Search

Background: Posttraumatic stress disorder (PTSD) is a debilitating condition that disproportionately impacts individuals who are female. Prior research indicates that males with PTSD exhibit hypoconnectivity of frontal brain regions measured with resting electroencephalography (EEG). The present study examined functional connectivity among females with PTSD and trauma-exposed controls, as well as the impact of sex hormones., Methods: Participants included 61 females ( M age = 31.41, SD = 8.64) who endorsed Criterion A trauma exposure. Resting state EEG data were recorded for five minutes in the eyes open position. Using a Linear Mixed Effects model, paired region-of-interest power envelope connectivity of the theta band (4-7 Hz) served as the response variables., Results: Compared to controls, the PTSD group displayed hyperconnectivity between visual brain regions and the rest of the cerebral cortex ( pFDR < 0.05). Additionally, participants with PTSD demonstrated enhanced connectivity between the default mode network and frontoparietal control network compared to controls ( pFDR < 0.05), as well as increased connectivity between the ventral attention network and the rest of the cerebral cortex ( pFDR < 0.05). Estradiol was associated with higher connectivity, while progesterone was associated with lower connectivity, but these did not survive correction., Conclusions: Results are consistent with prior research indicating that PTSD is associated with altered connectivity in visual brain regions, which may reflect disrupted visual processing related to reexperiencing symptoms (e.g., intrusive memories). Our findings provide additional support for the relevance of the theta frequency range in PTSD given its role in fear learning and regulation processes.

Depression and anxiety are linked to deep venous thrombosis (DVT) and posttraumatic disorder (PTSD) increases risk of venous thromboembolism in women. However, the mechanisms underlying this relationship remain unknown. We hypothesized that PTSD would associate with increased DVT risk, that neuroimmune mechanisms would mediate the PTSD-DVT link, and that these associations would be stronger in women. This cohort study included N = 106 427 participants from a large biobank. PTSD and DVT were defined using ICD-10 codes. A subset (N = 1520) underwent imaging, from which we assessed stress-associated neural activity (SNA). High-sensitivity C-reactive protein (hs-CRP) levels and heart rate variability (HRV) were used as indicators of systemic inflammation and autonomic activity, respectively. Linear, logistic, and Cox regressions and mediation analyses were used to test our hypotheses. Of 106 427 participants, 4192 (3.9%) developed DVT. PTSD associated with increased DVT risk (HR [95% CI]: 1.66 [1.34, 2.07], p < .001), and this finding remained significant after adjustment for age, sex, and traditional DVT risk factors. When analyzed separately by sex, PTSD was significantly associated with DVT risk in women but not men. Further, heightened SNA and lower HRV mediated the effect of PTSD on DVT risk. Results suggest that individuals with PTSD are at increased risk for DVT, and that risk is higher in women. This relationship was partially driven by alterations in stress-associated neural activity and autonomic function, suggesting potential targets for preventive therapies. Future studies are needed to investigate whether intervening on PTSD-DVT mechanisms has downstream beneficial effects on DVT, especially among women., (© 2024 Wiley Periodicals LLC.)

Background: Prior studies have incompletely assessed whether the development of cardiometabolic risk factors (CVDRF) (hypertension, hyperlipidemia, and diabetes mellitus) mediates the association between anxiety and depression (anxiety/depression) and cardiovascular disease (CVD)., Objectives: The authors aimed to evaluate the following: 1) the association between anxiety/depression and incident CVDRFs and whether this association mediates the increased CVD risk; and 2) whether neuro-immune mechanisms and age and sex effects may be involved., Methods: Using a retrospective cohort design, Mass General Brigham Biobank subjects were followed for 10 years. Presence and timing of anxiety/depression, CVDRFs, and CVD were determined using ICD codes. Stress-related neural activity, chronic inflammation, and autonomic function were measured by the assessment of amygdalar-to-cortical activity ratio, high-sensitivity CRP, and heart rate variability. Multivariable regression and mediation analyses were employed., Results: Among 71,214 subjects (median age 49.6 years; 55.3% female), 27,048 (38.0%) developed CVDRFs during follow-up. Pre-existing anxiety/depression associated with increased risk of incident CVDRF (OR: 1.71 [95% CI: 1.59-1.83], P  < 0.001) and with a shorter time to their development (β = -0.486 [95% CI: -0.62 to -0.35], P  < 0.001). The development of CVDRFs mediated the association between anxiety/depression and CVD events (log-odds: 0.044 [95% CI: 0.034-0.055], P  < 0.05). Neuro-immune pathways contributed to the development of CVDRFs ( P  < 0.05 each) and significant age and sex effects were noted: younger women experienced the greatest acceleration in the development of CVDRFs after anxiety/depression., Conclusions: Anxiety/depression accelerate the development of CVDRFs. This association appears to be most notable among younger women and may be mediated by stress-related neuro-immune pathways. Evaluations of tailored preventive measures for individuals with anxiety/depression are needed to reduce CVD risk., Competing Interests: Dr Osborne has received consulting fees from WCG Clinical for unrelated work; and is supported in part by NIH K23HL151909 and AHA 23SCISA1143491. Dr Tawakol’s institution has received grant support from Lung Biotechnologies for unrelated work. Dr Seligowski is supported in part by NIH MH125920. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.PerspectivesCOMPETENCY IN MEDICAL KNOWLEDGE: Important neuroimmune pathways underlie the association between anxiety, depression, and cardiovascular risk. Specific treatment of these pathways may reduce the cardiovascular risk associated with anxiety and depression. COMPETENCY IN PATIENT CARE: A close screening of cardiovascular risk factors should be performed in subjects with anxiety and depression. Younger female, although generally being at low risk of developing cardiovascular risk factors, are particularly susceptible to the cardiometabolic effects of anxiety and depression,, (© 2024 The Authors.)

The neurocardiac circuit is integral to physiological regulation of threat and trauma-related responses. However, few direct investigations of brain-behavior associations with replicable physiological markers of PTSD have been conducted. The current study probed the neurocardiac circuit by examining associations among its core regions in the brain (e.g., insula, hypothalamus) and the periphery (heart rate [HR], high frequency heart rate variability [HF-HRV], and blood pressure [BP]). We sought to characterize these associations and to determine whether there were differences by PTSD status. Participants were N = 315 (64.1 % female) trauma-exposed adults enrolled from emergency departments as part of the prospective AURORA study. Participants completed a deep phenotyping session (e.g., fear conditioning, magnetic resonance imaging) two weeks after emergency department admission. Voxelwise analyses revealed several significant interactions between PTSD severity 8-weeks posttrauma and psychophysiological recordings on hypothalamic connectivity to the prefrontal cortex (PFC), insula, superior temporal sulcus, and temporoparietaloccipital junction. Among those with PTSD, diastolic BP was directly correlated with right insula-hypothalamic connectivity, whereas the reverse was found for those without PTSD. PTSD status moderated the association between systolic BP, HR, and HF-HRV and hypothalamic connectivity in the same direction. While preliminary, our findings may suggest that individuals with higher PTSD severity exhibit compensatory neural mechanisms to down-regulate autonomic imbalance. Additional study is warranted to determine how underlying mechanisms (e.g., inflammation) may disrupt the neurocardiac circuit and increase cardiometabolic disease risk in PTSD., Competing Interests: Declaration of competing interest Dr. Neylan reports consultation for Jazz Pharmaceuticals; Dr. Rauch reports royalties from Oxford University Press, the American Psychiatric Publishing Inc., and Springer Publishing royalties; Dr. McLean reports consultation for Walter Reed Army Institute for Research and for Arbor Medical Innovations; Dr. Kessler reports consultation for Cambridge Health Alliance, Canandaigua VA Medical Center, Holmusk, Partners Healthcare, INC Mirah, PYM, and Roga Sciences; Dr. Koenen reports royalties from Guilford Press and Oxford University Press; Dr. Ressler reports consultation for Bioxcel, Bionomics, Acer, and Jazz Pharma; All other authors report no biomedical financial interests or potential conflicts of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Introduction: Post-traumatic stress symptoms (PTSS) have been shown to negatively impact treatment outcomes in outpatient settings, but few have investigated in acute settings, such as partial hospital programs (PHP). The present study examined how PTSS may influence treatment outcomes- depression, anxiety, overall functioning- among patients attending a PHP., Methods: 1298 (Female n = 728) adults underwent standard transdiagnostic treatment at a PHP in which patients attend the day-long program for approximately 2 weeks for stabilization primarily focused on mood and anxiety symptoms. We utilized previously validated questionnaires to measure PTSD severity (PCL-5), anxiety (GAD-7), depression (PHQ-9), and overall functioning (WSAS). Linear regression analyses were conducted to determine the degree of improved symptoms and functioning across three trauma groups: patients with no trauma history, patients with trauma exposure, and patients who had severe PTSS., Results: Patients in the PTSS group were more likely to endorse higher depression and anxiety symptoms, as well as functional impairment at admission. Severe PTSS, not trauma exposure, predicted less improvement of depression, anxiety, and overall functioning at discharge., Limitations: Due to the nature of the private hospital, results may not generalize to a wider clinical population. Further, we were unable to test any potential mechanisms because the current naturalistic treatment study relied on a deidentified clinical database that was not designed with these research questions., Conclusions: Severe PTSS above and beyond anxiety and depression symptoms potentially serve as predictors of treatment outcomes in acute psychiatric settings such as PHPs, further emphasizing the need for enhanced trauma-informed care., Competing Interests: Declaration of competing interest Authors have no known conflict of interest to disclose.

Background: Knowledge of sex differences in risk factors for posttraumatic stress disorder (PTSD) can contribute to the development of refined preventive interventions. Therefore, the aim of this study was to examine if women and men differ in their vulnerability to risk factors for PTSD., Methods: As part of the longitudinal AURORA study, 2924 patients seeking emergency department (ED) treatment in the acute aftermath of trauma provided self-report assessments of pre- peri- and post-traumatic risk factors, as well as 3-month PTSD severity. We systematically examined sex-dependent effects of 16 risk factors that have previously been hypothesized to show different associations with PTSD severity in women and men., Results: Women reported higher PTSD severity at 3-months post-trauma. Z -score comparisons indicated that for five of the 16 examined risk factors the association with 3-month PTSD severity was stronger in men than in women. In multivariable models, interaction effects with sex were observed for pre-traumatic anxiety symptoms, and acute dissociative symptoms; both showed stronger associations with PTSD in men than in women. Subgroup analyses suggested trauma type-conditional effects., Conclusions: Our findings indicate mechanisms to which men might be particularly vulnerable, demonstrating that known PTSD risk factors might behave differently in women and men. Analyses did not identify any risk factors to which women were more vulnerable than men, pointing toward further mechanisms to explain women's higher PTSD risk. Our study illustrates the need for a more systematic examination of sex differences in contributors to PTSD severity after trauma, which may inform refined preventive interventions.

Background and Aims: Chronic stress associates with cardiovascular disease, but mechanisms remain incompletely defined. Advanced imaging was used to identify stress-related neural imaging phenotypes associated with atherosclerosis., Methods: Twenty-seven individuals with post-traumatic stress disorder (PTSD), 45 trauma-exposed controls without PTSD, and 22 healthy controls underwent 18F-fluorodeoxyglucose positron emission tomography/magnetic resonance imaging (18F-FDG PET/MRI). Atherosclerotic inflammation and burden were assessed using 18F-FDG PET (as maximal target-to-background ratio, TBR max) and MRI, respectively. Inflammation was assessed using high-sensitivity C-reactive protein (hsCRP) and leucopoietic imaging (18F-FDG PET uptake in spleen and bone marrow). Stress-associated neural network activity (SNA) was assessed on 18F-FDG PET as amygdala relative to ventromedial prefrontal cortex (vmPFC) activity. MRI diffusion tensor imaging assessed the axonal integrity (AI) of the uncinate fasciculus (major white matter tract connecting vmPFC and amygdala)., Results: Median age was 37 years old and 54% of participants were female. There were no significant differences in atherosclerotic inflammation between participants with PTSD and controls; adjusted mean difference in TBR max (95% confidence interval) of the aorta 0.020 (-0.098, 0.138), and of the carotids 0.014 (-0.091, 0.119). Participants with PTSD had higher hsCRP, spleen activity, and aorta atherosclerotic burden (normalized wall index). Participants with PTSD also had higher SNA and lower AI. Across the cohort, carotid atherosclerotic burden (standard deviation of wall thickness) associated positively with SNA and negatively with AI independent of Framingham risk score., Conclusions: In this study of limited size, participants with PTSD did not have higher atherosclerotic inflammation than controls. Notably, impaired cortico-limbic interactions (higher amygdala relative to vmPFC activity or disruption of their intercommunication) associated with carotid atherosclerotic burden. Larger studies are needed to refine these findings., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Despite extensive research on sex/gender differences in posttraumatic stress disorder (PTSD), underlying mechanisms are still not fully understood. Here we present a systematic overview of three sex/gender-related risk pathways. We assessed 16 risk factors as well as 3-month PTSD severity in a prospective cohort study (n=2924) of acutely traumatized individuals and investigated potential mediators in the pathway between sex assigned at birth and PTSD severity using multiple mediation analysis with regularization. Six risk factors were more prevalent/severe in women, and none were more pronounced in men. Analyses showed that acute stress disorder, neuroticism, lifetime sexual assault exposure, anxiety sensitivity, and pre-trauma anxiety symptoms fully mediated and uniquely contributed to the relationship between sex assigned at birth and PTSD severity. Our results demonstrate different risk mechanisms for women and men. Such knowledge can inform targeted interventions. Our systematic approach to differential risk pathways can be transferred to other mental disorders to guide sex- and gender-sensitive mental health research., Competing Interests: Competing Interests Statement -Dr. Neylan has received research support from NIH, VA, and Rainwater Charitable Foundation, and consulting income from Jazz Pharmaceuticals. - In the last three years Dr. Clifford has received research funding from the NSF, NIH and LifeBell AI, and unrestricted donations from AliveCor Inc, Amazon Research, the Center for Discovery, the Gates Foundation, Google, the Gordon and Betty Moore Foundation, MathWorks, Microsoft Research, Nextsense Inc, One Mind Foundation, the Rett Research Foundation, and Samsung Research. Dr Clifford has financial interest in AliveCor Inc and Nextsense Inc. He also is the CTO of MindChild Medical and CSO of LifeBell AI and has ownership in both companies. These relationships are unconnected to the current work. - Dr. Germine receives funding from the National Institute of Mental Health (R01 MH121617) and is on the board of the Many Brains Project. Dr. Germine’s family also has equity in Intelerad Medical Systems, Inc. -Dr. Rauch reports grants from NIH during the conduct of the study; personal fees from SOBP (Society of Biological Psychiatry) paid role as secretary, other from Oxford University Press royalties, other from APP (American Psychiatric Publishing Inc.) royalties, other from VA (Veterans Administration) per diem for oversight committee, and other from Community Psychiatry/Mindpath Health paid board service, including equity outside the submitted work; other from National Association of Behavioral Healthcare for paid Board service; other from Springer Publishing royalties; and Leadership roles on Board or Council for SOBP, ADAA (Anxiety and Depression Association of America), and NNDC (National Network of Depression Centers). - Dr. Jones has no competing interests related to this work, though he has been an investigator on studies funded by AstraZeneca, Vapotherm, Abbott, and Ophirex. - Dr. Harte has no competing interest related to this work, though in the last three years he has received research funding from Aptinyx and Arbor Medical Innovations, and consulting payments from Indiana University and Memorial Sloan Kettering Cancer Center. - Dr. McLean served as a consultant for Walter Reed Army Institute for Research and for Arbor Medical Innovations. - In the past 3 years, Dr. Kessler was a consultant for Cambridge Health Alliance, Canandaigua VA Medical Center, Holmusk, Partners Healthcare, Inc., RallyPoint Networks, Inc., and Sage Therapeutics. He has stock options in Cerebral Inc., Mirah, PYM, and Roga Sciences. - Dr. Koenen’s research has been supported by the Robert Wood Johnson Foundation, the Kaiser Family Foundation, the Harvard Center on the Developing Child, Stanley Center for Psychiatric Research at the Broad Institute of MIT and Harvard, the National Institutes of Health, One Mind, the Anonymous Foundation, and Cohen Veterans Bioscience. She has been a paid consultant for Baker Hostetler, Discovery Vitality, and the Department of Justice. She has been a paid external reviewer for the Chan Zuckerberg Foundation, the University of Cape Town, and Capita Ireland. She has had paid speaking engagements in the last three years with the American Psychological Association, European Central Bank. Sigmund Freud University – Milan, Cambridge Health Alliance, and Coverys. She receives royalties from Guilford Press and Oxford University Press. - The remaining authors declare no competing interests.

Background: The mechanisms underlying the psychological and cardiovascular disease (CVD) benefits of physical activity (PA) are not fully understood., Objectives: This study tested whether PA: 1) attenuates stress-related neural activity, which is known to potentiate CVD and for its role in anxiety/depression; 2) decreases CVD in part through this neural effect; and 3) has a greater impact on CVD risk among individuals with depression., Methods: Participants from the Mass General Brigham Biobank who completed a PA survey were studied. A subset underwent 18 F-fluorodeoxyglucose positron emission tomography/computed tomographic imaging. Stress-related neural activity was measured as the ratio of resting amygdalar-to-cortical activity (AmygA C ). CVD events were ascertained from electronic health records., Results: A total of 50,359 adults were included (median age 60 years [Q1-Q3: 45-70 years]; 40.1% male). Greater PA was associated with both lower AmygA C (standardized β: -0.245; 95% CI: -0.444 to -0.046; P = 0.016) and CVD events (HR: 0.802; 95% CI: 0.719-0.896; P < 0.001) in multivariable models. AmygA C reductions partially mediated PA's CVD benefit (OR: 0.96; 95% CI: 0.92-0.99; P < 0.05). Moreover, PA's benefit on incident CVD events was greater among those with (vs without) preexisting depression (HR: 0.860; 95% CI: 0.810-0.915; vs HR: 0.929; 95% CI: 0.910-0.949; P interaction = 0.011). Additionally, PA above guideline recommendations further reduced CVD events, but only among those with preexisting depression (P interaction = 0.023)., Conclusions: PA appears to reduce CVD risk in part by acting through the brain's stress-related activity; this may explain the novel observation that PA reduces CVD risk to a greater extent among individuals with depression., Competing Interests: Funding Support and Author Disclosures This study is in part funded by National Institutes of Health (NIH) grants R56AR077187-01 and P01HL131478-05. This study was in part supported by NIH grants 1R01AR077187 (Dr Tawakol), P01HL131478 (Drs Tawakol and Fayad), K23HL151909 (Dr Osborne). Dr Osborne has received consulting fees from WCG Intrinsic Imaging, LLC, for unrelated work. Dr Choi has received support in part by funding from the National Institute of Mental Health (K08MH127413) and a NARSAD Brain and Behavior Foundation Young Investigator Award. Dr Smoller has received support for work outside the submitted research; is a member of the Scientific Advisory Board of Sensorium Therapeutics (with equity); has received an honorarium for an internal seminar at Tempus Labs and Biogen, Inc; and is PI of a study sponsored by 23andMe. Dr Tawakol has received grants from the National Institutes of Health, International Atomic Energy Agency, Osler/Harvard, and Lung Biotechnologies for work outside the submitted research. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

While posttraumatic stress disorder (PTSD) is known to associate with an elevated risk for major adverse cardiovascular events (MACE), few studies have examined mechanisms underlying this link. Recent studies have demonstrated that neuro-immune mechanisms, (manifested by heightened stress-associated neural activity (SNA), autonomic nervous system activity, and inflammation), link common stress syndromes to MACE. However, it is unknown if neuro-immune mechanisms similarly link PTSD to MACE. The current study aimed to test the hypothesis that upregulated neuro-immune mechanisms increase MACE risk among individuals with PTSD. This study included N = 118,827 participants from a large hospital-based biobank. Demographic, diagnostic, and medical history data collected from the biobank. SNA (n = 1,520), heart rate variability (HRV; [n = 11,463]), and high sensitivity C-reactive protein (hs-CRP; [n = 15,164]) were obtained for a subset of participants. PTSD predicted MACE after adjusting for traditional MACE risk factors (hazard ratio (HR) [95 % confidence interval (CI)] = 1.317 [1.098, 1.580], β = 0.276, p = 0.003). The PTSD-to-MACE association was mediated by SNA (CI = 0.005, 0.133, p < 0.05), HRV (CI = 0.024, 0.056, p < 0.05), and hs-CRP (CI = 0.010, 0.040, p < 0.05). This study provides evidence that neuro-immune pathways may play important roles in the mechanisms linking PTSD to MACE. Future studies are needed to determine if these markers are relevant targets for PTSD treatment and if improvements in SNA, HRV, and hs-CRP associate with reduced MACE risk in this patient population., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Women have twice the lifetime prevalence of posttraumatic stress disorder (PTSD) relative to men, and PTSD is a known risk factor for cardiovascular disease (CVD). Two sex hormones - estradiol and progesterone - have been found to impact both PTSD and CVD symptomatology, but the way in which sex hormones influence cardiovascular physiology among individuals with PTSD is not well understood. Objective: This study sought to clarify the association between sex hormones, PTSD, and CVD among trauma-exposed women. Method: Sixty-six trauma-exposed women ( M age = 31.45, SD  = 8.92) completed a clinical interview for PTSD and self-reported CVD symptoms; estradiol and progesterone were assayed from blood samples. The association between each sex hormone and CVD symptoms was analyzed, controlling for age, systolic blood pressure (BP), and diastolic BP. Results: Neither estradiol nor the PTSD-by-estradiol interaction was significantly associated with CVD symptoms. Higher progesterone and, relatedly, progesterone-to-estradiol ratio (PE ratio) were each significantly associated with greater CVD symptom severity, but only for individuals with lower relative PTSD severity. Conclusions: The findings indicate that PTSD moderates the relationship between progesterone and CVD symptoms, and further research is warranted to reconcile findings in existing literature regarding the direction of and mechanisms behind this relationship.

Considerable racial/ethnic disparities persist in exposure to life stressors and socioeconomic resources that can directly affect threat neurocircuitry, particularly the amygdala, that partially mediates susceptibility to adverse posttraumatic outcomes. Limited work to date, however, has investigated potential racial/ethnic variability in amygdala reactivity or connectivity that may in turn be related to outcomes such as post-traumatic stress disorder (PTSD). Participants from the AURORA study (n = 283), a multisite longitudinal study of trauma outcomes, completed functional magnetic resonance imaging and psychophysiology within approximately two-weeks of trauma exposure. Seed-based amygdala connectivity and amygdala reactivity during passive viewing of fearful and neutral faces were assessed during fMRI. Physiological activity was assessed during Pavlovian threat conditioning. Participants also reported the severity of posttraumatic symptoms 3 and 6 months after trauma. Black individuals showed lower baseline skin conductance levels and startle compared to White individuals, but no differences were observed in physiological reactions to threat. Further, Hispanic and Black participants showed greater amygdala connectivity to regions including the dorsolateral prefrontal cortex (PFC), dorsal anterior cingulate cortex, insula, and cerebellum compared to White participants. No differences were observed in amygdala reactivity to threat. Amygdala connectivity was associated with 3-month PTSD symptoms, but the associations differed by racial/ethnic group and were partly driven by group differences in structural inequities. The present findings suggest variability in tonic neurophysiological arousal in the early aftermath of trauma between racial/ethnic groups, driven by structural inequality, impacts neural processes that mediate susceptibility to later PTSD symptoms., (© 2023. The Author(s).)

Background: Posttraumatic stress disorder (PTSD) and depression are associated with increased risk for cardiovascular disease (CVD), which is the leading cause of death and disability worldwide. Epidemiological studies have revealed these illnesses to be highly comorbid, particularly among women. In the current study, we explored associations between indices of cardiovascular health, PTSD, and depression among a sample of trauma-exposed individuals assigned female at birth. Methods: Participants were N  = 49 individuals without CVD who reported lifetime Criterion A trauma exposure. Blood pressure (BP), heart rate (HR), and high-frequency heart rate variability (HF-HRV) were collected during a 5-minute resting period. Symptoms of CVD (e.g. extremity pain and swelling, shortness of breath), PTSD, and depression were assessed, along with an exploratory measure of anhedonia. Results: Trauma exposure was positively correlated with systolic BP ( r  = .32, p  = .029) and diastolic BP ( r  = .30, p  = .040). The number of reported CVD symptoms was positively correlated with symptoms of PTSD ( r  = .41, p  = .004), depression ( r  = .40, p  = .005) and anhedonia ( r  = .38, p  = .007). CVD symptoms were also significantly associated with PTSD ( β  = .41, t  = 2.43, p  = .023), depression ( β  = .40, t  = 2.76, p  = .009), and anhedonia ( β  = .38, t  = 2.51, p  = .017) after controlling for age and trauma exposure. These associations were not moderated by HF-HRV in our sample. Conclusions: Our results support the association between PTSD and depressive symptoms and worse cardiovascular functioning among an often-overlooked population that is particularly vulnerable to these illnesses. Future studies should investigate residual impacts of PTSD and depression treatment on CVD risk among trauma-exposed individuals, particularly women.

Objective: Individuals with posttraumatic stress disorder (PTSD) are significantly more likely to be diagnosed with cardiovascular disease (CVD) (e.g., myocardial infarction, stroke). The evidence for this link is so compelling that the National Institutes of Health convened a working group to determine gaps in the literature, including the need for large-scale genomic studies to identify shared genetic risk. The aim of the present study was to address some of these gaps by utilizing PTSD and CVD genome-wide association study (GWAS) summary statistics in a large biobank sample to determine the shared genetic risk of PTSD and CVD., Methods: A large health care biobank data set was used (N=36,412), combined with GWAS summary statistics from publicly available large-scale PTSD and CVD studies. Disease phenotypes (e.g., PTSD) were collected from electronic health records. De-identified genetic data from the biobank were genotyped using Illumina SNP array. Summary statistics data sets were processed with the following quality-control criteria: 1) SNP heritability h 2 >0.05, 2) compute z-statistics (z=beta/SE or z=log(OR)/SE), 3) filter nonvariable SNPs (0G =0.24, SE=0.06), and Mendelian randomization analyses indicated a potential causal link from PTSD to hypertension (β=0.20, SE=0.04), but not the reverse. PTSD summary statistics significantly predicted PTSD diagnostic status (R 2 =0.27), and this was significantly improved by incorporating summary statistics from CVD and major depressive disorder (R 2 =1.30). Further, pathway enrichment analyses indicated that genetic variants involved in shared PTSD-CVD risk included those involved in postsynaptic structure, synapse organization, and interleukin-7-mediated signaling pathways., Conclusions: The results from this study suggest that PTSD and CVD may share genetic risk. Further, these results implicate PTSD as a risk factor leading to the development of hypertension and coronary artery disease. Additional research is needed to determine the clinical utility of these findings.

Background: Individuals with posttraumatic stress disorder (PTSD) are more likely to present with metabolic diseases such as type-2 diabetes mellitus (T2DM), and cardiovascular dysfunction has been implicated in this link. These diseases disproportionately affect women and individuals exposed to chronic environmental stressors (e.g., community violence, poverty). We examined associations among PTSD, cardiovascular indices, and metabolic function in highly trauma-exposed Black women with T2DM., Methods: Participants ( N  = 80) were recruited for a follow-up study of stress and T2DM as part of the Grady Trauma Project. PTSD symptoms were assessed with the Clinician Administered PTSD Scale (CAPS-IV). Cardiovascular indices included heart rate (HR), blood pressure (BP), respiratory sinus arrhythmia (RSA), and endothelial function (assessed via flow-mediated dilation; FMD). An oral glucose tolerance test was used as an indicator of metabolic function., Results: Of the cardiovascular indices, only FMD was significantly associated with PTSD symptoms (CAPS Avoidance symptoms; β  = -0.37, p  = .042), and glucose tolerance ( β  = -0.44, p  = .019), controlling for age and body mass index. The association between FMD and PTSD Avoidance was moderated by RSA such that the effect of FMD was only significant at low levels of RSA (simple slopes β  = -0.87, p  = .004)., Conclusions: Our results indicate that endothelial function is significantly related to PTSD and glucose tolerance, over and above other cardiovascular measures (HR, BP, RSA). Further, our results suggest that low RSA may be a risk factor for the link between poor endothelial function and PTSD in women with T2DM., Competing Interests: KJR has received consulting income from Alkermes, research support from NIH, Genomind and Brainsway, and he is on scientific advisory boards for Janssen and Verily, all of which is unrelated to the present work. CFG has received consulting income from Cohen Veterans Bioscience which is unrelated to the present work. All other authors have no biomedical financial interests or conflicts of interest., (© 2022 The Authors.)

Posttraumatic stress disorder (PTSD) has long been associated with a heightened risk of cardiovascular disease (CVD). A number of mechanisms have been implicated to underlie this brain-heart axis relationship, such as altered functioning of the autonomic nervous system and increased systemic inflammation. While neural alterations have repeatedly been observed in PTSD, they are rarely considered in the PTSD-CVD link. The brain-heart axis is a pathway connecting frontal and limbic brain regions to the brainstem and periphery via the autonomic nervous system and it may be a promising model for understanding CVD risk in PTSD given its overlap with PTSD neural deficits. We first provide a summary of the primary mechanisms implicated in the association between PTSD and CVD. We then review the brain-heart axis and its relevance to PTSD, as well as findings from PTSD trials demonstrating that a number of PTSD treatments have effects on areas of the brain-heart axis. Finally, we discuss sex considerations in the PTSD-CVD link. A critical next step in this study is to determine if PTSD treatments that affect the brain-heart axis (e.g., brain stimulation that improves autonomic function) also reduce the risk of CVD., (© 2022 Wiley Periodicals LLC.)

Hippo campal impairments are reliably associated with post-traumatic stress disorder (PTSD); however, little research has characterized how increased threat sensitivity may interact with arousal responses to alter hippocampal reactivity, and further how these interactions relate to the sequelae of trauma-related symptoms. In a sample of individuals recently exposed to trauma ( N = 116, 76 female), we found that PTSD symptoms at 2 weeks were associated with decreased hippocampal responses to threat as assessed with fMRI. Further, the relationship between hippocampal threat sensitivity and PTSD symptomology only emerged in individuals who showed transient, high threat-related arousal, as assayed by an independently collected measure of fear potentiated startle. Collectively, our finding suggests that development of PTSD is associated with threat-related decreases in hippocampal function because of increases in fear-potentiated arousal. SIGNIFICANCE STATEMENT Alterations in hippocampal function linked to threat-related arousal are reliably associated with post-traumatic stress disorder (PTSD); however, how these alterations relate to the sequelae of trauma-related symptoms is unknown. Prior models based on nontrauma samples suggest that arousal may impact hippocampal neurophysiology leading to maladaptive behavior. Here we show that decreased hippocampal threat sensitivity interacts with fear-potentiated startle to predict PTSD symptoms. Specifically, individuals with high fear-potentiated startle and low, transient hippocampal threat sensitivity showed the greatest PTSD symptomology. These findings bridge literatures of threat-related arousal and hippocampal function to better understand PTSD risk., (Copyright © 2022 the authors.)

Background: Posttraumatic stress disorder (PTSD) is associated with autonomic dysfunction as indicated by deficits in the sympathetic and parasympathetic nervous systems. These abnormalities are expressed as elevated heart rate and reduced heart rate variability (HRV), respectively. Intermittent theta-burst stimulation (iTBS), a form of transcranial magnetic stimulation, has demonstrated effectiveness in PTSD. Nevertheless, it remains unclear whether HRV may be an iTBS biomarker for PTSD and whether iTBS impacts autonomic activity., Materials and Methods: Fifty veterans with PTSD participated in a randomized controlled trial, receiving ten daily sessions of sham-controlled iTBS (right dorsolateral prefrontal cortex, 1800 pulses/day, 80% active motor threshold, 9.5 min). With a usable dataset (N = 47), HRV parameters were assessed as predictors of clinical response immediately after stimulation. iTBS effects on autonomic response (mean RR interval, root mean square of successive differences [RMSSD], total power [TP], and low-frequency/high-frequency [LF/HF] ratio) were evaluated using an ultra-short approach., Results: TP and RMSSD were significant predictors of acute clinical response to iTBS. Individuals with higher TP had better response to iTBS with improved symptoms on the Clinician-Administered PTSD Scale (r s  = -0.58, p = 0.004), and higher functionality on the Social and Occupational Function Scale (r s  = 0.43, p = 0.04). Similarly, higher RMSSD was associated with superior outcomes (r s  = -0.44, p = 0.04). No other significant changes in HRV metrics were observed (p ≥ 0.05)., Conclusions: Our findings indicate that autonomic activity is a potential low-cost and technically simple predictive biomarker of iTBS response in PTSD. Less autonomic dysfunction was associated with superior clinical improvements with iTBS. Future studies might consider HRV acquisition during iTBS, as well as prospective testing of these findings in patients with elevated hyperarousal., (Published by Elsevier Inc.)

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., (Copyright © 2021 Society of Biological Psychiatry. All rights reserved.)

Background: Type 2 diabetes mellitus (T2DM) is a major public health problem in the United States. Although cardiovascular autonomic functioning, blood glucose control, and inflammation are known to play a role in T2DM, the interaction between these variables remains largely unexplored, particularly in the context of stress. To address this gap, we examined the relationship between these variables in a sample that is uniquely vulnerable to the health consequences of T2DM., Methods: Participants were 37 trauma-exposed Black women with a diagnosis of T2DM. High frequency heart rate variability (HF-HRV), blood glucose control (HbA1c), and a stressor-evoked biomarker of inflammation (interleukin 6; IL-6) were obtained as part of a larger study of the genetic risk factors for and consequences of trauma exposure., Results: The interaction of HbA1c and HF-HRV was significantly associated with IL-6 response calculated as area under the curve with respect to ground. Post-hoc simple slopes analyses revealed HbA1c, rather than HF-HRV, as the moderator in this association such that higher HF-HRV conferred higher circulating levels of IL-6 only in the presence of lower HbA1c, ( β  ​= ​0.60, t  ​= ​3.51, p  ​= ​.001)., Conclusions: Cardiovascular autonomic functioning and blood glucose control were significantly associated with stressor-evoked IL-6 responses when controlling for BMI and age. Moreover, the association between cardiovascular autonomic functioning and inflammation varied at different levels of HbA1c. This highlights the possibility that individuals with trauma exposure and T2DM may benefit from stratification by HbA1c levels for research analysis and treatment decision making., Competing Interests: KJR has received consulting income from Alkermes, research support from NIH, Genomind and Brainsway, and he is on scientific advisory boards for Janssen and Verily, all of which is unrelated to the present work. CFG has received consulting income from Cohen Veterans Bioscience which is unrelated to the present work. Remaining authors have no biomedical financial interests or conflicts of interest.ub., (© 2021 The Authors.)

Despite its prevalence, sexual assault remains a vastly underreported crime. Previous research suggests that engagement in certain types of resistance during an assault affects the way in which both victims and others perceive the attack; such perceptions influence victims' likelihood of reporting the assault to law enforcement as well as the criminal justice system response to reported allegations. Using a fight/flight/freeze theoretical framework, the current study sought to examine how forceful, nonforceful, and freeze responding influenced victim reporting and the extent to which reported assaults were pursued and investigated by law enforcement. Using data from the National Crime Victimization Survey between 2010 and 2016, logistic regression analysis indicated that victims are significantly less likely to report to law enforcement if they froze during the attack. Interestingly, although engagement in forceful resistance increases victims' likelihood of reporting to law enforcement, it has no bearing on law enforcement response beyond the effect of physical injury. Rather, physical injury (e.g., bruises, cuts, broken bones) is the only predictor of law enforcement response to sexual assault allegations. Findings suggest that whereas fight and freeze responses to sexual victimization influence victims' willingness to report to law enforcement, resistance is not uniquely predictive of law enforcement response once physical injury is considered.

Background: Evidence-based pharmacological treatments for posttraumatic stress disorder (PTSD) are few and of limited efficacy. Previous work suggests that angiotensin type 1 receptor inhibition facilitates fear inhibition and extinction, important for recovery from PTSD. This study tests the efficacy of the angiotensin type 1 receptor antagonist losartan, an antihypertensive drug, repurposed for the treatment of PTSD., Methods: A randomized controlled trial was conducted for 10 weeks in 149 men and women meeting DSM-5 PTSD criteria. Losartan (vs. placebo) was flexibly titrated from 25 to 100 mg/day by week 6 and held at highest tolerated dose until week 10. Primary outcome was the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) change score at 10 weeks from baseline. A key secondary outcome was change in CAPS-5 associated with a single nucleotide polymorphism of the ACE gene. Additional secondary outcomes included changes in the PTSD Checklist for DSM-5 and the Patient Health Questionnaire-9, and proportion of responders with a Clinical Global Impressions-Improvement scale of "much improved" or "very much improved.", Results: Both groups had robust improvement in PTSD symptoms, but there was no significant difference on the primary end point, CAPS-5 measured as week 10 change from baseline, between losartan and placebo (mean change difference, 0.9, 95% confidence interval, -3.2 to 5.0). There was no significant difference in the proportion of Clinical Global Impressions-Improvement scale responders for losartan (58.6%) versus placebo (57.9%), no significant differences in changes in PTSD Checklist for DSM-5 or Patient Health Questionnaire-9, and no association between ACE genotype and CAPS-5 improvement on losartan., Conclusions: At these doses and durations, there was no significant benefit of losartan compared with placebo for the treatment of PTSD. We discuss implications for failure to determine the benefit of a repurposed drug with strong a priori expectations of success based on preclinical and epidemiological data., (Copyright © 2021 Society of Biological Psychiatry. All rights reserved.)

Posttraumatic stress disorder (PTSD) is associated with lower gray matter volume (GMV) in brain regions critical for extinction of learned threat. However, relationships among volume, extinction learning, and PTSD symptom development remain unclear. We investigated subcortical brain volumes in regions supporting extinction learning and fear-potentiated startle (FPS) to understand brain-behavior interactions that may impact PTSD symptom development in recently traumatized individuals. Participants (N = 99) completed magnetic resonance imaging and threat conditioning two weeks following trauma exposure as part of a multisite observational study to understand the neuropsychiatric effects of trauma (AURORA Study). Participants completed self-assessments of PTSD (PTSD Checklist for DSM-5; PCL-5), dissociation, and depression symptoms two- and eight-weeks post-trauma. We completed multiple regressions to investigate relationships between FPS during late extinction, GMV, and PTSD symptom development. The interaction between thalamic GMV and FPS during late extinction at two weeks post-trauma predicted PCL-5 scores eight weeks (t (75) = 2.49, β = 0.28, p = 0.015) post-trauma. Higher FPS predicted higher PCL-5 scores in the setting of increased thalamic GMV. Meanwhile, lower FPS also predicted higher PCL-5 scores in the setting of decreased thalamic GMV. Thalamic GMV and FPS interactions also predicted posttraumatic dissociative and depressive symptoms. Amygdala and hippocampus GMV by FPS interactions were not associated with posttraumatic symptom development. Taken together, thalamic GMV and FPS during late extinction interact to contribute to adverse posttraumatic neuropsychiatric outcomes. Multimodal assessments soon after trauma have the potential to distinguish key phenotypes vulnerable to posttraumatic neuropsychiatric outcomes., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Cross-sectional studies have found that individuals with posttraumatic stress disorder (PTSD) exhibit deficits in autonomic functioning. While PTSD rates are twice as high in women compared to men, sex differences in autonomic functioning are relatively unknown among trauma-exposed populations. The current study used a prospective design to examine sex differences in posttraumatic autonomic functioning., Methods: 192 participants were recruited from emergency departments following trauma exposure ( Mean age = 35.88, 68.2% female). Skin conductance was measured in the emergency department; fear conditioning was completed two weeks later and included measures of blood pressure (BP), heart rate (HR), and high frequency heart rate variability (HF-HRV). PTSD symptoms were assessed 8 weeks after trauma., Results: 2-week systolic BP was significantly higher in men, while 2-week HR was significantly higher in women, and a sex by PTSD interaction suggested that women who developed PTSD demonstrated the highest HR levels. Two-week HF-HRV was significantly lower in women, and a sex by PTSD interaction suggested that women with PTSD demonstrated the lowest HF-HRV levels. Skin conductance response in the emergency department was associated with 2-week HR and HF-HRV only among women who developed PTSD., Conclusions: Our results indicate that there are notable sex differences in autonomic functioning among trauma-exposed individuals. Differences in sympathetic biomarkers (BP and HR) may have implications for cardiovascular disease risk given that sympathetic arousal is a mechanism implicated in this risk among PTSD populations. Future research examining differential pathways between PTSD and cardiovascular risk among men versus women is warranted., Competing Interests: In the last three years GDS has received research funding from the NSF, NIH and LifeBell AI, and unrestricted donations from AliveCor, Amazon Research, the Center for Discovery, the Gordon and Betty Moore Foundation, MathWorks, Microsoft Research, the Gates Foundation, Google, One Mind Foundation, and Samsung Research. GDS has financial interest in AliveCor and receives unrestricted funding from the company. He is also the CTO of MindChild Medical and CSO of LifeBell AI and has ownership in both companies. These relationships are unconnected to the current work. In the past three years, LTG has served on the Scientific Advisory Board of Sage Bionetworks, for which she received a small honorarium. SLR reports grants from NIH during the conduct of the study; personal fees from SOBP (Society of Biological Psychiatry) paid role as secretary, other from Oxford University Press royalties, other from APP (American Psychiatric Publishing Inc.) royalties, other from VA (Veterans Administration) per diem for oversight committee, and other from Community Psychiatry paid board service, including equity outside the submitted work; and Leadership roles on Board or Council for SOBP, ADAA (Anxiety and Depression Association of America), and NNDC (National Network of Depression Centers). SS has received funding from the Florida Medical Malpractice Joint Underwriter's Association Dr. Alvin E. Smith Safety of Healthcare Services Grant; Allergan Foundation; the NIH/NIA-funded Jacksonville Aging Studies Center (JAX-ASCENT; R33AG05654); and the Substance Abuse and Mental Health Services Administration (1H79TI083101-01); and the Florida Blue Foundation. CWJ reports no direct conflicts related to this paper. He has been an investigator on studies funded by Hologic Inc, Janssen, AstraZeneca, and Vapotherm, for which his department has received research funding. JJ receives consulting payments from Janssen Pharmaceuticals. Over the past three years, DAP has received consulting fees from Albright Stonebridge Group, BlackThorn Therapeutics, Boehringer Ingelheim, Compass Pathway, Concert Pharmaceuticals, Engrail Therapeutics, Neurocrine Biosciences, Otsuka Pharmaceuticals, and Takeda Pharmaceuticals as well as one honorarium from Alkermes. In addition, he has received stock options from BlackThorn Therapeutics, and research support from National Institute of Mental Health, Dana Foundation, Brain and Behavior Research Foundation, and Millennium Pharmaceuticals. No funding from these entities was used to support the current work, and all views expressed are solely those of the authors. JME reports support from the National Institutes of Health (NIH) through Grant Numbers R01HD079076 & R03HD094577, Eunice Kennedy Shriver National Institute of Child Health & Human Development, and National Center for Medical Rehabilitation Research. He also reports funding from the New South Wales Health Spinal Cord Injury Research Grants Program and consulting fees (<$15,000 per annum) from Orofacial Therapeutics, LLC. In the past 3 years, RCK was a consultant for Datastat, Inc., Holmusk, RallyPoint Networks, Inc., and Sage Pharmaceuticals. He has stock options in Mirah, PYM, and Roga Sciences. KJR has received consulting income from Alkermes, research support from NIH, Genomind and Brainsway, and he is on scientific advisory boards for Janssen and Verily, all of which is unrelated to the present work. All other authors have no conflicts of interest to disclose., (© 2021 The Authors.)

17β-estradiol (E2) levels in women correlate with multiple neuropsychiatric symptoms, including those that are stress-related. Furthermore, prior work from our group has demonstrated that E2 status influences DNA methylation (DNAm) across the genome. We developed and validated a DNAm-based predictor of E2 (one of four naturally occurring estrogens) using a training set of 183 females and a test set of 79 females from the same traumatized cohort. We showed that predicted E2 levels were highly correlated with measured E2 concentrations in our testing set (r ​= ​0.75, p ​= ​1.8e-15). We further demonstrated that predicted E2 concentrations, in combination with measured values, negatively correlated with current post-traumatic stress disorder (PTSD) (β ​= ​-0.38, p ​= ​0.01) and major depressive disorder (MDD) diagnoses (β ​= ​-0.45, p ​= ​0.02), as well as a continuous measure of PTSD symptom severity (β ​= ​-2.3, p ​= ​0.007) in females. Finally, we tested our predictor in an independent data set (n ​= ​85) also comprised of recently traumatized female subjects to determine if the predictor would generalize to a different population than the one on which it was developed. We found that the correlation between predicted and actual E2 concentrations in the external validation data set was also high (r ​= ​0.48, p ​= ​3.0e-6). While further validation is warranted, a DNAm predictor of E2 concentrations will advance our understanding of hormone-epigenetic interactions. Furthermore, such a DNAm predictor may serve as an epigenetic proxy for E2 concentrations and thus provide an important biomarker to better evaluate the contribution of E2 to current and potentially future psychiatric symptoms in samples for which E2 is not measured., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 The Authors.)

Prior observational studies have suggested that medications targeting the renin-angiotensin system, such as angiotensin-converting enzyme inhibitors (ACE-Is) and angiotensin receptor blockers (ARBs), may be associated with decreased PTSD symptoms. Given known sex differences in PTSD prevalence and cardiovascular disease, here we tested whether the effects of ACE-I/ARB status on PTSD differ by sex. We also expanded these observations with replication analyses in a large biorepository database. Participants in the initial sample included 840 trauma-exposed individuals recruited as part of the Grady Trauma Project. The Modified PTSD Symptom Scale (M-PSS) was administered and ACE-I/ARB status was determined by self-report. Replication analyses were conducted using a large biorepository database (Partners Healthcare Biobank, N = 116,389) with diagnoses and medication status based on available electronic health records. Among individuals treated with ACE-Is/ARBs in the initial sample, women had significantly higher M-PSS total and Re-experiencing severity compared to men (p's < 0.05). Analyses with the large biorepository sample robustly replicated the overall effects of ACE-I/ARB medication associated with lower rate of PTSD diagnosis (p < 0.001). We also demonstrated that this effect may be specific to the renin-angiotensin system as it did not replicate for beta-blockers, calcium channel blockers, or diuretics. When we examined more specific drug classes, results indicated that the ACE-I/ARB effect on PTSD may be driven more by ARBs (e.g., Losartan) than by ACE-Is. Post-hoc analyses indicated that racial differences may exist in these effects. Overall, our results replicate and extend prior observations that the renin-angiotensin system is associated with PTSD. Medications targeting this system may be worthy of further investigation for PTSD treatment. Our findings suggest that sex and race effects should be considered in future treatment research.

Background: Deficits in safety signal learning are well-established in fear-related disorders (e.g., PTSD, phobias). The current study used a fear conditioning paradigm to test associations among eye blink startle and event-related brain potential (ERP) latency measures of safety signal learning, as well as the role of cardiac vagal control (a measure of top-down inhibition necessary for safety learning)., Methods: Participants were 49 trauma-exposed women ages 17 to 28 years. Eyeblink startle response and ERP amplitudes/latencies were derived for conditioned stimuli associated (CS+) and not associated (CS-) with an aversive unconditioned stimulus. ERPs included the P100 and late positive potential (LPP), which index early visual processing and sustained emotional encoding, respectively. Cardiac vagal control was assessed with resting heart rate variability (HRV)., Results: P100 and LPP latencies for the CS- (safety signal stimulus) were significantly negatively associated with startle to the CS-, but not the CS + . LPP CS- latencies were significantly negatively associated with PTSD Intrusion scores, and this relationship was moderated by vagal control, such that the effect was only present among those with low HRV., Conclusions: ERP-based markers of safety signal learning were associated with startle response to the CS- (but not CS+) and PTSD symptoms, indicating that these markers may have relevance for fear-related disorders. Cardiac vagal control indexed by HRV is a moderating factor in these associations and may be relevant to safety signal learning., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Trauma and symptoms of posttraumatic stress disorder (PTSD) have repeatedly been linked to impaired cardiovascular functioning. Poor fear extinction is a well-established biomarker of PTSD that may provide insight into mechanisms underlying cardiovascular risk. The current study probed the cardiovascular response to extinction in a sample of trauma-exposed individuals., Methods: Participants were 51 trauma-exposed women who underwent a fear conditioning paradigm. Heart rate (HR) during extinction was examined in response to a conditioned stimulus that was previously paired with an aversive unconditioned stimulus (CS+) and one that was never paired (CS-). Heart rate variability (HRV) was calculated at baseline and during the extinction session., Results: Consistent with fear bradycardia, initial HR deceleration (.5-2s) after CS + onset occurred during early extinction and appeared to extinguish over time. Higher baseline HRV was significantly associated with greater fear bradycardia during early extinction., Conclusions: This is the first study to demonstrate a pattern of fear bradycardia in early extinction, which was associated with higher HRV levels and decreased over the course of the extinction phase. These results suggest that increased fear bradycardia may be indicative of greater vagal control (i.e., HRV), both of which are psychophysiological biomarkers that may influence cardiovascular and autonomic disease risk in trauma-exposed individuals., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Decades of research into the biological mechanisms of posttraumatic stress disorder (PTSD) suggests that chronic activation of the stress response leads to long-lasting changes in the structure and function of the nervous and endocrine systems. While the prevalence of PTSD is twice as high in females as males, little is known about how sex differences in neuroendocrine systems may contribute to PTSD. In response to the paucity of research on sex-related mechanisms, the National Institutes of Health created a policy that asks researchers to consider sex as a biological variable. This review provides an overview of the current understanding of nervous and endocrine dysfunction in PTSD (e.g., neural circuitry, autonomic arousal, hormonal response), highlighting areas where the influence of sex has been characterized and where further research is needed. We also provide recommendations for using the sex-as-a-biological-variable policy to address specific gaps in PTSD neuroscience research., (Copyright © 2019 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Translational models of fear have greatly informed our understanding of PTSD and its underlying fear circuitry. One of the most replicated findings in the field is the two-fold higher PTSD incidence in females compared to males. While sociocultural factors play a role, the most robust biological influencers to date are gonadal hormones, such as estradiol and progesterone, which fluctuate across the menstrual cycle. Among studies that account for these hormones, most do so in isolation or collect both and only report one. Variation in study findings suggests that the ratio between these two hormones (the P/E ratio) may be an important and missing variable to further understand gonadal hormone influences on fear. Here we review cross-species examinations of fear and PTSD, within the contexts of estradiol and progesterone as well as P/E ratios that were calculated based on extant literature. We then provide recommendations for best practices in assay methods and reporting to improve research on the P/E ratio in fear and PTSD. Ultimately, greater understanding of this important variable will advance efforts to characterize gonadal hormone influences on fear learning processes in humans and animals., (© 2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

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 self-reported childhood maltreatment, (2) estimate SNP-based heritability (h 2 snp ), (3) assess predictive value of polygenic risk scores (PRS) for childhood maltreatment, and (4) quantify genetic overlap of childhood maltreatment with mental and physical health-related phenotypes, and condition the top hits from our analyses when such overlap is present. 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 group (PGC-PTSD) (n = 26,290). h 2 snp for childhood maltreatment and genetic correlations with mental/physical health traits were calculated using linkage disequilibrium score regression. PRS was calculated using PRSice and mtCOJO was used to perform conditional analysis. Two genome-wide significant loci associated with childhood maltreatment (rs142346759, p = 4.35 × 10 -8 , FOXP1; rs10262462, p = 3.24 × 10 -8 , FOXP2) were identified in the discovery dataset but were not replicated in PGC-PTSD. h 2 snp for childhood maltreatment was ~6% and the PRS derived from the UKBB was significantly predictive of childhood maltreatment in PGC-PTSD (r 2  = 0.0025; p = 1.8 × 10 -15 ). The most significant genetic correlation of childhood maltreatment was with depressive symptoms (r g  = 0.70, p = 4.65 × 10 -40 ), although we show evidence that our top hits may be specific to childhood maltreatment. This is the first large-scale genetic study to identify specific variants associated with self-reported childhood maltreatment. Speculatively, FOXP genes might influence externalizing traits and so 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 a range of phenotypes, may ultimately be useful in in developing targeted treatment and prevention strategies.

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.

Childhood abuse is a serious and prevalent public health concern, both in the United States and around the world. The association between child abuse and adverse outcomes in adulthood is well-established, with those experiencing abuse more likely to be diagnosed with mental health disorders, including posttraumatic stress disorder (PTSD), into adulthood. One way to conceptualize the relationship between trauma and adverse mental health outcomes in adulthood is through resource loss. Previous research indicates that individuals who have experienced childhood abuse may not adequately develop resources, such as tangible (e.g., money) and intangible (e.g., emotional) support systems, with the loss of these resources associated with decreased ability to cope with distress. The current study investigated the relationship between resource loss and symptoms of posttraumatic stress longitudinally in a sample of women who had experienced both childhood abuse and a mass-shooting event. Results demonstrated that experiencing childhood physical abuse and sexual abuse predicted symptoms of posttraumatic stress after controlling for exposure to the mass-shooting event. Additionally, symptoms of posttraumatic stress and resource loss predicted each other at two time points after the shooting. Findings demonstrate the bidirectional nature of the relationship between posttraumatic stress and resource loss, as well as highlight how effects of childhood abuse can be long-standing and negatively impact psychosocial functioning in women throughout adulthood.

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., (© 2019 Wiley Periodicals, Inc.)

Although the fear response is an adaptive response to threatening situations, a number of psychiatric disorders feature prominent fear-related symptoms caused, in part, by failures of extinction and inhibitory learning. The translational nature of fear conditioning paradigms has enabled us to develop a nuanced understanding of extinction and inhibitory learning based on the molecular substrates to systems neural circuitry and psychological mechanisms. This knowledge has facilitated the development of novel interventions that may augment extinction and inhibitory learning. These interventions include nonpharmacological techniques, such as behavioral methods to implement during psychotherapy, as well as device-based stimulation techniques that enhance or reduce activity in different regions of the brain. There is also emerging support for a number of psychopharmacological interventions that may augment extinction and inhibitory learning specifically if administered in conjunction with exposure-based psychotherapy. This growing body of research may offer promising novel techniques to address debilitating transdiagnostic fear-related symptoms.

Post-traumatic stress disorder (PTSD) is characterized by a heightened emotional and physiological state and an impaired ability to suppress or extinguish traumatic fear memories. Exaggerated physiological responses may contribute to increased cardiovascular disease (CVD) risk in this population, but whether treatment for PTSD can offset CVD risk remains unknown. To further evaluate physiological correlates of fear learning, we used a novel pre-clinical conditioned cardiovascular testing paradigm and examined the effects of Pavlovian fear conditioning and extinction training on mean arterial pressure (MAP) and heart rate (HR) responses. We hypothesized that a fear conditioned cardiovascular response could be detected in a novel context and attenuated by extinction training. In a novel context, fear conditioned mice exhibited marginal increases in MAP (∼3 mmHg) and decreases in HR (∼20 bpm) during CS presentation. In a home cage context, the CS elicited significant increases in both HR (100 bpm) and MAP (20 mmHg). Following extinction training, the MAP response was suppressed while CS-dependent HR responses were variable. These pre-clinical data suggest that extinction learning attenuates the acute MAP responses to conditioned stimuli over time, and that MAP and HR responses may extinguish at different rates. These results suggest that in mouse models of fear learning, conditioned cardiovascular responses are modified by extinction training. Understanding these processes in pre-clinical disease models and in humans with PTSD may be important for identifying interventions that facilitate fear extinction and attenuate hyper-physiological responses, potentially leading to improvements in the efficacy of exposure therapy and PTSD-CVD comorbidity outcomes.

Fear-potentiated startle (FPS) paradigms provide insight into fear learning mechanisms that contribute to impairment among individuals with posttraumatic stress symptoms (PTSS). Electrophysiology also has provided insight into these mechanisms through the examination of event-related potentials (ERPs) such as the P100 and LPP. It remains unclear, however, whether the P100 and LPP may be related to fear learning processes within the FPS paradigm. To this end, we tested differences in ERP amplitudes for conditioned stimuli associated (CS+) and not associated (CS-) with an aversive unconditioned stimulus (US) during fear acquisition. Participants included 54 female undergraduate students (mean age = 20.26). The FPS response was measured via electromyography of the orbicularis oculi muscle. EEG data were collected during the FPS paradigm. While the difference between CS+ and CS- P100 amplitude was not significant, LPP amplitudes were significantly enhanced following the CS+ relative to CS-. Furthermore, the LPP difference wave (CS+ minus CS-) was associated with FPS scores for the CS- during the later portion of fear acquisition. These findings suggest that conditioned stimuli may have altered emotional encoding (LPP) during the FPS paradigm. Thus, the LPP may be a promising neurophysiological marker that is related to fear learning processes., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objective: Healing from trauma has been conceptualized as either facing the trauma head-on or moving beyond the trauma and focusing on the future. Emerging research suggests that the greatest healing may result from the ability to adaptively use both (i.e., coping flexibility). The current study sought to examine the psychometric properties of a self-report scale of coping flexibility: the Perceived Ability to Cope With Trauma (PACT) Scale., Method: Participants included 322 undergraduate students enrolled in an introductory psychology course at a large Midwestern university. Analyses used the PACT's 2 scales, Trauma Focus and Forward Focus, as well as its flexibility score that is derived from these scales. Confirmatory factor analysis of the PACT was performed in Mplus., Results: The PACT scales demonstrated high internal consistency and convergent validity with measures of experiential avoidance, distress tolerance, self-compassion, perceived stress, and PTSD symptoms. Discriminant validity was demonstrated by nonsignificant relations with fight and flight responding. All 3 PACT scores demonstrated significant relations with PTSD symptom clusters. The 2-factor model of the PACT demonstrated good fit after using item parceling., Conclusion: Overall, the current analyses support and replicate the psychometric properties and construct validity of the PACT as a measure of adaptive trauma-related coping. Further, the PACT scales are significantly negatively related to PTSD symptom clusters, suggesting that the greater one's perceived ability to use Trauma Focus and Forward Focus skills flexibly, the less severe he or she will experience symptoms of reexperiencing, avoidance/numbing, and hyperarousal. Future applications are discussed. (PsycINFO Database Record, ((c) 2017 APA, all rights reserved).)

Posttraumatic stress disorder (PTSD) is a common psychological disorder that affects a substantial minority of individuals. Previous research has suggested that PTSD can be partially explained as a disorder of impaired fear inhibition. The current study utilized a previously validated fear acquisition and extinction paradigm in a sample of 75 undergraduate women who were exposed to a campus mass shooting that occurred in 2008. We used a protocol in which conditioned fear was first acquired through the presentation of one colored shape (reinforced conditioned stimulus, CS+) that was paired with an aversive airblast to the larynx (unconditioned stimulus, US) and a different colored shape that was not paired with the airblast (non-reinforced conditioned stimulus, CS-). Fear was extinguished 10 min later through repeated presentations of the CSs without reinforcement. Number of clinically significant posttraumatic stress symptoms (PTSS) immediately following the mass shooting were positively associated with fear-potentiated startle (FPS) to the CS+ and CS- during late periods of acquisition. During early periods of fear extinction, PTSS was positively associated with FPS to the CS+. Results from the current study suggest that PTSS is related to altered fear inhibition and extinction during an FPS paradigm. In line with similar research, women with greater PTSS demonstrated a greater "fear load," suggesting that these women experienced elevated fear to the CS+ during extinction after conditioned fear was acquired.

Background: Emotion dysregulation has been implicated in the negative outcomes following trauma exposure. A proposed biomarker of emotion dysregulation, respiratory sinus arrhythmia (RSA), has demonstrated associations with trauma-related phenomena, such as the fear-potentiated startle (FPS) response. The current study aimed to examine the prospective association between emotion dysregulation and RSA and FPS several years following trauma exposure., Methods: Participants were 131 women exposed to a campus mass shooting on February 14, 2008. Pre-shooting emotion dysregulation was assessed in 2006-2008. Startle response, measured by orbicularis oculi electromyography (EMG), and RSA were gathered during an FPS paradigm conducted from 2012 to 2015., Results: No significant associations among emotion dysregulation, RSA, and FPS emerged among the full sample. However, emotion dysregulation predicted FPS during both acquisition (r = 0.40, p < 0.05) and extinction (r = 0.57, p < 0.01) among individuals with high resting RSA., Conclusions: Findings suggest that pre-shooting emotion dysregulation is a potent predictor of FPS several years following potential trauma exposure, and this association varies by RSA level. RESULTS emphasize the importance of examining autonomic regulation in the association between emotion dysregulation and recovery from trauma exposure.

Objective: Research suggests that 4-factor models of posttraumatic stress disorder (PTSD) may be improved upon by the addition of novel factors, such as Dysphoric Arousal, Externalizing Behaviors, and Anhedonia. However, a novel 7-factor hybrid model has demonstrated superior fit in veteran and undergraduate samples. The current study sought to replicate this finding in a trauma-exposed community sample and examined relations with positive (PA) and negative affect (NA)., Method: Participants included 403 adults (M(age) = 37.75) recruited through Amazon's MTurk. PTSD was measured using the PTSD Checklist-5 (PCL-5). Confirmatory factor analyses were conducted in Mplus., Results: The 7-factor hybrid model demonstrated good fit: CFI = .96, TLI = .95, RMSEA = .06 (90% CI [.05, .07]), SRMR = .03. This model was superior to the 5- and 6-factor models. All factors demonstrated significant relations with PA and NA, the largest of which were the Externalizing Behaviors (with NA) and Anhedonia (with PA) factors., Conclusion: Results provide support for the 7-factor hybrid model of PTSD using the PCL-5 in a community sample. Findings replicate previous research suggesting that PTSD is highly related to NA, which has been purported as an underlying dimension of PTSD. It is recommended that future research use clinical measures to further examine the hybrid model. (PsycINFO Database Record, ((c) 2016 APA, all rights reserved).)

Objective: Critiques of self-report indices of emotion regulation suggest that its measurement is in need of more critical investigation. The current study examined the factor structure of emotion regulation as informed by Gross' (1998a) Process Model: Situation Selection, Attentional Deployment, Cognitive Change, and Response Modulation., Method: A sample of 553 participants was recruited using Amazon's Mechanical Turk (M(age) = 37.12, SD = 13.66; n = 352 female). Confirmatory factor analysis with maximum likelihood estimation was performed in Mplus., Results: A four-factor model of emotion regulation demonstrated poor fit. An alternative five-factor model fit the data well: CFI = .94, TLI = .93, RMSEA = .07., Conclusion: Emotion regulation may be better conceptualized as a combination of specific strategy use and a broader construct, called "emotional distancing" (a trait-like disposition towards emotions). Further research is required to determine if the observed five-factor model can be replicated in more diverse samples., (© 2015 Wiley Periodicals, Inc.)

This study examined relations among experiential avoidance, state dissociation during writing, cognitive-emotional processing, and posttraumatic stress in the context of an expressive writing task among 58 undergraduate females who were students at a large midwestern university that had recently experienced a mass shooting. Experiential avoidance significantly predicted reported suppression during the writing task. Additionally, posttraumatic stress symptoms (PTSS) at the time of the writing task were significantly associated with state dissociation, suppression, and the use of positive emotion words during the writing. Finally, at the zero-order level, prospective PTSS were associated with state dissociation and suppression during the earlier writing task. However, in a full regression model, only experiential avoidance and PTSS at the time of the writing task significantly predicted prospective PTSS. Supplemental analyses suggest processes may operate differently across levels of exposure. Findings from the present study provide further support for the role of experiential avoidance, state dissociation during writing, and cognitive-emotional processing in predicting PTSS. Additionally, experiential avoidance may play an important role in how individuals use cognitive-emotional processing to narrate a traumatic event., ((c) 2015 APA, all rights reserved).)

Emotion regulation (ER) has been identified as a critical factor in the development and maintenance of posttraumatic stress symptoms (PTS; Bardeen, Kumpula, & Orcutt, 2013 [Journal of Anxiety Disorders, 27, 188-196]; Marx & Sloan, 2005 [Behaviour Research and Therapy, 43, 569-583]; Nightingale & Williams, 2000 [British Journal of Clinical Psychology, 39, 243-254]). The current meta-analysis aimed to provide a thorough, quantitative examination of the associations between PTS and several aspects of ER. A search of the PsychINFO database resulted in 2557 titles, of which 57 met full inclusion criteria (the cross-sectional association between PTS symptoms and ER was reported, participants were 18 years or older, the article was written in English, and sufficient information was reported to calculate effect sizes). From the 57 studies that were included, 74 effect sizes were obtained. All studies were independently coded by two of the study authors for the following: citation, sample type, total N size (and group n's if applicable), mean age of participants, type of traumatic event, study design, PTS measure(s), ER measure(s), and effect size information. Eight random effects models were conducted: seven for individual ER strategies (e.g., rumination) and one for general emotion dysregulation. The largest effects were observed for general emotion dysregulation (r = 0.53; k = 13), rumination (r = 0.51; k = 5), thought suppression (r = 0.47; k = 13), and experiential avoidance (r = 0.40; k = 20). Medium effects were observed for expressive suppression (r = 0.29; k = 3) and worry (r = 0.28; k = 6). Significant effects were not observed for acceptance or reappraisal. Moderator analyses (sample and trauma type) were conducted for general emotion dysregulation, experiential avoidance, and thought suppression; no significant differences were observed. Findings from the current analysis suggest that several aspects of ER are associated with PTS symptoms across a variety of samples. Additionally, the current study highlights a number of limitations in the existing ER and PTS symptom literature.

Objective: The goal of this study was to explore sleep quality as a potential mediator between depression symptoms and diabetes quality of life (DQOL), and anxiety symptoms and DQOL., Method: Participants were 83 male and 3 female veterans with type 2 diabetes (Mage = 62.4). Self-report measures were completed during the baseline assessment of a larger intervention study conducted at the VA Boston Healthcare System., Results: Depression symptoms, anxiety symptoms, and sleep quality were all associated with DQOL. Additionally, sleep quality had a partial indirect effect on the relationships between depression symptoms and DQOL, and between anxiety symptoms and DQOL., Conclusions: These findings suggest that sleep quality may have an important role in the way that psychological distress affects diabetes quality of life., (© 2012 Wiley Periodicals, Inc.)

Objective: To assess the discriminant validity of late-onset stress symptomatology (LOSS) in terms of its distinction from posttraumatic stress disorder (PTSD)., Method: The LOSS Scale, PTSD Checklist - Civilian Version, and related psychological measures were administered to 562 older male combat veterans via a mailed questionnaire. Analyses focused on: (a) comparing associations of LOSS and PTSD with other psychological variables and (b) examining a hypothesized curvilinear relationship between LOSS and PTSD scores., Results: Compared to PTSD, LOSS was more strongly associated with concerns about retirement and less strongly associated with depression, anxiety, sense of mastery, and satisfaction with life. LOSS also demonstrated a curvilinear relationship with PTSD, such that the positive association between LOSS and PTSD diminished at higher levels of PTSD., Conclusion: LOSS is conceptually and statistically more strongly associated with a normative late-life stressor than is PTSD, but is less strongly related to mental health symptoms and emotional well-being. Additionally, LOSS seems more related to subthreshold PTSD than it is to clinically significant PTSD. The present findings support the discriminant validity of LOSS.

Background: The purpose of this study was to document the associations of stressors (combat exposure, retirement concerns, and late-life stressful events), personal resources (social support, sense of mastery, and positive appraisal of military experiences), and functional health (both physical and mental) with life satisfaction in older veterans., Methods: Participants were 562 male combat veterans (mean age = 70). Self-report questionnaires were administered via mail survey. A hierarchical multiple regression analysis was performed., Results: Each step of the regression analysis demonstrated a significant contribution to variance in life satisfaction (48% in total). Although stressors were significant when entered as a set, their influence dissipated in the presence of personal resources and functional health. For the full model, seven of 11 independent variables were unique and significant predictors, including all personal resource factors and both functional health indices. Sense of mastery was most potent., Conclusions: Even in the presence of stressors, personal resources and functional health appear to serve protective roles in explaining levels of life satisfaction among aging veterans., (© 2012 The Authors. Applied Psychology: Health and Well-Being © 2012 The International Association of Applied Psychology.)

The goal of this study was to describe the contributions of community members (unaffiliated members) who serve on institutional review boards (IRBs) at large medical research centers and to compare their contributions to those of other IRB members. We observed and audiotaped 17 panel meetings attended by community members and interviewed 15 community members, as well as 152 other members and staff. The authors coded transcripts of the panel meetings and reviewed the interviews of the community members. Community members played a lesser role as designated reviewers than other members. They were infrequently primary reviewers and expressed hesitation about the role. As secondary or tertiary reviewers, they were less active participants than other members in those roles. Community members were more likely to focus on issues related to confidentiality when reviewing an application than other reviewers. When they were not designated reviewers, however, they played a markedly greater role and their discussion focused more on consent disclosures than other reviewers. They did not appear to represent the community so much as to provide a nonscientific view of the protocol and the consent form.