to specific neural circuits that might govern the development of PTSD. Converging evidence from human imaging studies and animal models of complex behaviors like fear-associated learning has generated powerful, neurocircuitry-based models of its pathophysiology. In the following sections, we selectively review the evolving picture, organizing it within dominant emergent models, identified as (1) an abnormal fear learning model (FL), which encompasses altered fear conditioning, fear extinction, and fear generalization hypotheses; (2) an exaggerated threat detection model (TD), which postulates altered attention, anticipation, or “alarm” functions; and (3) a diminished emotional regulation/executive function (ER/EF) model that postulates deficient regulatory capacity of cognitive/executive function regions over emotion-generating limbic structures. These models are distinct in their focus on different aspects of PTSD psychopathology and different brain circuits and may be driven by different cellular and molecular processes. However, they are not necessarily mutually exclusive. Each may explain different aspects of the disorder and a different subset of its biological abnormalities. We then identify important aspects of PTSD that are not explained by these models. Together, they can explain much, but they invoke at least three independent pathophysiological processes while leaving some key symptoms and findings unexplained. This is not very parsimonious or conceptually satisfying. It is possible, or even likely, that PTSD is not a single homogeneous disorder but rather is a syndrome that “houses” within it a number of sub-categories with somewhat different presentations, endophenotypes, and pathophysiological mechanisms. Nevertheless, the fact that important parts remain unexplained suggests a need for additional, alternative, or more mechanistically expansive models, which might parsimoniously explain both the complex symptomatology of PTSD and its existing neurobiological findings. Following discussion of the FL, TD, and ER/EF models, we present a novel model that is both more general and more parsimonious, explaining multiple, not previously explained symptoms, and integrating neurobiological findings within the framework of a focal pathophysiologic process—altered contextual processing (CP). The CP model focuses our attention on dysfunction within specific brain circuits governing the critical adaptive function of contextualization—involving hippocampus (Hpc) prefrontal cortex (PFC), thalamic circuits that modulate activity in amygdala, and other limbic and cortical regions. Prior work has identified clear abnormalities in PTSD in the Hpc, PFC, and amygdala, and we suggest that dysfunction within this circuit may be a key pathophysiologic process underlying expression of various PTSD symptoms, in a way that may be able to integrate the contributions of the altered noradrenergic and glucocorticoid functions that have been so consistently documented in this disorder.

Additional peripheral biological abnormalities linked to PTSD require replication but are consistent with the changes reported above. These include alterations in serotonin systems (), DHEA (), neuropeptide Y (), neurosteroids (), endocannabinoids (), and endogenous opioids (). Genetic work is rapidly expanding and has identified PTSD-linked polymorphisms in genes encoding elements within the HPA axis (FKBP5 [] and CRHR1 []), and the sympatho-adrenal system (ADRB2 [] and COMT []). These require confirmation in large-scale GWAS studies but are consistent with the peripheral findings and suggest that PTSD is characterized by ANS hypersensitivity, associated with or leading to hyperadrenergic states, and a hypersensitive glucocorticoid receptor system. However, potential linkages between these abnormalities and the central mechanisms that drive them remain unknown.

Association of FKBP5, COMT and CHRNA5 polymorphisms with PTSD among outpatients at risk for PTSD.

ANS abnormalities have been seen at rest and in reaction to trauma cue exposure () (for meta-analysis, see). Heart rate variability (HRV) is a sensitive index of ANS function () and reductions in it—which suggest arousal dysregulation and autonomic inflexibility due to sympathetic overdrive and/or parasympathetic insufficiency ()—predict PTSD development whether measured prior to () or immediately after trauma exposure (). PTSD is also associated with exaggerated catecholamine responses to trauma cues () and elevated levels of NE secretion in 24 hr urine collections (). PTSD may thus reflect a “hyper-adrenergic state” (). Dysregulation is also evident in HPA axis function, but this appears more complex. The more consistent abnormalities involve enhanced dexamethasone suppression of cortisol (), often attributed to glucocorticoid (GC) receptor hyper-sensitivity (). This is supported by in vivo assay evidence of GC receptor hyper-sensitivity on lymphocytes (). Measurement of cortisol levels in PTSD has generally suggested normal () or reduced levels (), though there are some inconsistent reports (). Reduced levels would be consistent with GC receptor hypersensitivity and early HPA axis “shutdown.”

Dose-response changes in plasma cortisol and lymphocyte glucocorticoid receptors following dexamethasone administration in combat veterans with and without posttraumatic stress disorder.

Effect of current and lifetime posttraumatic stress disorder on 24-h urinary catecholamines and cortisol: results from the Mind Your Heart Study.

Autonomic dysregulation in panic disorder and in post-traumatic stress disorder: application of power spectrum analysis of heart rate variability at rest and in response to recollection of trauma or panic attacks.

Autonomic dysregulation in panic disorder and in post-traumatic stress disorder: application of power spectrum analysis of heart rate variability at rest and in response to recollection of trauma or panic attacks.

Prior to development of in vivo functional neuroimaging and valid animal models, allowing direct examination of CNS structure and function, biological study of PTSD focused on identification of abnormal peripheral markers. The best replicated of these have been psychophysiological indices of autonomic nervous system (ANS) function, and altered blood, saliva, and urine concentration of stress hormones and catecholamines. Noradrenergic hyper-reactivity was the most reliably replicated finding in PTSD (), along with altered function of the hypothalamic-pituitary adrenal (HPA) axis, where hypersensitivity of glucocorticoid receptors was accompanied by unaltered or decreased levels of circulating cortisol ().

In the absence of scientific understanding of the pathophysiologic processes involved in PTSD development, the “gold standard” for defining it has been expert consensus as reflected in DSM criteria. These criteria have changed as clinical perspectives and scientific understanding have evolved, but they have remained phenomenological at their core since they are not yet grounded in biological processes and CNS neuro-circuitry. Despite periodic and sometimes substantial changes, there has been consistent agreement on three sets of symptom clusters considered characteristic of PTSD—the intrusive, avoidant, and hyperarousal clusters. These encompass unwanted and repeatedly re-experienced memories, sensations, or dreams associated with the trauma (intrusive cluster); behavioral avoidance of trauma reminders; and excessive physiological arousal both in response to trauma cues or independently (e.g., sleep problems). These core clusters have been embraced in DSM III, IV, and 5, but other symptoms or criteria have been added (negative affect or reckless behavior in DSM-5), deleted (trauma outside of usual human experience), or included descriptively (shame/guilt, dissociation). Shifting criteria create scientific challenges to sample homogeneity across time and undermine clinical efficacy when targets for intervention are imprecise and continuously moving. As clinician scientists, we will do better when we can target precisely defined dysregulations within specific neural circuits sub-serving particular, mechanistically relevant brain functions. As we identify underlying mechanisms rooted in specific neural circuits, diagnostic precision will sharpen and our ability to “personalize” interventions will be enhanced. For PTSD, we will also be able to go beyond treatment and apply preventive interventions before or immediately after trauma exposure.

The deleterious effects of severe trauma on the human psyche have been documented for centuries, generally depicted as “normative” responses to extraordinary circumstances. During the 19and early 20century, with emergence of psychiatry and psychology as clinical disciplines, the more debilitating consequences of trauma were re-conceptualized as clinical conditions, amenable to scientific inquiry and treatment (). Conceptual challenges persisted, however, in sometimes controversial efforts to differentiate true psychopathology from normative responses to extreme circumstances. Resolution of these controversies awaits empirical documentation of causative neurobiological pathways, which will facilitate an understanding of how brain-based vulnerabilities lead to dysregulated psychological responses, and emergence of disorder-specific neurobiological abnormalities. PTSD has been studied intensively in recent decades; but despite important breakthroughs, we still lack a comprehensive, integrated model that coherently and parsimoniously explains both its phenomenology and its neurobiology. In this Perspective, we will describe PTSD as a clinical entity and touch on its well-established neurobiological findings. We will then try to organize emerging findings within existing conceptual frameworks, highlighting the value and limitations of those frameworks. Finally, we will describe a new framework, focused on the neural circuitry of context processing, which adds additional explanatory power and can potentially better integrate more of what we currently know about this important disorder.

The past two decades have witnessed a fundamental transformation in our understanding and conceptualization of psychopathology. Cultural, clinical, and scientific perspectives increasingly converge on a view of psychiatric disorders as dysfunction within specific components of the CNS, rather than “functional” disorders unrelated to neurobiological substrates. This shift has forced theoretical approaches to grapple with the biological underpinning of psychological processes, grounding our models of illness in growing understanding of neural circuits, cellular mechanisms and molecular processes. This conceptual shift has been challenging but also transformational in the study of post-traumatic stress disorder (PTSD), which has seemed like a quintessentially psychological illness because it develops in reaction to specific environmental events.

The main PTSD symptoms left unexplained by these three models are spontaneous (non-cued) recollections, nightmares and other sleep abnormalities, emotional numbing, and reckless behavior leading to re-traumatization. Neurobiologically, they can account for exaggerated psychophysiologic reactivity and a hyperadrenergic state, triggered by trauma or trauma-like cues. However, they cannot readily integrate other neurobiologic abnormalties, such as structural hippocampal deficits, HPA axis dysregulation, genetic risk factors like FKBP5 or ADRB2, and altered sleep physiology. These models also require a number of independent pathophysiologic processes in several areas of the CNS to explain as much as they can explain, while leaving important symptoms and findings unexplained. Furthermore, as described above, existing empirical evidence in support of the proposed mechanisms is limited in some places and often contradictory. PTSD could actually be a collection of somewhat distinct neurobiological entities. If so, the FL, TD, and EF models might correspond to specific disorder subtypes. However, given the empirical gaps noted and important phenomenological and neurobiological features still unexplained, ongoing pursuit of a more general and parsimonious explanation of PTSD’s pathophysiology is clearly still warranted.

Exaggerated Threat Detection and Diminished EF/ER models, on the other hand, offer plausible explanation for the presence of threat-focused attentional bias, working memory deficits and hyperarousal in PTSD, which could lead to hypervigilance, and exaggerated emotional and physiologic responses. Exaggerated emotional responses and failure to regulate emotions could contribute to pervasive anger and impulsivity. They could also generate avoidance behavior and contribute to the emergence of intrusive memories in response to traumatic reminder cues. These models, however, have difficulty explaining the pervasiveness of trauma memories and, like the FL model, cannot explain spontaneous recollections and intrusions, sleep abnormalities, emotional numbing or re-traumatization.

The Fear Learning/Generalization, Threat Detection, and Emotional Regulation models can account for many of the signs and symptoms of PTSD. Abnormal Fear Learning and Generalization readily account for key features like the dominance of fear over safety memories, generalization of fear responses to any “trauma-related” stimuli, exaggerated psychophysiologic and adrenergic reactivity, and hypervigilance. Insofar as avoidance of trauma reminders represents a “defensive” strategy to prevent recurrence of these strong fear responses, avoidance symptoms could be explained as bi-products of altered fear learning. The Abnormal Fear Learning model, however, does not offer satisfying explanations for other key PTSD features such as spontaneous (non-cue-triggered) intrusions, nightmares and other sleep disturbances, emotional numbing or pervasive negative affect, or the behavioral recklessness often seen in PTSD, leading to re-traumatization. Emotional numbing and re-exposure to traumatic environments are in fact particularly difficult to reconcile with a view of PTSD as a disorder of exaggerated fear and diminished safety learning.

The cellular/molecular mechanisms involved in deficient ER/EF are unknown, largely due to the fact that valid animal models of volitional (and involuntary) emotional regulation are yet to be developed. Noradrenergic hyper-reactivity, postulated to be characteristic of PTSD, has been linked to diminished frontal lobe-mediated executive capacities (e.g., working memory;) and could contribute to diminished EF. Changes in ANS have been associated with reduced performance in a number of EF tasks (e.g., working memory, attention) (). Whether the peripheral changes “drive” these deficits in CNS function or are downstream effects that feedback is not known. In either case, they could be contributing to EF abnormalities in PTSD. However, while ER deficits are intuitively appealing and somewhat promising based on pilot data, direct evidence for them as contributing factors to PTSD pathophysiology, using established ER paradigms, remains sparse.

There is considerable face validity to the idea that deficits in cognitive control and associated top-down inhibitory modulation of autonomic and emotional activation areas might play a role in PTSD. Deficits in EF and/or ER may contribute to functional impairment following trauma and underlie some manifestations of PTSD, including biased attention to trauma cues, heightened emotionality, deficits in memory processes, irritability, and impulsivity (). There is in fact growing evidence of dysfunction within EF/ER circuits in PTSD patients. For example, EF-related networks show impaired within-network connectivity in dorsal attention frontoparietal regions in PTSD (A. Etkin, personal communication) and others have reported altered connectivity within and between EF networks in PTSD (). However, few PTSD studies have examined volitional ER. Only two imaging studies examined cognitive reappraisal in PTSD, with evidence suggesting generally reduced lateral and medial prefrontal activation during reappraisal (). Reappraisal-related changes were also examined before and after PTSD treatment, with evidence that treatment with selective serotonin inhibitors can ameliorate initial deficits in ER prefrontal brain function, and pretreatment ER-region deficits negatively predict treatment-related gains ().

Altered functional connectivity in the brain default-mode network of earthquake survivors persists after 2 years despite recovery from anxiety symptoms.

Abnormal function in these regions has been implicated in the Diminished Executive Function and Emotional Regulation model of PTSD (see text).

Neural activity in dorsal cortical networks, like fronto-parietal attentional networks, has been linked to EF (). EF participates in shifting neural engagement from a default mode network (DMN), involved in internally oriented self-directed mentation, to salience and task networks. Imbalance and discoordination between DMN and task networks may contribute to lapses in attention and decrements in performance (), as well as to psychiatric disorders (). ER involves some of the same cognitive control systems, such as memory and attention (), supporting the notion of a common set of prefrontal regions that are implicated in the regulation of affective and non-affective responses ( Figure 3 ). For example, the lPFC and mPFC regions activated by emotional regulation () overlap with those activated in working memory and response selection tasks (). The most commonly studied type of emotion regulation is reappraisal, which involves conscious, volitional efforts to modulate emotional responses by imposing a “less emotional” cognitive frame on them. In concert with the notion of common EF/ER mechanisms, reappraisal activates overlapping regions including dlPFC, vlPFC, dmPFC, dACC, lateral orbitofrontal cortex (OFC), and the posterior parietal lobe ().

An additional mechanism that could contribute to PTSD pathophysiology involves regulatory processes that modulate responses to emotionally evocative stimuli like threat. Successful navigation in daily life, including avoidance of danger, requires holding information in mind, resisting distractors, switching between tasks, and planning—tasks that are considered components of Executive Function (EF). EF is a family of capacities by which we manage cognitive processes and includes mechanisms of working memory, attention, inhibition, and task shifting. Deficits in multiple EF domains are seen in psychiatric disorders and associated with poor social and occupational functioning (). The same mechanisms, and their neural substrates, are also involved in regulation of emotions (ER), in that these cognitive resources are used to modulate emotionally driven behavior. There are multiple aspects of PTSD that could stem from deficits in EF/ER, including memory deficits, exaggerated emotional responses to salient cues, irritability, and impulsivity.

On the cellular/molecular level there is little information on specific processes supporting exaggerated Salience or Threat Detection (TD). Neuronal sensitization within the amygdala to repeated cue exposure is one potential pathway to amygdala hyper-reactivity (), but this has not yet been directly linked to enhanced Threat Detection or altered SN activity. A key challenge is the lack of animal models of SN hyperactivity, with amygdala reactivity models primarily focusing on conditioning and extinction processes. Another potential pathway to enhanced threat detection in PTSD patients could involve their peripheral ANS abnormalities. For example, low heart rate variability, which may reflect sympathetic-parasympathetic imbalance, is associated with increased threat detection () and with risk for development of PTSD (). Abnormalities in adrenergic tone or glucocorticoids could also contribute to enhanced Threat Detection, as noradrenergic hyperactivity is linked to increased amygdala reactivity () and glucocorticoid receptors, which are abundant in amygdala, have been linked to enhanced anxiety and fear (), but direct evidence for a mechanistic pathway through these systems to enhanced threat detection in PTSD is still missing.

Enhanced threat sensitivity expressed as hypervigilance is indeed a fundamental feature of PTSD. PTSD patients are biased to attend to threat (), at both supraliminal () and subliminal () levels. Insula appears to be hyperactive in PTSD during anticipation (); and increased activation by threat cues is seen in the amygdala (). There is evidence that the SN might be hypersensitive to threat in PTSD patients even before trauma exposure, and this sensitivity can predict subsequent symptom development (). Increased dACC reactivity is also seen in PTSD in response to conditioned fear cues (), demonstrating heightened sensitivity in all of the main nodes of the salience network. Excessive activity in all three nodes (dACC, insula, and amygdala) predicted poor response to treatment (), suggesting that enhanced SN activity might be involved in symptom persistence. Resting-state connectivity studies have also demonstrated hyper-connectivity within SN regions, involving amygdala, insula, and ACC (). Such connectivity could enhance processing of threat cues. There thus may be sensitivities at multiple levels within the SN that could contribute to enhanced fear behaviors.

Regional cerebral blood flow in the amygdala and medial prefrontal cortex during traumatic imagery in male and female Vietnam veterans with PTSD.

Abnormal function within Salience Network regions is implicated in the Exaggerated Threat Detection model of PTSD (see text).

Functional neuroimaging and resting-state studies have identified an interconnected network of brain regions, including amygdala, dorsal anterior cingulate cortex (dACC), and insula/operculum (), that activate when salience is detected in the environment ( Figure 2 ). The amygdala’s role in threat detection and fear expression () is well established (see above), but human fMRI work has also demonstrated amygdala reactivity to positive, rewarding, or social stimuli (e.g., human faces;). Similarly, dACC is implicated in error and conflict detection, and in autonomic arousal (); and anterior insula/operculum activity is associated with anticipation of meaningful events (), monitoring of internal states (), and pain perception (). Functional connectivity between regions of this network creates a circuit, identified as a Salience Network (SN), which activates in response to emotionally arousing information (). Hyper-reactivity in the nodes of this network, or enhanced connectivity between these nodes, could contribute to hypervigilance, exaggerated threat detection, exaggerated physiological reactivity, and other core symptoms of PTSD.

Disruptions in Fear/Safety learning or fear generalization can increase reactivity to potentially threatening stimuli. However, threat hyper-reactivity can also stem from processes independent of fear learning. One alternative potential source is in threat detection systems. An ability to detect “salience” in the environment, whether in the realm of threat or reward, is essential for survival, which requires a rapid detection system that can focus attention on salient cues, recruit multiple homeostatic systems to respond to them, and trigger automatic motor routines (). Hypersensitive salience detection could heighten vigilance and threat reactivity in PTSD and activate fear and protective responses disproportionate to actual threats. Exaggerated threat detection has in fact been implicated in PTSD pathophysiology by some investigators (for review, see).

Neuroimaging work has begun to examine the human neurocircuitry of fear generalization, revealing that activity in the amygdala and insula correlate selectively with generalized SCRs and that functional connectivity between the amygdala and extra-striate visual cortex was selectively enhanced for a perceptually similar cue of high emotional intensity that was never paired with US (). This suggests that amygdala-cortical communication might be active during generalization.reported that gradients of fMRI activity are present in insula and dmPFC, with activity levels declining as similarity to CS+ declined, with a reverse gradient in vmPFC and hippocampus, where activity is greatest to the safety cue. Clinically, some evidence shows that PTSD patients show a failure to discriminate CS+ (threat) from CS− (safety), perhaps due to overgeneralization (). However, there is very little experimental evidence specifically demonstrating overly broad generalization gradients in PTSD (). It is often assumed that patients with PTSD would exhibit broad generalization gradients based on their symptom profiles, but empirical documentation is still needed to substantiate this model.

Neurobiological studies of generalization in fear conditioning paradigms have been sparse (). Typical fear conditioning work uses easily discriminable stimuli to ensure strong CS+ versus CS− differentiation, avoiding potential for generalization (). Generalization studies demonstrate neuronally instantiated “tuning curves” that differentiate tones of differing frequencies within auditory cortex, auditory thalamus, and amygdala (). Multiple amygdalar regions are involved, including CE (), other subnuclei (), and LA (). The amygdala appears to play a role in generating graded generalization curves (), and amygdala neurons show tuning properties that could account for behavioral generalization (), perhaps contributing to the broad fear generalization gradients suggested for PTSD. However, amygdala changes in these studies could be due to inputs coming from other brain regions. For example, there is conflicting evidence about the role of auditory cortex in stimulus discrimination and in overgeneralization (). Complex interconnections make it difficult to isolate specific behavioral dysfunction, like overgeneralization, to disruptions at highly specific locations, and the complete circuit that mediates generalization of more complex real-life stimuli might involve interactions between microcircuits within the amygdala (), the prefrontal-cortex (), hippocampus (), and other regions.

Critical role of the 65-kDa isoform of glutamic acid decarboxylase in consolidation and generalization of Pavlovian fear memory.

Response properties of single units in areas of rat auditory thalamus that project to the amygdala. I. Acoustic discharge patterns and frequency receptive fields.

Sensory tuning beyond the sensory system: an initial analysis of auditory response properties of neurons in the lateral amygdaloid nucleus and overlying areas of the striatum.

Fear Generalization. Fear generalization is another aspect of fear learning implicated in PTSD. Fear generalization occurs when, following conditioning, stimuli other than the CS, but which share some similarities with CS, elicit a fear-related response. This is an adaptive process that facilitates protective responses to situations that are similar to but not identical with situations previously learned to be dangerous (). Disruption in generalization (e.g., over-generalization) could contribute to excessive fear expression in PTSD (). Generalization is demonstrated by stimulus “response gradients”—if during fear conditioning, the CS+ and CS− are chosen to represent two ends along a continuum, fear responses occur to the CS+ and to stimuli close to it on the continuum, with a declining response gradient as the cues approach the CS− end (). Importantly, the intensity of the US impacts the breadth of generalization beyond the CS+ (). A very strong US produces broad generalization. During PTSD-generative traumatic exposure, the US (e.g., threat to life) may be sufficient to lead to broad generalization, undermining discrimination between dangerous and safe cues, contributing to high reactivity to “reminders” that bear any resemblance to trauma cues.

Problems with safety signal learning and inability to modulate fear responses with safety cues () also suggest impairment in inhibition of fear pathways. However, other work suggests intact extinction learning in PTSD but impaired recall of fear extinction memories 24 hr later (). Intact extinction recall, however, requires cortical inputs from vmPFC to amygdala (), and intact safety learning after fear conditioning involves inputs from vmPFC and hippocampus (). Prefrontal regions have well-traced inputs to the amygdala through which they can amplify (prelimibic) or inhibit (infralimbic) fear expression (). The human homolog of IL (vmPFC) is linked to extinction recall and is smaller in volume and hypo-responsive in PTSD patients (). Reduced activation of this area is associated with impaired fear inhibition (), raising the possibility that core pathophysiologic processes contributing to deficits in extinction retention may be located in regions outside amygdala and involve neuro-behavioral functions beyond basic fear-associated learning processes.

Dissociable roles of prelimbic and infralimbic cortices, ventral hippocampus, and basolateral amygdala in the expression and extinction of conditioned fear.

Impaired contextual modulation of memories in PTSD: an fMRI and psychophysiological study of extinction retention and fear renewal.

Fear Extinction. Alternatively, it has been proposed that fear associative learning deficits in PTSD stem from abnormalities in extinction or safety learning rather than fear conditioning. A key feature of PTSD is inability to learn that cues once associated with trauma are no longer dangerous—a process akin to fear extinction in animal models. Dysregulation of extinction, undermining ability to learn that something once dangerous is now safe, may contribute to safety learning deficits in PTSD (). In general, extinction is less robust than conditioning and does not erase an established fear memory. Rather, it creates a safety memory trace that “overlays” the fear memory trace. It is context specific, decays with time, and involves learned inhibition of fear expression. It is mediated by distinct and dedicated pathways within BLC (). Dysregulation in the topographically organized BLC output systems may induce imbalances within the larger fear-on and extinction circuits, leading to extinction deficits and persistence of fear memories. Indeed, a number of fear extinction studies report heightened autonomic reactions during extinction learning in PTSD, including increased skin conductance and heart rate and sustained fear-potentiated startle ().

Though intuitively appealing, evidence that PTSD is a disorder of fear conditioning itself is sparse. Trauma exposure itself is readily thought of as an explicit conditioning episode (), but evidence for abnormalities in fear acquisition in PTSD is conflicting. In typical differential fear conditioning paradigms, where subjects are presented with a US-predicting CS (CS+) and a non-US-predicting CS (CS−), which acts as a safety signal (), PTSD patients have difficulty differentiating safety from threat (), but they generally do not show abnormal acquisition of the conditioned response (to CS+) itself (). Enhanced fear potentiated startle or skin conductance responses have been reported during fear learning by some (), but not others (). Trauma that can cause PTSD is much more severe than the simple US “threats” used in laboratory studies, but these studies do suggest that the basic ability to acquire new fear conditioned responses is not inherently abnormal in PTSD.

Impaired contextual modulation of memories in PTSD: an fMRI and psychophysiological study of extinction retention and fear renewal.

From Pavlov to PTSD: the extinction of conditioned fear in rodents, humans, and anxiety disorders.

How the neurocircuitry and genetics of fear inhibition may inform our understanding of PTSD.

Fear Conditioning/Acquisition. The basic circuits of fear conditioning/extinction have been well-worked out. They involve perceptual inputs to thalamus, then to amygdala and to effector systems (). Within the amygdala, the basolateral complex (BLC), composed of the lateral (LA), basolateral (BLA), and accessory basal (AB) nuclei, provides the main input to the central nucleus (CE), which constitutes the “final relay” in coordinated outputs to physiological and behavioral effector systems that “express fear” (e.g.,). The BLC is the region where associative fear learning, extinction learning, consolidation, and expression are thought to take place (). The cellular substrates for associative learning are long-term potentiation (LTP) and long-term depression (LTD) (), whereby associative LTP at BLC principal neurons () creates a neural link between an unconditioned stimulus (US) and a conditioned stimulus (CS). The phenomenology of PTSD readily suggests disruption in this process, since so many “CSs” (e.g., a backfiring car) seem to be inappropriately linked to the sense of threat carried by traumatic memories. However, BLC sub-networks also have specific connections with prefrontal cortical regions that modulate fear expression, including prelimbic and infralimbic areas. Specific BLC neurons can activate prelimbic PFC during fear learning, while others target infralimbic PFC during extinction (). The BLC can thus provide higher level processors with “information” about what is dangerous and what is safe, potentially for use in future situations that are ambiguous but carry threat potential.

Involvement of the central nucleus and basolateral complex of the amygdala in fear conditioning measured with fear-potentiated startle in rats trained concurrently with auditory and visual conditioned stimuli.

Topographic organization of neurons in the acoustic thalamus that project to the amygdala.

Altered functioning within basolateral complex (BLC) circuits has been implicated in the Abnormal Fear Learning model of PTSD (see text). Interrupted lines represent distal inputs to and outputs from BLC.

Learning what is threatening and what is safe is a critical, highly conserved function that has been extensively studied neurobiologically using fear associated learning paradigms and fear conditioning, fear extinction, and fear renewal, processes. PTSD has been conceptualized as heightened fear reactivity that develops in response to exposure to a threatening event, so abnormal fear learning was a logical initial place to look in searching for its neurobiology. Fear and safety learning studies have focused mechanistically on a key structure governing these processes—the amygdala—and the complex interplay within the amygdaloid complex ( Figure 1 ) between various nuclei and cell types. Additional processes clearly participate in fear/safety learning, like memory consolidation, fear generalization, and extinction retention, and these involve additional brain mechanisms and regions (e.g., sensory cortex, thalamus, hippocampus, vmPFC). However, within the fear-associated learning framework, these processes and regions have been seen through the prism of their impact on amygdala function and output, rather than as key psychological/pathophysiologic processes shaping PTSD development. Other conceptual models (Threat Detection, Emotional Regulation, and Contextual Processing) focus on these extra-amygdala processes as key contributors to PTSD pathophysiology, and they are discussed in subsequent sections.

A New Model: Deficient Context Processing

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Liberzon I. The contextual brain: implications for fear conditioning, extinction and psychopathology. In search of a more comprehensive and parsimonious explanation of the full range of PTSD symptoms and the disorder’s neurobiology, we have hypothesized a core pathophysiological deficit within neural circuits that process the contextual information that is used to modulate emotional responses (). This model is firmly rooted in prior work but it expands upon previous models, by reframing them through the lens of context processing, in an effort to better integrate existing understanding and evidence with the “missing pieces” that remain unexplained.

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Liberzon I. The contextual brain: implications for fear conditioning, extinction and psychopathology. Functionally, the concept of context has been used to refer to general cognitive, semantic, or “emotional” backgrounds that allow one to derive situation-informed meaning from the world (). Contexts are composed of many stimulus elements that are assembled into configural, or “contextual,” representations, perceived as a “gestalt” and acquired rapidly (). Salient cues may require radically different responses in different situations—the critical function of context processing is to match cued responses to the “needs” of a given situation or context (). For example, spotting a mountain lion in one’s back yard is life threatening, but in a zoo it is exciting (even though the safety features can be well hidden). Contextual information allows us to freeze, flee, or enjoy the view of the lion, depending on the situation. Considering the central role of context in the flexible representation and retrieval of information and in resolving ambiguity, contextual processing deficits would lead to cue-focused behavioral reactivity, which is less flexible and more likely to be situationally inappropriate, potentially contributing to a broad range of PTSD symptoms.

th annual meeting of the Anxiety & Depression Association of America, conference). Another laboratory further corroborated these results by showing that PTSD patients failed to utilize a contextual “warning” cue in a stop signal anticipation task, supporting the idea that the context processing deficit in PTSD is general and not isolated to fear processing ( van Rooij et al., 2015 van Rooij S.J.

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Vink M. Neural correlates of inhibition and contextual cue processing related to treatment response in PTSD. Subsequent studies from other laboratories have corroborated contextual processing deficits in PTSD. In a similar SCR fear conditioning paradigm, PTSD patients failed to “properly” renew conditioned fear when re-exposed to the conditioning context following full extinction that occurred 24 hr after the conditioning phase (E. Shvil et al., 2014, 34annual meeting of the Anxiety & Depression Association of America, conference). Another laboratory further corroborated these results by showing that PTSD patients failed to utilize a contextual “warning” cue in a stop signal anticipation task, supporting the idea that the context processing deficit in PTSD is general and not isolated to fear processing ().

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Milberg W.P.

Salat D.H. Brain network disturbance related to posttraumatic stress and traumatic brain injury in veterans. In addition to modulating fear-associated learning, contextual processing plays a key role in shaping memory processes, emotional responses and regulation, and in shaping flexible behavioral choices. As such, a context processing deficit based in dysfunction of a hippocampal-prefrontal-thalamic network could contribute to multiple aspect of post-traumatic psychopathology, beyond the documented specific deficits in extinction retention and fear renewal, and their associated symptomatology. For example, mPFC-Hpc circuitry creates associations between contexts, events, and corresponding emotional responses (), so dysfunction in this system could link erroneous emotional contexts to a given situation, triggering emotional responses that are “inappropriate.” For example, erroneous retrieval of an intensely negative emotional context of loss and pain during normally joyful/happy events will prevent experiencing the joyful event as happy, which can be experienced as “emotional numbing.” Similarly, excessive anger can emerge, following relatively innocuous triggers, if the context is perceived as dangerous or threatening. If context is identified as “unsafe,” attention is focused on potential threat cues, leading to hypervigilance; but if contextual information that should alert one to danger is missed, this might lead to recklessness and retraumatization. Being “unmoored” from current contexts that keeps trauma memories from emerging in response to partial cues can lead to the emergence of intrusive memories. These hypothesized links between CP and a broad range of PTSD symptomology are speculative, and extensive work is needed to test these ideas, but initial support linking connectivity within the CP circuit to specific PTSD symptoms has been emerging. For example, we have shown that diminished vmPFC/hippocampus connectivity at rest was associated with the severity of each of the three PTSD symptom clusters (i.e., intrusive, avoidant and hyperarousal) and that enhanced connectivity of these regions with SN regions was associated specifically with enhanced hyperarousal symptoms (). A more recent resting-state connectivity study replicated these findings, reporting that re-experiencing symptoms in PTSD are linked to “disconnection” of hippocampus from right PFC, interpreted by the authors as a failure of contextualization and associated overgeneralization of trauma memories ().

So what are the immediate implications and the next steps for development of the CP model, beyond improved conceptual coherence and explanatory power? A set of refutable hypothesis will need to be tested to enhance confidence in the model and demonstrate its utility in shaping future studies. First step will be to further document that the PTSD deficits seen in fear-associated learning paradigms are also present in a broader range of tasks that involve contextual processing and modulation. These include replication of fear renewal findings, and examination of fear reinstatement, contextual conditioning, and contextual modulation of responses to reward cues. Second, the hypothesized key role of Hpc-mPFC dysfunction should be examined by testing other Hpc-mPFC dependent functions in PTSD. These should include tasks that probe pattern separation and pattern completion capacities, visual-spatial navigation tasks, and tasks that require utilization of internal context (e.g., hunger, arousal). Finally the integrative, organizing concept of the CP deficit role predicts that other aspects of PTSD symptomatology, like emotional numbing, anger outbursts hypervigilance, etc., should be associated with CP deficits in both human studies and animal models.