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Background: Attention-deficit/hyperactivity disorder (ADHD) and posttraumatic stress disorder (PTSD) are associated, but it is unclear if this is a causal relationship or confounding. We used genetic analyses and sibling comparisons to clarify the direction of this relationship. Methods: Linkage disequilibrium score regression and 2-sample Mendelian randomization were used to test for genetic correlation (r g) and bidirectional causal effects using European ancestry genome-wide association studies of ADHD (20,183 cases and 35,191 controls) and 6 PTSD definitions (up to 320,369 individuals). Several additional variables were included in the analysis to verify the independence of the ADHD-PTSD relationship. In a population-based sibling comparison (N = 2,082,118 individuals), Cox regression models were fitted to account for time at risk, a range of sociodemographic factors, and unmeasured familial confounders (via sibling comparisons). Results: ADHD and PTSD had consistent r g (r g range, 0.43–0.52; p < .001). ADHD genetic liability was causally linked with increased risk for PTSD (β = 0.367; 95% CI, 0.186–0.552; p = 7.68 × 10 −5). This result was not affected by heterogeneity, horizontal pleiotropy (Mendelian randomization Egger intercept = 4.34 × 10 −4, p = .961), or other phenotypes and was consistent across PTSD datasets. However, we found no consistent associations between PTSD genetic liability and ADHD risk. Individuals diagnosed with ADHD were at a higher risk for developing PTSD than their undiagnosed sibling (hazard ratio = 2.37; 95% CI, 1.98–3.53). Conclusions: Our findings add novel evidence supporting the need for early and effective treatment of ADHD, as patients with this diagnosis are at significantly higher risk to develop PTSD later in life.

Anxiety sensitivity involves the fear of anxiety-related symptoms and can exacerbate both major depressive disorder and posttraumatic stress disorder (PTSD) symptoms. However, it is unclear if anxiety sensitivity plays a similar role in dissociative identity disorder (DID) where symptoms of depression and PTSD commonly co-occur. We examined the association between anxiety sensitivity, depression, PTSD and dissociative symptoms in DID, hypothesizing a positive association between all symptoms and anxiety sensitivity.Participants were 21 treatment-seeking adult females with histories of childhood trauma, current PTSD, and DID. Participants completed the Anxiety Sensitivity Index (ASI), Beck Depression Inventory-II, Childhood Trauma Questionnaire, Multidimensional Inventory of Dissociation, and PTSD Checklist for DSM-5. The ASI included subscales that assessed anxiety sensitivity in cognitive, physical, and social domains.Participants reported high levels of anxiety sensitivity. A multiple regression analysis demonstrated that the ASI cognitive subscale was the strongest predictor of depressive symptoms. No direct associations were identified between anxiety sensitivity and PTSD or dissociative symptoms. We conducted a mediation analysis to test an indirect relationship between cognitive anxiety sensitivity and dissociative symptoms, and found a significant indirect effect through depressive symptoms.Our results suggest that cognitive anxiety sensitivity or the fear of cognitive dyscontrol is linked with symptom severity in DID. These findings emphasize the need to assess for and utilize interventions that target anxiety sensitivity, which may in turn alleviate symptoms of depression and dissociation in DID.

BackgroundCurrent clinical assessments of Posttraumatic stress disorder (PTSD) rely solely on subjective symptoms and experiences reported by the patient, rather than objective biomarkers of the illness. Recent advances in data-driven computational approaches have been helpful in devising tools to objectively diagnose psychiatric disorders. Here we aimed to classify individuals with PTSD versus controls using heterogeneous brain datasets from the ENIGMA-PGC PTSD Working group.MethodsWe analyzed brain MRI data from 3,527 structural-MRI; 2,502 resting state-fMRI; and 1,953 diffusion-MRI. First, we identified the brain features that best distinguish individuals with PTSD from controls (TEHC and HC) using traditional machine learning methods. Second, we assessed the utility of the denoising variational autoencoder (DVAE) and evaluated its classification performance. Third, we assessed the generalizability and reproducibility of both models using leave-one-site-out cross-validation procedure for each modality.ResultsWe found lower performance in classifying PTSD vs. controls with data from over 20 sites (60% test AUC for s-MRI, 59% for rs-fMRI and 56% for d-MRI), as compared to other studies run on single-site data. The performance increased when classifying PTSD from HC without trauma history across all three modalities (75% AUC). The classification performance remained intact when applying the DVAE framework, which reduced the number of features. Finally, we found that the DVAE framework achieved better generalization to unseen datasets compared with the traditional machine learning frameworks, albeit performance was slightly above chance.ConclusionOur findings highlight the promise offered by machine learning methods for the diagnosis of patients with PTSD. The utility of brain biomarkers across three MRI modalities and the contribution of DVAE models for improving generalizability offers new insights into neural mechanisms involved in PTSD.Significance⍰Classifying PTSD from trauma-unexposed healthy controls (HC) using three imaging modalities performed well (∼75% AUC), but performance suffered markedly when classifying PTSD from trauma-exposed healthy controls (TEHC) using three imaging modalities (∼60% AUC).⍰Using deep learning for feature reduction (denoising variational auto-encoder; DVAE) dramatically reduced the number of features with no concomitant performance degradation.⍰Utilizing denoising variational autoencoder (DVAE) models improves generalizability across heterogeneous multi-site data compared with the traditional machine learning frameworks

BackgroundThe cerebellum critically contributes to higher-order cognitive and emotional functions such fear learning and memory. Prior research on cerebellar volume in PTSD is scant and has neglected neuroanatomical subdivisions of the cerebellum that differentially map on to motor, cognitive, and affective functions.MethodsWe quantified cerebellar lobule volumes using structural magnetic resonance imaging in 4,215 adults (PTSD n= 1640; Control n=2575) across 40 sites from the from the ENIGMA-PGC PTSD working group. Using a new state-of-the-art deep-learning based approach for automatic cerebellar parcellation, we obtained volumetric estimates for the total cerebellum and 28 subregions. Linear mixed effects models controlling for age, gender, intracranial volume, and site were used to compare cerebellum total and subregional volume in PTSD compared to healthy controls. The Benjamini-Hochberg procedure was used to control the false discovery rate (p-FDR< .05).ResultsPTSD was associated with significant grey and white matter reductions of the cerebellum. Compared to controls, people with PTSD demonstrated smaller total cerebellum volume. In addition, people with PTSD showed reduced volume in subregions primarily within the posterior lobe (lobule VIIB, crus II), but also the vermis (VI, VIII), flocculonodular lobe (lobule X), and cerebellar white matter (allp-FDR< 0.05). Effects of PTSD on volume were consistent, and generally more robust, when examining symptom severity rather than diagnostic status.ConclusionsThese findings implicate regionally specific cerebellar volumetric differences in the pathophysiology of PTSD. The cerebellum appears to play an important role in high-order cognitive and emotional processes, far beyond its historical association with vestibulomotor function. Further examination of the cerebellum in trauma-related psychopathology will help to clarify how cerebellar structure and function may disrupt cognitive and affective processes at the center of translational models for PTSD.

Background: Posttraumatic stress disorder (PTSD) is accompanied by disrupted cortical neuroanatomy. We investigated alteration in covariance of structural networks associated with PTSD in regions that demonstrate the case-control differences in cortical thickness (CT) and surface area (SA). Methods: Neuroimaging and clinical data were aggregated from 29 research sites in >1300 PTSD cases and >2000 trauma-exposed control subjects (ages 6.2–85.2 years) by the ENIGMA-PGC (Enhancing Neuro Imaging Genetics through Meta Analysis–Psychiatric Genomics Consortium) PTSD working group. Cortical regions in the network were rank ordered by the effect size of PTSD-related cortical differences in CT and SA. The top-n (n = 2–148) regions with the largest effect size for PTSD > non-PTSD formed hypertrophic networks, the largest effect size for PTSD < non-PTSD formed atrophic networks, and the smallest effect size of between-group differences formed stable networks. The mean structural covariance (SC) of a given n-region network was the average of all positive pairwise correlations and was compared with the mean SC of 5000 randomly generated n-region networks. Results: Patients with PTSD, relative to non-PTSD control subjects, exhibited lower mean SC in CT-based and SA-based atrophic networks. Comorbid depression, sex, and age modulated covariance differences of PTSD-related structural networks. Conclusions: Covariance of structural networks based on CT and cortical SA are affected by PTSD and further modulated by comorbid depression, sex, and age. The SC networks that are perturbed in PTSD comport with converging evidence from resting-state functional connectivity networks and networks affected by inflammatory processes and stress hormones in PTSD.

The variety of instruments used to assess posttraumatic stress disorder (PTSD) allows for flexibility, but also creates challenges for data synthesis. The objective of this work was to use a multisite mega analysis to derive quantitative recommendations for equating scores across measures of PTSD severity.Empirical Bayes harmonization and linear models were used to describe and mitigate site and covariate effects. Quadratic models for converting scores across PTSD assessments were constructed using bootstrapping and tested on hold out data.We aggregated 17 data sources and compiled anThese methods allow PTSD symptom severity to be placed on multiple scales and offers interesting empirical perspectives on the role of harmonization in the behavioral sciences. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Background Dissociative identity disorder (DID) is a psychobiological syndrome associated with a history of exposure to childhood abuse and neglect. The consequences of these traumatic events often include a profound impact on the way individuals inhabit and experience their bodies. Despite this, there is a paucity of empirical research on the subject. The aim of this study was to systematically document the occurrence of distorted body perceptions in DID and examine childhood maltreatment, posttraumatic stress disorder (PTSD) symptom severity, and posttraumatic cognitions as predictors of distorted body perceptions in DID. Methods Participants were adult women with histories of childhood abuse and neglect and a current DID diagnosis receiving treatment at a psychiatric care facility. Data were obtained through a battery of self-report measures, including the Body Uneasiness Test, Childhood Trauma Questionnaire, PTSD Checklist for DMS-5, and Posttraumatic Cognitions Inventory. Results A series of unpaired t-tests documented elevated levels of weight phobia, body image concerns, body avoidance, compulsive self-monitoring, and depersonalization in DID compared to published non-clinical data on the Body Uneasiness Test. A series of multiple regression models including measures of childhood trauma, PTSD symptoms, and posttraumatic cognitions demonstrated that over and above childhood trauma and PTSD symptom severity, posttraumatic cognitions significantly predicted distorted body perceptions. Conclusions In a treatment-seeking sample of women with DID, distorted body perceptions were elevated. Furthermore, posttraumatic cognitive distortions significantly predicted distorted body perceptions when controlling for childhood maltreatment and PTSD symptom severity. This suggests that distorted cognitions are a key target for therapeutic intervention.

Studies of posttraumatic stress disorder (PTSD) report volume abnormalities in multiple regions of the cerebral cortex. However, findings for many regions, particularly regions outside commonly studied emotion-related prefrontal, insular, and limbic regions, are inconsistent and tentative. Also, few studies address the possibility that PTSD abnormalities may be confounded by comorbid depression. A mega-analysis investigating all cortical regions in a large sample of PTSD and control subjects can potentially provide new insight into these issues. Given this perspective, our group aggregated regional volumes data of 68 cortical regions across both hemispheres from 1379 PTSD patients to 2192 controls without PTSD after data were processed by 32 international laboratories using ENIGMA standardized procedures. We examined whether regional cortical volumes were different in PTSD vs. controls, were associated with posttraumatic stress symptom (PTSS) severity, or were affected by comorbid depression. Volumes of left and right lateral orbitofrontal gyri (LOFG), left superior temporal gyrus, and right insular, lingual and superior parietal gyri were significantly smaller, on average, in PTSD patients than controls (standardized coefficients = −0.111 to −0.068, FDR corrected P values < 0.039) and were significantly negatively correlated with PTSS severity. After adjusting for depression symptoms, the PTSD findings in left and right LOFG remained significant. These findings indicate that cortical volumes in PTSD patients are smaller in prefrontal regulatory regions, as well as in broader emotion and sensory processing cortical regions.

BackgroundTrauma-related pathological dissociation is a multidimensional and disabling phenomenon that involves disruptions or discontinuities in psychological functioning. Despite its prevalence, personal and societal burden, dissociation remains underappreciated in clinical practice, and it lacks a synthesized neurobiological model that could place it in context with other common psychiatric symptoms. To identify a nuanced neurobiological model of pathological dissociation, we examined the functional connectivity of three core neurocognitive networks as related to the dimensional dissociation subtypes of depersonalization/derealization and partially-dissociated intrusions, and the diagnostic category of a complex dissociation disorder, dissociative identity disorder (DID).MethodsParticipants were 91 adult women with and without: a history of childhood trauma, current posttraumatic stress disorder (PTSD) and varied levels of pathological dissociation. Participants provided interview and self-report data about pathological dissociation, PTSD symptoms, childhood maltreatment history, and completed a resting-state functional magnetic resonance imaging scan.ResultsAfter controlling for age, childhood maltreatment and PTSD symptom severity, we found that pathological dissociation was associated with hyperconnectivity within central executive, default, and salience networks, and decreased connectivity of central executive and salience networks with other areas. Moreover, we isolated unique connectivity markers linked to depersonalization/derealization, to partially-dissociated intrusions, and to DID.ConclusionsOur work suggests subtypes of pathological dissociation have robust, discernable, and unique functional connectivity signatures. The neural correlates of dissociation may serve as potential targets for treatment engagement to facilitate recovery from PTSD and pathological dissociation. These results underscore dissociation assessment as crucial in clinical and medical care settings.

Funding Information: This work was supported by the National Institute of Mental Health / U.S. Army Medical Research and Development Command (Grant No. R01MH106595 [to CMN, IL, MBS, KJRe, and KCK], National Institutes of Health (Grant No. 5U01MH109539 to the Psychiatric Genomics Consortium ), and Brain & Behavior Research Foundation (Young Investigator Grant [to KWC]). Genotyping of samples was provided in part through the Stanley Center for Psychiatric Genetics at the Broad Institute supported by Cohen Veterans Bioscience . Statistical analyses were carried out on the LISA/Genetic Cluster Computer ( https://userinfo.surfsara.nl/systems/lisa ) hosted by SURFsara. This research has been conducted using the UK Biobank resource (Application No. 41209). This work would have not been possible without the financial support provided by Cohen Veterans Bioscience, the Stanley Center for Psychiatric Genetics at the Broad Institute, and One Mind. Funding Information: MBS has in the past 3 years received consulting income from Actelion, Acadia Pharmaceuticals, Aptinyx, Bionomics, BioXcel Therapeutics, Clexio, EmpowerPharm, GW Pharmaceuticals, Janssen, Jazz Pharmaceuticals, and Roche/Genentech and has stock options in Oxeia Biopharmaceuticals and Epivario. In the past 3 years, NPD has held a part-time paid position at Cohen Veterans Bioscience, has been a consultant for Sunovion Pharmaceuticals, and is on the scientific advisory board for Sentio Solutions for unrelated work. In the past 3 years, KJRe has been a consultant for Datastat, Inc., RallyPoint Networks, Inc., Sage Pharmaceuticals, and Takeda. JLM-K has received funding and a speaking fee from COMPASS Pathways. MU has been a consultant for System Analytic. HRK is a member of the Dicerna scientific advisory board and a member of the American Society of Clinical Psychopharmacology Alcohol Clinical Trials Initiative, which during the past 3 years was supported by Alkermes, Amygdala Neurosciences, Arbor Pharmaceuticals, Dicerna, Ethypharm, Indivior, Lundbeck, Mitsubishi, and Otsuka. HRK and JG are named as inventors on Patent Cooperative Treaty patent application number 15/878,640, entitled “Genotype-guided dosing of opioid agonists,” filed January 24, 2018. RP and JG are paid for their editorial work on the journal Complex Psychiatry. OAA is a consultant to HealthLytix. All other authors report no biomedical financial interests or potential conflicts of interest. Funding Information: This work was supported by the National Institute of Mental Health/ U.S. Army Medical Research and Development Command (Grant No. R01MH106595 [to CMN, IL, MBS, KJRe, and KCK], National Institutes of Health (Grant No. 5U01MH109539 to the Psychiatric Genomics Consortium), and Brain & Behavior Research Foundation (Young Investigator Grant [to KWC]). Genotyping of samples was provided in part through the Stanley Center for Psychiatric Genetics at the Broad Institute supported by Cohen Veterans Bioscience. Statistical analyses were carried out on the LISA/Genetic Cluster Computer (https://userinfo.surfsara.nl/systems/lisa) hosted by SURFsara. This research has been conducted using the UK Biobank resource (Application No. 41209). This work would have not been possible without the financial support provided by Cohen Veterans Bioscience, the Stanley Center for Psychiatric Genetics at the Broad Institute, and One Mind. This material has been reviewed by the Walter Reed Army Institute of Research. There is no objection to its presentation and/or publication. The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting true views of the U.S. Department of the Army or the Department of Defense. We thank the investigators who comprise the PGC-PTSD working group and especially the more than 206,000 research participants worldwide who shared their life experiences and biological samples with PGC-PTSD investigators. We thank Mark Zervas for his critical input. Full acknowledgments are in Supplement 1. MBS has in the past 3 years received consulting income from Actelion, Acadia Pharmaceuticals, Aptinyx, Bionomics, BioXcel Therapeutics, Clexio, EmpowerPharm, GW Pharmaceuticals, Janssen, Jazz Pharmaceuticals, and Roche/Genentech and has stock options in Oxeia Biopharmaceuticals and Epivario. In the past 3 years, NPD has held a part-time paid position at Cohen Veterans Bioscience, has been a consultant for Sunovion Pharmaceuticals, and is on the scientific advisory board for Sentio Solutions for unrelated work. In the past 3 years, KJRe has been a consultant for Datastat, Inc. RallyPoint Networks, Inc. Sage Pharmaceuticals, and Takeda. JLM-K has received funding and a speaking fee from COMPASS Pathways. MU has been a consultant for System Analytic. HRK is a member of the Dicerna scientific advisory board and a member of the American Society of Clinical Psychopharmacology Alcohol Clinical Trials Initiative, which during the past 3 years was supported by Alkermes, Amygdala Neurosciences, Arbor Pharmaceuticals, Dicerna, Ethypharm, Indivior, Lundbeck, Mitsubishi, and Otsuka. HRK and JG are named as inventors on Patent Cooperative Treaty patent application number 15/878,640, entitled ?Genotype-guided dosing of opioid agonists,? filed January 24, 2018. RP and JG are paid for their editorial work on the journal Complex Psychiatry. OAA is a consultant to HealthLytix. All other authors report no biomedical financial interests or potential conflicts of interest. Publisher Copyright: © 2021 Society of Biological Psychiatry Background: Posttraumatic stress disorder (PTSD) is heritable and a potential consequence of exposure to traumatic stress. Evidence suggests that a quantitative approach to PTSD phenotype measurement and incorporation of lifetime trauma exposure (LTE) information could enhance the discovery power of PTSD genome-wide association studies (GWASs). Methods: A GWAS on PTSD symptoms was performed in 51 cohorts followed by a fixed-effects meta-analysis (N = 182,199 European ancestry participants). A GWAS of LTE burden was performed in the UK Biobank cohort (N = 132,988). Genetic correlations were evaluated with linkage disequilibrium score regression. Multivariate analysis was performed using Multi-Trait Analysis of GWAS. Functional mapping and annotation of leading loci was performed with FUMA. Replication was evaluated using the Million Veteran Program GWAS of PTSD total symptoms. Results: GWASs of PTSD symptoms and LTE burden identified 5 and 6 independent genome-wide significant loci, respectively. There was a 72% genetic correlation between PTSD and LTE. PTSD and LTE showed largely similar patterns of genetic correlation with other traits, albeit with some distinctions. Adjusting PTSD for LTE reduced PTSD heritability by 31%. Multivariate analysis of PTSD and LTE increased the effective sample size of the PTSD GWAS by 20% and identified 4 additional loci. Four of these 9 PTSD loci were independently replicated in the Million Veteran Program. Conclusions: Through using a quantitative trait measure of PTSD, we identified novel risk loci not previously identified using prior case-control analyses. PTSD and LTE have a high genetic overlap that can be leveraged to increase discovery power through multivariate methods. publishersversion published

Funding Information: This work was supported by the National Institute of Mental Health/U.S. Army Medical Research and Development Command (Grant No. R01MH106595 [to CMN, MBS, KJRe, and KCK]), and National Institutes of Health (Grant No. 5U01MH109539 [to the Psychiatric Genomics Consortium] and Grant No. U19 MH069056 [to BWD])). Financial support for the PTSD PGC was provided by the Cohen Veterans Bioscience, Stanley Center for Psychiatric Research at the Broad Institute, and One Mind. Genotyping of samples was provided in part through the Stanley Center for Psychiatric Genetics at the Broad Institute supported by Cohen Veterans Bioscience Statistical analyses were carried out on the LISA/Genetic Cluster Computer ( https://userinfo.surfsara.nl/systems/lisa ) hosted by SURFsara. This research has been conducted using the UK Biobank resource (Application No. 41209). Posttraumatic stress disorder (PTSD) is a heritable (h2 = 24–71%) psychiatric illness. Copy number variation (CNV) is a form of rare genetic variation that has been implicated in the etiology of psychiatric disorders, but no large-scale investigation of CNV in PTSD has been performed. We present an association study of CNV burden and PTSD symptoms in a sample of 114,383 participants (13,036 cases and 101,347 controls) of European ancestry. CNVs were called using two calling algorithms and intersected to a consensus set. Quality control was performed to remove strong outlier samples. CNVs were examined for association with PTSD within each cohort using linear or logistic regression analysis adjusted for population structure and CNV quality metrics, then inverse variance weighted meta-analyzed across cohorts. We examined the genome-wide total span of CNVs, enrichment of CNVs within specified gene-sets, and CNVs overlapping individual genes and implicated neurodevelopmental regions. The total distance covered by deletions crossing over known neurodevelopmental CNV regions was significant (beta = 0.029, SE = 0.005, P = 6.3 × 10−8). The genome-wide neurodevelopmental CNV burden identified explains 0.034% of the variation in PTSD symptoms. The 15q11.2 BP1-BP2 microdeletion region was significantly associated with PTSD (beta = 0.0206, SE = 0.0056, P = 0.0002). No individual significant genes interrupted by CNV were identified. 22 gene pathways related to the function of the nervous system and brain were significant in pathway analysis (FDR q < 0.05), but these associations were not significant once NDD regions were removed. A larger sample size, better detection methods, and annotated resources of CNV are needed to explore this relationship further. publishersversion published

Results of neuroimaging datasets aggregated from multiple sites may be biased by site- specific profiles in participants’ demographic and clinical characteristics, as well as MRI acquisition protocols and scanning platforms. We compared the impact of four different harmonization methods on results obtained from analyses of cortical thickness data: (1) linear mixed-effects model (LME) that models site-specific random intercepts (LMEINT), (2) LME that models both site-specific random intercepts and age-related random slopes (LMEINT+SLP), (3) ComBat, and (4) ComBat with a generalized additive model (ComBat-GAM). Our test case for comparing harmonization methods was cortical thickness data aggregated from 29 sites, which included 1,343 cases with posttraumatic stress disorder (PTSD) (6.2-81.8 years old) and 2,067 trauma-exposed controls without PTSD (6.3-85.2 years old). We found that, compared to the other data harmonization methods, data processed with ComBat-GAM were more sensitive to the detection of significant case-control differences in regional cortical thickness (X2(3) = 34.339, p < 0.001), and case-control differences in age-related cortical thinning (X2(3) = 15.128, p = 0.002). Specifically, ComBat-GAM led to larger effect size estimates of cortical thickness reductions (corrected p-values < 0.001), smaller age-appropriate declines (corrected p-values < 0.001), and lower female to male contrast (corrected p-values < 0.001) in cases compared to controls relative to other harmonization methods. Harmonization with ComBat-GAM also led to greater estimates of age-related declines in cortical thickness (corrected p-values < 0.001) in both cases and controls compared to other harmonization methods. Our results support the use of ComBat-GAM for harmonizing cortical thickness data aggregated from multiple sites and scanners to minimize confounds and increase statistical power.

A growing number of studies have examined alterations in white matter organization in people with posttraumatic stress disorder (PTSD) using diffusion MRI (dMRI), but the results have been mixed, which may be partially due to relatively small sample sizes among studies. Altered structural connectivity may be both a neurobiological vulnerability for, and a result of, PTSD. In an effort to find reliable effects, we present a multi-cohort analysis of dMRI metrics across 3,047 individuals from 28 cohorts currently participating in the PGC-ENIGMA PTSD working group (a joint partnership between the Psychiatric Genomics Consortium and the Enhancing NeuroImaging Genetics through Meta-Analysis consortium). Comparing regional white matter metrics across the full brain in 1,426 individuals with PTSD and 1,621 controls (2174 males/873 females) between ages 18–83, 92% of whom were trauma-exposed, we report associations between PTSD and disrupted white matter organization measured by lower fractional anisotropy (FA) in the tapetum region of the corpus callosum (Cohen’s d=−0.11, p=0.0055). The tapetum connects the left and right hippocampus, structures for which structure and function have been consistently implicated in PTSD. Results remained significant/similar after accounting for the effects of multiple potentially confounding variables: childhood trauma exposure, comorbid depression, history of traumatic brain injury, current alcohol abuse or dependence, and current use of psychotropic medications. Our results show that PTSD may be associated with alterations in the broader hippocampal network.

Posttraumatic stress disorder (PTSD) is a complex psychiatric condition that has generated much attention in the neuroimaging literature. A neurocircuitry model supporting fronto-limbic dysfunction as a major player in facilitating clinical symptoms of PTSD is well-characterized; however, recent literature suggests that network-based approaches may provide additional insight into neural dysfunction in PTSD. Our analysis uses resting-state neuroimaging scans of 1063 adults from the PGC-ENIGMA PTSD Consortium to investigate a network-based model of functional connectivity in PTSD. With a novel, resolution limit-free community detection approach, 16 communities corresponding to functionally meaningful networks were detected with high quality. After group-level community detection, participants were classified into three groups (PTSD, n=418, trauma-exposed controls without PTSD, n=434, and non-trauma exposed healthy controls, n=211). Individual network connectivity metrics were calculated, including whole-brain, default mode network, and central executive network participation coefficient and connectivity strength. Linear mixed effects models revealed group differences in the whole-brain, default mode, and central executive network participation coefficient and connectivity strength such that individuals with PTSD demonstrated overall greater values. We also described sex differences such that males demonstrate greater whole-brain participation coefficient vs. females and females demonstrate greater default mode network connectivity strength vs. males. Our results suggest that PTSD in adults is associated with reduced specialization and enhanced inter-module communication throughout the brain network, which may contribute to inefficient information processing and poor emotional regulation. This study presents a novel use of resolution limit-free community detection in a large PTSD sample, revealing robust differences in resting-state network topology.

IntroductionCortical thickness (CT) and surface area (SA) are established biomarkers of brain pathology in posttraumatic stress disorder (PTSD). Structural covariance networks (SCN) constructed from CT and SA may represent developmental associations, or unique interactions between brain regions, possibly influenced by a common causal antecedent. The ENIGMA-PGC PTSD Working Group aggregated PTSD and control subjects’ data from 29 cohorts in five countries (n=3439).MethodsUsing Destrieux Atlas, we built SCNs and compared centrality measures between PTSD subjects and controls. Centrality is a graph theory measure derived using SCN.ResultsNotable nodes with higher CT-based centrality in PTSD compared to controls were left fusiform gyrus, left superior temporal gyrus, and right inferior temporal gyrus. We found sex-based centrality differences in bilateral frontal lobe regions, left anterior cingulate, left superior occipital cortex and right ventromedial prefrontal cortex (vmPFC). Comorbid PTSD and MDD showed higher CT-based centrality in the right anterior cingulate gyrus, right parahippocampal gyrus and lower SA-based centrality in left insular gyrus.ConclusionUnlike previous studies with smaller sample sizes (≤318), our study found differences in centrality measures using a sample size of 3439 subjects. This is the first cross-sectional study to examine SCN interactions with age, sex, and comorbid MDD. Although limited to group level inferences, centrality measures offer insights into a node’s relationship to the entire functional connectome unlike approaches like seed-based connectivity or independent component analysis. Nodes having higher centrality have greater structural or functional connections, lending them invaluable for translational treatments like neuromodulation.

OBJECTIVE: Dissociative experiences commonly occur in response to trauma, and while their presence strongly affects treatment approaches in posttraumatic spectrum disorders, their etiology remains poorly understood and their phenomenology incompletely characterized. Methods to reliably assess the severity of dissociation symptoms, without relying solely on self-report, would have tremendous clinical utility. Brain-based measures have the potential to augment symptom reports, although it remains unclear whether brain-based measures of dissociation are sufficiently sensitive and robust to enable individual-level estimation of dissociation severity based on brain function. The authors sought to test the robustness and sensitivity of a brain-based measure of dissociation severity. METHODS: An intrinsic network connectivity analysis was applied to functional MRI scans obtained from 65 women with histories of childhood abuse and current posttraumatic stress disorder (PTSD). The authors tested for continuous measures of trauma-related dissociation using the Multidimensional Inventory of Dissociation. Connectivity estimates were derived with a novel machine learning technique using individually defined homologous functional regions for each participant. RESULTS: The models achieved moderate ability to estimate dissociation, after controlling for childhood trauma and PTSD severity. Connections that contributed the most to the estimation mainly involved the default mode and frontoparietal control networks. By contrast, all models performed at chance levels when using a conventional group-based network parcellation. CONCLUSIONS: Trauma-related dissociative symptoms, distinct from PTSD and childhood trauma, can be estimated on the basis of network connectivity. Furthermore, between-network brain connectivity may provide an unbiased estimate of symptom severity, paving the way for more objective, clinically useful biomarkers of dissociation and advancing our understanding of its neural mechanisms.

Background Recovery from dissociative identity disorder (DID) is associated with the process of integration, which includes an increasing sense of self-cohesion and ownership over one's own emotions. Emotion perception is a construction based on interplay between stored knowledge (past experience), and incoming sensory inputs, suggesting changes in emotion perception might occur at different levels of integration – but this remains unexplored. Therefore, we examined the association between integration, psychiatric symptoms, and facial emotion perception. We hypothesized higher integration would be associated with fewer psychiatric symptoms, and differences in the perception of emotions. Methods Participants were 82 respondents to a cross-sectional web-based study. All participants met self-report cutoff scores for posttraumatic stress disorder (PTSD) and DID using the PTSD Checklist for DSM-5 and Multiscale Dissociation Inventory, respectively. Participants completed a psychometrically-matched test of facial emotion perception for anger, fear, and happiness called the Belmont Emotion Sensitivity Test. Participants also completed the Beck Depression Inventory II, Childhood Trauma Questionnaire, and Integration Measure, a validated measure of self-cohesion. Results Higher integration scores were associated with lower depression, PTSD, and autobiographical memory disturbance scores. Repeated-measures ANCOVA confirmed integration significantly interacted with emotion category on the facial emotion perception task. Specifically, higher integration scores were associated with greater accuracy to fearful and angry faces. Conclusions While acknowledging the limitations of a cross-sectional design, our results suggest that the process of integration is associated with fewer psychiatric symptoms, and more accurate facial emotion perception. This supports treatment guidelines regarding integration as a therapeutic goal for DID.

Background Many studies report smaller hippocampal and amygdala volumes in posttraumatic stress disorder (PTSD), but findings have not always been consistent. Here, we present the results of a large-scale neuroimaging consortium study on PTSD conducted by the Psychiatric Genomics Consortium (PGC)–Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) PTSD Working Group. Methods We analyzed neuroimaging and clinical data from 1868 subjects (794 PTSD patients) contributed by 16 cohorts, representing the largest neuroimaging study of PTSD to date. We assessed the volumes of eight subcortical structures (nucleus accumbens, amygdala, caudate, hippocampus, pallidum, putamen, thalamus, and lateral ventricle). We used a standardized image-analysis and quality-control pipeline established by the ENIGMA consortium. Results In a meta-analysis of all samples, we found significantly smaller hippocampi in subjects with current PTSD compared with trauma-exposed control subjects (Cohen’s d = −0.17, p = .00054), and smaller amygdalae (d = −0.11, p = .025), although the amygdala finding did not survive a significance level that was Bonferroni corrected for multiple subcortical region comparisons (p Conclusions Our study is not subject to the biases of meta-analyses of published data, and it represents an important milestone in an ongoing collaborative effort to examine the neurobiological underpinnings of PTSD and the brain’s response to trauma.

The dissociative subtype of posttraumatic stress disorder (PTSD) is estimated to characterize about 12-30% of those with PTSD. Some research links this subtype with increased severity of PTSD symptoms compared to samples with "classic" PTSD. However, prevalence and severity rates reported in the literature have varied. One possible explanation for these discrepancies could be related to where the populations were sampled. Therefore, we investigated whether these differences are still observed when holding level of care constant. We collected data from 104 women at a partial and residential psychiatric hospital program focused on trauma-related disorders. Participants completed self-report questionnaires assessing trauma exposure, symptoms and provisional diagnosis of PTSD, trauma-related thoughts and beliefs, and feelings of shame. All participants reported a history of childhood and/or adulthood trauma exposure. Eighty-eight (85%) met criteria for PTSD, and of those, seventy-three (83%) met criteria for the dissociative subtype as assessed by the Dissociative Subtype of PTSD Scale. A series of independent t-tests revealed no significant differences between the "classic" and dissociative PTSD groups with respect to lifetime or childhood trauma exposure, posttraumatic cognitions, shame, or overall PTSD severity. Our results suggest that samples with classic PTSD and the dissociative subtype may not differ in some types of symptom severity when holding level of care constant. Importantly, however, we found at partial/residential level of care the majority of patients with PTSD were dissociative. Given the elevated prevalence rate in this sample, these findings support the need to assess dissociative symptoms, particularly in more acute psychiatric settings.

The risk of posttraumatic stress disorder (PTSD) following trauma is heritable, but robust common variants have yet to be identified. In a multi-ethnic cohort including over 30,000 PTSD cases and 170,000 controls we conduct a genome-wide association study of PTSD. We demonstrate SNP-based heritability estimates of 5–20%, varying by sex. Three genome-wide significant loci are identified, 2 in European and 1 in African-ancestry analyses. Analyses stratified by sex implicate 3 additional loci in men. Along with other novel genes and non-coding RNAs, a Parkinson’s disease gene involved in dopamine regulation, PARK2, is associated with PTSD. Finally, we demonstrate that polygenic risk for PTSD is significantly predictive of re-experiencing symptoms in the Million Veteran Program dataset, although specific loci did not replicate. These results demonstrate the role of genetic variation in the biology of risk for PTSD and highlight the necessity of conducting sex-stratified analyses and expanding GWAS beyond European ancestry populations., Post-traumatic stress disorder (PTSD) is a common mental health problem. Here, the authors report a GWAS from the Psychiatric Genomics Consortium in which they identify two risk loci in European ancestry and one locus in African ancestry individuals and find that PTSD is genetically correlated with several other psychiatric traits.

BackgroundPTSD and depression commonly co-occur and have been associated with smaller hippocampal volumes compared to healthy and trauma-exposed controls. However, the hippocampus is heterogeneous, with subregions that may be uniquely affected in individuals with PTSD and depression.MethodsWe used random effects regressions and a harmonized neuroimaging protocol based on FreeSurfer (v6.0) to identify sub-structural hippocampal markers of current PTSD (C-PTSD), depression, and the interaction of these conditions across 31 cohorts worldwide (N=3,115;Mage=38.9±13.9 years). Secondary analyses tested these associations by sex and after modeling the simultaneous effects of remitted PTSD, childhood trauma, mild traumatic brain injury, and alcohol use disorder.ResultsA significant negative main effect of depression (n=800, vs. no depression, n=1456) was observed in the hippocampal tail (ß=−0.13) and CA1 (ß=−0.09) after adjusting for covariates and multiple testing (adjusted p’s (q)=0.028). A main effect of C-PTSD (n=1042 vs. control, n=1359) was not significant, but an interaction between C-PTSD and depression was significant in the CA1 (ß=−0.24, q=0.044). Pairwise comparisons revealed significantly smaller CA1 volumes in individuals with C-PTSD+Depression than controls (ß=−0.12, q=0.012), C-PTSD-only (ß=−0.17, q=0.001), and Depression-only (ß=−0.18, q=0.023). Follow-up analyses revealed sex effects in the hippocampal tail of depressed females, and an interaction effect of C-PTSD and depression in the fimbria of males.ConclusionsCollectively our results suggest that depression is a stronger predictor of hippocampal volumetry than PTSD, particularly in the CA1, and provide compelling evidence of more pronounced hippocampal phenotypes in comorbid PTSD and depression compared to either condition alone.

Childhood maltreatment is highly prevalent and serves as a risk factor for mental and physical disorders. Self-reported childhood maltreatment appears heritable, but the specific genetic influences on this phenotype are largely unknown. The aims of this study were to 1) identify genetic variation associated with reported childhood maltreatment, 2) calculate the relevant SNP-based heritability estimates, and 3) quantify the genetic overlap of reported childhood maltreatment with mental and physical health-related phenotypes. Genome-wide association analysis for childhood maltreatment was undertaken, using a discovery sample from the UK Biobank (UKBB) (n=124,000) and a replication sample from the Psychiatric Genomics Consortium–posttraumatic stress disorder working group (PGC-PTSD) (n=26,290). Heritability estimations for childhood maltreatment and genetic correlations with mental/physical health traits were calculated using linkage disequilibrium score regression (LDSR). Two genome-wide significant loci associated with childhood maltreatment, located on chromosomes 3p13 (rs142346759, beta=0.015, p=4.35×10−8,FOXP1) and 7q31.1 (rs10262462, beta=-0.016, p=3.24×10−8,FOXP2), were identified in the discovery dataset but were not replicated in the PGC-PTSD sample. SNP-based heritability for childhood maltreatment was estimated to be ∼6%. Childhood maltreatment was most significantly genetically correlated with depressive symptoms (rg=0.70, p=4.65×10−40). This is the first large-scale genetic study to identify specific variants associated with self-reported childhood maltreatment.FOXPgenes could influence traits such as depression and thereby be relevant to childhood maltreatment. Alternatively, these variants may be associated with a greater likelihood of reporting maltreatment. A clearer understanding of the genetic relationships of childhood maltreatment, including particular abuse subtypes, with various psychiatric disorders, may ultimately be useful in in developing targeted treatment and prevention strategies.

The dissociative subtype of posttraumatic stress disorder (D-PTSD) is estimated to occur in approximately 14% of those with posttraumatic stress disorder (PTSD), and is characterized by clinically significant dissociative symptoms in addition to typical PTSD symptoms. Prior research has found childhood maltreatment contributes to dissociation and D-PTSD susceptibility, but more nuanced questions about the nature of childhood maltreatment remain unexplored. We investigated how childhood maltreatment type and severity are associated with the dissociative symptoms of D-PTSD among women with PTSD (N = 106) receiving psychiatric care at a program specializing in trauma-related disorders. Participants completed self-report surveys of psychiatric symptoms and prior trauma exposure including the PTSD Checklist for DSM-5, the Dissociative Subtype of PTSD Scale, and the Childhood Trauma Questionnaire. We used multivariate linear regression to model the association of childhood maltreatment types and dissociation. In our final model childhood emotional abuse and physical abuse significantly predicted the dissociative symptoms of D-PTSD. This suggests childhood maltreatment type and severity, in particular of emotional and physical abuse, are associated with the dissociative symptoms of D-PTSD. This work points toward potential etiological contributions to D-PTSD.

Failing to recognize one's mirror image can signal an abnormality in one's sense of self. In dissociative identity disorder (DID), individuals often report that their mirror image can feel unfamiliar or distorted. They also experience some of their own thoughts, emotions, and bodily sensations as if they are nonautobiographical and sometimes as if instead, they belong to someone else. To assess these experiences, we designed a novel backwards masking paradigm in which participants were covertly shown their own face, masked by a stranger's face. Participants rated feelings of familiarity associated with the strangers' faces. 21 control participants without trauma-generated dissociation rated masks, which were covertly preceded by their own face, as more familiar compared to masks preceded by a stranger's face. In contrast, across two samples, 28 individuals with DID and similar clinical presentations (DSM-IV Dissociative Disorder Not Otherwise Specified type 1) did not show increased familiarity ratings to their own masked face. However, their familiarity ratings interacted with self-reported identity state integration. Individuals with higher levels of identity state integration had response patterns similar to control participants. These data provide empirical evidence of aberrant self-referential processing in DID/DDNOS and suggest this is restored with identity state integration.

Post-traumatic stress disorder (PTSD) is a common and debilitating disorder. The risk of PTSD following trauma is heritable, but robust common variants have yet to be identified by genome-wide association studies (GWAS). We have collected a multi-ethnic cohort including over 30,000 PTSD cases and 170,000 controls. We first demonstrate significant genetic correlations across 60 PTSD cohorts to evaluate the comparability of these phenotypically heterogeneous studies. In this largest GWAS meta-analysis of PTSD to date we identify a total of 6 genome-wide significant loci, 4 in European and 2 in African-ancestry analyses. Follow-up analyses incorporated local ancestry and sex-specific effects, and functional studies. Along with other novel genes, a non-coding RNA (ncRNA) and a Parkinson’s Disease gene,PARK2, were associated with PTSD. Consistent with previous reports, SNP-based heritability estimates for PTSD range between 10-20%. Despite a significant shared liability between PTSD and major depressive disorder, we show evidence that some of our loci may be specific to PTSD. These results demonstrate the role of genetic variation contributing to the biology of differential risk for PTSD and the necessity of expanding GWAS beyond European ancestry.

Post-traumatic stress disorder (PTSD) is a debilitating psychiatric disorder with an estimated genetic component accounting for 30%–40% of the variance contributing to risk for the disease. This chapter starts with a review of the biological hypotheses and related genetic mechanisms currently proposed to be associated with PTSD and trauma-related disorders. It will follow with a description of the state-of-the-art on the methodologies and their application to map genetic loci and identify biomarkers associated with PTSD. Finally, we will review the latest results from genome-wide association studies of genetic variants as well as those derived from the emerging fields of epigenetics and gene expression.

Background Individuals with posttraumatic stress disorder (PTSD) demonstrate alterations in autonomic responses to fear conditioning, such as exaggerated startle and poor fear inhibition. However, there is a paucity of research on fear conditioning among individuals with PTSD and dissociative symptoms, which represents 10-30% of those with PTSD. The current study used a fear-potentiated startle (FPS) conditioning paradigm to examine autonomic responses among women with PTSD and a range of dissociative symptoms. Methods Participants included 39 women with PTSD and dissociation, and 53 women with PTSD with unknown levels of dissociation. The FPS paradigm consisted of conditioned stimuli associated and not associated with an aversive unconditioned stimulus. FPS response (eyeblink startle), electrocardiogram (ECG), and skin conductance response (SCR) were collected during the FPS paradigm. Results Compared to the PTSD-unknown dissociation sample, the PTSD-dissociation sample demonstrated significantly lower FPS during the last block of conditioning. Among the PTSD-dissociation sample, higher dissociation scores were associated with decreased FPS and SCR, and higher respiratory sinus arrhythmia (derived from ECG). Conclusions Results suggest that autonomic responses to fear conditioning differ depending on the presence and severity of dissociative symptoms. Given that treatment response may differ depending on dissociative symptoms, it is important to understand the mechanisms that underlie different subtypes of PTSD and that may affect treatment response and outcome.

First responders are regularly confronted with exposure to traumatic events, including potentially life-threatening situations as well as the grave injuries and deaths of colleagues and civilians. Evidence indicates that the prevalence of posttraumatic stress disorder (PTSD) is substantially higher among first responders than the general population. This article provides information about the outpatient trauma services at McLean Hospital's LEADER (Law Enforcement, Active Duty, Emergency Responder) program to assist clinicians who encounter these first responders in their practices or who are specifically interested in working with this patient population. We begin by synthesizing the literature on the prevalence of PTSD in first responders following work-related exposure to traumatic stress, and by addressing the occupation-specific risk factors and the third-variable risk factors that may contribute to potentiated risk. We then discuss assessment strategies and treatment options used in our program, which is tailored for individuals who are dealing with mental health issues stemming from occupation-specific traumatic-stress exposure. We also address the unique challenges of treating traumatized first responders with more complex issues such as traumatic stress exposure across the lifespan and safety issues, including acute suicidality. We conclude by discussing notable gaps in the literature, including the need to investigate why and how women present with different PTSD symptoms than men and how these differences need to be taken into account in determining appropriate treatment for women.

While multiple effective pharmacotherapies and psychotherapies exist for anxiety disorders, to many they lack efficacy, tolerability, and/or accessibility. Only one-third of those with anxiety disorders seek mental health treatment and, of those who do, nonadherence and nonresponse (or incomplete response) remain substantial problems. There is thus a great need for novel treatments. In this chapter, we discuss approaches for the development of new anxiety treatments based on an improved understanding of the neurobiology underlying anxiety and fear-related disorders. We define novel treatments as those that hold potential promise but are not yet fully proven or available, or those that are recently available but not widely implemented.

This paper explores the experiences of women who “hear voices” (auditory verbal hallucinations). We begin by examining historical understandings of women hearing voices, showing these have been driven by androcentric theories of how women’s bodies functioned leading to women being viewed as requiring their voices be interpreted by men. We show the twentieth century was associated with recognition that the mental violation of women’s minds (represented by some voice-hearing) was often a consequence of the physical violation of women’s bodies. We next report the results of a qualitative study into voice-hearing women’s experiences (n = 8). This found similarities between women’s relationships with their voices and their relationships with others and the wider social context. Finally, we present results from a quantitative study comparing voice-hearing in women (n = 65) and men (n = 132) in a psychiatric setting. Women were more likely than men to have certain forms of voice-hearing (voices conversing) and to have antecedent events of trauma, physical illness, and relationship problems. Voices identified as female may have more positive affect than male voices. We conclude that women voice-hearers have and continue to face specific challenges necessitating research and activism, and hope this paper will act as a stimulus to such work.

Fourteen veterans with posttraumatic stress disorder (PTSD) and 14 without PTSD participated in a contingent negative variation (CNV)-distraction paradigm. Subjects were instructed to press a button after hearing a high-pitched tone (S2) preceded by a low-pitched tone (S1). One-half of the trials included a white-noise distracter placed in the S1-S2 interval. Posttraumatic stress disorder subjects had larger frontal, but smaller central and parietal CNVs, regardless of condition (distracter, no distracter) or epoch (early CNV, late CNV). In PTSD subjects, the N1/P2 complex was smaller to warning (S1) and distracter stimuli and did not show the extent of facilitation present in non-PTSD subjects. Findings highlight PTSD-related differences in phasic cortical excitability and attention.

A recent study found that female rape victims with acute posttraumatic stress disorder (PTSD) who received a high score on the Peritraumatic Dissociative Experiences Questionnaire exhibited suppression of physiological responses during exposure to trauma-related stimuli. The goal of our present study was to test whether the same relationship holds true for male Vietnam combat veterans with chronic PTSD, using secondary analyses applied to data derived from a Veteran's Affairs Cooperative Study. Vietnam combat veterans (N = 1238) completed measures to establish combat-related PTSD diagnostic status, extent of PTSD-related symptomatic distress, and presence of dissociative symptoms during their most stressful combat-related experiences. Extreme subgroups of veterans with current PTSD were classified as either low dissociators (N = 118) or high dissociators (N = 256) based on an abbreviated version of the Peritraumatic Dissociative Experiences Questionnaire. Dependent variables reflected subjective distress along with heart rate, skin conductance, electromyographic, and blood pressure data when responding to neutral and trauma-related audiovisual and imagery presentations. Veterans in the current PTSD group had significantly higher dissociation scores than did veterans in the lifetime and never PTSD groups. Among veterans with current PTSD, high dissociators reported greater PTSD-related symptomatic distress than did low dissociators, but the groups did not differ with respect to physiological reactivity to the trauma-related laboratory presentations. Our results replicate the previously reported relationship between peritraumatic dissociation and PTSD status in Vietnam combat veterans. However, we found no association between peritraumatic dissociation and the extent of physiological responding to trauma-relevant cues in male veterans with chronic combat-related PTSD.

Objective To apply an improved air-dry procedure for the light microscopic identification of both degenerate and aberrant meiotic configurations in cultured human oocytes. Material and Design Meiotically immature, normal appearing human oocytes retrieved after oophorectomy were placed into culture for 9 to 46 hours. Subsequently, oocytes were assessed morphologically and then air dried for light microscopic examination of chromatin configurations. Main Outcome Measures Oocyte chromatin configurations were identified as normal, degenerate, or aberrant and then classified according to meiotic stage. Retrospective analyses were conducted to determine if [1] normal meiotic configurations were associated with morphologically viable oocytes and [2] degenerate or aberrant meiotic configurations were always associated with degenerate oocytes. In addition, for each meiotic stage, the proportion of oocytes exhibiting either degenerate or aberrant chromatin configurations was calculated. Results Of 101 oocyte chromatin configurations analyzed, 71.3% were normal, 11.9% were degenerate, and 16.8% displayed meiotic aberrations. Retrospective analyses revealed that the majority of both normal and aberrant chromatin configurations were associated with morphologically viable oocytes (93.1% and 88.2%, respectively), whereas all of the degenerate chromatin configurations were associated with morphologically degenerate oocytes. When assessed by stage, nuclear degeneration was observed exclusively at the germinal vesicle and diakinesis stages, whereas meiotic aberrations occurred most frequently after chromosome condensation. These aberrations were manifested either as clumped metaphase I configurations or as two distinct groups of bivalents that appeared to result from bivalent migration along the meiotic spindle without homologue segregation. Conclusions Slightly >25% of human oocytes recovered after oophorectomy were incapable of undergoing normal meiotic maturation in culture. The majority of these abnormal oocytes appeared morphologically normal and yet possessed meiotic aberrations. These observations indicate that caution should be taken when using oocytes matured in vitro for application in assisted reproductive technology programs.

To modify Tarkowski's air-dry technique for mouse oocytes to develop a rapid, consistent procedure for human oocytes that enables accurate scoring of meiotic stage.Meiotically immature human oocytes, obtained after oophorectomy, were cultured for various periods and then subjected to Tarkowski's air-dry procedure (n = 104) or to our modified procedure (n = 175) that used a brief exposure to protease (20 to 40 seconds) before fixation.Air-dried oocytes were assessed for readability and for whether they contained overspread or overlapping chromosomes. In addition, discrete meiotic stages in human oocytes were identified.Our protease procedure significantly increased readability of air-dried oocytes (96% versus 79% readable for protease versus Tarkowski, respectively; P less than 0.001) by significantly reducing the number of preparations with either overscattered (0.7% versus 3.4% for protease versus Tarkowski, respectively, P less than 0.05) or overlapping (1.3% versus 18% for protease versus Tarkowski, respectively, P less than 0.001) chromosomes.Protease exposure of oocytes, combined with a modification of Tarkowski's procedure, resulted in high quality air-dries of human oocytes. This rapid and reliable procedure should have clinical application in in vitro fertilization programs for meiotic assessment of oocytes failing to fertilize.

Knowledge about the biological basis of psychological trauma is changing at an exponential rate. A PsychlNFO search on the search terms "locus coeruleus" and "PTSD" revealed one peer-reviewed journal article between 1982 and 1992 and 51 in the subsequent decade. A similar search revealed zero articles on "hippocampus" and "PTSD" between 1982 and 1992 and 170 in the past decade. As clinicians, it is important to become increasingly familiar with this growing literature to use that knowledge to treat and educate patients. Imagine the relief that can be provided to survivors of trauma if clinicians can tell them that they have a good idea about what causes their symptoms and even clearer ideas about how to treat them.One ancillary but invaluable outcome to this work is the fact that understanding the neurological underpinnings of PTSD will go a long way to establishing a necessary equilibrium in nature and nurture's role in the etiology and maintenance of the disorder. In its early conceptualization, PTSD was thought by many to be an ordinary reaction to an extraordinary event, thus placing responsibility for the disorder firmly in the hands of environmental factors. A subsequent emphasis on vulnerability and resiliency factors in the disorder, however, gave the impression that genetic and potentially hard-wired neurological factors were dominant in the expression of the disorder. Appreciating the balance between nature and nurture in the development of stress disorders like PTSD will allow clinicians and patients alike to appreciate the role of personal responsibility in the process of recovery. A parallel, albeit more mature process, has occurred in the area of schizophrenia in the past four decades. Early conceptualizations of schizophrenia placed a heavy burden on parenting and behavioral factors, leaving the patients angry at their parents and parents with unnecessary guilt. The later dominance of genetic and biological theories in the disorder allayed parents of their guilt, but left both parents and patients wondering what might be done in the face of such an affliction. Modern theories of schizophrenia seem to have achieved an appropriate balance that recognizes biological vulnerabilities, but also emphasizes familial and patient responsibilities in recovery and care. In PTSD, a similar equilibrium needs to be found, and understanding the neurobiology of the disorder will go far in achieving that goal. When it is understood how trauma affects the brain and how treatment produces neurobiological changes that may remediate trauma-related effects, the patient will be in a better position to make choices about what can and cannot be done in the process of recovery. Giving patients this critical internal locus of control will provide therapeutic benefits such as confidence,self-esteem, and hope that are likely to enhance changes that occur with intervention.