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Background: The 11 September 2001 (9/11) attacks were unprecedented in magnitude and mental health impact. While a large body of research has emerged since the attacks, published reviews are few, and are limited by an emphasis on cross-sectional research, short time frame, and exclusion of treatment studies. Additionally, to date, there has been no systematic review of available longitudinal information as a unique data set. Consequently, knowledge regarding long-term trajectories of 9/11-related post-traumatic stress disorder (PTSD) among highly exposed populations, and whether available treatment approaches effectively address PTSD within the context of mass, man-made disaster, remains limited. Methods: The present review aimed to address these gaps using a systematic review of peer-reviewed reports from October 2001 to May 2016. Eligible reports were of longitudinal studies of PTSD among highly exposed populations. We identified 20 reports of 9/11-related PTSD, including 13 longitudinal prevalence studies and seven treatment studies. Results: Findings suggest a substantial burden of 9/11-related PTSD among those highly exposed to the attack, associated with a range of sociodemographic and back-ground factors, and characteristics of peri-event exposure. While most longitudinal studies show declining rates of prevalence of PTSD, studies of rescue/recovery workers have documented an increase over time. Treatment studies were few, and generally limited by methodological shortcomings, but support exposure-based therapies. Conclusion: Future directions for research, treatment, and healthcare policy are discussed. [ABSTRACT FROM AUTHOR]

Although the cerebellum contributes to higher-order cognitive and emotional functions relevant to posttraumatic stress disorder (PTSD), prior research on cerebellar volume in PTSD is scant, particularly when considering subregions that differentially map on to motor, cognitive, and affective functions. In a sample of 4215 adults (PTSD n = 1642; Control n = 2573) across 40 sites from the ENIGMA-PGC PTSD working group, we employed a new state-of-the-art deep-learning based approach for automatic cerebellar parcellation to obtain 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 volumes in PTSD compared to healthy controls (88% trauma-exposed). PTSD was associated with significant grey and white matter reductions of the cerebellum. Compared to controls, people with PTSD demonstrated smaller total cerebellum volume, as well as reduced volume in subregions primarily within the posterior lobe (lobule VIIB, crus II), vermis (VI, VIII), flocculonodular lobe (lobule X), and corpus medullare (all p -FDR  < 0.05). Effects of PTSD on volume were consistent, and generally more robust, when examining symptom severity rather than diagnostic status. These findings implicate regionally specific cerebellar volumetric differences in the pathophysiology of PTSD. The cerebellum appears to play an important role in higher-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., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Posttraumatic stress disorder (PTSD) is associated with lower cortical thickness (CT) in prefrontal, cingulate, and insular cortices in diverse trauma-affected samples. However, some studies have failed to detect differences between PTSD patients and healthy controls or reported that PTSD is associated with greater CT. Using data-driven dimensionality reduction, we sought to conduct a well-powered study to identify vulnerable networks without regard to neuroanatomic boundaries. Moreover, this approach enabled us to avoid the excessive burden of multiple comparison correction that plagues vertex-wise methods. We derived structural covariance networks (SCNs) by applying non-negative matrix factorization (NMF) to CT data from 961 PTSD patients and 1124 trauma-exposed controls without PTSD. We used regression analyses to investigate associations between CT within SCNs and PTSD diagnosis (with and without accounting for the potential confounding effect of trauma type) and symptom severity in the full sample. We performed additional regression analyses in subsets of the data to examine associations between SCNs and comorbid depression, childhood trauma severity, and alcohol abuse. NMF identified 20 unbiased SCNs, which aligned closely with functionally defined brain networks. PTSD diagnosis was most strongly associated with diminished CT in SCNs that encompassed the bilateral superior frontal cortex, motor cortex, insular cortex, orbitofrontal cortex, medial occipital cortex, anterior cingulate cortex, and posterior cingulate cortex. CT in these networks was significantly negatively correlated with PTSD symptom severity. Collectively, these findings suggest that PTSD diagnosis is associated with widespread reductions in CT, particularly within prefrontal regulatory regions and broader emotion and sensory processing cortical regions., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: Recent advances in data-driven computational approaches have been helpful in devising tools to objectively diagnose psychiatric disorders. However, current machine learning studies limited to small homogeneous samples, different methodologies, and different imaging collection protocols, limit the ability to directly compare and generalize their results. Here we aimed to classify individuals with PTSD versus controls and assess the generalizability using a large heterogeneous brain datasets from the ENIGMA-PGC PTSD Working group., Methods: We analyzed brain MRI data from 3,477 structural-MRI; 2,495 resting state-fMRI; and 1,952 diffusion-MRI. First, we identified the brain features that best distinguish individuals with PTSD from controls 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., Results: We 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 in each modality (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., Conclusion: These results have the potential to provide a baseline classification performance for PTSD when using large scale neuroimaging datasets. Our findings show that the control group used can heavily affect classification performance. The DVAE framework provided better generalizability for the multi-site data. This may be more significant in clinical practice since the neuroimaging-based diagnostic DVAE classification models are much less site-specific, rendering them more generalizable., Competing Interests: Declaration of Competing Interest Dr. Thompson received partial grant support from Biogen, Inc., and Amazon, Inc., for work unrelated to the current study; Dr. Lebois reports unpaid membership on the Scientific Committee for International Society for the Study of Trauma and Dissociation (ISSTD), grant support from the National Institute of Mental Health, K01 MH118467 and the Julia Kasparian Fund for Neuroscience Research, McLean Hospital. Dr. Lebois also reports spousal IP payments from Vanderbilt University for technology licensed to Acadia Pharmaceuticals unrelated to the present work. ISSTD and NIMH were not involved in the analysis or preparation of the manuscript; Dr. Etkin reports salary and equity from Alto Neuroscience, equity from Mindstrong Health and Akili Interactive. Other authors have no conflicts of interest to declare., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: In a recent eye-tracking study we found a differential dwell time pattern for negatively-valenced and neutral faces among patients with posttraumatic stress disorder (PTSD), trauma-exposed healthy control (TEHCs), and healthy control (HC) participants. Here, we explored whether these group differences relate to resting-state functional connectivity (rsFC) patterns of brain areas previously linked to both attention processes and PTSD. These encompass the amygdala, dorsal anterior cingulate cortex (dACC), dorsolateral prefrontal cortex (dlPFC), ventrolateral prefrontal cortex (vlPFC), and nucleus accumbens (NAcc)., Methods: Ten minutes magnetic resonance imaging rsFC scans were recorded in 17 PTSD patients, 21 TEHCs, and 16 HCs. Participants then completed a free-viewing eye-tracking task assessing attention allocation outside the scanner. Dwell time on negatively-valenced stimuli (DT%) were assessed relative to functional connectivity in the aforementioned seed regions of interest (amygdala, dACC, dlPFC, vlPFC, and NAcc) to whole-brain voxel-wise rsFC., Results: As previously reported, group differences occurred in attention allocation to negative-valence stimuli, with longer dwell time on negatively valence stimuli in the PTSD and TEHC groups than the HC group. Higher DT% correlated with weaker NAcc-orbitofrontal cortex (OFC) connectivity in patients with PTSD. Conversely, a positive association emerged in the HC group between DT% and NAcc-OFC connectivity., Conclusions: While exploratory in nature, present findings may suggest that reward-related brain areas are involved in disengaging attention from negative-valenced stimuli, and possibly in regulating ensuing negative emotions.

Background: Intrusive traumatic re-experiencing domain (ITRED) was recently introduced as a novel perspective on posttraumatic psychopathology, proposing to focus research of posttraumatic stress disorder (PTSD) on the unique symptoms of intrusive and involuntary re-experiencing of the trauma, namely, intrusive memories, nightmares, and flashbacks. The aim of the present study was to explore ITRED from a neural network connectivity perspective., Methods: Data were collected from 9 sites taking part in the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) PTSD Consortium ( n = 584) and included itemized PTSD symptom scores and resting-state functional connectivity (rsFC) data. We assessed the utility of rsFC in classifying PTSD, ITRED-only (no PTSD diagnosis), and trauma-exposed (TE)-only (no PTSD or ITRED) groups using a machine learning approach, examining well-known networks implicated in PTSD. A random forest classification model was built on a training set using cross-validation, and the averaged cross-validation model performance for classification was evaluated using the area under the curve. The model was tested using a fully independent portion of the data (test dataset), and the test area under the curve was evaluated., Results: rsFC signatures differentiated TE-only participants from PTSD and ITRED-only participants at about 60% accuracy. Conversely, rsFC signatures did not differentiate PTSD from ITRED-only individuals (45% accuracy). Common features differentiating TE-only participants from PTSD and ITRED-only participants mainly involved default mode network-related pathways. Some unique features, such as connectivity within the frontoparietal network, differentiated TE-only participants from one group (PTSD or ITRED-only) but to a lesser extent from the other group., Conclusions: Neural network connectivity supports ITRED as a novel neurobiologically based approach to classifying posttrauma psychopathology., (© 2023 The Authors.)

Amplified attention allocation to negative information in one's environment has been implicated in posttraumatic stress disorder (PTSD). Attention bias variability (ABV), the magnitude of attention fluctuation between negative and neutral cues, has also been found to be elevated in PTSD. While eye-tracking methodology has been used in research on attention allocation in PTSD, ABV was only explored using manual reaction-time-based indices. Thirty-seven participants with PTSD, 34 trauma-exposed healthy controls (TEHC), and 30 non-exposed healthy controls (HC) completed an eye-tracking free-viewing task in which matrices comprised of neutral and negatively-valenced faces were presented. Threat-related attention allocation was calculated as the proportion of dwell time (DT%) on negatively-valenced faces. Eye-tracking-based ABV was calculated as the standard deviation of DT% across matrices. DT% on negatively-valenced faces was greater in participants with PTSD compared to both TEHC (p = .036, d = 0.50) and HC (p < .001, d = 1.03), with TEHCs showing a greater attentional bias compared to HCs (p = .001, d = 0.84). Controlling for average fixation duration, ABV was higher in both the PTSD and TEHC groups relative to the HC group (p = .004, d = 0.40), with no difference between the two trauma-exposed groups. Biased attention allocation toward negative social information is related to PTSD pathology, whereas elevated ABV measured with eye-tracking appear to be related to trauma-exposure per-se., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: The hippocampus plays an important role in the pathophysiology of posttraumatic stress disorder (PTSD) and its prognosis. Accumulating findings suggest that individuals with larger pretreatment hippocampal volume are more likely to benefit from PTSD treatment, but the mechanism underlying this effect is unknown. We investigated whether further increase in hippocampal volume during treatment explains the better prognosis of individuals with greater pretreatment hippocampal volume., Methods: We collected structural magnetic resonance imagesfrom patients with PTSD before and after treatment. We examined whether larger hippocampal volume moderates the effect of increased hippocampal volume during treatment on symptom reduction. Given the relatively small sample sizes of treatment studies with pre- and posttreatment magnetic resonance imaging, we focused on effect sizes and sought to replicate findings in an external sample. We tested our hypothesis in study 1 ( N  = 38; prolonged exposure therapy) and then tested whether the results could be externally replicated in study 2 ( N  = 20; ketamine infusion followed by exposure therapy)., Results: Findings from study 1 revealed that increased right hippocampal volume during treatment was associated with greater PTSD symptom reduction only in patients with greater pretreatment right hippocampal volume ( p  = .03; η 2  = 0.13, a large effect). Findings were partially replicated in study 2 for depressive symptoms ( p  = .034; η 2  = 0.25, a very large effect) and for PTSD symptoms ( p  = .15; η 2  = 0.15, a large effect)., Conclusions: Elucidating increased hippocampal volume as one of the neural mechanisms predictive of therapeutic outcome for individuals with larger pretreatment hippocampal volume may help identify clinical targets for this subgroup., (© 2023 The Authors.)

Background: Patients with posttraumatic stress disorder (PTSD) tend to overgeneralize threat to safe stimuli, potentially reflecting aberrant stimuli discrimination. Yet, it is not clear whether threat overgeneralization reflects general discrimination deficits, or rather a specific bias related to aversive stimuli. Here we tested this question and characterized the neural correlates of threat discrimination., Methods: One-hundred and eight participants (33 PTSD; 43 trauma-exposed controls; 32 healthy controls) completed an emotionally neutral complex shape discrimination task involving identifying in 42 similar pairs the previously observed shape; and an emotionally aversive discrimination task, involving providing risk ratings for an aversive conditioned stimulus (CS+), and for several stimuli gradually differing in size from the original CS+. Resting state functional connectivity (rsFC) was collected before completing the tasks., Results: No group differences emerged on the emotionally neutral task. Conversely, on the emotionally aversive task, individuals with PTSD had steeper linear risk rating slopes as the stimuli more resembled the conditioned stimulus. Finally, lower rsFC of amygdala-default mode network (DMN) and DMN-salience network (SN) were associated with steeper risk slopes, while for hippocampus-SN, lower rsFC was found only among participants with PTSD., Conclusions: Individuals with PTSD show deficits in discrimination only when presented with aversive stimuli. Dysregulated discrimination pattern may relate to a lack of input from regulatory brain areas (e.g., DMN/hippocampus) to threat-related brain areas (e.g., SN/amygdala)., (© 2022 Wiley Periodicals LLC.)

While impaired fear generalization is known to underlie a wide range of psychopathology, the extent to which exposure to trauma by itself results in deficient fear generalization and its neural abnormalities is yet to be studied. Similarly, the neural function of intact fear generalization in people who endured trauma and did not develop significant psychopathology is yet to be characterized. Here, we utilize a generalization fMRI task, and a network connectivity approach to clarify putative behavioral and neural markers of trauma and resilience. The generalization task enables longitudinal assessments of threat discrimination learning. Trauma-exposed participants (TE; N = 62), compared to healthy controls (HC; N = 26), show lower activity reduction in salience network (SN) and right executive control network (RECN) across the two sequential generalization stages, and worse discrimination learning in SN measured by linear deviation scores (LDS). Comparison of resilient, trauma-exposed healthy control participants (TEHC; N = 31), trauma exposed individuals presenting with psychopathology (TEPG; N = 31), and HC, reveals a resilience signature of network connectivity differences in the RECN during generalization learning measured by LDS. These findings may indicate a trauma exposure phenotype that has the potential to advance the development of innovative treatments by targeting and engaging specific neural dysfunction among trauma-exposed individuals, across different psychopathologies., (© 2022. The Author(s).)

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 (LME INT ), (2) LME that models both site-specific random intercepts and age-related random slopes (LME INT+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 1,340 cases with posttraumatic stress disorder (PTSD) (6.2-81.8 years old) and 2,057 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 was more sensitive to the detection of significant case-control differences (Χ 2 (3) = 63.704, p < 0.001) as well as case-control differences in age-related cortical thinning (Χ 2 (3) = 12.082, p = 0.007). Both ComBat and ComBat-GAM outperformed LME methods in detecting sex differences (Χ 2 (3) = 9.114, p = 0.028) in regional cortical thickness. ComBat-GAM also led to stronger estimates of age-related declines in cortical thickness (corrected p-values < 0.001), stronger estimates of case-related cortical thickness reduction (corrected p-values < 0.001), weaker estimates of age-related declines in cortical thickness in cases than controls (corrected p-values < 0.001), stronger estimates of cortical thickness reduction in females than males (corrected p-values < 0.001), and stronger estimates of cortical thickness reduction in females relative to males in cases than controls (corrected p-values < 0.001). Our results support the use of ComBat-GAM to minimize confounds and increase statistical power when harmonizing data with non-linear effects, and the use of either ComBat or ComBat-GAM for harmonizing data with linear effects., Competing Interests: Conflicts of Interest Dr. Abdallah has served as a consultant, speaker and/or on advisory boards for FSV7, Lundbeck, Psilocybin Labs, Genentech and Janssen, and editor of Chronic Stress for Sage Publications, Inc.; he has filed a patent for using mTOR inhibitors to augment the effects of antidepressants (filed on August 20, 2018). Dr. Davidson is the founder and president of, and serves on the board of directors for, the non-profit organization Healthy Minds Innovations, Inc. Dr. Jahanshad, Dr. Thompson and Dr. Ching received partial research support from Biogen, Inc. (Boston, USA) for research unrelated to the content of this manuscript. Dr. Krystal is a consultant for AbbVie, Inc., Amgen, Astellas Pharma Global Development, Inc., AstraZeneca Pharmaceuticals, Biomedisyn Corporation, Bristol-Myers Squibb, Eli Lilly and Company, Euthymics Bioscience, Inc., Neurovance, Inc., FORUM Pharmaceuticals, Janssen Research & Development, Lundbeck Research USA, Novartis Pharma AG, Otsuka America Pharmaceutical, Inc., Sage Therapeutics, Inc., Sunovion Pharmaceuticals, Inc., and Takeda Industries; is on the Scientific Advisory Board for Lohocla Research Corporation, Mnemosyne Pharmaceuticals, Inc., Naurex, Inc., and Pfizer; is a stockholder in Biohaven Pharmaceuticals; holds stock options in Mnemosyne Pharmaceuticals, Inc.; holds patents for Dopamine and Noradrenergic Reuptake Inhibitors in Treatment of Schizophrenia, US Patent No. 5,447,948 (issued September 5, 1995), and Glutamate Modulating Agents in the Treatment of Mental Disorders, U.S. Patent No. 8,778,979 (issued July 15, 2014); and filed a patent for Intranasal Administration of Ketamine to Treat Depression. U.S. Application No. 14/197,767 (filed on March 5, 2014); US application or Patent Cooperation Treaty international application No. 14/306,382 (filed on June 17, 2014); Filed a patent for using mTOR inhibitors to augment the effects of antidepressants (filed on August 20, 2018). Dr. Schmahl is a consultant for Boehringer Ingelheim International GmbH. Dr. Stein has received research grants and/or consultancy honoraria from Lundbeck and Sun. Dr. Lebois reports unpaid membership on the Scientific Committee for the International Society for the Study of Trauma and Dissociation (ISSTD) and spousal license payment for Vanderbilt IP from Acadia Pharmaceuticals unrelated to the topic of this manuscript. All other authors have no conflicts of interest to declare., (Copyright © 2022. Published by Elsevier Inc.)

Background: Studies have searched for neurobiological markers of trauma exposure, posttraumatic stress disorder (PTSD) diagnosis, and resilience to trauma to identify therapeutic targets for PTSD. Despite some promising results, findings are inconsistent., Aims: The present study adopted a data-driven approach to systematically explore whether structural brain markers of trauma, PTSD, or resilience emerge when all are explored., Materials & Methods: Differences between clusters in the proportion of PTSD, healthy controls (HC), and trauma-exposed healthy controls (TEHC) served to indicate the presence of PTSD, trauma, and resilience markers, respectively. A total of 129 individuals, including 46 with PTSD, 49 TEHCs, and 34 HCs not exposed to trauma were scanned. Volumes, cortical thickness, and surface areas of interest were obtained from T1 structural MRI and used to identify data-driven clusters., Results: Two clusters were identified, differing in the proportion of TEHCs but not of PTSDs or HCs. The cluster with the higher proportion of TEHCs, referred to as the resilience cluster, was characterized by higher volume in brain regions implicated in trauma exposure, especially the thalamus and rostral middle frontal gyrus. Cross-validation established the robustness and consistency of the identified clusters., Discussion & Conclusion: Findings support the existence of structural brain markers of resilience., (© 2022 The Authors. Depression and Anxiety published by Wiley Periodicals LLC.)

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., (Copyright © 2022 Society of Biological Psychiatry. All rights reserved.)

Background: Psychotherapy noncompletion rates for veterans and their families are high. This study sought to (a) measure noncompletion rates of such patients at a university-based treatment center, (b) compare veteran and family member attrition rates, (c) identify dropout predictors, and (d) explore clinicians' perspectives on treatment noncompletion., Method: Using quantitative and qualitative approaches, we analyzed demographic and clinical characteristics of 141 patients (90 military veterans; 51 family members) in a university treatment center. We defined dropout as not completing the time-limited therapy contract. Reviewing semistructured interview data assessing clinicians' perspectives on their patients' dropout, three independent raters agreed on key themes, with interrater coefficient kappa range .74 to 1., Results: Patient attrition was 24%, not differing significantly between veterans and family members. Diagnosis of major depression (MDD) and exposure-based therapies predicted noncompletion, as did higher baseline Hamilton Depression Rating Scale (HDRS) total scores, severe depression (HDRS > 20), lack of Beck Depression Inventory weekly improvement, and history of military sexual trauma. Clinicians mostly attributed noncompletion to patient difficulties coping with intense emotions, especially in exposure-based therapies., Conclusion: Noncompletion rate at this study appeared relatively low compared to other veteran-based treatment centers, if still unfortunately substantial. Patients with comorbid MDD/PTSD and exposure-based therapies carried greater noncompletion risk due to the MDD component, and this should be considered in treatment planning. Ongoing discussion of dissatisfaction and patient discontinuation, in the context of a strong therapeutic alliance, might reduce noncompletion in this at-risk population. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Background: Posttraumatic stress disorder (PTSD) is associated with markers of accelerated aging. Estimates of brain age, compared to chronological age, may clarify the effects of PTSD on the brain and may inform treatment approaches targeting the neurobiology of aging in the context of PTSD., Method: Adult subjects (N = 2229; 56.2% male) aged 18-69 years (mean = 35.6, SD = 11.0) from 21 ENIGMA-PGC PTSD sites underwent T1-weighted brain structural magnetic resonance imaging, and PTSD assessment (PTSD+, n = 884). Previously trained voxel-wise (brainageR) and region-of-interest (BARACUS and PHOTON) machine learning pipelines were compared in a subset of control subjects (n = 386). Linear mixed effects models were conducted in the full sample (those with and without PTSD) to examine the effect of PTSD on brain predicted age difference (brain PAD; brain age - chronological age) controlling for chronological age, sex, and scan site., Results: BrainageR most accurately predicted brain age in a subset (n = 386) of controls (brainageR: ICC = 0.71, R = 0.72, MAE = 5.68; PHOTON: ICC = 0.61, R = 0.62, MAE = 6.37; BARACUS: ICC = 0.47, R = 0.64, MAE = 8.80). Using brainageR, a three-way interaction revealed that young males with PTSD exhibited higher brain PAD relative to male controls in young and old age groups; old males with PTSD exhibited lower brain PAD compared to male controls of all ages., Discussion: Differential impact of PTSD on brain PAD in younger versus older males may indicate a critical window when PTSD impacts brain aging, followed by age-related brain changes that are consonant with individuals without PTSD. Future longitudinal research is warranted to understand how PTSD impacts brain aging across the lifespan., (© 2021 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

Anxiety disorders are characterized by maladaptive defensive responses to distal or uncertain threats. Elucidating neural mechanisms of anxiety is essential to understand the development and maintenance of anxiety disorders. In fMRI, patients with pathological anxiety (ANX, n = 23) and healthy controls (HC, n = 28) completed a contextual threat learning paradigm in which they picked flowers in a virtual environment comprising a danger zone in which flowers were paired with shock and a safe zone (no shock). ANX compared with HC showed 1) decreased ventromedial prefrontal cortex and anterior hippocampus activation during the task, particularly in the safe zone, 2) increased insula and dorsomedial prefrontal cortex activation during the task, particularly in the danger zone, and 3) increased amygdala and midbrain/periaqueductal gray activation in the danger zone prior to potential shock delivery. Findings suggest that ANX engage brain areas differently to modulate context-appropriate emotional responses when learning to discriminate cues within an environment., (© 2021. The Author(s).)

Background: Posttraumatic stress disorder (PTSD) is twice as prevalent among females as compared to males following potentially traumatic events. While there is evidence for aberrant functional connectivity between hubs of the central executive network (CEN), salience network (SN), and the default mode network (DMN) in PTSD, little is known regarding sex-specificity of this connectivity. The current study aims to directly examine sex-specific resting-state functional connectivity (rs-FC) in trauma exposed males and females, with and without PTSD., Methods: One hundred and seventy-eight individuals underwent functional magnetic resonance imaging (fMRI) at rest, of them 85 females (45 with PTSD) and 93 males (57 with PTSD). We conducted whole-brain seed-based analysis using CEN (lateral prefrontal cortex [lPFC]), SN (anterior cingulate cortex [ACC], insula, amygdala [AMG]), and DMN (medial prefrontal cortex [mPFC], posterior parietal cortex [PCC], and hippocampus [HIP]) hubs as seed regions. Group-by-Sex ANOVA was conducted., Results: The amygdala-precuneus, ACC-precuneus, and hippocampus-precuneus pathways exhibited significant group-by-sex interaction effects, with females with PTSD consistently differing in connectivity patterns from males with PTSD and from trauma-exposed healthy females., Conclusions: Sex-specific neural connectivity patterns were found within and between key nodes of the CEN, DMN, and the SN, suggesting opposite patterns of connectivity in PTSD and trauma-exposed controls as a function of sex as a biological variable (SABV). This may point to mechanistic sex differences in adaptation following trauma and may inform differential neural targets for treatment of females and males with PTSD., (© 2021 The Authors.)

Objective: As veterans have high rates of posttraumatic stress disorder (PTSD) and historically poor treatment outcomes and high attrition, alternative treatments have gained much popularity despite lack of rigorous research. In this study, a recently developed and manualized 8-session group Equine-Assisted Therapy for PTSD (EAT-PTSD) was tested in an open trial to assess its preliminary feasibility, acceptability, and outcomes for military veterans., Methods: The study was conducted from July 2016 to July 2019. Sixty-three treatment-seeking veterans with PTSD enrolled. PTSD diagnosis was ascertained using the Structured Clinical Interview for DSM-5 , Research Version (SCID-5-RV) and confirmed using the Clinician-Administered PTSD Scale (CAPS-5). Mean age was 50 years, and 23 patients (37%) were women. Clinician and self-report measures of PTSD and depression were assessed at pretreatment, midtreatment, and posttreatment and at a 3-month follow-up. An intent-to-treat analysis and a secondary analysis of those who completed all 4 clinical assessments were utilized., Results: Only 5 patients (8%) withdrew from treatment, 4 before midtreatment and 1 afterward. Posttreatment assessment revealed marked reductions in both clinician-rated and self-reported PTSD and depression symptoms, which persisted at 3-month follow-up. Specifically, mean (SD) CAPS-5 scores fell from 38.6 (8.1) to 26.9 (12.4) at termination. Thirty-two patients (50.8%) showed clinically significant change (≥ 30% decrease in CAPS-5 score) at posttreatment and 34 (54.0%) at follow-up., Conclusions: Manualized EAT-PTSD shows promise as a potential new intervention for veterans with PTSD. It appears safe, feasible, and clinically viable. These preliminary results encourage examination of EAT-PTSD in larger, randomized controlled trials., Trial Registration: ClinicalTrials.gov identifier: NCT03068325., (© Copyright 2021 Physicians Postgraduate Press, Inc.)

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 3047 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 1426 individuals with PTSD and 1621 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, for which structure and function have been consistently implicated in PTSD. Results were consistent even 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., (© 2019. The Author(s), under exclusive licence to Springer Nature Limited.)

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., (© 2020. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: While effective treatments for posttraumatic stress disorder (PTSD) exist, many individuals, including military personnel and veterans fail to respond to them. Equine-assisted therapy (EAT), a novel PTSD treatment, may complement existing PTSD interventions. This study employs longitudinal neuro-imaging, including structural magnetic resonance imaging (sMRI), resting state-fMRI (rs-fMRI), and diffusion tensor imaging (DTI), to determine mechanisms and predictors of EAT outcomes for PTSD., Method: Nineteen veterans with PTSD completed eight weekly group sessions of EAT undergoing multimodal MRI assessments before and after treatment. Clinical assessments were conducted at baseline, post-treatment and at 3-month follow-up., Results: At post-treatment patients showed a significant increase in caudate functional connectivity (FC) and reduction in the gray matter density of the thalamus and the caudate. The increase of caudate FC was positively associated with clinical improvement seen immediately at post-treatment and at 3-month follow-up. In addition, higher baseline caudate FC was associated with greater PTSD symptom reduction post-treatment., Conclusions: This exploratory study is the first to demonstrate that EAT can affect functional and structural changes in the brains of patients with PTSD. The findings suggest that EAT may target reward circuitry responsiveness and produce a caudate pruning effect from pre- to post-treatment., (© 2021 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Background: Eye-tracking-based attentional research implicates sustained attention to threat in posttraumatic stress disorder (PTSD). However, most of this research employed small stimuli set-sizes, small samples that did not include both trauma-exposed healthy participants and non-trauma-exposed participants, and generally failed to report the reliability of used tasks and attention indices. Here, using an established eye-tracking paradigm, we explore attention processes to different negatively-valenced cues in PTSD while addressing these limitations., Methods: PTSD patients (n = 37), trauma-exposed healthy controls (TEHC; n = 34), and healthy controls (HC; n = 30) freely viewed three blocks of 30 different matrices of faces, each presented for 6 s. Each block consisted of matrices depicting eight negatively-valenced faces (anger, fear, or sadness) and eight neutral faces. Gaze patterns on negative and neural areas of interest were compared. Internal consistency and test-retest reliability were evaluated for the entire sample and within groups., Results: The two trauma-exposed groups dwelled longer on negatively-valenced faces over neutral faces, while HC participants showed the opposite pattern. This attentional bias was more prominent in the PTSD than the TEHC group. Similar results emerged for first-fixation dwell time, but with no differences between the two trauma-exposed groups. No group differences emerged for first-fixation latency or location. Internal consistency and 1-week test-retest reliability were adequate, across and within groups., Conclusions: Sustained attention on negatively-valenced stimuli emerges as a potential target for therapeutic intervention in PTSD designed to divert attention away from negatively-valenced stimuli and toward neutral ones.

Background: In the network approach to psychopathology, psychiatric disorders are considered networks of causally active symptoms (nodes), with node centrality hypothesized to reflect symptoms' causal influence within a network. Accordingly, centrality measures have been used in numerous network-based cross-sectional studies to identify specific treatment targets, based on the assumption that deactivating highly central nodes would proliferate to other nodes in the network, thereby collapsing the network structure and alleviating the overall psychopathology (i.e., the centrality hypothesis)., Methods: Here, we summarize three types of evidence pertaining to the centrality hypothesis in psychopathology. First, we discuss the validity of the theoretical assumptions underlying the centrality hypothesis in psychopathology. We then summarize the methodological aspects of extant studies using centrality measures as predictors of symptom change following treatment, while delineating their main findings and several of their limitations. Finally, using a specific dataset of 710 treatment-seeking patients with posttraumatic stress disorder (PTSD) as an example, we empirically examine node centrality as a predictor of therapeutic change, replicating the approach taken by previous studies, while addressing some of their limitations. Specifically, we investigated whether three pre-treatment centrality indices (strength, predictability, and expected influence) were significantly correlated with the strength of the association between a symptom's change and the change in the severity of all other symptoms in the network from pre- to post-treatment (Δnode-Δnetwork association). Using similar analyses, we also examine the predictive validity of two simple non-causal node properties (mean symptom severity and infrequency of symptom endorsement)., Results: Of the three centrality measures, only expected influence successfully predicted how strongly changes in nodes/symptoms were associated with change in the remainder of the nodes/symptoms. Importantly, when excluding the amnesia node, a well-documented outlier in the phenomenology of PTSD, none of the tested centrality measures predicted symptom change. Conversely, both mean symptom severity and infrequency of symptom endorsement, two standard non-network-derived indices, were found to be more predictive than expected influence and remained significantly predictive also after excluding amnesia from the network analyses., Conclusions: The centrality hypothesis in its current form is ill-defined, showing no consistent supporting evidence in the context of cross-sectional, between-subject networks.

Background: Establishing neurobiological markers of posttraumatic stress disorder (PTSD) is essential to aid in diagnosis and treatment development. Fear processing deficits are central to PTSD, and their neural signatures may be used as such markers., Methods: Here, we conducted a meta-analysis of seven Pavlovian fear conditioning fMRI studies comparing 156 patients with PTSD and 148 trauma-exposed healthy controls (TEHC) using seed-based d-mapping, to contrast neural correlates of experimental phases, namely conditioning, extinction learning, and extinction recall., Results: Patients with PTSD, as compared to TEHCs, exhibited increased activation in the anterior hippocampus (extending to the amygdala) and medial prefrontal cortex during conditioning; in the anterior hippocampus-amygdala regions during extinction learning; and in the anterior hippocampus-amygdala and medial prefrontal areas during extinction recall. Yet, patients with PTSD have shown an overall decreased activation in the thalamus during all phases in this meta-analysis., Conclusion: Findings from this metanalysis suggest that PTSD is characterized by increased activation in areas related to salience and threat, and lower activation in the thalamus, a key relay hub between subcortical areas. If replicated, these fear network alterations may serve as objective diagnostic markers for PTSD, and potential targets for novel treatment development, including pharmacological and brain stimulation interventions. Future longitudinal studies are needed to examine whether these observed network alteration in PTSD are the cause or the consequence of PTSD.

Background: Comorbidity between posttraumatic stress disorder (PTSD) and major depressive disorder (MDD) has been commonly overlooked by studies examining resting-state functional connectivity patterns in PTSD. The current study used a data-driven approach to identify resting-state functional connectivity biomarkers to 1) differentiate individuals with PTSD (with or without MDD) from trauma-exposed healthy control subjects (TEHCs), 2) compare individuals with PTSD alone with those with comorbid PTSD+MDD, and 3) explore the clinical utility of the identified biomarkers by testing their associations with clinical symptoms and treatment response., Methods: Resting-state magnetic resonance images were obtained from 51 individuals with PTSD alone, 52 individuals with PTSD+MDD, and 76 TEHCs. Of the 103 individuals with PTSD, 55 were enrolled in prolonged exposure treatment. A support vector machine model was used to identify resting-state functional connectivity biomarkers differentiating individuals with PTSD (with or without MDD) from TEHCs and differentiating individuals with PTSD alone from those with PTSD+MDD. The associations between the identified features and symptomatology were tested with Pearson correlations., Results: The support vector machine model achieved 70.6% accuracy in discriminating between individuals with PTSD and TEHCs and achieved 76.7% accuracy in discriminating between individuals with PTSD alone and those with PTSD+MDD for out-of-sample prediction. Within-network connectivity in the executive control network, prefrontal network, and salience network discriminated individuals with PTSD from TEHCs. The basal ganglia network played an important role in differentiating individuals with PTSD alone from those with PTSD+MDD. PTSD scores were inversely correlated with within-executive control network connectivity (p < .001), and executive control network connectivity was positively correlated with treatment response (p < .001)., Conclusions: Results suggest that unique brain-based abnormalities differentiate individuals with PTSD from TEHCs, differentiate individuals with PTSD from those with PTSD+MDD, and demonstrate clinical utility in predicting levels of symptomatology and treatment response., (Copyright © 2020 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: The hippocampus plays an important role in psychopathology and treatment outcome. While posterior hippocampus (PH) may be crucial for the learning process that exposure-based treatments require, affect-focused treatments might preferentially engage anterior hippocampus (AH). Previous studies have distinguished the different functions of these hippocampal sub-regions in memory, learning, and emotional processes, but not in treatment outcome. Examining two independent clinical trials, we hypothesized that anterior hippocampal volume would predict outcome of affect-focused treatment outcome [Interpersonal Psychotherapy (IPT); Panic-Focused Psychodynamic Psychotherapy (PFPP)], whereas posterior hippocampal volume would predict exposure-based treatment outcome [Prolonged Exposure (PE); Cognitive Behavioral Therapy (CBT); Applied Relaxation Training (ART)]., Methods: Thirty-five patients with posttraumatic stress disorder (PTSD) and 24 with panic disorder (PD) underwent structural magnetic resonance imaging (MRI) before randomization to affect-focused (IPT for PTSD; PFPP for PD) or exposure-based treatments (PE for PTSD; CBT or ART for PD). AH and PH volume were regressed with clinical outcome changes., Results: Baseline whole hippocampal volume did not predict post-treatment clinical severity scores in any treatment. For affect-focused treatments, but not exposure-based treatments, anterior hippocampal volume predicted clinical improvement. Smaller AH correlated with greater affect-focused treatment improvement. Posterior hippocampal volume did not predict treatment outcome., Conclusions: This is the first study to explore associations between hippocampal volume sub-regions and treatment outcome in PTSD and PD. Convergent results suggest that affect-focused treatment may influence the clinical outcome through the 'limbic' AH, whereas exposure-based treatments do not. These preliminary, theory-congruent, therapeutic findings require replication in a larger clinical trial.

Background: Randomized control trials (RCTs) comparing attention control training (ACT) and attention bias modification (ABM) in posttraumatic stress disorder (PTSD) have shown mixed results. The current RCT extends the extant literature by comparing the efficacy of ACT and a novel bias-contingent-ABM (BC-ABM), in which direction of training is contingent upon the direction of pre-treatment attention bias (AB), in a sample of civilian patients with PTSD., Methods: Fifty treatment-seeking civilian patients with PTSD were randomly assigned to either ACT or BC-ABM. Clinician and self-report measures of PTSD and depression, as well as AB and attention bias variability (ABV), were acquired pre- and post-treatment., Results: ACT yielded greater reductions in PTSD and depressive symptoms on both clinician-rated and self-reported measures compared with BC-ABM. The BC-ABM condition successfully shifted ABs in the intended training direction. In the ACT group, there was no significant change in ABV or AB from pre- to post-treatment., Conclusions: The current RCT extends previous results in being the first to apply ABM that is contingent upon AB at pre-treatment. This personalized BC-ABM approach is associated with significant reductions in symptoms. However, ACT produces even greater reductions, thereby emerging as a promising treatment for PTSD.

Background: Cognitive models of posttraumatic stress disorder (PTSD) implicate threat-related attentional biases in the etiology and phenomenology of the disorder. However, extant attentional research using reaction time (RT)-based paradigms and measures has yielded mixed results. Eye-tracking methodology has emerged in recent years to overcome several inherent drawbacks of RT-based tasks, striving to better delineate attentional processes., Methods: A systematic review of experimental studies examining threat-related attention biases in PTSD, using eye-tracking methodology and group-comparison designs, was conducted conforming to Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. Studies were selected following a systematic search for publications between 1980 and December 2017 in PsycINFO, MEDLINE and the National Center for PTSD Research's Published International Literature on Traumatic Stress (PILOTS) database. Additional records were identified by employing the Similar Articles feature in PubMed, and the Cited Reference Search in ISI Web of Science. Reference sections of review articles, book chapters and studies selected for inclusion were searched for further studies. Ongoing studies were also sought through Clinicaltrials.gov., Results: A total of 11 studies (n = 456 participants in total) were included in the final review. Results indicated little support for enhanced threat detection, hypervigilance and attentional avoidance. However, consistent evidence emerged for sustained attention on threat (i.e. attention maintenance) in PTSD., Conclusions: This review is the first to systematically evaluate extant findings in PTSD emanating from eye-tracking studies employing group-comparison designs. Results suggest that sustained attention on threat might serve as a potential target for therapeutic intervention.

The Military Family Wellness Center at Columbia University Irving Medical Center provides cost-free, confidential mental health services to military service members, veterans, and their families in a nongovernmental setting, with an emphasis on addressing gaps in available care. Partnerships with academic institutions and collaboration with veteran organizations, regional stakeholders, and local Veterans Administration centers facilitate cross-site referrals, enhance knowledge and expertise, and advance shared goals. This article describes the development of these relationships, focusing on key priorities, barriers overcome, and lessons learned. Future directions are discussed.

Background: Recent research suggests that posttraumatic stress disorder (PTSD) is associated with altered amygdala and hippocampal resting-state functional connectivity (rsFC). However, less research has examined whether Prolonged Exposure (PE), a first line exposure-based treatment for PTSD, has the potential to alter resting state neural networks., Methods: A total of 24 patients with PTSD and 26 matched trauma-exposed healthy controls (TEHCs) underwent resting-state functional magnetic resonance imaging (fMRI) at baseline. PTSD patients were scanned a second time after completing 10-session PE in which patients narrated a detailed trauma account (imaginal exposure) and confronted trauma reminders (in vivo exposure) to extinguish trauma-related fear responses. TEHC were scanned again following a 10-week waiting period. Seed regions of interest (ROIs) included centromedial amygdala (CMA), basolateral amygdala (BLA), and the hippocampus., Results: Post- versus pretreatment comparisons indicated increased rsFC of the BLA and CMA with the orbitofrontal cortex (OFC), and hippocampus-medial prefrontal cortex (mPFC) among patients with PTSD, but not among TEHC participants., Conclusions: Enhanced amygdala and hippocampus rsFC with prefrontal cortical regions following PE could underlie improved capacity for inhibition and re-evaluation of threat, and heightened memory encoding and retrieval ability, respectively. These findings encourage further investigation of this circuitry as a therapeutic target in PTSD., (© 2018 Wiley Periodicals, Inc.)

Learning locations of danger within our environment is a vital adaptive ability whose neural bases are only partially understood. We examined fMRI brain activity while participants navigated a virtual environment in which flowers appeared and were "picked." Picking flowers in the danger zone (one-half of the environment) predicted an electric shock to the wrist (or "bee sting"); flowers in the safe zone never predicted shock; and household objects served as controls for neutral spatial memory. Participants demonstrated learning with shock expectancy ratings and skin conductance increases for flowers in the danger zone. Patterns of brain activity shifted between overlapping networks during different task stages. Learning about environmental threats, during flower approach in either zone, engaged the anterior hippocampus, amygdala, and ventromedial prefrontal cortex (vmPFC), with vmPFC-hippocampal functional connectivity increasing with experience. Threat appraisal, during approach in the danger zone, engaged the insula and dorsal anterior cingulate (dACC), with insula-hippocampal functional connectivity. During imminent threat, after picking a flower, this pattern was supplemented by activity in periaqueductal gray (PAG), insula-dACC coupling, and posterior hippocampal activity that increased with experience. We interpret these patterns in terms of multiple representations of spatial context (anterior hippocampus); specific locations (posterior hippocampus); stimuli (amygdala); value (vmPFC); threat, both visceral (insula) and cognitive (dACC); and defensive behaviors (PAG), interacting in different combinations to perform the functions required at each task stage. Our findings illuminate how we learn about location-specific threats and suggest how they might break down into overgeneralization or hypervigilance in anxiety disorders., Competing Interests: The authors declare no conflict of interest.

Purpose of Review: Sex differences in the epidemiology and clinical presentation of trauma-related psychopathology have long been documented. Multiple underlying mechanisms have been examined, both psychosocial and biological. Among the most promising biological mechanisms are neural substrates of trauma-related psychopathology that have been uncovered in recent years., Recent Findings: Neuroimaging studies of sex-related heterogeneity published over the past 3 years (2014-2017) demonstrate an interaction between sex and type, timing, and load of trauma exposure. These studies suggest that, for males, early trauma exposure may involve a loss of gray matter in the limbic system, including the prefrontal cortex (PFC), amygdala, and hippocampus, and an over-activity and increased connectivity of salience hubs, and particularly dorsal anterior cingulate cortex (dACC). For females, however, early trauma exposure may involve overactive and possibly an enlarged amygdala, as well as decreased connectivity of salience hubs such as the dACC. Underlying mechanisms may include interaction with several endocrine systems and result in differential neural response to naturally occurring and added endocrine ligands, as well as sex-specific genetic and epigenetic risk and resilience factors. This complex interaction between multiple biological systems may be associated with sex-specific behavioral patterns, in turn associated with trauma-related psychopathology. While substantial number of published studies present preliminary evidence for neural mechanisms of sex-specific posttraumatic responses, there is a paucity of research directly designed to examine sex as a biological factor in trauma-related psychopathology. Specific foci for future studies aiming to bridge current gaps in the literature are discussed.

Posttraumatic stress disorder (PTSD) has been associated with altered resting-state functional connectivity (rs-FC) of several brain regions within the salience (SN) and default-mode (DMN) networks, including the hippocampus. However, most rs-FC studies have not focused primarily on the hippocampus, nor have they appreciated its structural heterogeneity, despite clear evidence for a dissociation between posterior and anterior hippocampal connectivity. Here, we examine rs-FC of anterior and posterior hippocampus with key regions in the SN (amygdala, insula, and dorsal anterior cingulate cortex/pre-supplementary motor area) and DMN (ventromedial prefrontal cortex, posterior cingulate cortex, and precuneus) previously implicated in PTSD, using a seed-based approach. Resting-state magnetic resonance images were obtained from 48 PTSD patients and 34 trauma-exposed healthy participants (TEHC). Results indicated no group differences when examining the hippocampus as a whole. However, examining the anterior and posterior hippocampus revealed a loss of anterior to posterior connectivity differentiation in PTSD patients. The PTSD group also demonstrated lower negative connectivity of the posterior hippocampus-precuneus pathway compared with the TEHC group. Finally, as differences in anterior and posterior hippocampus connectivity have been also related to age, we performed a secondary analysis exploring the association between age and posterior- and anterior-hippocampus connectivity in both groups. Results showed that among PTSD patients, increased age had the effect of normalizing posterior hippocampus-precuneus and hippocampus-posterior cingulate cortex connectivity, whereas no such effect was noted for the control group. These findings highlight the need for PTSD connectivity research to consider sub-parts of the hippocampus and to account for age-related connectivity differences., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Testosterone (T) has repeatedly been shown to have anxiolytic properties in rodents, but findings in primates are more mixed. To examine the effects of exogenous T on anxiety, we tested pharmacologically-castrated adult male rhesus monkeys in a modified version of the Human Intruder Paradigm, which measured defensive responses to an unfamiliar human staring directly at them for 2 min. Monkeys were tested at 2 week intervals during 4 experimental conditions lasting 4 weeks each: at baseline, during treatment with the gonadotropin releasing hormone (GnRH) agonist leuprolide acetate (200 μg/kg; Lupron phase), during treatment with Lupron+T enanthate (TE, 5 mg/kg; TE phase) and during treatment with Lupron+oil vehicle (oil phase). We found that the number of anxious behaviors was lower during periods of low T (Lupron only and Lupron+oil phases) than during the Lupron+TE phase. No change in pacing or watching behavior was observed. Thus, in contrast to rodent data, we found no evidence for anxiolytic properties of T in male rhesus monkeys. Rather, T supplementation restored baseline levels of anxiety in Lupron-treated monkeys. These discrepant findings may be best explained by the low levels of gonadotropins achieved by the GnRH agonist. We suggest that Lupron-induced luteinizing hormone (LH) suppression reduced anxiety and that this effect was abolished by T administration. This interpretation is consistent with the view that T increases emotional reactivity to a potential threat and facilitates adaptive arousal response in face of immediate social challenge., (Copyright © 2013 Elsevier Inc. All rights reserved.)

In humans, temperament plays an important role in socialization and personality. Some temperaments, such as behavioral inhibition are associated with an increased risk for psychopathology. Nonhuman primates can serve as a model for neurobiological and developmental contributions to emotional development and several recent studies have begun to investigate temperament in nonhuman primates. In rhesus monkeys, dominance rank is inherited from the mother and is associated with social and emotional tendencies that resemble differences in temperament. The current study assessed differences in temperament in infant rhesus monkeys as a function of maternal dominance rank. Temperament was assessed in 26 infants (13 males) from birth until 6 months of age with a battery that included Brazelton test, human intruder test, human intruder-startle, cortisol stress reactivity, and home cage observations of interactions with peers and the mother. Throughout testing, infants lived with their mothers and a small group of other monkeys in indoor/outdoor runs. Dominance rank of the mothers within each run was rated as either low/middle (N = 18, 9 male) or high/alpha (N = 8, 4 female). Infants of high-ranking mothers displayed more intruder-directed aggression and reduced startle potentiation in the human intruder tests. Dominant offspring also had reduced levels cortisol and startle across development and spent more time away from mothers in the interaction tests. These results suggest that dominance of the mother may be reflected in behavioral reactivity of infants early in life. These findings set up future studies, which may focus on contributing factors to both dominance and temperament such as genetics, rearing, and socialization. Such factors are likely to interact across development in meaningful ways. These results also suggest future human-based studies of a similar relationship may be warranted, although social dominance is clearly more complex in human than macaque societies., (Published 2012 by Wiley Periodicals, Inc.†)

The development of separation response behaviors in infant rhesus macaques across the first 6 months of life was assessed. Seventeen infants underwent a neonatal assessment at 7, 14, 21, and 30 days of age which included a brief period of social isolation. At 3 and 6 months of age these same monkeys and four additional subjects were again subjected to a period of brief social isolation and also exposed to a novel environment with their sedated mother. Results indicate a developmental increase followed by a steady decline in the frequency of separation vocalizations. A modest relationship between early-infancy locomotor profiles and separation responses was also observed at several time points suggesting a possible relationship between these measures. However, stable inter-individual measures of separation distress did not emerge until late in the infantile period. This could suggest that high levels of maternal contact-seeking behavior early in infancy are context specific and not a reliable index of enduring temperament., (Copyright © 2011 Wiley Periodicals, Inc.)