Long-term risk for mental health symptoms in Dutch ISAF veterans: the role of perceived social support.

BACKGROUND: Military personnel deployed to combat and peacekeeping missions are exposed to high rates of traumatic events. Accumulating evidence suggests an important association between deployment and the development of other mental health symptoms beyond post-traumatic stress disorder. METHODS: This study examined the prevalence of agoraphobia, anxiety, depression, and hostility symptoms in a cohort of Dutch ISAF veterans (N = 978) from pre-deployment up to 10 years after homecoming. The interaction of potential moderating factors with the change in mental health symptoms relative to pre-deployment was investigated at each time point. RESULTS: The probable prevalence of agoraphobia, anxiety, depression, and hostility symptoms significantly increased over time to respectively 6.5, 2.7, 3.5, and 6.2% at 10 years after deployment. Except for hostility symptoms, the probable prevalence at 10 years after deployment was the highest compared to all previous follow-up assessments. Importantly, less perceived social support after returning from deployment was found as a risk factor for all different mental health symptoms. Unit support was not associated with the development of mental health problems. CONCLUSIONS: This study suggests a probable broad and long-term impact of deployment on the mental health of military service members. Due to the lack of a non-deployed control group, causal effects of deployment could not be demonstrated. Continued effort should nevertheless be made in the diagnosis and treatment of a wide range of mental health symptoms, even a decade after deployment. The findings also underscore the importance of social support after homecoming and its potential for the prevention of long-term mental health problems.

Epigenome-wide meta-analysis of PTSD symptom severity in three military cohorts implicates DNA methylation changes in genes involved in immune system and oxidative stress.

Epigenetic factors modify the effects of environmental factors on biological outcomes. Identification of epigenetic changes that associate with PTSD is therefore a crucial step in deciphering mechanisms of risk and resilience. In this study, our goal is to identify epigenetic signatures associated with PTSD symptom severity (PTSS) and changes in PTSS over time, using whole blood DNA methylation (DNAm) data (MethylationEPIC BeadChip) of military personnel prior to and following combat deployment. A total of 429 subjects (858 samples across 2 time points) from three male military cohorts were included in the analyses. We conducted two different meta-analyses to answer two different scientific questions: one to identify a DNAm profile of PTSS using a random effects model including both time points for each subject, and the other to identify a DNAm profile of change in PTSS conditioned on pre-deployment DNAm. Four CpGs near four genes (F2R, CNPY2, BAIAP2L1, and TBXAS1) and 88 differentially methylated regions (DMRs) were associated with PTSS. Change in PTSS after deployment was associated with 15 DMRs, of those 2 DMRs near OTUD5 and ELF4 were also associated with PTSS. Notably, three PTSS-associated CpGs near F2R, BAIAP2L1 and TBXAS1 also showed nominal evidence of association with change in PTSS. This study, which identifies PTSD-associated changes in genes involved in oxidative stress and immune system, provides novel evidence that epigenetic differences are associated with PTSS.

Toward staging differentiation for posttraumatic stress disorder treatment.

OBJECTIVES: Several medical and psychiatric disorders have stage-based treatment decision-making methods. However, international treatment guidelines for posttraumatic stress disorder (PTSD) fail to give specific treatment recommendations based on chronicity or stage of the disorder. There is convincing evidence of a finite range of PTSD symptom trajectories, implying that different phenotypes of the disorder can be distinguished, which are highly relevant for a staging typology of PTSD. METHODS: State-of-the-art review building on prior work on staging models in other disorders as a mapping tool to identify and synthesize toward PTSD. RESULTS: We propose a four-stage model of PTSD ranging from stage 0: trauma-exposed asymptomatic but at risk to stage 4: severe unremitting illness of increasing chronicity. We favor a symptom description in various chronological characteristics based on neurobiological markers, information processing systems, stress reactivity, and consciousness dimensions. We also advocate for a separate phenomenology of treatment resistance since this can yield treatment recommendations. CONCLUSION: A staging perspective in the field of PTSD is highly needed. This can facilitate the selection of interventions that are proportionate to patients' current needs and risk of illness progression and can also contribute to an efficient framework to organize biomarker data and guide service delivery. Therefore, we propose that a neurobiologically driven trajectory-based typology of PTSD can help deduct several treatment recommendations leading to a more personalized and refined grid to strategize, plan and evaluate treatment interventions.

Risk and resilience in trajectories of post-traumatic stress symptoms among first responders after the 2011 Great East Japan Earthquake: 7-year prospective cohort study.

BACKGROUND: First responders to disasters are at risk of developing post-traumatic stress disorder (PTSD). The trajectories of post-traumatic stress symptom severity differ among individuals, even if they are exposed to similar events. These trajectories have not yet been reported in non-Western first responders. AIMS: We aimed to explore post-traumatic stress symptom severity trajectories and their risk factors in first responders to the 2011 Great East Japan Earthquake (GEJE) - a historically large earthquake that resulted in a tsunami and a nuclear disaster. METHOD: A total of 55 632 Japan Ground Self-Defense Force (JGSDF) personnel dispatched to the GEJE were enrolled in this 7-year longitudinal cohort study. PTSD symptom severity was measured using the Impact of Event Scale-Revised. Trajectories were identified using latent growth mixture models (LGMM). Nine potential risk factors for the symptom severity trajectories were analysed using multinomial logistic regression. RESULTS: Five symptom severity trajectories were identified: 'resilient' (54.8%), 'recovery' (24.6%), 'incomplete recovery' (10.7%), 'late-onset' (5.7%), and 'chronic' (4.3%). The main risk factors for the four non-resilient trajectories were older age, personal disaster experiences and working conditions. These working conditions included duties involving body recovery or radiation exposure risk, longer deployment length, later or no post-deployment leave and longer post-deployment overtime. CONCLUSIONS: The majority of first responders to GEJE were resilient and developed few or no PTSD symptoms. A substantial minority experienced late-onset and chronic symptom severity trajectories. The identified risk factors can inform policies for prevention, early detection and intervention in individuals at risk of developing symptomatic trajectories.

Successful treatment of post-traumatic stress disorder reverses DNA methylation marks.

Epigenetic mechanisms play a role in the detrimental effects of traumatic stress and the development of post-traumatic stress disorder (PTSD). However, it is unknown whether successful treatment of PTSD restores these epigenetic marks. This study investigated longitudinal changes of blood-based genome-wide DNA methylation levels in relation to trauma-focused psychotherapy for PTSD in soldiers that obtained remission (N = 21), non-remitted PTSD patients (N = 23), and trauma-exposed military controls (N = 23). In an independent prospective cohort, we then examined whether these DMRs were also relevant for the development of deployment-related PTSD (N = 85). Successful treatment of PTSD was accompanied by significant changes in DNA methylation at 12 differentially methylated regions (DMRs) in the genes: APOB, MUC4, EDN2, ZFP57, GPX6, CFAP45, AFF3, TP73, UBCLP1, RPL13P, and two intergenic regions (p values < 0.0001 were confirmed using permutation and sensitivity analyses). Of the 12 DMRs related to PTSD symptom reduction, consistent prospective evidence was found for ZFP57 methylation changes related to changing PTSD symptoms (B = -0.84, t = -2.49, p = 0.014). Increasing ZFP57 methylation related to PTSD symptom reduction was present over and above the relation with symptoms, suggesting that psychological treatments exert biological effects independent of symptom reduction. Together, these data provide longitudinal evidence that ZFP57 methylation is involved in both the development and successful treatment of deployment-related PTSD. This study is a first step to disentangle the interaction between psychological and biological systems to identify genomic regions relevant for the etiology and treatment of stress-related disorders such as PTSD.

A systematic scoping review of dissociation in borderline personality disorder and implications for research and clinical practice: Exploring the fog.

BACKGROUND: Borderline Personality Disorder (BPD) is frequently complicated by the presence of dissociative symptoms. Pathological dissociation is linked with earlier and more severe trauma exposure, emotional dysregulation and worse treatment outcomes in Posttraumatic Stress Disorder and Dissociative Disorders, with implications for BPD. OBJECTIVE: A systematic scoping review was conducted to assess the extent of current literature regarding the impact of dissociation on BPD and to identify knowledge gaps. METHODS: Four electronic databases (MEDLINE, APA PsycINFO, EMBASE, CINAHL Plus) were searched, and English peer-reviewed studies with adults with BPD were included, following Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA) extension for scoping reviews (PRISMA-ScR) 2018 guidelines. RESULTS: Most of the 70 included studies were observational (98%) with first authors from Germany (59%). Overall, dissociation was associated with increased BPD symptom severity, self-harm and reduced psychotherapy treatment response; findings regarding suicide risk were mixed. Dissociation was associated with working memory and cognitive deficits, decreased pain perception, altered body ownership, no substance abuse or the abuse of sedative substances, increased fantasy proneness, personality fragmentation, fearful attachment, dream anxiety, perceived stress and altered stress responses, increased cumulative body mass index, decreased water consumption, several neurological correlates and changes in gene expression. CONCLUSION: BPD with significant dissociative symptoms may constitute a more severe and at-risk subgroup of BPD patients. However, there are significant research gaps and methodological issues in the area, including the possibility of unrecognized Dissociative Disorders in BPD study populations confounding results. Further studies are needed to better understand the impact of dissociation on BPD course and treatment, and to clarify the most appropriate assessment tools for clinical practice. In addition, interventional studies are needed to develop dissociation-specific BPD treatments to determine whether targeting dissociation in BPD can improve treatment outcomes.

Correction: MicroRNA regulation of persistent stress-enhanced memory.

A correction to this paper has been published and can be accessed via a link at the top of the paper.

MicroRNA regulation of persistent stress-enhanced memory.

Disruption of persistent, stress-associated memories is relevant for treating posttraumatic stress disorder (PTSD) and related syndromes, which develop in a subset of individuals following a traumatic event. We previously developed a stress-enhanced fear learning (SEFL) paradigm in inbred mice that produces PTSD-like characteristics in a subset of mice, including persistently enhanced memory and heightened cFos in the basolateral amygdala complex (BLC) with retrieval of the remote (30-day-old) stress memory. Here, the contribution of BLC microRNAs (miRNAs) to stress-enhanced memory was investigated because of the molecular complexity they achieve through their ability to regulate multiple targets simultaneously. We performed small-RNA sequencing (smRNA-Seq) and quantitative proteomics on BLC tissue collected from mice 1 month after SEFL and identified persistently changed microRNAs, including mir-135b-5p, and proteins associated with PTSD-like heightened fear expression. Viral-mediated overexpression of mir-135b-5p in the BLC of stress-resilient animals enhanced remote fear memory expression and promoted spontaneous renewal 14 days after extinction. Conversely, inhibition of BLC mir-135b-5p in stress-susceptible animals had the opposite effect, promoting a resilient-like phenotype. mir-135b-5p is highly conserved across mammals and was detected in post mortem human amygdala, as well as human serum samples. The mir-135b passenger strand, mir-135b-3p, was significantly elevated in serum from PTSD military veterans, relative to combat-exposed control subjects. Thus, miR-135b-5p may be an important therapeutic target for dampening persistent, stress-enhanced memory and its passenger strand a potential biomarker for responsivity to a mir-135-based therapeutic.

Sleep Quality Improvements After MDMA-Assisted Psychotherapy for the Treatment of Posttraumatic Stress Disorder.

Sleep disturbances (SDs) are among the most distressing and commonly reported symptoms in posttraumatic stress disorder (PTSD). Despite increased attention on sleep in clinical PTSD research, SDs remain difficult to treat. In Phase 2 trials, 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy has been shown to greatly improve PTSD symptoms. We hypothesized that MDMA-assisted psychotherapy would improve self-reported sleep quality (SQ) in individuals with PTSD and be associated with declining PTSD symptoms. Participants in four studies (n = 63) were randomized to receive 2-3 sessions of active MDMA (75-125 mg; n = 47) or placebo/control MDMA (0-40 mg, n = 16) during all-day psychotherapy sessions. The PSQI was used to assess change in SQ from baseline to the primary endpoint, 1-2 months after the blinded sessions. Additionally, PSQI scores were measured at treatment exit (TE) and 12-month follow-up. Symptoms of PTSD were measured using the CAPS-IV. At the primary endpoint, CAPS-IV total severity scores dropped more after active MDMA than after placebo/control (-34.0 vs. -12.4), p = .003. Participants in the active dose group showed more improvement in SQ compared to those in the control group (PSQI total score ΔM = -3.5 vs. 0.6), p = .003. Compared to baseline, SQ had improved at TE, p < .001, with further significant gains reported at 12-month follow-up (TE to 12-months ΔM = -1.0), p = .030. Data from these randomized controlled double-blind studies provide evidence for the beneficial effects of MDMA-assisted psychotherapy in treating SDs in individuals with PTSD.

Testing the applicability of a virtual reality simulation platform for stress training of first responders.

The current study explores whether different stressors in a virtual reality (VR) military training scenario cause increases in physiological stress. This would validate the use of VR simulation for stress training, as well as the physiological monitoring of trainees for educational purposes. Military cadets (n = 63) performed a patrol scenario (military convoy) in which they answered questions about their surroundings. Stressors (task difficulty, noise, lighting changes, social evaluations, electric muscle stimulation, and a simulated attack on the convoy) were stepwise added in four phases. Electrocardiogram, blood pressure, electrodermal activity, cortisol, and the cadets' subjective threat/challenge appraisal were measured. We found that only the first phase caused a significant increase in physiological stress, as measured with heart rate, heart rate variability, and electrodermal activity. Physiological stress appeared to stay high in the second phase as well, but decreased to baseline level in the third and fourth phases, even though these phases were designed to be the most stressful. Cadets classified as threat responders based on physiological data (n = 3) scored significantly higher on subjective threat/challenge appraisal than those classified as challenge responders (n = 21). It seems that in the tested VR training scenario, the novelty of the scenario was the only effective stress stimuli, whereas the other implemented stressors did not cause a measurable physiological response. We conclude that if VR training scenarios are to be used for stress training, these should confront trainees with unpredictable but context-specific demands.

Reviewing the Potential of Psychedelics for the Treatment of PTSD.

There are few medications with demonstrated efficacy for the treatment of posttraumatic stress disorder (PTSD). Treatment guidelines have unequivocally designated psychotherapy as a first line treatment for PTSD. Yet, even after psychotherapy, PTSD often remains a chronic illness, with high rates of psychiatric and medical comorbidity. Meanwhile, the search for and development of drugs with new mechanisms of action has stalled. Therefore, there is an urgent need to explore not just novel compounds but novel approaches for the treatment of PTSD. A promising new approach involves the use of psychedelic drugs. Within the past few years, 2 psychedelics have received breakthrough designations for psychiatric indications from the US Food and Drug Administration, and several psychedelics are currently being investigated for the treatment of PTSD. This review discusses 4 types of compounds: 3,4-methylenedioxymethamphetamine, ketamine, classical psychedelics (e.g., psilocybin and lysergic acid diethylamide), and cannabinoids. We describe the therapeutic rationale, the setting in which they are being administered, and their current state of evidence in the treatment of PTSD. Each compound provides unique qualities for the treatment of PTSD, from their use to rapidly target symptoms to their use as adjuncts to facilitate psychotherapeutic treatments. Several questions are formulated that outline an agenda for future research.

Interactive Motion-Assisted Exposure Therapy for Veterans with Treatment-Resistant Posttraumatic Stress Disorder: A Randomized Controlled Trial.

BACKGROUND: Veterans with posttraumatic stress disorder (PTSD) tend to benefit less from evidence-based treatments than other PTSD populations. A novel virtual reality and motion-assisted exposure therapy, called 3MDR, provides treatment in an immersive, personalized and activating context. OBJECTIVE: To study the efficacy of 3MDR for veterans with treatment-resistant PTSD. METHOD: In a randomized controlled trial (n = 43) 3MDR was compared to a non-specific treatment component control group. Primary outcome was clinician-rated PTSD symptoms at baseline, after 3MDR, and at the 12-week and 16-week follow-up (primary end point). Intention-to-treat analyses of covariance and mixed models were applied to study differences between groups at the end point and over the course of intervention, controlling for baseline scores. RESULTS: The decrease in PTSD symptom severity from baseline to end point was significantly greater for 3MDR as compared to the control group, with a large effect size (F[1, 37] = 6.43, p = 0.016, d = 0.83). No significant between-group difference was detected in the course of PTSD symptoms during treatment when including all time points. The dropout rate was low (7%), and 45% of the patients in the 3MDR group improved clinically. The number needed to treat was 2.86. CONCLUSIONS: In this trial, 3MDR significantly decreased PTSD symptoms in veterans with, on average, a history of 4 unsuccessful treatments. The low dropout rate may be indicative of high engagement. However, a lack of significant differences on secondary outcomes limits conclusions that can be drawn on its efficacy and underlines the need for larger phase III trials. These data show emerging evidence for 3MDR and its potential to progress PTSD treatment for veterans (Dutch Trial Register Identifier: NL5126).

Cortical Thickness in Dutch Police Officers: An Examination of Factors Associated with Resilience.

Previous neuroimaging studies on resilience have generally compared resilience and psychopathology after stress exposure, which does not allow for conclusions regarding correlates specific to resilience. The aim of the present study was to investigate resilience-specific correlates in cortical thickness and/or cortical surface area and their correlations with psychometric measurements, using a three-group design that included a non-trauma-exposed control group in order to disentangle effects related to resilience from those related to psychopathology. Structural magnetic resonance imaging scans were acquired from 82 Dutch police officers. Participants were categorized into resilient (n = 31; trauma exposure, no psychopathology), vulnerable (n = 32; trauma exposure, psychopathology), and control groups (n = 19; no trauma exposure, no psychopathology). Specific regions of interest (ROIs) were identified based on previous studies that found the rostral and caudal anterior cingulate cortex (ACC) to be implicated in trauma-related psychopathology. Cortical thickness and surface area of the ROIs-the rostral and caudal ACC-and of the whole brain were examined. No significant differences in cortical thickness or surface area were found between the resilient group and other groups in the ROI and whole-brain analyses. Thus, the results of the present study provide no evidence of an association between resilience to traumatic stress and measures of thickness and surface area in cortical regions of the brain in a sample of Dutch police officers.

Exposure to combat and deployment; reviewing the military context in The Netherlands.

This paper reviews the military context of exposure to combat and deployment in Dutch soldiers. It does so by reviewing war victims and military psychiatry after WWII in the Netherlands, and describes Dutch deployments from the late 1970s to the present. 'Who is the Dutch soldier' is asked to articulate the mental load on the individual soldier before, during, and after deployment. The narrative review of this paper allows one to review how the armed forces personnel is challenged in relation to their specific assignment and in what respect the psychological dimensions are addressed and met in the face of risk and adversity. Finally, some critical considerations for future veterans care programmes are raised.

The Dissociative Subtype of PTSD Interview (DSP-I): Development and Psychometric Properties.

The inclusion of the dissociative subtype of post-traumatic stress disorder (PTSD-DS) in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) reflects the importance of assessing PTSD-DS. We developed the Dissociative Subtype of PTSD Interview (DSP-I). This clinician-administered instrument assesses the presence and severity of PTSD-DS (i.e., symptoms of depersonalization or derealization) and contains a supplementary checklist that enables assessment and differentiation of other trauma-related dissociative symptoms (i.e., blanking out, emotional numbing, alterations in sensory perception, amnesia, and identity confusion). The psychometric properties were tested in 131 treatment-seeking individuals with PTSD and histories of multiple trauma, 17.6 % of whom met criteria for PTSD-DS in accordance with the DSP-I. The checklist was tested in 275 treatment-seeking individuals. Results showed the DSP-I to have high internal consistency, good convergent validity with PTSD-DS items of the CAPS-5, and good divergent validity with scales of somatization, anxiety and depression. The depersonalization and derealization scales were highly associated. Moreover, the DSP-I accounted for an additional variance in PTSD severity scores of 8% over and above the CAPS-5 and number of traumatic experiences. The dissociative experiences of the checklist were more strongly associated with scales of overall distress, somatization, depression, and anxiety than scales of depersonalization and derealization. In conclusion, the DSP-I appears to be a clinically relevant and psychometrically sound instrument that is valuable for use in clinical and research settings.

A Review of the Neurobiological Basis of Trauma-Related Dissociation and Its Relation to Cannabinoid- and Opioid-Mediated Stress Response: a Transdiagnostic, Translational Approach.

Dissociative experiences have been associated with increased disease severity, chronicity, and, in some cases, reduced treatment response across trauma-related and other psychiatric disorders. A better understanding of the neurobiological mechanisms through which dissociative experiences occur may assist in identifying novel pharmacological and non-pharmacological treatment approaches. Here, we review emerging work on the dissociative subtype of posttraumatic stress disorder (PTSD), and other trauma-related disorders providing evidence for two related overarching neurobiological models of dissociation, the defense cascade model of dissociation and Mobb's threat detection model. In particular, we review neuroimaging studies highlighting alterations in functional connectivity of key brain regions associated with these models, including connectivity between the prefrontal cortex, the amygdala and its complexes, the insula, and the periaqueductal gray. Work implicating the kappa-opioid and endocannabinoid systems in trauma-related dissociative experiences is also reviewed. Finally, we hypothesize mechanisms by which pharmacological modulation of these neurochemical systems may serve as promising transdiagnostic treatment modalities for individuals experiencing clinically significant levels of dissociation. Specifically, whereas kappa-opioid receptor antagonists may serve as a pharmacological vehicle for the selective targeting of dissociative symptoms and associated emotion overmodulation in the dissociative subtype of posttraumatic stress disorder and transdiagnostically, modulation of the endocannabinoid system may reduce symptoms associated with emotional undermodulation of the fight or flight components of the defense cascade model.

No Effects of Successful Bidirectional SMR Feedback Training on Objective and Subjective Sleep in Healthy Subjects.

There is a growing interest in the application of psychophysiological signals in more applied settings. Unidirectional sensory motor rhythm-training (SMR) has demonstrated consistent effects on sleep. In this study the main aim was to analyze to what extent participants could gain voluntary control over sleep-related parameters and secondarily to assess possible influences of this training on sleep metrics. Bidirectional training of SMR as well as heart rate variability (HRV) was used to assess the feasibility of training these parameters as possible brain computer interfaces (BCI) signals, and assess effects normally associated with unidirectional SMR training such as the influence on objective and subjective sleep parameters. Participants (n = 26) received between 11 and 21 training sessions during 7 weeks in which they received feedback on their personalized threshold for either SMR or HRV activity, for both up- and down regulation. During a pre- and post-test a sleep log was kept and participants used a wrist actigraph. Participants were asked to take an afternoon nap on the first day at the testing facility. During napping, sleep spindles were assessed as well as self-reported sleep measures of the nap. Although the training demonstrated successful learning to increase and decrease SMR and HRV activity, no effects were found of bidirectional training on sleep spindles, actigraphy, sleep diaries, and self-reported sleep quality. As such it is concluded that bidirectional SMR and HRV training can be safely used as a BCI and participants were able to improve their control over physiological signals with bidirectional training, whereas the application of bidirectional SMR and HRV training did not lead to significant changes of sleep quality in this healthy population.

Posttraumatic Stress Disorder and Somatic Complaints in a Deployed Cohort of Georgian Military Personnel: Mediating Effect of Depression and Anxiety.

Several studies have shown the relationship between symptoms of posttraumatic stress disorder (PTSD), somatic symptoms, and the mediating effect of depression and anxiety. The following study was conducted to investigate the relationship between PTSD symptoms and somatic complaints through underlying symptoms of depression and anxiety. The participants of the study were 2,799 veterans who were examined after a 6-month deployment. They were assessed using the PTSD Checklist (PCL-5) and Patient Health Questionnaire (PHQ) for depression, anxiety, and somatic complaints. To check the indirect effect of PTSD on somatic complaints through depression and anxiety, mediation model 4 (parallel mediation) of the SPSS PROCESS macro was used. There was a significant total indirect effect of PTSD through depression and anxiety on somatic complaints, b = 0.14, 95% confidence interval (CI) [0.12, 0.16], from which an indirect effect of PTSD on somatic complaints through depression was b = 0.08, 95% CI [0.06, 0.10], and through anxiety it equaled b = 0.06, 95% CI [0.04, 0.07]. The ratio of indirect to total effect was 0.66, 95% CI [0.59, 0.75]. The present study helps us to understand the role of depression and anxiety symptoms when the symptoms of PTSD and somatic complaints are present. These new findings may have implications for the management as well as treatment of PTSD because they recognize the importance of symptoms of anxiety and depression when somatic complaints are present.

Epigenome-wide association of PTSD from heterogeneous cohorts with a common multi-site analysis pipeline.

Compelling evidence suggests that epigenetic mechanisms such as DNA methylation play a role in stress regulation and in the etiologic basis of stress related disorders such as Post traumatic Stress Disorder (PTSD). Here we describe the purpose and methods of an international consortium that was developed to study the role of epigenetics in PTSD. Inspired by the approach used in the Psychiatric Genomics Consortium, we brought together investigators representing seven cohorts with a collective sample size of N = 1147 that included detailed information on trauma exposure, PTSD symptoms, and genome-wide DNA methylation data. The objective of this consortium is to increase the analytical sample size by pooling data and combining expertise so that DNA methylation patterns associated with PTSD can be identified. Several quality control and analytical pipelines were evaluated for their control of genomic inflation and technical artifacts with a joint analysis procedure established to derive comparable data over the cohorts for meta-analysis. We propose methods to deal with ancestry population stratification and type I error inflation and discuss the advantages and disadvantages of applying robust error estimates. To evaluate our pipeline, we report results from an epigenome-wide association study (EWAS) of age, which is a well-characterized phenotype with known epigenetic associations. Overall, while EWAS are highly complex and subject to similar challenges as genome-wide association studies (GWAS), we demonstrate that an epigenetic meta-analysis with a relatively modest sample size can be well-powered to identify epigenetic associations. Our pipeline can be used as a framework for consortium efforts for EWAS.

Persistent and reversible consequences of combat stress on the mesofrontal circuit and cognition.

Prolonged stress can have long-lasting effects on cognition. Animal models suggest that deficits in executive functioning could result from alterations within the mesofrontal circuit. We investigated this hypothesis in soldiers before and after deployment to Afghanistan and a control group using functional and diffusion tensor imaging. Combat stress reduced midbrain activity and integrity, which was associated to compromised sustained attention. Long-term follow-up showed that the functional and structural changes had normalized within 1.5 y. In contrast, combat stress induced a persistent reduction in functional connectivity between the midbrain and prefrontal cortex. These results demonstrate that combat stress has adverse effects on the human mesofrontal circuit and suggests that these alterations are partially reversible.