Behavioural and functional evidence revealing the role of RBFOX1 variation in multiple psychiatric disorders and traits.

Common variation in the gene encoding the neuron-specific RNA splicing factor RNA Binding Fox-1 Homolog 1 (RBFOX1) has been identified as a risk factor for several psychiatric conditions, and rare genetic variants have been found causal for autism spectrum disorder (ASD). Here, we explored the genetic landscape of RBFOX1 more deeply, integrating evidence from existing and new human studies as well as studies in Rbfox1 knockout mice. Mining existing data from large-scale studies of human common genetic variants, we confirmed gene-based and genome-wide association of RBFOX1 with risk tolerance, major depressive disorder and schizophrenia. Data on six mental disorders revealed copy number losses and gains to be more frequent in ASD cases than in controls. Consistently, RBFOX1 expression appeared decreased in post-mortem frontal and temporal cortices of individuals with ASD and prefrontal cortex of individuals with schizophrenia. Brain-functional MRI studies demonstrated that carriers of a common RBFOX1 variant, rs6500744, displayed increased neural reactivity to emotional stimuli, reduced prefrontal processing during cognitive control, and enhanced fear expression after fear conditioning, going along with increased avoidance behaviour. Investigating Rbfox1 neuron-specific knockout mice allowed us to further specify the role of this gene in behaviour. The model was characterised by pronounced hyperactivity, stereotyped behaviour, impairments in fear acquisition and extinction, reduced social interest, and lack of aggression; it provides excellent construct and face validity as an animal model of ASD. In conclusion, convergent translational evidence shows that common variants in RBFOX1 are associated with a broad spectrum of psychiatric traits and disorders, while rare genetic variation seems to expose to early-onset neurodevelopmental psychiatric disorders with and without developmental delay like ASD, in particular. Studying the pleiotropic nature of RBFOX1 can profoundly enhance our understanding of mental disorder vulnerability.

One year after the COVID-19 outbreak in Germany: long-term changes in depression, anxiety, loneliness, distress and life satisfaction.

Several studies have linked the COVID-19 pandemic to unfavorable mental health outcomes. However, we know little about long-term changes in mental health due to the pandemic so far. Here, we used longitudinal data from a general population sample of 1388 adults from Germany, who were initially assessed between April and May 2020 (i.e., at the beginning of the COVID-19 pandemic in Germany) and prospectively followed up after 6 (n = 1082) and 12 months (n = 945). Depressive and anxiety symptoms as well as loneliness did not change from baseline to 6-month follow-up. While anxiety symptoms did not change in the long run, depressive symptoms and loneliness increased and life satisfaction decreased from baseline to 12-month follow-up. Moreover, vulnerable groups such as younger individuals or those with a history of mental disorders exhibited an overall higher level of psychopathological symptoms across all assessment waves. Our findings suggest a deterioration in mental health during the course of the COVID-19 pandemic, which emphasizes the importance to implement targeted health promotions to prevent a further symptom escalation especially in vulnerable groups.

Genome-wide association study of panic disorder reveals genetic overlap with neuroticism and depression.

Panic disorder (PD) has a lifetime prevalence of 2-4% and heritability estimates of 40%. The contributory genetic variants remain largely unknown, with few and inconsistent loci having been reported. The present report describes the largest genome-wide association study (GWAS) of PD to date comprising genome-wide genotype data of 2248 clinically well-characterized PD patients and 7992 ethnically matched controls. The samples originated from four European countries (Denmark, Estonia, Germany, and Sweden). Standard GWAS quality control procedures were conducted on each individual dataset, and imputation was performed using the 1000 Genomes Project reference panel. A meta-analysis was then performed using the Ricopili pipeline. No genome-wide significant locus was identified. Leave-one-out analyses generated highly significant polygenic risk scores (PRS) (explained variance of up to 2.6%). Linkage disequilibrium (LD) score regression analysis of the GWAS data showed that the estimated heritability for PD was 28.0-34.2%. After correction for multiple testing, a significant genetic correlation was found between PD and major depressive disorder, depressive symptoms, and neuroticism. A total of 255 single-nucleotide polymorphisms (SNPs) with p < 1 × 10-4 were followed up in an independent sample of 2408 PD patients and 228,470 controls from Denmark, Iceland and the Netherlands. In the combined analysis, SNP rs144783209 showed the strongest association with PD (pcomb = 3.10 × 10-7). Sign tests revealed a significant enrichment of SNPs with a discovery p-value of <0.0001 in the combined follow up cohort (p = 0.048). The present integrative analysis represents a major step towards the elucidation of the genetic susceptibility to PD.

An investigation of genetic variability of DNA methyltransferases DNMT3A and 3B does not provide evidence for a major role in the pathogenesis of panic disorder and dimensional anxiety phenotypes.

While DNA methylation patterns have been studied for a role in the pathogenesis of anxiety disorders, the role of the enzymes establishing DNA methylation-DNA methyltransferases (DNMTs)-has yet to be investigated. In an effort to investigate DNMT genotype-specific effects on dimensional anxiety traits in addition to the categorical phenotype of panic disorder, 506 panic disorder patients and 3112 healthy participants were assessed for anxiety related cognition [Agoraphobic Cognitions Questionnaire (ACQ)], anxiety sensitivity [Anxiety Sensitivity Index (ASI)] as well as pathological worry [Penn State Worry Questionnaire (PSWQ)] and genotyped for five single nucleotide polymorphisms (SNPs) in the DNMT3A (rs11683424, rs1465764, rs1465825) and DNMT3B (rs2424932, rs4911259) genes, which have previously been found associated with clinical and trait-related phenotypes. There was no association with the categorical phenotype panic disorder. However, a significant association was discerned between DNMT3A rs1465764 and PSWQ scores in healthy participants, with the minor allele conveying a protective effect. In addition, a marginally significant association between questionnaire scores (PSWQ, ASI) in healthy participants and DNMT3B rs2424932 was detected, again with the minor allele conveying a protective effect. The present results suggest a possible minor role of DNMT3A and DNMT3B gene variation in conveying resilience towards anxiety disorders. As the observed associations indicated a protective effect of two SNPs particularly with pathological worry, future studies are proposed to explore these variants in generalized anxiety disorder rather than panic disorder.

Interplay between RGS2 and childhood adversities in predicting anxiety and depressive disorders: Findings from a general population sample.

BACKGROUND: It remains unresolved whether childhood adversities interact with genetic variation in regulator of G-protein signaling 2 (RGS2) rs4606 in predicting various anxiety and depressive disorders and whether diagnostic specificity exists in these interactions. METHODS: The genotype of RGS2 rs4606 was determined for N = 2,263 adults with European ancestry from the Study of Health in Pomerania. Lifetime anxiety and depressive disorders according to the Diagnostic and Statistical Manual of Mental Disorders, fourth edition, were assessed with the Munich Composite International Diagnostic Interview (DIA-X/M-CIDI). Childhood adversities were assessed with the Childhood Trauma Questionnaire (CTQ, when participants were aged 29-89). RESULTS: Logistic regressions adjusted for sex and age revealed that rs4606 interacted with total childhood adversity in predicting each diagnostic outcome except for panic disorder and generalized anxiety disorder, uncorrected and corrected for multiple testing (odds ratio [OR] = 1.06-1.16). That is, carriers of the GG (vs. CC/CG) genotype were at decreased risk for anxiety and/or depression in the presence of low, but at increased risk in the presence of high total childhood adversity. Respective gene-environment (G × E) interactions were found for (a) comorbid anxiety and depressive disorders (OR = 1.13), but neither pure anxiety nor pure depressive disorders and (b) pure/temporally primary anxiety disorders (OR = 1.07), but not pure/temporally primary depressive disorders. The G × E interaction remained associated with depressive disorders after introducing pure/temporally primary anxiety disorders as additional predictor (OR = 1.09). CONCLUSIONS: rs4606 alters the risk of developing a range of anxiety but also depressive disorders after childhood adversities. A complex risk pattern of genotype, environmental factors, and preexisting anxiety contributes to subsequent depression development.

Do Interoceptive Sensations Provoke Fearful Responses in Adolescents With Chronic Headache or Chronic Abdominal Pain? A Preliminary Experimental Study.

Objective: To determine whether fear can be triggered when experiencing interoceptive sensations locally proximal to the primary pain region. Two groups of adolescents (11-18 years) with chronic headache ( n = 20) or chronic abdominal pain (CAP; n = 20) completed three muscle tensing tasks to induce proximal versus distal sensations: (1) "frown" task (proximal for chronic headache; distal for CAP), (2) "tighten stomach" task (proximal for CAP; distal for chronic headache), and (3) safe comparison task (clench fist). Fear and avoidance were assessed via self-report. Adolescents with CAP reported greater fear and avoidance after the proximal compared with the distal task, while adolescents with chronic headache did not. Both groups reported similar levels of fear and avoidance in the frown and safe comparison task. Results suggest that the perception of proximal interoceptive sensations appears to activate the fear system in adolescents with CAP. Future research is warranted.

"The mere imagination scares me"-evidence for fear responses during mental imagery of pain-associated interoceptive sensations in adolescents with chronic pain.

ABSTRACT: According to the bio-informational theory of emotion by Lang, mental imagery of fearful stimuli activates physiological and behavioural response systems, even in the absence of sensory input. We investigated whether instructed mental imagery of pain-associated (not painful) interoceptive sensations entails a threat value and elicits increased startle response, skin conductance level (SCL), and heart rate (HR) indicative of defensive mobilization in adolescents with chronic pain. Additionally, self-reported measures (fear, fear of pain, desire to avoid) were assessed. Adolescents (11-18 years) with chronic headache (CH, n = 46) or chronic abdominal pain (CAP, n = 29) and a control group (n = 28) were asked to imagine individualized pain-associated, neutral and standardized fear scripts. During pain-associated compared with neutral imagery, both pain groups showed higher mean HR, with CH also showing higher HR reactivity, while HR acceleration was not observed within control group. In contrast, during pain-associated compared with neutral imagery, startle response magnitude and SCL remained unchanged in all groups. Additionally, overall levels in self-reports were higher during pain-associated compared with neutral imagery, but significantly more pronounced in the pain groups compared with the control group. Results suggest that the mere imagination of pain-associated sensations elicits specific autonomic fear responses accompanied by increased self-reported fear in adolescents with chronic pain. The specific modulation of heart rate shed new light on our understanding of multimodal fear responses in adolescents with chronic pain and may help to refine paradigms to decrease fear of interoceptive sensations in chronic pain.

Temporal dynamics in mental health symptoms and loneliness during the COVID-19 pandemic in a longitudinal probability sample: a network analysis.

Figuring out which symptoms are central for symptom escalation during the COVID-19 pandemic is important for targeting prevention and intervention. Previous studies have contributed to the understanding of the course of psychological distress during the pandemic, but less is known about key symptoms of psychological distress over time. Going beyond a pathogenetic pathway perspective, we applied the network approach to psychopathology to examine how psychological distress unfolds in a period of maximum stress (pre-pandemic to pandemic onset) and a period of repeated stress (pandemic peak to pandemic peak). We conducted secondary data analyses with the Understanding Society data (N = 17,761), a longitudinal probability study in the UK with data before (2019), at the onset of (April 2020), and during the COVID-19 pandemic (November 2020 & January 2021). Using the General Health Questionnaire and one loneliness item, we computed three temporal cross-lagged panel network models to analyze psychological distress over time. Specifically, we computed (1) a pre-COVID to first incidence peak network, (2) a first incidence peak to second incidence peak network, and (3) a second incidence peak to third incidence peak network. All networks were highly consistent over time. Loneliness and thinking of self as worthless displayed a high influence on other symptoms. Feeling depressed and not overcoming difficulties had many incoming connections, thus constituting an end-product of symptom cascades. Our findings highlight the importance of loneliness and self-worth for psychological distress during COVID-19, which may have important implications in therapy and prevention. Prevention and intervention measures are discussed, as single session interventions are available that specifically target loneliness and worthlessness to alleviate mental health problems.

Defensive Mobilization During Anticipation of Symptom Provocation: Association With Panic Pathology.

BACKGROUND: Anxious apprehension about feared body symptoms is thought to play a crucial role in the development, chronicity, and treatment of panic disorder (PD). In this study, we therefore aimed to elucidate the role of defensive reactivity to anticipated unpleasant symptoms in PD that can contribute to a better understanding of pathomechanisms of PD as well as identification of potential targets in PD-focused interventions. By measuring amygdala-dependent potentiation of the startle reflex, we aimed to investigate whether 1) patients with PD exhibit a specifically increased defensive reactivity to anticipated unpleasant body symptoms and 2) whether clinical severity of panic symptomatology varies with magnitude of defensive activation. METHODS: Defensive mobilization to anticipated threat was investigated in 73 patients with a primary diagnosis of PD with agoraphobia (PDA) and 52 healthy control subjects. Threat of symptom provocation was established by a standardized hyperventilation task and contrasted to threat of shock to the forearm of the participant. RESULTS: Patients with PDA and healthy control subjects did not differ in their defensive responses during anticipation of shock. In contrast, patients with severe PDA as compared with healthy control subjects exhibited increased defensive response mobilization and reported more anxiety and panic symptoms during anticipation of feared body symptoms. Moreover, startle potentiation during anticipation of hyperventilation covaried with the severity of panic symptomatology. CONCLUSIONS: The present findings suggest that increased defensive mobilization during anticipation of body symptoms is a neurobiological correlate of severe PDA that should be specifically targeted in PD interventions and might be used to monitor treatment success.

Anxiety sensitivity elevates the risk of mental health problems in employees with higher probability of contacting COVID-19 at work.

Individuals with increased risk of being in contact with COVID-19 cases at work have been reported to suffer from higher fear of infection and associated mental health problems. The present study examines whether this risk is further increased by higher anxiety sensitivity (AS, i.e., fear of bodily symptoms such as breathlessness, which also are core symptoms of COVID-19) that is also known to be associated with an increased risk of psychopathology. In spring 2020, 783 German health care and social workers participated in a cross-sectional online-survey, in which anxiety sensitivity, depression, anxiety, health anxiety, fear of a COVID-19 infection as well as panic symptoms were assessed. Of these participants, 28.7% affirmed contact with COVID-19 cases, which was associated with greater fear of the virus. Individuals with high AS reported more severe anxiety, health anxiety, depressive symptoms, as well as incident and recurrent panic symptoms. Moreover, the risk association of exposure to COVID-19 cases at work with health anxiety, general anxiety, and panic symptoms was further increased by higher levels of AS. These findings suggest that especially employees with contact to COVID-19 cases who also are high in AS might profit from targeted interventions to prevent excessive fear and associated mental health problems.

On the current psychotherapeutic situation for persons with pornography use disorder in Germany.

Background and aims: For the first time, the ICD-11 provides the diagnosis compulsive sexual behavior disorder (CSBD) that can be assigned for pornography use disorder (PUD). This study aimed to estimate the prevalence of PUD and associated consequences in Germany, to identify the psychotherapy demand among likely PUD (lPUD) cases and the treatment supply in different psychotherapeutic settings, to survey psychotherapists' level of expertise regarding PUD, and to identify predictors for psychotherapy demand. Methods: Four studies were conducted: 1. Online study in the general population (n = 2070; m = 48.9%, f = 50.8%, d = 0.2%), 2. Survey among practicing psychotherapists (n = 983), 3. Survey of psychotherapists in psychotherapeutic outpatient clinics (n = 185), 4. Interviews with psychotherapeutic inpatient clinics (n = 28). Results: The estimated prevalence of lPUD in the online study was 4.7% and men were 6.3 times more often affected than women. Compared to individuals without PUD, individuals with lPUD more often indicated negative consequences in performance-related areas. Among lPUD cases, 51.2% of men and 64.3% of women were interested in a specialized PUD treatment. Psychotherapists reported 1.2%-2.9% of lPUD cases among their patients. 43.2%-61.5% of psychotherapists stated to be poorly informed about PUD. Only 7% of psychotherapeutic inpatient clinics provided specific treatments to patients with PUD. While, among other factors, negative consequences attributed to lPUD were predictive for psychotherapy demand, weekly pornography consumption, subjective well-being, and religious attachment were not. Discussion and conclusions: Although PUD occurs quite often in Germany, availability of mental health care services for PUD is poor. Specific PUD treatments are urgently needed.

Brain activation during anticipation of interoceptive threat.

The current study investigated the neural networks activated during the anticipation of potentially threatening body symptoms evoked by a guided hyperventilation task in a group of participants reporting either high or low fear of unexplained somatic sensations. 15 subjects reporting high and 14 subjects reporting low fear of somatic symptoms first learned that one of two cues predicted the occurrence of a hyperventilation task reliably producing body symptoms in all participants that were rated as more intense and unpleasant in the high fear group. During anticipation of unpleasant symptoms, high fear participants reported more intense body symptoms and showed potentiation of the startle reflex. After this learning session, participants were taken into the fMRI where the same cues either predicted the occurrence of hyperventilation or normoventilation, although the task was never performed in the scanner. During anticipation of hyperventilation all participants showed an increased activation of anterior insula/orbitofrontal cortex and rostral parts of the dorsal anterior cingulate cortex/dorsomedial prefrontal cortex (dACC/dmPFC). Brain activation of high compared to low fear participants differed in two ways. First, high fear participants showed an overall stronger activation of this network during threat and safe conditions indexing stronger anxious apprehension during the entire context. Second, while low fear participants no longer responded with stronger activation to the threat cue after experiencing that the hyperventilation challenge did not follow this cue, high fear participants continued to show stronger activation of the network to this cue. Activation of the rostral dACC/dmPFC was significantly correlated with reported fear of somatic symptoms. These data demonstrate that anticipation of interoceptive threat activates the same network that has been found to be active during anticipation of exteroceptive threat cues. Thus, the current paradigm might provide an innovative method to study anxious apprehension and treatment effects in patients with panic disorder.

The role of pre-pandemic depression for changes in depression, anxiety, and loneliness during the COVID-19 pandemic: Results from a longitudinal probability sample of adults from Germany.

BACKGROUND: The present study aims to delineate the role of preexisting depression for changes in common mental health problems during the COVID-19 pandemic. METHODS: Using mixed-effects linear regression models, we analyzed data on the course of depressive (Patient Health Questionnaire-2) and anxiety (Generalized Anxiety Disorder-2) symptoms as well as loneliness (three-item UCLA Loneliness Scale) in a subset of the Socio-Economic Panel Study, a large and nationally representative household panel study from Germany. Participants were assessed during the first COVID-19 wave in Germany (March 31 to July 4, 2020; n = 6,694) and prospectively followed up at the peak of the second COVID-19 wave (January 18 to February 15, 2021; n = 6,038). RESULTS: Overall, anxiety and depressive symptoms decreased, whereas loneliness increased from the first to the second COVID-19 wave. However, depressive symptoms increased and the surge in loneliness was steeper in those with versus without clinically relevant depressive symptoms in 2019 or a history of a depressive disorder before the COVID-19 pandemic. Anxiety symptoms remained stable throughout the pandemic in individuals with versus without clinically relevant depressive symptoms in 2019. Pre-pandemic depression was associated with overall higher depressive and anxiety symptoms and loneliness across both assessments. The stringency of lockdown measures did not affect the results. CONCLUSIONS: Our findings suggest that individuals with a history of depressive symptoms before the COVID-19 pandemic are at increased risk to experience an escalation of mental health problems due to the COVID-19 pandemic. Therefore, they might particularly profit from targeted prevention and early intervention programs.

Health anxiety is associated with fearful imagery of contracting COVID-19: An experimental study.

BACKGROUND: Aversive mental images of contracting or having a severe disease are assumed to contribute to the development and maintenance of health anxiety (HA) via the elicitation of fear, arousal and defensive mobilization. The current COVID-19 pandemic is known to trigger fears of contracting COVID-19. METHODS: In this study, we used an experimental approach to investigate whether COVID-19-related mental images lead to a fearful response and whether this is associated with levels of HA. 139 participants vividly imagined neutral, standard fear and COVID-19 related narrative scenes. RESULTS: Standard fear and COVID-19 scripts prompted higher anxiety, arousal, displeasure and avoidance tendencies as compared to neutral scripts. HA was associated with higher anxiety, arousal, displeasure, imagery vividness and stronger avoidance tendencies during imagery of COVID-19 scenes. No associations were found for anxiety sensitivity, trait anxiety as well as depressive and anxiety symptoms. Moreover, there was no association of HA with emotional responses during imagery of standard fear scenes. LIMITATIONS: Fear responses were assessed via verbal reports. Future studies should also assess behavioral and physiological correlates of fear. CONCLUSIONS: The present results indicate that individuals with high levels of HA are prone to fearful mental imagery of contracting COVID-19 which might be crucial factor contributing to the exacerbation and chronicity of excessive HA in times of a pandemic.

Purchasing under threat: Changes in shopping patterns during the COVID-19 pandemic.

The spreading of COVID-19 has led to panic buying all over the world. In this study, we applied an animal model framework to elucidate changes in human purchasing behavior under COVID-19 pandemic conditions. Purchasing behavior and potential predictors were assessed in an online questionnaire format (N = 813). Multiple regression analyses were used to evaluate the role of individually Perceived Threat of COVID-19, anxiety related personality traits (trait-anxiety, intolerance of uncertainty) and the role of media exposure in predicting quantity and frequency of purchasing behavior. High levels of Perceived Threat of COVID-19 were associated significantly with a reported reduction in purchasing frequency (b = -.24, p < .001) and an increase in the quantity of products bought per purchase (b = .22, p < .001). These results are comparable to observed changes in foraging behavior in rodents under threat conditions. Higher levels of intolerance of uncertainty (b = .19, p < .001) and high extend of media exposure (b = .27, p < .001) were positively associated with Perceived Threat of COVID-19 and an increase in purchasing quantity. This study contributes to our understanding of aberrated human purchasing behavior and aims to link findings from animal research to human behavior beyond experimental investigations.

Hold your breath: Voluntary breath-holding time predicts defensive activation to approaching internal threat.

Bodily disturbances, like dyspnea, elicit responses to regain homeostasis and ensure survival. However, this life-saving function can become hyperreactive, which may lead to the emergence of psychopathology. This study investigated whether maximal voluntary breath-holding time (mvBHT), a biobehavioral marker that characterizes sensitivity to respiratory stimulation, predicts defensive mobilization to cues signaling the proximity of a mild electric shock vs. a respiratory threat (shortness of breath elicited by forced breath-holding) and the opportunity to avoid threat delivery in 60 healthy participants. While the startle reflex, a measure of defensive mobilization, generally increased with the proximity of an inevitable threat, shorter breath-holding time was specifically associated with greater startle potentiation when anticipating a respiratory threat but not an electric shock. In contrast, when both threats were avoidable, the startle reflex was comparably inhibited, irrespective of mvBHT. This study suggests that mvBHT specifically predicts hypersensitive responding to an anticipated inevitable respiratory threat.

Decreased defensive reactivity to interoceptive threat after successful exposure-based psychotherapy in patients with panic disorder.

Panic disorder (PD) is characterized by a dysfunctional defensive responding to panic-related body symptoms that is assumed to contribute to the persistence of panic symptomatology. The present study aimed at examining whether this dysfunctional defensive reactivity to panic-related body symptoms would no longer be present following successful cognitive behavior therapy (CBT) but would persist when patients show insufficient symptom improvement. Therefore, in the present study, effects of CBT on reported symptoms and defensive response mobilization during interoceptive challenge were investigated using hyperventilation as a respiratory symptom provocation procedure. Changes in defensive mobilization to body symptoms in the course of CBT were investigated in patients with a primary diagnosis of PD with or without agoraphobia by applying a highly standardized hyperventilation task prior to and after a manual-based CBT (n = 38) or a waiting period (wait-list controls: n = 20). Defensive activation was indexed by the potentiation of the amygdala-dependent startle eyeblink response. All patients showed a pronounced defensive response mobilization to body symptoms at baseline. After treatment, no startle reflex potentiation was found in those patients who showed a clinically significant improvement. However, wait-list controls and treatment non-responders continued to show increased defensive responses to actually innocuous body symptoms after the treatment/waiting period. The present results indicate that the elimination of defensive reactivity to actually innocuous body symptoms might be a neurobiological correlate and indicator of successful CBT in patients with PD, which may help to monitor and optimize CBT outcomes.

Vagal control of the heart decreases during increasing imminence of interoceptive threat in patients with panic disorder and agoraphobia.

Theoretically, panic disorder and agoraphobia pathology can be conceptualized as a cascade of dynamically changing defensive responses to threat cues from inside the body. Guided by this trans-diagnostic model we tested the interaction between defensive activation and vagal control as a marker of prefrontal inhibition of subcortical defensive activation. We investigated ultra-short-term changes of vagally controlled high frequency heart rate variability (HRV) during a standardized threat challenge (entrapment) in n = 232 patients with panic disorder and agoraphobia, and its interaction with various indices of defensive activation. We found a strong inverse relationship between HRV and heart rate during threat, which was stronger at the beginning of exposure. Patients with a strong increase in heart rate showed a deactivation of prefrontal vagal control while patients showing less heart rate acceleration showed an increase in vagal control. Moreover, vagal control collapsed in case of imminent threat, i.e., when body symptoms increase and seem to get out of control. In these cases of defensive action patients either fled from the situation or experienced a panic attack. Active avoidance, panic attacks, and increased sympathetic arousal are associated with an inability to maintain vagal control over the heart suggesting that teaching such regulation strategies during exposure treatment might be helpful to keep prefrontal control, particularly during the transition zone from post-encounter to circa strike defense.Trial Registration Number: ISRCTN80046034.