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Understanding why only a subset of trauma-exposed individuals develop posttraumatic stress disorder is critical for advancing clinical strategies. A few behavioral (deficits in fear extinction) and biological (blunted glucocorticoid levels, small hippocampal size, and rapid-eye-movement sleep [REMS] disturbances) traits have been identified as potential vulnerability factors. However, whether and to what extent these traits are interrelated and whether one of them could causally engender the others are not known. In a genetically selected rat model of reduced corticosterone responsiveness to stress, we explored posttraumatic stress disorder–related biobehavioral traits using ex vivo magnetic resonance imaging, cued fear conditioning, and polysomnographic recordings combined with in vivo photometric measurements. We showed that genetic selection for blunted glucocorticoid responsiveness led to a correlated multitrait response, including impaired fear extinction (observed in males but not in females), small hippocampal volume, and REMS disturbances, supporting their interrelatedness. Fear extinction deficits and concomitant disruptions in REMS could be normalized through postextinction corticosterone administration, causally implicating glucocorticoid deficiency in two core posttraumatic stress disorder–related risk factors and manifestations. Furthermore, reduced REMS was accompanied by higher norepinephrine levels in the hippocampal dentate gyrus that were also reversed by postextinction corticosterone treatment. Our results indicate a predominant role for glucocorticoid deficiency over the contribution of reduced hippocampal volume in engendering both REMS alterations and associated deficits in fear extinction consolidation, and they causally implicate blunted glucocorticoids in sustaining neurophysiological disturbances that lead to fear extinction deficits. [ABSTRACT FROM AUTHOR]

The ventromedial prefrontal cortex has been viewed as a locus for storage and recall of extinction memory. However, the synaptic and cellular mechanisms underlying these processes remain elusive. We combined transgenic mice, electrophysiological recording, activity-dependent cell labeling, and chemogenetic manipulation to analyze the role of adaptor protein APPL1 in the ventromedial prefrontal cortex in fear extinction retrieval. We found that both constitutive and conditional APPL1 knockout decreased NMDA receptor (NMDAR) function in the ventromedial prefrontal cortex and impaired fear extinction retrieval. Moreover, APPL1 undergoes nuclear translocation during extinction retrieval. Blocking APPL1 nucleocytoplasmic translocation reduced NMDAR currents and disrupted extinction retrieval. We also identified a prefrontal neuronal ensemble that is both necessary and sufficient for the storage of extinction memory. Inducible APPL1 knockout in this ensemble abolished NMDAR-dependent synaptic potentiation and disrupted extinction retrieval, while chemogenetic activation of this ensemble simultaneously rescued the impaired behaviors. Our results indicate that a prefrontal neuronal ensemble stores extinction memory, and APPL1 signaling supports these neurons in retrieving extinction memory by controlling NMDAR-dependent potentiation. [ABSTRACT FROM AUTHOR]

While effective, exposure therapy can be distressing, which creates problems with treatment acceptance. Can exposure be effectively delivered unconsciously—and thus without causing phobic people to experience distress? No study has tested this hypothesis in a sufficiently rigorous experiment that selected between mechanisms for reducing fear unconsciously. We conducted a psychophysiological experiment of an unconscious exposure intervention to discern its mechanism of therapeutic action. We identified 98 highly spider-phobic participants with a validated fear questionnaire and a Behavioral Avoidance Test in which they gradually approached and exhibited impairment of a live tarantula, which was indicative of a DSM-5 diagnosis of specific phobia. These participants were randomized to viewing unconscious exposure to spiders, visible exposure to spiders, or unconscious exposure to flowers (control). In a novel psychophysiological design, concurrent changes in sympathetic arousal and subjective fear were monitored throughout exposure. Shortly thereafter, phobic participants approached the tarantula again in order to measure exposure-induced changes in real-life avoidance behavior and experienced fear. Unconscious exposure did not induce concurrent changes in sympathetic arousal or subjective fear, and subsequently reduced fear of the tarantula. Visible exposure to the same phobic stimuli, by contrast, induced significant arousal and fear, but did not affect fear of the tarantula. Levels of arousal during exposure moderated effects on fear of the tarantula: lower arousal during unconscious exposure, but not during conscious exposure, predicted greater fear reduction. Unconscious exposure reduces fear by generating new implicit learning of nonaversive, stimulus-response associations that facilitate fear extinction in phobic persons. [ABSTRACT FROM AUTHOR]

This brief review article will describe treatment approaches for posttraumatic stress disorder (PTSD) based on findings from basic research. The focus of this review will be fear conditioning and extinction models, which provide a translational model of PTSD that can help translate basic research in nonhuman animals through well-controlled trials confirming the efficacy of treatment approaches in humans with PTSD such as prolonged exposure therapy. Specific cognitive aspects of fear extinction processes, including consolidation and reconsolidation, are reviewed along with behavioral and pharmacological treatment strategies based on basic research in these areas including attempts to prevent the development of PTSD as well as the treatment of chronic PTSD. Pharmacological, behavioral, and device-based augmentation strategies of PTSD treatment based in basic science findings are reviewed, including those that disrupt noradrenergic receptor processes, medications that act on NMDA receptors, physical exercise, cannabinoids, estradiol, dexamethasone, yohimbine, losartan, dopamine, and MDMA, along with the evidence for their efficacy in human clinical samples. While fear extinction provides an exciting translational opportunity to improve PTSD based on basic science findings, we review limitations and challenges of the extant literature as well as future directions., (Copyright © 2024 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Rodents and humans show an attenuation of fear extinction during adolescence, which coincides with the onset of several psychiatric disorders. Although the ethological relevance and the underlying mechanism are largely unknown, the suppression of fear extinction during adolescence is associated with a diminished plasticity in the glutamatergic neurons of the infralimbic medial prefrontal cortex, a brain region critical for fear extinction. Given the putative effect of synaptic inhibition on glutamatergic neuron activity, we studied whether gamma-aminobutyric acidergic neurons in the infralimbic medial prefrontal cortex are involved in the suppression of fear extinction during adolescence. We assessed membrane and synaptic properties in parvalbumin-positive interneurons (PVINs) and somatostatin-positive interneurons (SSTINs) in male preadolescent, adolescent, and adult mice. The effect of fear conditioning and extinction on PVIN-pyramidal neuron and SSTIN-pyramidal neuron synapses in male preadolescent, adolescent, and adult mice was evaluated using an optogenetic approach. The development of the membrane excitability of PVINs is delayed and reaches maturity only by adulthood, while the SSTIN membrane properties are developed early and remain stable during development from preadolescence to adulthood. Although the synaptic inhibition mediated by PVINs undergoes a protracted development, it does not exhibit a fear behavior–specific plasticity. However, the synaptic inhibition mediated by SSTINs undergoes an adolescence-specific enhancement, and this increased inhibition is suppressed by fear learning but is not restored by extinction training. This altered plasticity during adolescence overlapped with a reduction in calcium-permeable glutamate receptors in SSTINs. The adolescence-specific plasticity in the SSTINs might play a role in fear extinction suppression during adolescence in mice. [ABSTRACT FROM AUTHOR]

Exposure therapy is a first-line treatment for anxiety disorders but remains ineffective in a large proportion of patients. A proposed mechanism of exposure involves inhibitory learning whereby the association between a stimulus and an aversive outcome is suppressed by a new association with an appetitive or neutral outcome. The blood pressure medication losartan augments fear extinction in rodents and may have similar synergistic effects on human exposure therapy, but the exact cognitive mechanisms underlying these effects remain unknown. We used a reinforcement learning paradigm with compound rewards and punishments to test the prediction that losartan augments learning from appetitive relative to aversive outcomes. In a double-blind parallel design, healthy volunteers were randomly assigned to single-dose losartan (50 mg) (n = 28) versus placebo (n = 25). Participants then performed a reinforcement learning task, which simultaneously probes appetitive and aversive learning. Participant choice behavior was analyzed using both a standard reinforcement learning model and analysis of choice switching behavior. Losartan significantly reduced learning rates from aversive events (losses) when participants were first exposed to the novel task environment, while preserving learning from positive outcomes. The same effect was seen in choice switching behavior. This study shows that losartan enhances learning from positive relative to negative events. This effect may represent a computationally defined neurocognitive mechanism by which the drug could enhance the effect of exposure in clinical populations. [ABSTRACT FROM AUTHOR]

The prefrontal cortex (PFC) integrates information from multiple inputs to exert top-down control allowing for appropriate responses in a given context. In psychiatric disorders such as posttraumatic stress disorder, PFC hyperactivity is associated with inappropriate fear in safe situations. We previously reported a form of muscarinic acetylcholine receptor (mAChR)–dependent long-term depression in the PFC that we hypothesize is involved in appropriate fear responding and could serve to reduce cortical hyperactivity following stress. However, it is unknown whether this long-term depression occurs at fear-related inputs. Using optogenetics with extracellular and whole-cell electrophysiology, we assessed the effect of mAChR activation on the synaptic strength of specific PFC inputs. We used selective pharmacological tools to assess the involvement of M 1 mAChRs in conditioned fear extinction in control mice and in the stress-enhanced fear-learning model. M 1 mAChR activation induced long-term depression at inputs from the ventral hippocampus and basolateral amygdala but not from the mediodorsal nucleus of the thalamus. We found that systemic M 1 mAChR antagonism impaired contextual fear extinction. Treatment with an M 1 positive allosteric modulator enhanced contextual fear extinction consolidation in stress-enhanced fear learning–conditioned mice. M 1 mAChRs dynamically modulate synaptic transmission at two PFC inputs whose activity is necessary for fear extinction, and M 1 mAChR function is required for proper contextual fear extinction. Furthermore, an M 1 positive allosteric modulator enhanced the consolidation of fear extinction in the stress-enhanced fear-learning model, suggesting that M 1 positive allosteric modulators may provide a novel treatment strategy to facilitate exposure therapy in the clinic for the treatment of posttraumatic stress disorder. [ABSTRACT FROM AUTHOR]

Background Animal fear conditioning studies have illuminated neuronal mechanisms of learned associations between sensory stimuli and fear responses. In rats, brief electrical stimulation of the infralimbic cortex has been shown to reduce conditioned freezing during recall of extinction memory. Here, we translated this finding to humans with magnetic resonance imaging–navigated transcranial magnetic stimulation (TMS). Methods Subjects ( N = 28) were aversively conditioned to two different cues (day 1). During extinction learning (day 2), TMS was paired with one of the conditioned cues but not the other. TMS parameters were similar to those used in rat infralimbic cortex: brief pulse trains (300 ms at 20 Hz) starting 100 ms after cue onset, total of four trains (28 TMS pulses). TMS was applied to one of two targets in the left frontal cortex, one functionally connected (target 1) and the other unconnected (target 2, control) with a human homologue of infralimbic cortex in the ventromedial prefrontal cortex. Skin conductance responses were used as an index of conditioned fear. Results During extinction recall (day 3), the cue paired with TMS to target 1 showed significantly reduced skin conductance responses, whereas TMS to target 2 had no effect. Further, we built group-level maps that weighted TMS-induced electric fields and diffusion magnetic resonance imaging connectivity estimates with fear level. These maps revealed distinct cortical regions and large-scale networks associated with reduced versus increased fear. Conclusions The results showed that spatiotemporally focused TMS may enhance extinction learning and/or consolidation of extinction memory and suggested novel cortical areas and large-scale networks for targeting in future studies. [ABSTRACT FROM AUTHOR]

Background Disruption of the endocannabinoid system through pharmacological or genetic invalidation of cannabinoid CB 1 receptors has been linked to depression in humans and depression-like behaviors in mice. The two main endogenous cannabinoids, anandamide and 2-arachidonoyl glycerol (2-AG), are produced on demand from phospholipids. The pathways and enzymes involved in endocannabinoid biosynthesis thus play a major role in regulating the activity of this system. This study investigates the role of the main 2-AG producing enzyme diacylglycerol lipase α (DAGL-α). Methods We generated and used knockout mice lacking DAGL-α ( Dagla −/− ) to assess the behavioral consequences of reduced endocannabinoid levels in the brain. We performed different behavior tests to determine anxiety- and depression-related behavioral changes in Dagla −/− mice. We also analyzed expression of genes related to the endocannabinoid system via real-time polymerase chain reaction and used the mitotic marker 5-bromo-2′-deoxyuridine to analyze adult neurogenesis. Results Dagla −/− animals show an 80% reduction of brain 2-AG levels but also a reduction in cortical and amygdalar anandamide. The behavioral changes induced by Dagla deletion include a reduced exploration of the central area of the open field, a maternal neglect behavior, a fear extinction deficit, increased behavioral despair, increased anxiety-related behaviors in the light/dark box, and reduced hippocampal neurogenesis. Some of these behavioral changes resemble those observed in animals lacking the CB 1 receptor. Conclusions Our findings demonstrate that the deletion of Dagla adversely affects the emotional state of animals and results in enhanced anxiety, stress, and fear responses. [ABSTRACT FROM AUTHOR]

Background Current neurocircuitry models of anxiety disorders posit a lack of inhibitory tone in the amygdala during acquisition of Pavlovian fear responses and deficient encoding of extinction responses in amygdala–medial prefrontal cortex circuits. Competition between these two responses often results in a return of fear, limiting control over anxiety. However, one hypothesis holds that a pharmacologic strategy aimed at reducing amygdala activity while simultaneously augmenting medial prefrontal cortex function could facilitate the extinction of conditioned fear. Methods Key among the endogenous inhibitors of amygdala activity in response to social fear signals is the hypothalamic peptide oxytocin. To address the question whether oxytocin can strengthen Pavlovian extinction beyond its role in controlling social fear, we conducted a functional magnetic resonance imaging experiment with 62 healthy male participants in a randomized, double-blind, parallel-group, placebo-controlled design. Specifically, subjects were exposed to a Pavlovian fear conditioning paradigm before receiving an intranasal dose (24 IU) of synthetic oxytocin or placebo. Results Oxytocin, when administered intranasally after Pavlovian fear conditioning, was found to increase electrodermal responses and prefrontal cortex signals to conditioned fear in the early phase of extinction and to enhance the decline of skin conductance responses in the late phase of extinction. Oxytocin also evoked an unspecific inhibition of amygdalar responses in both phases. Conclusions Collectively, our findings identify oxytocin as a differentially acting modulator of neural hubs involved in Pavlovian extinction. This specific profile of oxytocin action may open up new avenues for enhancing extinction-based therapies for anxiety disorders. [ABSTRACT FROM AUTHOR]

Background The neural projections from the infralimbic region of the prefrontal cortex to the amygdala are important for the maintenance of conditioned fear extinction. Neurons in this pathway exhibit a unique pattern of structural plasticity that is sex-dependent, but the relationship between the morphologic characteristics of these neurons and successful extinction in male and female subjects is unknown. Methods Using classic cued fear conditioning and an extinction paradigm in large cohorts of male and female rats, we identified subpopulations of both sexes that exhibited high (HF) or low (LF) levels of freezing on an extinction retrieval test, representing failed or successful extinction maintenance, respectively. We combined retrograde tracing with fluorescent intracellular microinjections to perform three-dimensional reconstructions of infralimbic neurons that project to the basolateral amygdala in these groups. Results The HF and LF male rats exhibited neuroanatomical distinctions that were not observed in HF or LF female rats. A retrospective analysis of behavior during fear conditioning and extinction revealed that despite no overall sex differences in freezing behavior, HF and LF phenotypes emerged in male rats during extinction and in female rats during fear conditioning, which does not involve infralimbic–basolateral amygdala neurons. Conclusions Our results suggest that the neural processes underlying successful or failed extinction maintenance may be sex-specific. These findings are relevant not only to future basic research on sex differences in fear conditioning and extinction but also to exposure-based clinical therapies, which are similar in premise to fear extinction and which are primarily used to treat disorders that are more common in women than in men. [ABSTRACT FROM AUTHOR]

Background: The most effective treatment for posttraumatic stress disorder (PTSD) is exposure therapy, which aims to facilitate extinction of conditioned fear. Recent evidence suggests that brain-derived neurotrophic factor (BDNF) facilitates extinction learning. This study assessed whether the Met-66 allele of BDNF, which results in lower activity-dependent secretion, predicts poor response to exposure therapy in PTSD. Methods: Fifty-five patients with PTSD underwent an 8-week exposure-based cognitive behavior therapy program and provided mouth swabs or saliva to extract genomic DNA to determine their BDNF Val66Met genotype (30 patients with the Val/Val BDNF allele, 25 patients with the Met-66 allele). We examined whether BDNF genotype predicted reduction in PTSD severity following exposure therapy. Results: Analyses revealed poorer response to exposure therapy in the PTSD patients with the Met-66 allele of BDNF compared with patients with the Val/Val allele. Pretreatment Clinician Administered PTSD Scale severity and BDNF Val66Met polymorphism predicted response to exposure therapy using hierarchical regression. Conclusions: This study provides the first evidence that the BDNF Val66Met genotype predicts response to cognitive behavior therapy in PTSD and is in accord with evidence that BDNF facilitates extinction learning. [ABSTRACT FROM AUTHOR]

Background: Whereas some studies have shown clear evidence for an augmentation effect of D-cycloserine (DCS) on exposure therapy for anxiety disorders, other studies have shown weak effects or no effect at all. Some preclinical data suggest that the DCS augmentation effect is moderated by the success of extinction learning. Therefore, we conducted a reanalysis of existing data to examine whether the effects of DCS on clinical outcome would vary as a function of response to the exposure session (i.e., exposure success). Methods: In a clinical trial, patients with height phobia received two sessions involving 30 minutes of virtual reality exposure therapy and were randomly assigned to a pill placebo (n = 14) or 50 mg of DCS (n = 15) immediately after each session. Results: Mixed-effects regression analysis showed that the effects of DCS administration on clinical improvement was moderated by the level of fear experienced just before concluding exposure sessions. Patients receiving DCS exhibited significantly greater improvement in symptoms relative to patients who received placebo when fear was low at the end of the exposure. In contrast, when end fear was still elevated, patients receiving DCS improved less compared with those receiving placebo. Conclusions: D-cycloserine appears to enhance the benefits of exposure treatment when applied after a successful session, but it seems to have detrimental effects when administered after inadequate/unsuccessful exposure sessions. [ABSTRACT FROM AUTHOR]

Background: Women are twice as likely to develop posttraumatic stress disorder (PTSD) than men. As shown in our previous work, the inability to suppress fear responses in safe conditions may be a biomarker for PTSD. Low estrogen in naturally cycling women is associated with deficits in fear extinction. On the basis of these findings, we have now examined the influence of estrogen levels on fear extinction in women with and without PTSD. Methods: We measured fear-potentiated startle during fear conditioning and extinction in women. The study sample (N = 81) was recruited from an urban, highly traumatized civilian population at Grady Memorial Hospital in Atlanta, Georgia. We assayed serum estrogen levels and used a median split to divide the sample into high and low estradiol (E2) groups. Seventeen of 41 women (41.5%) in the low E2 group and 15 of 40 women (37.5%) met criteria for PTSD in the high E2 group. Results: The results showed that all groups had equivalent levels of fear conditioning. However, we found significant interaction effects between high versus low E2 groups and PTSD diagnosis [F(1,71) = 4.55, p < .05] on extinction. Among women with low estrogen levels, fear-potentiated startle was higher during extinction in the PTSD group compared with traumatized control women [F(1,38) = 5.04, p < .05]. This effect was absent in the High E2 group. Conclusion: This study suggests that low estrogen may be a vulnerability factor for development of PTSD in women with trauma histories. Research on the role of estrogen in fear regulation may provide insight into novel treatment strategies for PTSD. [ABSTRACT FROM AUTHOR]

Background: The symptoms of posttraumatic stress disorder (PTSD) can be explained, at least in part, as an inability to inhibit learned fear during conditions of safety. Our group has shown that fear inhibition is impaired in both combat and civilian PTSD populations. On the basis of our earlier findings, we employed an established fear extinction paradigm to further explore fear dysregulation in a civilian traumatized population. Methods: Fear-potentiated startle (FPS) was examined in 127 trauma-exposed individuals with and without PTSD. We used a protocol in which conditioned fear was first acquired through the presentation of one colored shape (reinforced conditioned stimulus, [CS+]) that was paired with an aversive air blast to the larynx (unconditioned stimulus) and a different colored shape that was not paired to the air blast (nonreinforced condition stimulus). Fear was extinguished 10 min later through repeated presentations of the CSs without reinforcement. Results: Both groups demonstrated successful fear conditioning on the basis of startle and unconditioned stimulus–expectancy ratings; however, participants with PTSD displayed greater FPS responses to the CS+ and nonreinforced conditioned stimulus compared with the group without PTSD. During fear extinction, the PTSD group showed elevated FPS responses to the previously reinforced CS+ during the early and middle stages of extinction. During the acquisition and extinction phases, PTSD participants with higher levels of reexperiencing symptoms exhibited greater potentiated startle responses to the CS+ compared with PTSD participants with lower reexperiencing symptoms. Conclusions: These results suggest that PTSD is associated with enhanced fear learning and a greater “fear load” to extinguish after conditioned fear is acquired. [ABSTRACT FROM AUTHOR]

Background: Neuroendocrine hormones, which regulate both homeostasis and stress responses, provide homeostatic recovery and sleep suppression to brains under stress. We examined the effects of total sleep deprivation on subsequent enhancement of aversive event memory, implicit fear recognition, and fear conditioning in healthy humans. Methods: Three different recognitions (explicit event, implicit emotion, and physiological response) were assessed in two groups of 14 healthy young volunteers (sleep control and sleep deprived) with aversive (motor vehicle accident films) and nonaversive episodic memory stimuli. Both groups were tested on Day 1 of the experiment and again on Days 3 and 10; the sleep-deprived group was totally deprived of initial nocturnal sleep after the first trial on Day 1. Results: Event recognition performances were similar in both groups throughout the study. Implicit fear recognition remained high for aversive stimuli, with generalization of implicit fear recognition occurring for nonaversive stimuli on Day 3 in the sleep control group. Physiological fear and generalized fear responses were observed for every episode, and delayed enhancement of physiological response was only observed for misidentified aversive episodes in the sleep control group on Day 3. However, in the sleep-deprived group, generalization of implicit fear recognition for nonaversive stimuli on Day 3 and all physiological and generalized fear responses on Days 3 and 10 were comprehensively extinguished. Conclusions: Clinically, trauma-exposed victims often experience acute insomnia, indicating that such insomnia might provide prophylactic benefits in reducing the development of posttraumatic stress disorder via extinction of the fear-magnifying effects of memory. [ABSTRACT FROM AUTHOR]

Background: Auditory P50 suppression, assessed by using a paired auditory stimulus (S1 and S2) paradigm to record P50 mid-latency evoked potential, is assumed to reflect sensory gating. Recently, P50 suppression deficits were found in patients with anxiety disorders, including panic disorder, obsessive compulsive disorder, and posttraumatic stress disorder. The processes of fear conditioning are thought to play roles in pathophysiology of anxiety disorders. Our aim was to investigate whether sensory gating would be physiologically altered by fear conditioning. Methods: To clarify the relationship between classical fear conditioning and the sensory gating mechanism, we measured changes of P50 and N100 suppression of 21 healthy volunteers in control (baseline) phase, in fear acquisition phase, and in fear extinction phase. Results: The mean P50 S2/S1 ratio in fear acquisition phase was significantly elevated in comparison with that in control phase, and it recovered into basal level in extinction phase. In contrast, the mean N100 S2/S1 ratio showed no changes through all phases from fear acquisition to extinction. Conclusions: These results suggest that the P50 but not N100 sensory gating mechanism might be physiologically associated with fear acquisition and extinction. [Copyright &y& Elsevier]

Background: Neuroimaging studies report that individuals with posttraumatic stress disorder show abnormal responses in the amygdala and medial prefrontal cortex (mPFC)/anterior cingulate cortex (ACC) during exposure to traumatic reminders. However, neural responses arising in the early aftermath of a traumatic event have not been studied. Methods: Twenty-two motor vehicle collision survivors and 12 nontraumatized control subjects participated. Regional cerebral blood flow (rCBF) was measured using [15O]-H2O positron emission tomography (PET) at rest and as subjects listened to scripts of traumatic and neutral events. Self-report measures rated emotional responses to the scripts; standardized assessments (Impact of Events—Revised) evaluated acute stress symptoms at scanning and at 3-month follow-up. Most subjects improved symptomatically. Results: At rest, trauma subjects showed hyperperfusion in right mPFC/ACC and hypoperfusion in right amygdala compared with control subjects. In trauma subjects, listening to trauma scripts versus neutral scripts resulted in decreased flow in the right amygdala and left amygdala/perirhinal cortex, and symptom scores correlated negatively with right hippocampal flow changes. Symptom improvement at 3 months correlated negatively with rCBF changes in right perirhinal cortex and hippocampus during the trauma versus neutral script contrast. Subjective disturbance during the trauma versus neutral contrast correlated positively with rCBF changes in right amygdala and left mPFC. Functional connectivity analyses of rCBF changes during trauma versus neutral scripts demonstrated left amygdala coupling with right ACC and bilateral anterior insula, as well as coupling between the amygdala and contralateral hippocampus. Conclusions: In recently traumatized subjects functional interactions between the amygdala, perirhinal cortex and ACC/mPFC that occur during exposure to traumatic reminders may underlie adaptive/recuperative processes. [Copyright &y& Elsevier]