Search

BACKGROUND: While self-construal and posttraumatic stress disorder (PTSD) are independently associated with altered self-referential processes and underlying default mode network (DMN) functioning, no study has examined how self-construal affects DMN connectivity in PTSD. METHODS: A final sample of 93 refugee participants (48 with DSM-5 PTSD or sub-syndromal PTSD and 45 matched trauma-exposed controls) completed a 5-minute resting state fMRI scan to enable the observation of connectivity in the DMN and other core networks. A self-construal index was calculated by substracting scores on the collectivistic and individualistic sub-scales of the Self Construal Scale. RESULTS: Independent components analysis identified 9 active networks-of-interest, and functional network connectivity was determined. A significant interaction effect between PTSD and self-construal index was observed in the anterior ventromedial DMN, with spatial maps localizing this to the left ventromedial prefrontal cortex (vmPFC), extending to the ventral anterior cingulate cortex. This effect revealed that connectivity in the vMPFC showed greater reductions in those with PTSD with higher levels of collectivistic self-construal. LIMITATIONS: This is an observational study and causality cannot be assumed. The specialized sample of refugees means that the findings may not generalize to other trauma-exposed populations. CONCLUSIONS: Such a finding indicates that self-construal may shape the core neural architecture of PTSD, given that functional disruptions to the vmPFC underpin the core mechanisms of extinction learning, emotion dysregulation and self-referential processing in PTSD. Results have important implications for understanding the universality of neural disturbances in PTSD, and suggest that self-construal could be an important consideration in the assessment and treatment of post-traumatic stress reactions.

Evidence now suggests that traumatic-stress impacts brain functions even in the absence of acute-onset post-traumatic stress disorder (PTSD) symptoms. These neurophysiological changes have also been suggested to account for increased risks of PTSD symptoms later developing in the aftermath of subsequent trauma. However, surprisingly few studies have explicitly examined brain function dynamics in high-risk populations, such as combat exposed military personnel without diagnosable PTSD. To extend available research, facial expression sensitive N170 event-related potential (ERP) amplitudes were examined in a clinically healthy sample of active service military personnel with recurrent combat exposure history. Consistent with several established theories of delayed-onset PTSD vulnerability, higher N170 amplitudes to backward-masked fearful and neutral facial expressions correlated with higher levels of past combat exposure. Significantly elevated amplitudes to nonthreatening neutral facial expressions also resulted in an absence of normal threat-versus-nonthreat signal processing specificity. While a modest sample size and cross-sectional design are key limitations here, ongoing prospective-longitudinal follow-ups may shed further light on the precise aetiology and prognostic utility of these preliminary findings in the near future.

Meta-analyses indicate differences in Pavlovian fear responses between anxious and non-anxious individuals using electrodermal activity (EDA). Recent research, however, has cast doubt on whether these effects are robust to different analytic choices. Using the multiverse approach conceived by Steegen et al. (2016), we surveyed analytic choices typically implemented in clinical fear conditioning research by conducting 1240 analyses reflecting different choice permutations. Only 1.45% of our analyses produced theoretically congruent statistically significant effects, and the strength and direction of the estimated effects varied substantially across EDA processing methods. We conclude that EDA-estimated fear learning differences are vulnerable to researcher degrees of freedom and make recommendations regarding which analytical choices should be approached with a high degree of caution.

The brain's default mode network has a central role in the processing of information concerning oneself. Dysfunction in this self-referential processing represents a key component of multiple mental health conditions, particularly social anxiety disorder (SAD). This case-control study aimed to clarify alterations to network dynamics present during self-appraisal in SAD participants. A total of 38 adolescents and young adults with SAD and 72 healthy control participants underwent a self-referential processing fMRI task. The task involved two primary conditions of interest: direct self-appraisal (thinking about oneself) and reflected self-appraisal (thinking about how others might think about oneself). Dynamic causal modeling and parametric empirical Bayes were then used to explore differences in the effective connectivity of the default mode network between groups. We observed connectivity differences between SAD and healthy control participants in the reflected self-appraisal but not the direct self-appraisal condition. Specifically, SAD participants exhibited greater excitatory connectivity from the posterior cingulate cortex (PCC) to medial prefrontal cortex (MPFC) and greater inhibitory connectivity from the inferior parietal lobule (IPL) to MPFC. In contrast, SAD participants exhibited reduced intrinsic connectivity in the absence of task modulation. This was illustrated by reduced excitatory connectivity from the PCC to MPFC and reduced inhibitory connectivity from the IPL to MPFC. As such, participants with SAD showed changes to afferent connections to the MPFC which occurred during both reflected self-appraisal as well as intrinsically. The presence of connectivity differences in reflected and not direct self-appraisal is consistent with the characteristic fear of negative social evaluation that is experienced by people with SAD.

BACKGROUND: Emotion regulation deficits are characteristic of youth depression and are underpinned by altered frontoamygdalar function. However, the causal dynamics of frontoamygdalar pathways in depression and how these dynamics relate to treatment prognosis remain unexplored. This study aimed to assess frontoamygdalar effective connectivity during cognitive reappraisal in youths with depression and to test whether pathway dynamics are predictive of individual response to combined cognitive behavioral therapy plus treatment with fluoxetine or placebo. METHODS: One hundred seven young people with moderate to severe depression and 94 healthy control participants completed a functional magnetic resonance imaging cognitive reappraisal task. After the task, 87 participants with depression were randomized and received 12 weeks of cognitive behavioral therapy plus either fluoxetine or placebo. Dynamic causal modeling was used to map frontoamygdalar effective connectivity during reappraisal and to assess the predictive capacity of baseline frontoamygdalar effective connectivity on depression diagnosis and posttreatment depression remission. RESULTS: Young people with depression showed weaker inhibitory modulation of ventrolateral prefrontal cortex to amygdala connectivity during reappraisal (0.29 Hz, posterior probability = 1.00). Leave-one-out cross-validation demonstrated that this effect was sufficiently large to predict individual diagnostic status (r = 0.20, p = .003). Posttreatment depression remission was associated with weaker excitatory ventromedial prefrontal cortex to amygdala connectivity (-0.56 Hz, posterior probability = 1.00) during reappraisal at baseline, though this effect did not predict individual remission status (r = -0.02, p = .561). CONCLUSIONS: Frontoamygdalar effective connectivity shows promise in identifying youth depression diagnosis, and circuits responsible for negative affect regulation are implicated in responsiveness to first-line depressi

BACKGROUND: Emotion processing deficits have been identified as a critical transdiagnostic factor that facilitates distress after trauma exposure. Limited skills in identifying and labelling emotional states (i.e. alexithymia) may present on the more automated (less conscious) end of the spectrum of emotional awareness and clarity. Individuals with alexithymia tend to exhibit a disconcordance between subjective experience and autonomic activity (e.g. where high levels of subjective emotional intensity are associated with low physiological arousal), which may exacerbate distress. Although there is a robust link between alexithymia and trauma exposure, no work to date has explored whether alexithymia is associated with emotional response disconcordance among trauma-exposed adults. METHOD: Using a validated trauma script paradigm, the present study explored the impact of alexithymia on emotion response concordance [skin conductance (Galvanic Skin Response, GSR) and Total Mood Disturbance (TMD)] among 74 trauma-exposed adults recruited via a posttraumatic stress disorder (PTSD) treatment clinic and student research programme. RESULTS: Unlike posttraumatic symptom severity, age, sex, participant type and mood (which showed no effect on emotion response concordance), alexithymia was associated with heightened emotion response disconcordance between GSR and TMD [F(1, 37) = 8.93, p = 0.006], with low GSR being associated with high TMD. Observed effects of the trauma script were entirely accounted for by the interaction with alexithymia, such that those with alexithymia showed a negligible association between subjective and physiological states. CONCLUSION: This finding is paramount as it shows that a large proportion of trauma-exposed adults have a divergent emotion engagement profile.

Dysregulated consolidation of emotional memories is a core feature of posttraumatic stress disorder (PTSD). Brain Derived Neurotrophic Factor (BDNF) influences synaptic plasticity and emotional memory consolidation. The BDNF Val66Met polymorphism has been associated with PTSD risk and memory deficits respectively, although findings have been inconsistent, potentially due to a failure to control for important confounds such as sex, ethnicity, and the timing/extent of previous trauma experiences. Furthermore, very little research has examined the impact of BDNF genotypes on emotional memory in PTSD populations. This study investigated the interaction effects of Val66Met and PTSD symptomatology in an emotional recognition memory task in 234 participants divided into healthy control (n = 85), trauma exposed (TE: n = 105) and PTSD (n = 44) groups. Key findings revealed impaired negative recognition memory in PTSD compared to control and TE groups and in participants with the Val/Met compared to the Val/Val genotype. There was a group × genotype interaction showing no Met effect in the TE group despite significant effects in PTSD and controls. Results suggest that people previously exposed to trauma who do not develop PTSD may be protected from the BDNF Met effect, however more research is needed to replicate findings and to explore the epigenetic and neural processes involved.

At least one-third posttraumatic stress disorder (PTSD) patients do not respond to trauma-focused psychotherapy (TF-psychotherapy), which is the treatment of choice for PTSD. To clarify the change mechanisms that may be associated with treatment response, this study examined changes in neural activations during affective and non-affective processing that occur with improvement of symptoms after TF-psychotherapy. This study assessed PTSD treatment-seeking patients (n = 27) prior to and after TF-psychotherapy using functional magnetic resonance imaging when they completed three tasks: (a) passive viewing of affective faces, (b) cognitive reappraisal of negative images, and (c) non-affective response inhibition. Patients then underwent 9 sessions of TF-psychotherapy, and were assessed on the Clinician-Administered PTSD Scale following treatment. Changes in neural responses in affect and cognitive processing regions-of-interest for each task were correlated with reduction of PTSD severity from pretreatment to posttreatment in the PTSD cohort. Data from 21 healthy controls was used for comparison. Improvement of symptoms in PTSD were associated with increased activation of left anterior insula, reductions in the left hippocampus and right posterior insula during viewing of supraliminally presented affective images, and reduced connectivity between the left hippocampus with the left amygdala and rostral anterior cingulate. Treatment response was also associated with reduced activation in the left dorsolateral prefrontal cortex during reappraisal of negative images. There were no associations between response and activation change during response inhibition. This pattern of findings indicates that improvement of PTSD symptoms following TF-psychotherapy is associated with changes in affective rather than non-affective processes. These findings accord with prevailing models that TF-psychotherapy promotes engagement and mastery of affective stimuli.Clinical Trials Registratio

Core regions of the salience network (SN), including the anterior insula (aINS) and dorsal anterior cingulate cortex (dACC), coordinate rapid adaptive changes in attentional and autonomic processes in response to negative emotional events. In doing so, the SN incorporates bottom-up signals from subcortical brain regions, such as the amygdala and periaqueductal gray (PAG). However, the precise influence of these subcortical regions is not well understood. Using ultra-high field 7-Tesla functional magnetic resonance imaging, this study investigated the bottom-up interactions of the amygdala and PAG with the SN during negative emotional salience processing. Thirty-seven healthy participants completed an emotional oddball paradigm designed to elicit a salient negative emotional response via the presentation of random, task-irrelevant negative emotional images. Negative emotional processing was associated with prominent activation in the SN, spanning the amygdala, PAG, aINS, and dACC. Consistent with previous research, analysis using dynamic causal modelling revealed an excitatory influence from the amygdala to the aINS, dACC, and PAG. In contrast, the PAG showed an inhibitory influence on amygdala, aINS and dACC activity. Our findings suggest that the amygdala may amplify the processing of negative emotional stimuli in the SN to enable upstream access to attentional resources. In comparison, the inhibitory influence of the PAG possibly reflects its involvement in modulating sympathetic-parasympathetic autonomic arousal mediated by the SN. This PAG-mediated effect may be driven by amygdala input and facilitate bottom-up processing of negative emotional stimuli. Overall, our results show that the amygdala and PAG modulate divergent functions of the SN during negative emotional processing.

Negative self-beliefs are a core feature of psychopathology, encompassing both negative appraisals about oneself directly (i.e. self-judgment) and negative inferences of how the self is appraised by others (i.e. social judgment). Challenging maladaptive self-beliefs via cognitive restructuring is a core treatment mechanism of gold-standard psychotherapies. However, the neural mechanisms underlying the restructuring of these two kinds of negative self-beliefs are poorly understood. Eighty-six healthy participants cognitively restructured self-judgment and social-judgment negative self-belief statements during 7 Tesla functional magnetic resonance imaging scanning. Cognitive restructuring broadly elicited activation in the core default mode network (DMN), salience and frontoparietal control regions. Restructuring self-judgment relative to social-judgment beliefs was associated with comparatively higher activation in the ventral posterior cingulate cortex (PCC)/retrosplenial cortex, while challenging social-judgment statements was associated with higher activation in the dorsal PCC/precuneus. While both regions showed increased functional connectivity with the supplementary and pre-supplementary motor areas during restructuring, the dorsal PCC displayed greater task-dependent connectivity with distributed regions involved in salience, attention and social cognition. Our findings indicate distinct patterns of PCC engagement contingent upon self- and social domains, highlighting a specialized role of the dorsal PCC in supporting neural interactions between the DMN and frontoparietal/salience networks during cognitive restructuring.

Torture has profound psychological and physiological consequences for survivors. While some brain structures and functions appear altered in torture survivors, it is unclear how torture exposure influences functional connectivity within and between core intrinsic brain networks. In this study, 37 torture survivors (TS) and 62 non-torture survivors (NTS) participated in a resting-state fMRI scan. Data-driven independent components analysis identified active intrinsic networks. Group differences in functional connectivity in the default mode network (DMN), salience network (SN) and central executive network (CEN) of the triple network model, as well any prefrontal network, were examined while controlling for PTSD symptoms and exposure to other potentially traumatic events. The analysis identified 25 networks; eight comprised our networks of interest. Within-network group differences were observed in the left CEN (lCEN), where the TS group showed less spectral power in the low-frequency band. Differential internetwork dynamic connectivity patterns were observed, where the TS group showed stronger positive coupling between the lCEN and anterior dorsomedial and ventromedial DMN, and stronger negative coupling between a lateral frontal network and the lCEN and anterior dorsomedial DMN (when contrasted with the NTS group). Group differences were not attributed to torture severity or dissociative symptoms. Torture survivors showed disrupted dynamic functional connectivity between a laterally-aligned lCEN that serves top-down control functions over external processes and the midline DMN that underpins internal self-referential processes, which may be an adaptive response to mitigate the worst effects of the torture experience. This study provides a critical step in mapping the neural signature of torture exposure to guide treatment development and selection.

Social attachment systems are disrupted for refugees through trauma and forced displacement. This study tested how the attachment system mitigates neural responses to threat in refugees with posttraumatic stress disorder (PTSD). Refugees with PTSD (N = 28) and refugee trauma-exposed controls (N = 22) viewed threat-related stimuli primed by attachment cues during a functional magnetic resonance imaging scan. Group differences and the moderating effects of avoidant or anxious attachment style and grief related to separation from family on brain activity and connectivity patterns were examined. Separation grief was associated with increased amygdala but decreased ventromedial prefrontal cortical (VMPFC) activity to the attachment prime and decreased VMPFC and hippocampal activity to attachment primed threat in the PTSD (vs trauma-exposed control) group. Avoidant attachment style was connected with increased dorsal frontoparietal attention regional activity to attachment prime cues in the PTSD group. Anxious attachment style was associated with reduced left amygdala connectivity with left medial prefrontal regions to attachment primed threat in the PTSD group. Separation grief appears to reduce attachment buffering of threat reactivity in refugees with PTSD, while avoidant and anxious attachment style modulated attentional and prefrontal regulatory mechanisms in PTSD, respectively. Considering social attachments in refugees could be important to post-trauma recovery, based within changes in key emotion regulation brain systems.

Fear conditioning paradigms are critical to understanding anxiety-related disorders, but studies use an inconsistent array of methods to quantify the same underlying learning process. We previously demonstrated that selection of trials from different stages of experimental phases and inconsistent use of average compared to trial-by-trial analysis can deliver significantly divergent outcomes, regardless of whether the data is analysed with extinction as a single effect, as a learning process over the course of the experiment, or in relation to acquisition learning. Since small sample sizes are attributed as sources of poor replicability in psychological science, in this study we aimed to investigate if changes in sample size influences the divergences that occur when different kinds of fear conditioning analyses are used. We analysed a large data set of fear acquisition and extinction learning (N = 379), measured via skin conductance responses (SCRs), which was resampled with replacement to create a wide range of bootstrapped databases (N = 30, N = 60, N = 120, N = 180, N = 240, N = 360, N = 480, N = 600, N = 720, N = 840, N = 960, N = 1080, N = 1200, N = 1500, N = 1750, N = 2000) and tested whether use of different analyses continued to produce deviating outcomes. We found that sample size did not significantly influence the effects of inconsistent analytic strategy when no group-level effect was included but found strategy-dependent effects when group-level effects were simulated. These findings suggest that confounds incurred by inconsistent analyses remain stable in the face of sample size variation, but only under specific circumstances with overall robustness strongly hinging on the relationship between experimental design and choice of analyses. This supports the view that such variations reflect a more fundamental confound in psychological science-the measurement of a single process by multiple methods.

Facing your fears, or exposure therapy, is an effective psychological intervention for anxiety disorders that is often thought to work through fear extinction learning. Fear extinction learning is a type of associative learning where fear reduces through repeated encounters with a feared situation or stimulus in the absence of aversive outcomes. Laboratory research suggests fear extinction learning is driven by threat prediction errors, defined as when fearful predictions do not eventuate. Threat prediction error and its relationship to exposure therapy outcomes haven't been studied enough in actual therapy settings. It remains unclear whether prediction error and extinction learning are central mechanisms of exposure therapy. We are conducting a longitudinal and observational study of how threat prediction error during exposure in social anxiety disorder (SAD) treatment relates to session-by-session symptom change and treatment outcome in addition to exposure surprise and learning outcome. We aim to recruit 65 adults with a primary diagnosis of SAD through an outpatient psychology clinic. Participants will receive 12 sessions of individual manualized cognitive behavioral therapy (CBT), adapted from an efficacious group protocol, that includes graded exposure. Exposure processes, including self-report measures of anxiety, threat prediction, threat outcomes, surprise, and learning outcome, will be measured with smartphone-based event-contingent ecological momentary assessments (EMAs) of all behavioral experiments completed during treatment. Clinical outcomes include self-reported social anxiety symptoms and social threat appraisals, at each session, post and 3-months after treatment. Prediction error will be operationalized as the mismatch between the threat prediction and threat outcome. The joint effect of threat prediction and threat outcome on session-by-session symptom change, treatment outcome, exposure surprise, and learning outcome will be explored using mult

Safety learning generates associative links between neutral stimuli and the absence of threat, promoting the inhibition of fear and security-seeking behaviors. Precisely how safety learning is mediated at the level of underlying brain systems, particularly in humans, remains unclear. Here, we integrated a novel Pavlovian conditioned inhibition task with ultra-high field (7 Tesla) fMRI to examine the neural basis of safety learning in 49 healthy participants. In our task, participants were conditioned to two safety signals: a conditioned inhibitor that predicted threat omission when paired with a known threat signal (A+/AX-), and a standard safety signal that generally predicted threat omission (BC-). Both safety signals evoked equivalent autonomic and subjective learning responses but diverged strongly in terms of underlying brain activation (PFDR whole-brain corrected). The conditioned inhibitor was characterized by more prominent activation of the dorsal striatum, anterior insular, and dorsolateral PFC compared with the standard safety signal, whereas the latter evoked greater activation of the ventromedial PFC, posterior cingulate, and hippocampus, among other regions. Further analyses of the conditioned inhibitor indicated that its initial learning was characterized by consistent engagement of dorsal striatal, midbrain, thalamic, premotor, and prefrontal subregions. These findings suggest that safety learning via conditioned inhibition involves a distributed cortico-striatal circuitry, separable from broader cortical regions involved with processing standard safety signals (e.g., CS-). This cortico-striatal system could represent a novel neural substrate of safety learning, underlying the initial generation of "stimulus-safety" associations, distinct from wider cortical correlates of safety processing, which facilitate the behavioral outcomes of learning.SIGNIFICANCE STATEMENT Identifying safety is critical for maintaining adaptive levels of anxiety, but the neu

Safety learning creates associations between conditional stimuli and the absence of threat. Studies of human fear conditioning have accumulated evidence for the neural signatures of safety over various paradigms, aligning on several common brain systems. While these systems are often interpreted as underlying safety learning in a generic sense, they may instead reflect the expression of learned safety, pertaining to processes of fear inhibition, positive affect, and memory. Animal models strongly suggest these can be separable from neural circuits implicated in the conditioning process itself (or safety acquisition). While acquisition-expression distinctions are ubiquitous in behavioural science, this lens has not been applied to safety learning, which remains a novel area in the field. In this mini-review, we overview findings from prevalent safety paradigms in humans, and synthesise these with insights from animal models to propose that the neurobiology of safety learning be conceptualised along an acquisition-expression model, with the aim of stimulating richer brain-based characterisations of this important process.

Sleep has been found to play a key role in fear conditioning, extinction learning and extinction recall, and sleep disturbances are linked to many mental disorders including post-traumatic stress disorder (PTSD). Previous studies examining associations between sleep and fear or extinction processes primarily focused on objectively measured sleep architecture. Little research has so far focused on subjective sleep measures and particularly in clinical populations, which often experience subjectively poor sleep, including PTSD. Here we investigated whether subjective sleep disturbance, sleep onset latency, wake after sleep onset or sleep efficiency were related to fear conditioning, extinction learning or extinction recall in a large sample of individuals with a range of PTSD symptom severity (n = 248). Overall, we did not find that subjective sleep was associated with fear conditioning or extinction processes. However, exploratory analyses examining the moderating effect of sex found that shorter sleep onset latency and greater sleep efficiency were associated with improved extinction recall in women with higher PTSD symptom severity. This suggests that less time falling asleep and longer time asleep while in bed may be protective in highly symptomatic women against the commonly observed impaired extinction recall in PTSD. More studies are needed to explore sex-specific effects further.

Social attachment systems are disrupted for refugees through trauma and forced displacement. This study tested how the attachment system mitigates neural responses to threat in refugees with posttraumatic stress disorder (PTSD). Refugees with PTSD (N = 28) and refugee trauma-exposed controls (N = 22) viewed threat-related stimuli primed by attachment cues during a functional magnetic resonance imaging scan. Group differences and the moderating effects of avoidant or anxious attachment style and grief related to separation from family on brain activity and connectivity patterns were examined. Separation grief was associated with increased amygdala but decreased ventromedial prefrontal cortical (VMPFC) activity to the attachment prime and decreased VMPFC and hippocampal activity to attachment primed threat in the PTSD (vs trauma-exposed control) group. Avoidant attachment style was connected with increased dorsal frontoparietal attention regional activity to attachment prime cues in the PTSD group. Anxious attachment style was associated with reduced left amygdala connectivity with left medial prefrontal regions to attachment primed threat in the PTSD group. Separation grief appears to reduce attachment buffering of threat reactivity in refugees with PTSD, while avoidant and anxious attachment style modulated attentional and prefrontal regulatory mechanisms in PTSD, respectively. Considering social attachments in refugees could be important to post-trauma recovery, based within changes in key emotion regulation brain systems.

BACKGROUND: Deficits in emotional processing are conceptualized in prevailing models of anxiety to underpin key symptoms of panic disorder (PD). Neuroimaging studies show evidence of aberrant neural functioning in PD patients during emotional processing, however little is understood about how non-conscious emotional processing impacts neural processes. METHOD: We examined activation and functional connectivity differences in brain regions involved in emotional processing between PD and healthy controls (HC) during subliminal and supraliminal presentations of facial emotions. Twenty-two PD and 33 HC participants were shown happy, sad, neutral, fear, anger and disgust facial expressions during functional magnetic resonance imaging using a 3T MRI scanner. We performed voxelwise ROI analyses at FWE-corrected p < 0.05 for main effects of group and group*emotion interactions. RESULTS: There was less pregenual anterior cingulate cortex (pgACC) activation to subliminal presentations of happy and sad faces in PD compared to HC participants (group*emotion). In addition, PD patients had less pgACC - right amygdala connectivity than HC participants during sad and fear subliminal processing (group*emotion). PD patients also exhibited lower right cerebellum activity across all supraliminal presentations of facial expressions compared to HC. CONCLUSION: These findings suggest that there is aberrant neural processing in PD patients during both conscious and preconscious processing of both positive and negative stimuli, suggesting impaired recruitment of implicit regulatory networks during affective processing. It appears that PD patients may experience deficits in key regulatory connections between inhibitory and emotional neural networks at very early stages of processing of negative affective states.

Trauma-focused cognitive behavior therapy (TF-CBT) is the gold standard treatment for posttraumatic stress disorder (PTSD), up to one-half of PTSD patients remain treatment non-responders. Although studies have used functional MRI to understand the neurobiology of treatment response, there is less understanding of the role of white matter brain structures in response to TF-CBT. Thirty-six treatment-seeking PTSD patients and 33 age-gender matched healthy controls completed diffusion-weighted imaging scans at baseline. Patients underwent nine sessions of TF-CBT treatment and PTSD symptom severity was assessed with the Clinician-Administered PTSD Scale before and after completing treatment. Patients were assessed to estimate the reduction in overall symptoms and also specifically fear and dysphoric symptoms of PTSD. Tract-based spatial statistical analyses were performed for the PTSD group to evaluate whole-brain correlations of fractional anisotropy (FA) with improvement in overall, fear, and dysphoric symptoms using non-parametric permutation inference testing (pFWE < 0.05). Next, we evaluated if these significant measures also characterized PTSD from controls. Greater improvement in dysphoric symptoms was found correlated with lower FA in white matter regions associated with the limbic system, frontal cortex, thalamic association and projection fibers, corpus callosum, and tracts related to the brainstem. White matter anisotropy was not found associated with either overall or fear symptoms. FA in the significant clusters was similar between PTSD and controls. White-matter related to key functional regions may also play an important role in response to TF-CBT. Our results underscore the heterogeneity of PTSD and the need to evaluate distinct symptom phenotypes in treatment studies.

Although trauma-focused cognitive behavioural therapy (TF-CBT) is the frontline treatment for posttraumatic stress disorder (PTSD), up to one half of patients do not respond optimally to this treatment. Inhibitory functions are important for successful management of PTSD, yet there is a dearth of knowledge regarding the extent to which neural mechanisms unpinning response inhibition are associated with TF-CBT response. Treatment-seeking PTSD patients (n = 40) were assessed during a response inhibition task (the Go/No-Go task) while undergoing functional magnetic imaging (fMRI) and event-related potentials (ERP) in separate sessions. PTSD symptom severity was assessed with the Clinician-Administered PTSD Scale, before undergoing nine sessions of TF-CBT. They were then reassessed post-treatment to estimate reduction in fear and dysphoric symptoms of PTSD. Although neural responses during the inhibitory task did not predict overall symptom change, reduced activation in the left precuneus and the right superior parietal cortex predicted greater improvement in dysphoric symptoms. ERP responses during response inhibition indicated that lower P3 peak latency predicted greater reduction of dysphoric symptoms. There were no significant predictors of changes of fear symptoms. These findings indicate that neural activity associated with response inhibition can act as a predictive biomarker of TF-CBT response for PTSD symptoms. This pattern of findings underscores the importance of delineating the role of biomarkers to predict remission of subtypes of PTSD.

BACKGROUND: Many refugees experience bereavement, and as a result they suffer elevated rates of prolonged grief disorder. Evidence also indicates that elevated rates of psychological disturbance in refugee children can be associated with parental mental health. This study examined the extent to which prolonged grief disorder in refugees is associated with their parenting behaviour and in turn with their children's mental health. METHODS: This study recruited participants from the Building a New Life in Australia prospective cohort study of refugees admitted to Australia between October 2013 and February 2014. The current data were collected in 2015-2016 and comprised 1799 adults, as well as 411 children of the adult respondents. Adult refugees were assessed for trauma history, post-migration difficulties, harsh and warm parenting, probable prolonged grief disorder and posttraumatic stress disorder. Children were administered the Strengths and Difficulties Questionnaire. The current analyses on bereaved refugees comprise 110 caregivers and 178 children. RESULTS: In this cohort, 37% of bereaved refugees reported probable prolonged grief disorder. Path analysis indicated that caregivers' grief was directly associated with children's emotional difficulties. Caregiver warmth was associated with reduced emotional problems in children of refugees with minimal grief but associated with more emotional problems in caregivers with more severe grief. More harsh parenting was associated with children's conduct problems, and this was more evident in those with less severe grief. CONCLUSION: Severity of prolonged grief disorder is directly linked to refugee children's mental health. The association between parenting style, grief severity and children's mental health highlights that managing grief reactions in refugees can benefit both refugees and their children.

Background: PTSD is characterised by severe sleep disturbances, which is increasingly recognised to in many cases consist of similar symptomology to sleep disorders such as REM Behaviour Disorder (RBD). The present study aimed to investigate whether different aspects of sleep quality influence intrusive memory development and whether PTSD status moderates this relationship. Participants and Methods: 34 PTSD, 52 trauma-exposed (TE) and 42 non-trauma exposed (NTE) participants completed an emotional memory task, where they viewed 60 images (20 positive, 20 negative and 20 neutral) and, two days later, reported how many intrusive memories they had of each valence category. Participants also completed three measures of sleep quality: the Pittsburgh Sleep Quality Index, the REM Behaviour Disorder Screening Questionnaire and total hours slept before each session. Results: The PTSD group reported poorer sleep quality than both TE and NTE groups on all three measures, and significantly more negative intrusive memories than the NTE group. Mediation analyses revealed that self-reported RBD symptomology before the second session mediated the relationship between PTSD status and intrusive memories. Follow-up moderation analyses revealed that self-reported RBD symptomology before the second session was only a significant predictor of intrusion in the PTSD group, though with a small effect size. Conclusions: These findings suggest that RBD symptomology is an indicator of consolidation of intrusive memories in PTSD but not trauma-exposed or healthy participants, which supports the relevance of characterising RBD in PTSD.

The Unified Protocol for Transdiagnostic Treatment of Emotional Disorders (UP) is an intervention that targets common mechanisms that maintain symptoms across multiple disorders. The UP has been shown to be effective across many disorders, including generalized anxiety disorder, major depressive episode (MDE), and panic disorder, that commonly codevelop following trauma exposure. The present study represented the first randomized controlled trial of the UP in the treatment of trauma-related psychopathology, including posttraumatic stress disorder (PTSD), depression, and anxiety symptoms. Adults (N = 43) who developed posttraumatic psychopathology that included PTSD, MDE, or an anxiety disorder after sustaining a severe injury were randomly assigned to receive 10-14 weekly, 60-min sessions of UP (n = 22) or usual care (n = 21). The primary treatment outcome was PTSD symptom severity, with secondary outcomes of depression and anxiety symptom severity and loss of diagnosis for any trauma-related psychiatric disorder. Assessments were conducted at intake, posttreatment, and 6-month follow-up. Posttreatment, participants who received the UP showed significantly larger reductions in PTSD, Hedges' g = 1.27; anxiety, Hedges' g = 1.20; and depression symptom severity, Hedges' g = 1.40, compared to those receiving usual care. These treatment effects were maintained at 6-month follow-up for PTSD, anxiety, and depressive symptom severity. Statistically significant posttreatment loss of PTSD, MDE, and agoraphobia diagnoses was observed for participants who received the UP but not usual care. This study provides preliminary evidence that the UP may be an effective non-trauma-focused treatment for PTSD and other trauma-related psychopathology.

Robustness of fear conditioning and extinction paradigms has become increasingly important for many researchers interested in improving the study of anxiety and trauma disorders. We recently illustrated the wide variability in data analysis techniques in this paradigm, which we argued may result in a lack of robustness. In the current study, we resampled data from six of our own fear acquisition and extinction data sets, with skin conductance as the outcome. In the resampled and original data sets, we found that effect sizes that were calculated using discrepant statistical strategies, sourced from a non-exhaustive search of high-impact articles, were often poorly correlated. The main contributors to poor correlations were the selection of trials from different stages of each experimental phase and the use of average compared to trial-by-trial analysis. These findings reinforce the importance of focusing on robustness in the psychophysiological measurement of fear acquisition and extinction in the laboratory and may guide prospective researchers in which decisions may most impact the robustness of their results.

Although trauma-focused cognitive behavior therapy (TF-CBT) is the frontline treatment for post-traumatic stress disorder (PTSD), up to one-half of patients are treatment nonresponders. To understand treatment nonresponse, it is important to understand the neural mechanisms of TF-CBT. Here, we used whole-brain intrinsic functional connectivity analysis to identify neural connectomic signatures of treatment outcome. In total, 36 PTSD patients and 36 healthy individuals underwent functional MRI at pre-treatment baseline. Patients then underwent nine sessions of TF-CBT and completed clinical and follow-up MRIs. We used an established large-scale brain network atlas to parcellate the brain into 343 brain regions. Pairwise intrinsic task-free functional connectivity was calculated and used to identify pre-treatment connectomic features that were correlated with reduction of PTSD severity from pretreatment to post treatment. We formed a composite metric of intrinsic connections associated with therapeutic outcome, and then interrogated this composite metric to determine if it distinguished PTSD treatment responders and nonresponders from healthy control status and changed post treatment. Lower pre-treatment connectivity for the cingulo-opercular, salience, default mode, dorsal attention, and frontoparietal executive control brain networks was associated with treatment improvement. Treatment responders had lower while nonresponders had significantly greater connectivity than controls at pretreatment. With therapy, connectivity significantly increased for responders and decreased for nonresponders, while controls remain unchanged over this time period. We provide evidence that the intrinsic functional architecture of the brain, specifically connectivity within and between brain networks associated with external vigilance, self-awareness, and cognitive control, may characterize a positive response to TF-CBT for PTSD.

Although it is well documented that exposure to severe, cumulative trauma and postdisplacement stress increases the risk for posttraumatic stress symptom disorder (PTSD), less is known about the representation and predictors of complex PTSD (CPTSD) symptoms in refugee populations. We examined PTSD and CPTSD symptom profiles (co-occurring PTSD and disturbances in self-organization [DSO] symptoms) and their premigration, postmigration, and demographic predictors, using latent class analysis (LCA), in a cohort of 112 refugees resettled in Australia. The LCA identified a four-factor model as the best fit to the data, comprising classes categorized as: (a) CPTSD, exhibiting high levels of PTSD and DSO symptoms (29.5%); (b) PTSD only (23.5%); (c) high affective dysregulation (AD) symptoms (31.9%); and (d) low PTSD and DSO symptoms (15.1%). Membership in the CPTSD and PTSD classes was specifically associated with cumulative traumatization, CPTSD OR = 1.56, 95% CI [1.15, 2.12], and PTSD OR = 1.64, 95% CI [1.15, 2.34]; and female gender, CPTSD OR = 14.18, 95% CI [1.66, 121.29], and PTSD OR = 16.84, 95% CI [1.78, 159.2], relative to the low-symptom class. Moreover, CPTSD and AD class membership was significantly predicted by insecure visa status, CPTSD OR = 7.53, 95% CI [1.26, 45.08], and AD OR = 7.19, 95% CI [1.23, 42.05]. These findings are consistent with the ICD-11 model of CPTSD and highlight the contributions of cumulative trauma to CPTSD and PTSD profiles as well as of contextual stress from visa uncertainty to DSO symptom profiles in refugee cohorts, particularly those characterized by AD.

In this review, we describe the sex differences in prevalence, onset, symptom profiles, and disease outcome that are evident in schizophrenia, bipolar disorder, and post-traumatic stress disorder. Women with schizophrenia tend to exhibit less disease impairment than men. By contrast, women with post-traumatic stress disorder are more affected than men. The most likely candidates to explain these sex differences are gonadal hormones. This review details the clinical evidence that oestradiol and progesterone are dysregulated in these psychiatric disorders. Notably, existing data on oestradiol, and to a lesser extent, progesterone, suggest that low levels of these hormones may increase the risk of disease development and worsen symptom severity. We argue that future studies require a more inclusive, considered analysis of gonadal steroid hormones and the intricacies of the interactions between them, with methodological rigour applied, to enhance our understanding of the roles of steroid hormones in psychiatric disorders. LINKED ARTICLES: This article is part of a themed section on The Importance of Sex Differences in Pharmacology Research. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.21/issuetoc.

AIMS: Despite the frequency that refugees suffer bereavement, there is a dearth of research into the prevalence and predictors of problematic grief reactions in refugees. To address this gap, this study reports a nationally representative population-based study of refugees to determine the prevalence of probable prolonged grief disorder (PGD) and its associated problems. METHODS: This study recruited participants from the Building a New Life in Australia (BNLA) prospective cohort study of refugees admitted to Australia between October 2013 and February 2014. The current data were collected in 2015-2016, and comprised 1767 adults, as well as 411 children of the adult respondents. Adult refugees were assessed for trauma history, post-migration difficulties, probable PGD, post-traumatic stress disorder (PTSD) and mental illness. Children were administered the Strengths and Difficulties Questionnaire. RESULTS: In this cohort, 38.1% of refugees reported bereavement, of whom 15.8% reported probable PGD; this represents 6.0% of the entire cohort. Probable PGD was associated with a greater likelihood of mental illness, probable PTSD, severe mental illness, currently unemployed and reported disability. Children of refugees with probable PGD reported more psychological difficulties than those whose parents did not have probable PGD. Probable PGD was also associated with the history of imprisonment, torture and separation from family. Only 56.3% of refugees with probable PGD had received psychological assistance. CONCLUSIONS: Bereavement and probable PGD appear highly prevalent in refugees, and PGD seems to be associated with disability in the refugees and psychological problems in their children. The low rate of access to mental health assistance for these refugees highlights that there is a need to address this issue in refugee populations.

OBJECTIVE: The number of refugees worldwide is unprecedented in recent history. Little is known, however, about profiles of psychological symptoms following persecution and displacement. METHODS: This study reports on a latent class analysis that identified profiles of posttraumatic stress disorder (PTSD), depression and anxiety symptoms in a nationally representative sample of 1625 refugees in Australia. The association between specific symptom profiles, exposure to potentially traumatic events and post-migration stressors, and overall health and help-seeking was examined. RESULTS: Latent class analysis yielded an optimal five-class solution. These classes comprised the Pervasive Symptom class (19.2%), the High PTSD Symptom class (17.1%), the High Depression/Anxiety Symptom class (16.4%), the Moderate PTSD Symptom class (16.2%) and the Low Symptom class (31.1%). Participants in the symptomatic classes were more likely to be female, older and report greater post-migration stressors than those in the Low Symptom class. In addition, individuals in classes characterized by PTSD symptoms had been exposed to more types of potentially traumatic events. Membership in symptomatic classes was associated with poorer overall heath and greater help-seeking. CONCLUSION: Qualitatively distinct symptom profiles were observed in a nationally representative sample of refugees. In addition to a group of people who reported high symptoms across psychological disorders and may warrant clinical intervention, we identified two subclinical classes who may be missed by existing diagnostic classification systems. Post-migration stressors play an important role in influencing refugee symptom profiles over and above exposure to potentially traumatic events. Clinicians should consider specific symptom profiles and contextual factors when planning interventions with refugees.

BACKGROUND: A key mechanism thought to underlie Posttraumatic Stress Disorder (PTSD) is enhanced emotional memory consolidation. Recent evidence in healthy controls revealed that women have greater negative memory consolidation following stress relative to men. This study examined emotional memory consolidation in women and men with PTSD, and in trauma-exposed and non-trauma controls to test the hypothesis that emotionally negative memory consolidation would be greater in women with PTSD. METHOD: One hundred and forty-seven men and women (47 with PTSD, 49 trauma-exposed controls, and 51 non-trauma controls) completed an emotional memory task where they looked at negative, neutral and positive images from the International Affective Picture System (IAPS). Delayed recall and an intrusive memory diary were completed two days later. RESULTS: Women displayed greater recall, and reported more negative intrusive memories than men. A gender x group interaction effect showed that both women with PTSD and trauma-exposed women reported more intrusive memories than women without trauma exposure or men. CONCLUSION: This study provided preliminary evidence of sex differences in intrusive memories in those with PTSD as well as those with a history of trauma exposure. Future research should include measures of sex hormones to further examine sex differences on memory consolidation in the context of trauma exposure and PTSD.

Cognitive deficits in Posttraumatic Stress Disorder (PTSD) and dissociative symptoms suggest there may be an underlying and persistent problem with temporal processing in PTSD, but this question has not been systematically examined. We investigated the ability of a group of PTSD participants in estimating the duration of supra-second visual stimuli relative to healthy controls. The data of 59 participants with PTSD and 62 healthy controls, collected from the BRID database, have been examined. Overall, our results indicate that PTSD patients overestimate the duration of the displayed stimuli. Moreover, we found that PTSD are more variable in the time estimation compared to the control group. Finally, we found evidence that working memory and attention impairments were associated with time overestimation in PTSD. The finding of time overestimation in PTSD accords with previous reports of time overestimation during stressful experiences associated with fear and arousal, but extends findings to suggest it remains in chronic PTSD populations processing non-emotional stimuli. The evidence of time overestimation in PTSD suggests the potential relevance of this factor as a cognitive marker in assessing the neuropsychological profile of this clinical population.

The S allele of the functional 5-HTTLPR polymorphism has previously been associated with reductions in memory function. Given the change in function of the serotonergic system in older adults, and the functional consequences of memory decline in this age group, further investigation into the impact of 5-HTTLPR in healthy older adults is required. This investigation examined the effect of 5-HTTLPR variants (S carriers versus L/L homozygotes) on verbal and visual episodic memory in 438 healthy older adults participating in the Tasmanian Healthy Brain Project (age range 50-79 years, M=60.35, s.d.=6.75). Direct effects of 5-HTTLPR on memory processes, in addition to indirect effects through interaction with age and gender, were assessed. Although no direct effects of 5-HTTLPR on memory processes were identified, our results indicated that gender significantly moderated the impact that 5-HTTLPR variants exerted on the relationship between age and verbal episodic memory function as assessed by the Rey Auditory Verbal Learning Test. No significant direct or indirect effects were identified in relation to visual memory performance. Overall, this investigation found evidence to suggest that 5-HTTLPR genotype affects the association of age and verbal episodic memory for males and females differently, with the predicted negative effect of S carriage present in males but not females. Such findings indicate a gender-dependent role for 5-HTTLPR in the verbal episodic memory system of healthy older adults.

The FKBP5 polymorphism is a key regulator of the glucocorticoid system underpinning stress responsivity, and risk alleles can increase vulnerability for developing posttraumatic stress disorder. To delineate the specific role of FKBP5 risk alleles unencumbered by the confounds of psychopathology, this study investigated whether high-risk alleles of the FKBP5 polymorphism are characterized by distinctive neural activity during resting state. Thirty-seven healthy participants were selected on the basis of four SNPs in the FKBP5 gene region (rs3800373, rs9296158, rs1360780 and rs9470080) to determine participants who were carriers of the FKBP5 high- and low-risk alleles. Spatial maps, power spectra and connectivity in neural networks active during resting state were assessed with functional magnetic resonance imaging (fMRI). During resting-state fMRI, FKBP5 low-risk allele group displayed more power in the low frequency range (<0.1 Hz) than the high-risk allele group, who had significantly more power in higher frequency bins (>0.15 Hz). This difference was apparent only in a frontotemporoparietal network underpinning salience detection and emotion processing. This study provides initial evidence that the risk alleles of the FKBP5 polymorphism are associated with different resting-state activity in a frontotemporal-parietal network, and may point to mechanisms underpinning high-risk carriers' vulnerability to severe stress reactions.

BACKGROUND: Prior research has demonstrated that time-of-day may play an important role in the extinction of conditioned fear, with extinction better learned earlier in the day rather than later. Impaired fear extinction memory is widely considered a key mechanism of posttraumatic stress disorder (PTSD). The relationship between fear extinction and PTSD symptoms may be moderated by hours-since-waking. METHOD: In the present experiment, we examined whether hours-since-waking would moderate fear extinction learning ability in a clinical PTSD sample (n = 15), compared to trauma-exposed (n = 33) and nonexposed controls (n = 22). Participants completed a standardized differential fear conditioning and extinction paradigm, providing skin conductance response measures to quantify conditioned responding. RESULTS: Mixed-model analysis of variance revealed a PTSD-specific impairment in extinction learning ability in the late extinction phase. A moderation analysis showed that hours-since-waking was a significant moderator of the relationship between impaired late extinction and PTSD symptoms. Specifically, we found that participants with higher PTSD symptoms demonstrated poorer fear extinction learning ability as they were awake for longer. CONCLUSIONS: The results of the current study add to a growing literature indicating deficits in fear extinction learning in PTSD samples, compared to trauma-exposed and nonexposed controls. These results support previous findings that fear extinction is impaired later in the day, and extends this to a clinical sample, suggesting that exposure-therapy may be optimized by scheduling sessions in the morning.

Differences in self-orientation (or "self-construal") may affect how the visual environment is attended, but the neural and cultural mechanisms that drive this remain unclear. Behavioral studies have demonstrated that people from Western backgrounds with predominant individualistic values are perceptually biased towards local-level information; whereas people from non-Western backgrounds that support collectivist values are preferentially focused on contextual and global-level information. In this study, we compared two groups differing in predominant individualistic (N = 15) vs collectivistic (N = 15) self-orientation. Participants completed a global/local perceptual conflict task whilst undergoing functional Magnetic Resonance Imaging (fMRI) scanning. When participants high in individualistic values attended to the global level (ignoring the local level), greater activity was observed in the frontoparietal and cingulo-opercular networks that underpin attentional control, compared to the match (congruent) baseline. Participants high in collectivistic values activated similar attentional control networks o only when directly compared with global processing. This suggests that global interference was stronger than local interference in the conflict task in the collectivistic group. Both groups showed increased activity in dorsolateral prefrontal regions involved in resolving perceptual conflict during heightened distractor interference. The findings suggest that self-orientation may play an important role in driving attention networks to facilitate interaction with the visual environment.

There has been a growing recognition of the importance of reward processing in PTSD, yet little is known of the underlying neural networks. This study tested the predictions that (1) individuals with PTSD would display reduced responses to happy facial expressions in ventral striatal reward networks, and (2) that this reduction would be associated with emotional numbing symptoms. 23 treatment-seeking patients with Posttraumatic Stress Disorder were recruited from the treatment clinic at the Centre for Traumatic Stress Studies, Westmead Hospital, and 20 trauma-exposed controls were recruited from a community sample. We examined functional magnetic resonance imaging responses during the presentation of happy and neutral facial expressions in a passive viewing task. PTSD participants rated happy facial expression as less intense than trauma-exposed controls. Relative to controls, PTSD participants revealed lower activation to happy (-neutral) faces in ventral striatum and and a trend for reduced activation in left amygdala. A significant negative correlation was found between emotional numbing symptoms in PTSD and right ventral striatal regions after controlling for depression, anxiety and PTSD severity. This study provides initial evidence that individuals with PTSD have lower reactivity to happy facial expressions, and that lower activation in ventral striatal-limbic reward networks may be associated with symptoms of emotional numbing.

BACKGROUND: Predominant dissociation in posttraumatic stress disorder (PTSD) is characterized by restricted affective responses to positive stimuli. To date, no studies have examined neural responses to a range of emotional expressions in PTSD with high dissociative symptoms. OBJECTIVE: This study tested the hypothesis that PTSD patients with high dissociative symptoms will display increased event-related potential (ERP) amplitudes in early components (N1, P1) to threatening faces (angry, fearful), and reduced later ERP amplitudes (Vertex Positive Potential (VPP), P3) to happy faces compared to PTSD patients with low dissociative symptoms. METHODS: Thirty-nine civilians with PTSD were classified as high dissociative (n=16) or low dissociative (n=23) according to their responses on the Clinician Administered Dissociative States Scale. ERPs were recorded, whilst participants viewed emotional (happy, angry, fear) and neutral facial expressions in a passive viewing task. RESULTS: High dissociative PTSD patients displayed significantly increased N120 amplitude to the majority of facial expressions (neutral, happy, and angry) compared to low dissociative PTSD patients under conscious and preconscious conditions. The high dissociative PTSD group had significantly reduced VPP amplitude to happy faces in the conscious condition. CONCLUSION: High dissociative PTSD patients displayed increased early (preconscious) cortical responses to emotional stimuli, and specific reductions to happy facial expressions in later (conscious), face-specific components compared to low dissociative PTSD patients. Dissociation in PTSD may act to increase initial pre-attentive processing of affective stimuli, and specifically reduce cortical reactivity to happy faces when consciously processing these stimuli.

Intrusive memories are a common feature of many psychological disorders. Recent evidence has potentially extended cognitive models of intrusions by identifying the role of biological markers of arousal at the time of consolidation in subsequent memory for emotional events. This study investigated the role of arousal during consolidation in the development of intrusive memories. Seventy-eight university students (37 men and 41 women) viewed 20 negative and 20 neutral images. Half the participants then underwent a cold pressor test (High Stress), immersing their hand in ice water, while the remaining participants immersed their hand in warm water (Low Stress). Samples of salivary alpha-amylase (sAA) and cortisol were collected from participants at baseline and following the stressor challenge. Participants completed a delayed free recall test and intrusion questionnaires two days later. Participants in the High Stress condition reported more intrusions of negative images than participants in the Low Stress condition. An interaction variable in a linear regression of increased noradrenergic and cortisol values predicted intrusive memories of emotional stimuli for men but not women. These findings are consistent with recent evidence of the combined effects of noradrenaline and corticoid responses to stress on emotional memories, and also with increasing evidence of gender differences in how stress hormones influence formation of emotional memories. These findings point to possible mechanisms by which development of intrusions may be prevented after consolidation of traumatic experiences.

Difficulties in emotion regulation have been implicated as a potential mechanism underlying anxiety and mood disorders. It is possible that sex differences in emotion regulation may contribute towards the heightened female prevalence for these disorders. Previous fMRI studies of sex differences in emotion regulation have shown mixed results, possibly due to difficulties in discriminating the component processes of early emotional reactivity and emotion regulation. The present study used event-related potentials (ERPs) to examine sex differences in N1 and N2 components (reflecting early emotional reactivity) and P3 and LPP components (reflecting emotion regulation). N1, N2, P3, and LPP were recorded from 20 men and 23 women who were instructed to "increase," "decrease," and "maintain" their emotional response during passive viewing of negative images. Results indicated that women had significantly greater N1 and N2 amplitudes (reflecting early emotional reactivity) to negative stimuli than men, supporting a female negativity bias. LPP amplitudes increased to the "increase" instruction, and women displayed greater LPP amplitudes than men to the "increase" instruction. There were no differences to the "decrease" instruction in women or men. These findings confirm predictions of the female negativity bias hypothesis and suggest that women have greater up-regulation of emotional responses to negative stimuli. This finding is highly significant in light of the female vulnerability for developing anxiety disorders.

CONTEXT: There is evidence that heart rate variability (HRV) is reduced in major depressive disorder (MDD), although there is debate about whether this effect is caused by medication or the disorder per se. MDD is associated with a two to fourfold increase in the risk of cardiac mortality, and HRV is a robust predictor of cardiac mortality; determining a direct link between HRV and not only MDD, but common comorbid anxiety disorders, will point to psychiatric indicators for cardiovascular risk reduction. OBJECTIVE: To determine in physically healthy, unmedicated patients whether (1) HRV is reduced in MDD relative to controls, and (2) HRV reductions are driven by MDD alone, comorbid generalized anxiety disorder (GAD, characterized by anxious anticipation), or comorbid panic and posttraumatic stress disorders (PD/PTSD, characterized by anxious arousal). DESIGN, SETTING, AND PATIENTS: A case-control study in 2006 and 2007 on 73 MDD patients, including 24 without anxiety comorbidity, 24 with GAD, and 14 with PD/PTSD. Seventy-three MDD and 94 healthy age- and sex-matched control participants were recruited from the general community. Participants had no history of drug addiction, alcoholism, brain injury, loss of consciousness, stroke, neurological disorder, or serious medical conditions. There were no significant differences between the four groups in age, gender, BMI, or alcohol use. MAIN OUTCOME MEASURES: HRV was calculated from electrocardiography under a standardized short-term resting state condition. RESULTS: HRV was reduced in MDD relative to controls, an effect associated with a medium effect size. MDD participants with comorbid generalized anxiety disorder displayed the greatest reductions in HRV relative to controls, an effect associated with a large effect size. CONCLUSIONS: Unmedicated, physically healthy MDD patients with and without comorbid anxiety had reduced HRV. Those with comorbid GAD showed the greatest reductions. Implications for cardiovascular ris

An epistatic interaction of 5-HTTLPR and BDNF Val66Met polymorphisms has been implicated in the structure of rostral anterior cingulate cortex (rACC) and amygdala (AMY): key regions associated with emotion processing. However, a functional epistasis of 5-HTTLPR and BDNF Val66Met on overt emotion processing has yet to be determined. Twenty-eight healthy, Caucasian female participants provided saliva samples for genotyping and underwent functional magnetic resonance imaging (fMRI) during which an emotion processing protocol were presented. Confirming the validity of this protocol, we observed blood oxygen level-dependent (BOLD) activity consistent with fMRI meta-analyses on emotion processing. Region-of-interest analysis of the rACC and AMY revealed main effects of 5-HTTLPR and BDNF Val66Met, and an interaction of 5-HTTLPR and BDNF Val66Met. The effect of the BDNF Met66 allele was dependent on 5-HTTLPR alleles, such that participants with S and Met alleles had the greatest rACC and AMY activation during the presentation of emotional images relative to other genetic groupings. Increased activity in these regions was interpreted as increased reactivity to emotional stimuli, suggesting that those with S and Met alleles are more reactive to emotional stimuli relative to other groups. Although limited by a small sample, this study contributes novel and preliminary findings relating to a functional epistasis of the 5-HTTLPR and BDNF Val66Met genes in emotion processing and provides guidance on appropriate methods to determine genetic epistasis in fMRI.