Publications by authors named "Kerry J Ressler"

360 Publications

Prefrontal cortex, amygdala, and threat processing: implications for PTSD.

Neuropsychopharmacology 2021 Sep 20. Epub 2021 Sep 20.

Department of Psychology, Harvard University, Cambridge, MA, USA.

Posttraumatic stress disorder can be viewed as a disorder of fear dysregulation. An abundance of research suggests that the prefrontal cortex is central to fear processing-that is, how fears are acquired and strategies to regulate or diminish fear responses. The current review covers foundational research on threat or fear acquisition and extinction in nonhuman animals, healthy humans, and patients with posttraumatic stress disorder, through the lens of the involvement of the prefrontal cortex in these processes. Research harnessing advances in technology to further probe the role of the prefrontal cortex in these processes, such as the use of optogenetics in rodents and brain stimulation in humans, will be highlighted, as well other fear regulation approaches that are relevant to the treatment of posttraumatic stress disorder and involve the prefrontal cortex, namely cognitive regulation and avoidance/active coping. Despite the large body of translational research, many questions remain unanswered and posttraumatic stress disorder remains difficult to treat. We conclude by outlining future research directions related to the role of the prefrontal cortex in fear processing and implications for the treatment of posttraumatic stress disorder.
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http://dx.doi.org/10.1038/s41386-021-01155-7DOI Listing
September 2021

Multiomic biological approaches to the study of child abuse and neglect.

Pharmacol Biochem Behav 2021 Sep 8:173271. Epub 2021 Sep 8.

Depression & Anxiety Division, McLean Hospital, Mass General Brigham, Belmont, MA, United States of America; Department of Psychiatry, Harvard Medical School, United States of America. Electronic address:

Childhood maltreatment, occurring in up to 20-30% of the population, remains far too common, and incorporates a range of active and passive factors, from abuse, to neglect, to the impacts of broader structural and systemic adversity. Despite the effects of childhood maltreatment and adversity on a wide range of adult physical and psychological negative outcomes, not all individuals respond similarly. Understanding the differential biological mechanisms contributing to risk vs. resilience in the face of developmental adversity is critical to improving preventions, treatments, and policy recommendations. This review begins by providing an overview of childhood abuse, neglect, maltreatment, threat, and toxic stress, and the effects of these forms of adversity on the developing body, brain, and behavior. It then examines examples from the current literature of genomic, epigenomic, transcriptomic, and proteomic discoveries and biomarkers that may help to understand risk and resilience in the aftermath of trauma, predictors of traumatic exposure risk, and potential targets for intervention and prevention. While the majority of genetic, epigenetic, and gene expression analyses to date have focused on targeted genes and hypotheses, large-scale consortia are now well-positioned to better understand interactions of environment and biology with much more statistical power. Ongoing and future work aimed at understanding the biology of childhood adversity and its effects will help to provide targets for intervention and prevention, as well as identify paths for how science, health care, and policy can combine efforts to protect and promote the psychological and physiological wellbeing of future generations.
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http://dx.doi.org/10.1016/j.pbb.2021.173271DOI Listing
September 2021

A prospective examination of sex differences in posttraumatic autonomic functioning.

Neurobiol Stress 2021 Nov 21;15:100384. Epub 2021 Aug 21.

Department of Psychology, Temple University, Philadelphia, PA, 19121, USA.

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 ( 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.
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http://dx.doi.org/10.1016/j.ynstr.2021.100384DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8397921PMC
November 2021

Development and Validation of a Model to Predict Posttraumatic Stress Disorder and Major Depression After a Motor Vehicle Collision.

JAMA Psychiatry 2021 Sep 1. Epub 2021 Sep 1.

Department of Emergency Medicine, University of Florida College of Medicine, Jacksonville.

Importance: A substantial proportion of the 40 million people in the US who present to emergency departments (EDs) each year after traumatic events develop posttraumatic stress disorder (PTSD) or major depressive episode (MDE). Accurately identifying patients at high risk in the ED would facilitate the targeting of preventive interventions.

Objectives: To develop and validate a prediction tool based on ED reports after a motor vehicle collision to predict PTSD or MDE 3 months later.

Design, Setting, And Participants: The Advancing Understanding of Recovery After Trauma (AURORA) study is a longitudinal study that examined adverse posttraumatic neuropsychiatric sequalae among patients who presented to 28 US urban EDs in the immediate aftermath of a traumatic experience. Enrollment began on September 25, 2017. The 1003 patients considered in this diagnostic/prognostic report completed 3-month assessments by January 31, 2020. Each patient received a baseline ED assessment along with follow-up self-report surveys 2 weeks, 8 weeks, and 3 months later. An ensemble machine learning method was used to predict 3-month PTSD or MDE from baseline information. Data analysis was performed from November 1, 2020, to May 31, 2021.

Main Outcomes And Measures: The PTSD Checklist for DSM-5 was used to assess PTSD and the Patient Reported Outcomes Measurement Information System Depression Short-Form 8b to assess MDE.

Results: A total of 1003 patients (median [interquartile range] age, 34.5 [24-43] years; 715 [weighted 67.9%] female; 100 [weighted 10.7%] Hispanic, 537 [weighted 52.7%] non-Hispanic Black, 324 [weighted 32.2%] non-Hispanic White, and 42 [weighted 4.4%] of non-Hispanic other race or ethnicity were included in this study. A total of 274 patients (weighted 26.6%) met criteria for 3-month PTSD or MDE. An ensemble machine learning model restricted to 30 predictors estimated in a training sample (patients from the Northeast or Midwest) had good prediction accuracy (mean [SE] area under the curve [AUC], 0.815 [0.031]) and calibration (mean [SE] integrated calibration index, 0.040 [0.002]; mean [SE] expected calibration error, 0.039 [0.002]) in an independent test sample (patients from the South). Patients in the top 30% of predicted risk accounted for 65% of all 3-month PTSD or MDE, with a mean (SE) positive predictive value of 58.2% (6.4%) among these patients at high risk. The model had good consistency across regions of the country in terms of both AUC (mean [SE], 0.789 [0.025] using the Northeast as the test sample and 0.809 [0.023] using the Midwest as the test sample) and calibration (mean [SE] integrated calibration index, 0.048 [0.003] using the Northeast as the test sample and 0.024 [0.001] using the Midwest as the test sample; mean [SE] expected calibration error, 0.034 [0.003] using the Northeast as the test sample and 0.025 [0.001] using the Midwest as the test sample). The most important predictors in terms of Shapley Additive Explanations values were symptoms of anxiety sensitivity and depressive disposition, psychological distress in the 30 days before motor vehicle collision, and peritraumatic psychosomatic symptoms.

Conclusions And Relevance: The results of this study suggest that a short set of questions feasible to administer in an ED can predict 3-month PTSD or MDE with good AUC, calibration, and geographic consistency. Patients at high risk can be identified in the ED for targeting if cost-effective preventive interventions are developed.
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http://dx.doi.org/10.1001/jamapsychiatry.2021.2427DOI Listing
September 2021

Association of Racial Discrimination With Neural Response to Threat in Black Women in the US Exposed to Trauma.

JAMA Psychiatry 2021 Sep;78(9):1005-1012

Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia.

Importance: Racial discrimination has a clear impact on health-related outcomes, but little is known about how discriminatory experiences are associated with neural response patterns to emotionally salient cues, which likely mediates these outcomes.

Objective: To examine associations of discriminatory experiences with brainwide response to threat-relevant cues in trauma-exposed US Black women as they engage in an attentionally demanding task.

Design, Setting, And Participants: A cross-sectional study was conducted from May 1, 2014, to July 1, 2019, among 55 trauma-exposed US Black women to examine associations of racial discrimination experiences with patterns of neural response and behavior to trauma-relevant images in an affective attentional control task. Posttraumatic stress disorder (PTSD) symptoms and trauma exposure were entered as covariates to isolate variance associated with experiences of racial discrimination.

Exposures: Varying levels of trauma, PTSD symptoms, and experiences of racial discrimination.

Main Outcomes And Measures: Experiences of Discrimination Questionnaire (EOD) (range, 0-9) for count of the number of situations for which each participant reported having unfair treatment for a racial reason. Experiences of trauma and PTSD symptoms were assessed with the Traumatic Events Inventory (TEI) (number of times the person was exposed to trauma; score range, 0-112) and PTSD Symptom Scale (PSS) (score range, 0-51). Response to trauma-relevant vs neutral distractor cues were assessed via functional magnetic resonance imaging during performance of an affective Stroop (attentional control) task. Statistical analyses were conducted at a whole-brain, voxelwise level with familywise error correction.

Results: In this study of 55 Black women in the US (mean [SD] age, 37.7 [10.7] years; range, 21-61 years), participants reported a mean (SD) TEI frequency of 33.0 (18.8) and showed moderate levels of current PTSD symptoms (mean [SD] PSS score, 15.4 [12.9]). Mean (SD) EOD scores were 2.35 (2.44) and were moderately correlated with current PTSD symptoms (PSS total: r = 0.36; P=.009) but not with age (r = 0.20; P = .15) or TEI frequency (r = -0.02; P = .89). During attention to trauma-relevant vs neutral images, more experiences of racial discrimination were associated with significantly greater response in nodes of emotion regulation and fear inhibition (ventromedial prefrontal cortex) and visual attention (middle occipital cortex) networks, even after accounting for trauma and severity of PTSD symptoms (brainwide familywise error corrected; r = 0.33 for ventromedial prefrontal cortex; P = .02). Racial discrimination was also associated with affective Stroop task performance; errors on trials with threat-relevant stimuli were negatively correlated with experiences of racial discrimination (r = -0.41; P = .003).

Conclusions And Relevance: These findings suggest that experiences of racial discrimination associate with disproportionately greater response in brain regions associated with emotion regulation and fear inhibition and visual attention. Frequent racism experienced by Black individuals may potentiate attentional and regulatory responses to trauma-relevant stressors and lead to heightened modulation of regulatory resources. This may represent an important neurobiological pathway for race-related health disparities.
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http://dx.doi.org/10.1001/jamapsychiatry.2021.1480DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8319825PMC
September 2021

Thalamic volume and fear extinction interact to predict acute posttraumatic stress severity.

J Psychiatr Res 2021 09 14;141:325-332. Epub 2021 Jul 14.

Department of Emergency Medicine, Saint Joseph Mercy Hospital, Ann Arbor, MI, USA.

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.
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http://dx.doi.org/10.1016/j.jpsychires.2021.07.023DOI Listing
September 2021

Randomized, Placebo-Controlled Trial of the Angiotensin Receptor Antagonist Losartan for Posttraumatic Stress Disorder.

Biol Psychiatry 2021 Oct 21;90(7):473-481. Epub 2021 May 21.

Department of Psychiatry, Harvard Medical School, Boston, Massachusetts; McLean Hospital, Belmont, Massachusetts. Electronic address:

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.
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http://dx.doi.org/10.1016/j.biopsych.2021.05.012DOI Listing
October 2021

Deep Transcranial Magnetic Stimulation Combined With Brief Exposure for Posttraumatic Stress Disorder: A Prospective Multisite Randomized Trial.

Biol Psychiatry 2021 May 4. Epub 2021 May 4.

McLean Hospital, Harvard Medical School, Belmont, Massachusetts. Electronic address:

Background: Posttraumatic stress disorder (PTSD) is both prevalent and debilitating. While deep transcranial magnetic stimulation (dTMS) has shown preliminary efficacy, exposure therapy remains the most efficacious, though limited, treatment in PTSD. The medial prefrontal cortex (mPFC) is implicated in extinction learning, suggesting that concurrent mPFC stimulation may enhance exposure therapy. In this randomized controlled multicenter trial, the efficacy and safety of mPFC dTMS combined with a brief exposure procedure were studied in patients with PTSD.

Methods: Immediately following exposure to their trauma narrative, 125 outpatients were randomly assigned to receive dTMS or sham. Twelve sessions were administered over 4 weeks, with a primary end point of change in 5-week Clinician-Administered PTSD Scale for DSM-5 score. This clinical study did not include biological markers.

Results: Clinician-Administered PTSD Scale for DSM-5 score improved significantly in both groups at 5 weeks, though the improvement was smaller in the dTMS group (16.32) compared with the sham group (20.52; p = .027). At 9 weeks, improvement continued in Clinician-Administered PTSD Scale for DSM-5 score in both groups but remained smaller in dTMS (19.0) versus sham (24.4; p = .024).

Conclusions: Both groups showed significant PTSD symptom improvement, possibly from the brief script-driven imagery exposure. While our design was unable to rule out placebo effects, the magnitude and durability of improvement suggest that repeated ultrabrief exposure therapy alone may be an effective treatment for PTSD, warranting additional study. The surprising and unexpected effect in the dTMS group also suggests that repeated mPFC stimulation with the H7 coil may interfere with trauma memory-mediated extinction. Our results provide new insight for dTMS approaches for possible future avenues to treat PTSD.
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http://dx.doi.org/10.1016/j.biopsych.2021.04.019DOI Listing
May 2021

Structural Racism as a Proximal Cause for Race-Related Differences in Psychiatric Disorders.

Am J Psychiatry 2021 07;178(7):579-581

Division of Depression and Anxiety, McLean Hospital, Belmont, Mass.; Department of Psychiatry, Harvard Medical School, Boston.

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http://dx.doi.org/10.1176/appi.ajp.2021.21050486DOI Listing
July 2021

Examining Individual and Synergistic Contributions of PTSD and Genetics to Blood Pressure: A Trans-Ethnic Meta-Analysis.

Front Neurosci 2021 23;15:678503. Epub 2021 Jun 23.

Department of Psychiatry, Case Western Reserve University, Cleveland, OH, United States.

Growing research suggests that posttraumatic stress disorder (PTSD) may be a risk factor for poor cardiovascular health, and yet our understanding of who might be at greatest risk of adverse cardiovascular outcomes after trauma is limited. In this study, we conducted the first examination of the individual and synergistic contributions of PTSD symptoms and blood pressure genetics to continuous blood pressure levels. We harnessed the power of the Psychiatric Genomics Consortium-PTSD Physical Health Working Group and investigated these associations across 11 studies of 72,224 trauma-exposed individuals of European ( = 70,870) and African ( = 1,354) ancestry. Genetic contributions to blood pressure were modeled via polygenic scores (PGS) for systolic blood pressure (SBP) and diastolic blood pressure (DBP) that were derived from a prior trans-ethnic blood pressure genome-wide association study (GWAS). Results of trans-ethnic meta-analyses revealed significant main effects of the PGS on blood pressure levels [SBP: β = 2.83, standard error (SE) = 0.06, < 1E-20; DBP: β = 1.32, SE = 0.04, < 1E-20]. Significant main effects of PTSD symptoms were also detected for SBP and DBP in trans-ethnic meta-analyses, though there was significant heterogeneity in these results. When including data from the largest contributing study - United Kingdom Biobank - PTSD symptoms were negatively associated with SBP levels (β = -1.46, SE = 0.44, = 9.8E-4) and positively associated with DBP levels (β = 0.70, SE = 0.26, = 8.1E-3). However, when excluding the United Kingdom Biobank cohort in trans-ethnic meta-analyses, there was a nominally significant positive association between PTSD symptoms and SBP levels (β = 2.81, SE = 1.13, = 0.01); no significant association was observed for DBP (β = 0.43, SE = 0.78, = 0.58). Blood pressure PGS did not significantly moderate the associations between PTSD symptoms and blood pressure levels in meta-analyses. Additional research is needed to better understand the extent to which PTSD is associated with high blood pressure and how genetic as well as contextual factors may play a role in influencing cardiovascular risk.
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http://dx.doi.org/10.3389/fnins.2021.678503DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8262489PMC
June 2021

Transcriptome-wide association study of post-trauma symptom trajectories identified GRIN3B as a potential biomarker for PTSD development.

Neuropsychopharmacology 2021 09 29;46(10):1811-1820. Epub 2021 Jun 29.

Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA, USA.

Biomarkers that predict symptom trajectories after trauma can facilitate early detection or intervention for posttraumatic stress disorder (PTSD) and may also advance our understanding of its biology. Here, we aimed to identify trajectory-based biomarkers using blood transcriptomes collected in the immediate aftermath of trauma exposure. Participants were recruited from an Emergency Department in the immediate aftermath of trauma exposure and assessed for PTSD symptoms at baseline, 1, 3, 6, and 12 months. Three empirical symptom trajectories (chronic-PTSD, remitting, and resilient) were identified in 377 individuals based on longitudinal symptoms across four data points (1, 3, 6, and 12 months), using latent growth mixture modeling. Blood transcriptomes were examined for association with longitudinal symptom trajectories, followed by expression quantitative trait locus analysis. GRIN3B and AMOTL1 blood mRNA levels were associated with chronic vs. resilient post-trauma symptom trajectories at a transcriptome-wide significant level (N = 153, FDR-corrected p value = 0.0063 and 0.0253, respectively). We identified four genetic variants that regulate mRNA blood expression levels of GRIN3B. Among these, GRIN3B rs10401454 was associated with PTSD in an independent dataset (N = 3521, p = 0.04). Examination of the BrainCloud and GTEx databases revealed that rs10401454 was associated with brain mRNA expression levels of GRIN3B. While further replication and validation studies are needed, our data suggest that GRIN3B, a glutamate ionotropic receptor NMDA type subunit-3B, may be involved in the manifestation of PTSD. In addition, the blood mRNA level of GRIN3B may be a promising early biomarker for the PTSD manifestation and development.
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http://dx.doi.org/10.1038/s41386-021-01073-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8357796PMC
September 2021

Mineralocorticoid receptors dampen glucocorticoid receptor sensitivity to stress via regulation of FKBP5.

Cell Rep 2021 Jun;35(9):109185

Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, MA 02478, USA. Electronic address:

Responding to different dynamic levels of stress is critical for mammalian survival. Disruption of mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) signaling is proposed to underlie hypothalamic-pituitary-adrenal (HPA) axis dysregulation observed in stress-related psychiatric disorders. In this study, we show that FK506-binding protein 51 (FKBP5) plays a critical role in fine-tuning MR:GR balance in the hippocampus. Biotinylated-oligonucleotide immunoprecipitation in primary hippocampal neurons reveals that MR binding, rather than GR binding, to the Fkbp5 gene regulates FKBP5 expression during baseline activity of glucocorticoids. Notably, FKBP5 and MR exhibit similar hippocampal expression patterns in mice and humans, which are distinct from that of the GR. Pharmacological inhibition and region- and cell type-specific receptor deletion in mice further demonstrate that lack of MR decreases hippocampal Fkbp5 levels and dampens the stress-induced increase in glucocorticoid levels. Overall, our findings demonstrate that MR-dependent changes in baseline Fkbp5 expression modify GR sensitivity to glucocorticoids, providing insight into mechanisms of stress homeostasis.
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http://dx.doi.org/10.1016/j.celrep.2021.109185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8244946PMC
June 2021

Genomic factors underlying sex differences in trauma-related disorders.

Neurobiol Stress 2021 May 23;14:100330. Epub 2021 Apr 23.

McLean Hospital, Harvard Medical School, Belmont, MA, USA.

Post-traumatic stress disorder (PTSD) is a devastating illness with treatment that is effective in only approximately half of the population. This limited rate of response highlights the necessity for research into underlying individual biological mechanisms that mediate development and progression of this disease, allowing for identification of patient-specific treatments. PTSD has clear sex differences in both risk and symptom patterns. Thus, one approach is to characterize trauma-related changes between men and women who exhibit differences in treatment efficacy and response to trauma. Recent technological advances in sequencing have identified several genomic loci and transcriptional changes that are associated with post-trauma symptomatology. However, although the diagnosis of PTSD is more prevalent in women, the genetic factors underlying sex differences remain poorly understood. Here, we review recent work that highlights current understanding and limitations in the field of sex differences in PTSD and related symptomatology.
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http://dx.doi.org/10.1016/j.ynstr.2021.100330DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8102626PMC
May 2021

Trauma exposure and stress-related disorders in a large, urban, predominantly African-American, female sample.

Arch Womens Ment Health 2021 May 15. Epub 2021 May 15.

Department of Psychiatry and Behavioral Sciences, Yerkes National Primate Research Center, Emory University School of Medicine, 954 Gatewood Rd, Atlanta, GA, 30329, USA.

The current study investigated the relationship between trauma exposure and psychopathology in a sample of predominately African-American women of low socioeconomic status (SES). Women (N = 7430) were recruited from medical clinics at two large public hospitals in Atlanta, GA, from 2005 to 2017. Women were assessed for sociodemographics, life-course trauma burden, posttraumatic stress disorder (PTSD), and major depressive disorder (MDD) utilizing self-report and structured clinical interview assessments. The effects of trauma exposure on current and lifetime PTSD and MDD were examined. Ninety-one percent of women reported trauma exposure, 83% reported a monthly household income of less than $2000, and 41% reported a history of arrest. Regarding psychiatric diagnoses, 30.8% met the criteria for probable MDD, and 32.3% met the criteria for probable PTSD. History of childhood abuse and total lifetime trauma significantly increased PTSD and depressive symptoms with additional incremental trauma exposure. PTSD and depressive symptom scores (95% CI) increased from 5.5 (5.0-6.1) and 8.4 (7.9-9.0) in the no trauma group to 20.8 (20.1-21.5) and 20.4 (19.7-21.2), respectively, in those exposed to four or more types of trauma. These results show high rates of adult and childhood trauma exposure, PTSD, MDD, and an additive effect of lifetime trauma exposure on the development of PTSD and MDD in a sample of low SES African-American women. These findings bring light to the high psychiatric symptom burden in this population and call for increased availability of interventions to address symptoms as well as policies aimed at reducing trauma exposure across the lifespan.
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http://dx.doi.org/10.1007/s00737-021-01141-4DOI Listing
May 2021

Integration of peripheral transcriptomics, genomics, and interactomics following trauma identifies causal genes for symptoms of post-traumatic stress and major depression.

Mol Psychiatry 2021 May 7. Epub 2021 May 7.

Department of Psychiatry, Dell School of Medicine, Univerity of Texas, Austin, TX, USA.

Posttraumatic stress disorder (PTSD) is a debilitating syndrome with substantial morbidity and mortality that occurs in the aftermath of trauma. Symptoms of major depressive disorder (MDD) are also a frequent consequence of trauma exposure. Identifying novel risk markers in the immediate aftermath of trauma is a critical step for the identification of novel biological targets to understand mechanisms of pathophysiology and prevention, as well as the determination of patients most at risk who may benefit from immediate intervention. Our study utilizes a novel approach to computationally integrate blood-based transcriptomics, genomics, and interactomics to understand the development of risk vs. resilience in the months following trauma exposure. In a two-site longitudinal, observational prospective study, we assessed over 10,000 individuals and enrolled >700 subjects in the immediate aftermath of trauma (average 5.3 h post-trauma (range 0.5-12 h)) in the Grady Memorial Hospital (Atlanta) and Jackson Memorial Hospital (Miami) emergency departments. RNA expression data and 6-month follow-up data were available for 366 individuals, while genotype, transcriptome, and phenotype data were available for 297 patients. To maximize our power and understanding of genes and pathways that predict risk vs. resilience, we utilized a set-cover approach to capture fluctuations of gene expression of PTSD or depression-converting patients and non-converting trauma-exposed controls to find representative sets of disease-relevant dysregulated genes. We annotated such genes with their corresponding expression quantitative trait loci and applied a variant of a current flow algorithm to identify genes that potentially were causal for the observed dysregulation of disease genes involved in the development of depression and PTSD symptoms after trauma exposure. We obtained a final list of 11 driver causal genes related to MDD symptoms, 13 genes for PTSD symptoms, and 22 genes in PTSD and/or MDD. We observed that these individual or combined disorders shared ESR1, RUNX1, PPARA, and WWOX as driver causal genes, while other genes appeared to be causal driver in the PTSD only or MDD only cases. A number of these identified causal pathways have been previously implicated in the biology or genetics of PTSD and MDD, as well as in preclinical models of amygdala function and fear regulation. Our work provides a promising set of initial pathways that may underlie causal mechanisms in the development of PTSD or MDD in the aftermath of trauma.
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http://dx.doi.org/10.1038/s41380-021-01084-3DOI Listing
May 2021

Utilization of machine learning for identifying symptom severity military-related PTSD subtypes and their biological correlates.

Transl Psychiatry 2021 04 20;11(1):227. Epub 2021 Apr 20.

Center for Alcohol Use Disorder and PTSD, Department of Psychiatry, New York University Grossman School of Medicine, New York, NY, USA.

We sought to find clinical subtypes of posttraumatic stress disorder (PTSD) in veterans 6-10 years post-trauma exposure based on current symptom assessments and to examine whether blood biomarkers could differentiate them. Samples were males deployed to Iraq and Afghanistan studied by the PTSD Systems Biology Consortium: a discovery sample of 74 PTSD cases and 71 healthy controls (HC), and a validation sample of 26 PTSD cases and 36 HC. A machine learning method, random forests (RF), in conjunction with a clustering method, partitioning around medoids, were used to identify subtypes derived from 16 self-report and clinician assessment scales, including the clinician-administered PTSD scale for DSM-IV (CAPS). Two subtypes were identified, designated S1 and S2, differing on mean current CAPS total scores: S2 = 75.6 (sd 14.6) and S1 = 54.3 (sd 6.6). S2 had greater symptom severity scores than both S1 and HC on all scale items. The mean first principal component score derived from clinical summary scales was three times higher in S2 than in S1. Distinct RFs were grown to classify S1 and S2 vs. HCs and vs. each other on multi-omic blood markers feature classes of current medical comorbidities, neurocognitive functioning, demographics, pre-military trauma, and psychiatric history. Among these classes, in each RF intergroup comparison of S1, S2, and HC, multi-omic biomarkers yielded the highest AUC-ROCs (0.819-0.922); other classes added little to further discrimination of the subtypes. Among the top five biomarkers in each of these RFs were methylation, micro RNA, and lactate markers, suggesting their biological role in symptom severity.
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http://dx.doi.org/10.1038/s41398-021-01324-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8058082PMC
April 2021

Brain proteome-wide association study implicates novel proteins in depression pathogenesis.

Nat Neurosci 2021 06 12;24(6):810-817. Epub 2021 Apr 12.

Department of Psychiatry, Emory University School of Medicine, Atlanta, GA, USA.

Depression is a common condition, but current treatments are only effective in a subset of individuals. To identify new treatment targets, we integrated depression genome-wide association study (GWAS) results (N = 500,199) with human brain proteomes (N = 376) to perform a proteome-wide association study of depression followed by Mendelian randomization. We identified 19 genes that were consistent with being causal in depression, acting via their respective cis-regulated brain protein abundance. We replicated nine of these genes using an independent depression GWAS (N = 307,353) and another human brain proteomic dataset (N = 152). Eleven of the 19 genes also had cis-regulated mRNA levels that were associated with depression, based on integration of the depression GWAS with human brain transcriptomes (N = 888). Meta-analysis of the discovery and replication proteome-wide association study analyses identified 25 brain proteins consistent with being causal in depression, 20 of which were not previously implicated in depression by GWAS. Together, these findings provide promising brain protein targets for further mechanistic and therapeutic studies.
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http://dx.doi.org/10.1038/s41593-021-00832-6DOI Listing
June 2021

Hippocampal activation during contextual fear inhibition related to resilience in the early aftermath of trauma.

Behav Brain Res 2021 06 2;408:113282. Epub 2021 Apr 2.

Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA.

Background: Impaired contextual fear inhibition is often associated with posttraumatic stress disorder (PTSD). Our previous work has demonstrated that more hippocampal activation during a response inhibition task after trauma exposure was related to greater resilience and fewer future PTSD symptoms. In the current study, we sought to extend our previous findings by employing a contextual fear conditioning and extinction paradigm to further determine the role of the hippocampus in resilience and PTSD in the early aftermath of trauma.

Methods: Participants (N = 28) were recruited in the Emergency Department shortly after experiencing a traumatic event. A contextual fear inhibition task was conducted in a 3 T MRI scanner approximately two months post-trauma. Measures of resilience (CD-RISC) at time of scan and PTSD symptoms three months post-trauma were collected. The associations between hippocampal activation during fear conditioning and during the effect of context during extinction, and post-trauma resilience and PTSD symptoms at three-months were assessed.

Results: During fear conditioning, activation of the bilateral hippocampal region of interest (ROI) correlated positively with resilience (r = 0.48, p = 0.01). During the effect of context during extinction, greater bilateral hippocampal activation correlated with lower PTSD symptoms three months post-trauma after controlling for baseline PTSD symptoms, age and gender (r=-0.59, p=0.009).

Conclusions: Greater hippocampal activation was related to post-trauma resilience and lower PTSD symptoms three months post-trauma. The current study supports and strengthens prior findings suggesting the importance of hippocampus-dependent context processing as a mechanism for resilience versus PTSD risk, which could be a potential mechanistic target for novel early interventions.
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http://dx.doi.org/10.1016/j.bbr.2021.113282DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8128041PMC
June 2021

Polygenic risk scores differentiate schizophrenia patients with toxoplasma gondii compared to toxoplasma seronegative patients.

Compr Psychiatry 2021 05 2;107:152236. Epub 2021 Mar 2.

Dept. of Epidemiology, Rollins School of Public Health; 1518 Clifton Rd., Atlanta, GA 30322, USA. Electronic address:

Schizophrenia (SCZ) is an etiologically heterogeneous disease with genetic and environmental risk factors (e.g., Toxoplasma gondii infection) differing among affected individuals. Distinguishing such risk factors may point to differences in pathophysiological pathways and facilitate the discovery of individualized treatments. Toxoplasma gondii (TOXO) has been implicated in increasing the risk of schizophrenia. To determine whether TOXO-positive individuals with SCZ have a different polygenic risk burden than uninfected people, we applied the SCZ polygenic risk score (SCZ-PRS) derived from the Psychiatric GWAS Consortium separately to the TOXO-positive and TOXO-negative subjects with the diagnosis of SCZ as the outcome variable. The SCZ-PRS does not include variants in the major histocompatibility complex. Of 790 subjects assessed for TOXO, the 662 TOXO-negative subjects (50.8% with SCZ) reached a Bonferroni corrected significant association (p = 0.00017, R = 0.023). In contrast, the 128 TOXO-positive individuals (53.1% with SCZ) showed no significant association (p = 0.354) for SCZ-PRS and had a much lower R (R = 0.007). To account for Type-2 error in the TOXO-positive dataset, we performed a random sampling of the TOXO-negative subpopulation (n = 130, repeated 100 times) to simulate equivalent power between groups: the p-value was <0.05 for SCZ-PRS 55% of the time but was rarely (6% of the time) comparable to the high p-value of the seropositive group at p > 0.354. We found intriguing evidence that the SCZ-PRS predicts SCZ in TOXO-negative subjects, as expected, but not in the TOXO-positive individuals. This result highlights the importance of considering environmental risk factors to distinguish a subgroup with independent or different genetic components involved in the development of SCZ.
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http://dx.doi.org/10.1016/j.comppsych.2021.152236DOI Listing
May 2021

Nucleus Accumbens Medium Spiny Neuron Subtypes Differentially Regulate Stress-Associated Alterations in Sleep Architecture.

Biol Psychiatry 2021 06 13;89(12):1138-1149. Epub 2021 Jan 13.

Basic Neuroscience Division, Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, Massachusetts. Electronic address:

Background: Stress is implicated in the pathophysiology of major depression and posttraumatic stress disorder. These conditions share core features, including motivational deficits, heighted anxiety, and sleep dysregulation. Chronic stress produces these same features in rodents, with some individuals being susceptible or resilient, as seen in humans. While stress-induced neuroadaptations within the nucleus accumbens are implicated in susceptibility-related dysregulation of motivational and emotional behaviors, their effects on sleep are unclear.

Methods: We used chemogenetics (DREADDs [designer receptors exclusively activated by designer drugs]) to examine the effects of selective alterations in activity of nucleus accumbens medium spiny neurons expressing dopamine D receptors (D1-MSNs) or dopamine D receptors (D2-MSNs) on sleep-related end points. Mice were implanted with wireless transmitters enabling continuous collection of data to quantify vigilance states over a 20-day test period. Parallel cohorts were examined in behavioral tests assessing stress susceptibility.

Results: D1- and D2-MSNs play dissociable roles in sleep regulation. Stimulation of inhibitory or excitatory DREADDs expressed in D1-MSNs exclusively affects rapid eye movement sleep, whereas targeting D2-MSNs affects slow wave sleep. The combined effects of D1-MSN inhibition and D2-MSN activation on sleep resemble those of chronic social defeat stress. Alterations in D1-MSN function also affect stress susceptibility in social behavior tests. Elevation of CREB (cAMP response element-binding protein) within D1-MSNs is sufficient to produce stress-like effects on rapid eye movement sleep.

Conclusions: In addition to regulation of motivational and emotional behaviors, the nucleus accumbens also influences sleep, an end point with high translational relevance. These findings provide a neural basis for comorbidity in key features of stress-related illness.
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http://dx.doi.org/10.1016/j.biopsych.2020.12.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8178228PMC
June 2021

A Perspective for Understanding Trauma and the Criminal Juvenile Justice System: Using a Trauma-Informed Lens for Meaningful and Sustained Change.

Harv Rev Psychiatry 2021 May-Jun 01;29(3):216-224

From the Department of Psychiatry, Oregon Health Sciences University (Dr. Moreland); Harvard Medical School (Dr. Ressler); McLean Hospital, Belmont, MA (Dr. Ressler).

Abstract: Trauma exposure and posttraumatic stress disorder are common and are associated with a wide range of negative psychiatric and physical outcomes. Furthermore, a large percentage of justice-involved youth have high rates of trauma exposure and trauma-related symptoms. Addressing these issues would improve outcomes at the level of the justice system overall and in the lives of justice-involved youth. Nonetheless, awareness, education, and implementation of trauma-informed approaches in the criminal juvenile justice system are lacking. This article explores current literature that operationalizes trauma-informed practices and approaches in the criminal and juvenile justice systems. Unfortunately, there is no shared understanding or definition of trauma and no predictability in trauma-informed practices and approaches in the criminal juvenile justice system. Despite the presence of written policies, the application and execution of such policies are limited and inconsistent throughout the system. These limitations contribute to ongoing, systemic institutional racism, lack of mental health or substance abuse treatment, limited diversion options, and unnecessary jail and prison sentences, which together amplify financial and humanitarian costs. We argue that in order for the criminal juvenile justice system to become trauma-informed, it should (1) meet basic needs of clients, (2) check and change narratives, and check underlying assumptions, (3) focus on skill building/habilitation, (4) move away from punishment and toward rehabilitation and humanitarian approaches, and (5) heal and support members that work in and for the system. We conclude that there is a need to improve processes for education, training, and coaching in, and consistent application of, trauma-informed practices and approaches within the criminal and juvenile justice systems.
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http://dx.doi.org/10.1097/HRP.0000000000000290DOI Listing
March 2021

The co-chaperone Fkbp5 shapes the acute stress response in the paraventricular nucleus of the hypothalamus of male mice.

Mol Psychiatry 2021 Mar 1. Epub 2021 Mar 1.

Research Group Neurobiology of Stress Resilience, Max Planck Institute of Psychiatry, Munich, Germany.

Disturbed activation or regulation of the stress response through the hypothalamic-pituitary-adrenal (HPA) axis is a fundamental component of multiple stress-related diseases, including psychiatric, metabolic, and immune disorders. The FK506 binding protein 51 (FKBP5) is a negative regulator of the glucocorticoid receptor (GR), the main driver of HPA axis regulation, and FKBP5 polymorphisms have been repeatedly linked to stress-related disorders in humans. However, the specific role of Fkbp5 in the paraventricular nucleus of the hypothalamus (PVN) in shaping HPA axis (re)activity remains to be elucidated. We here demonstrate that the deletion of Fkbp5 in Sim1 neurons dampens the acute stress response and increases GR sensitivity. In contrast, Fkbp5 overexpression in the PVN results in a chronic HPA axis over-activation, and a PVN-specific rescue of Fkbp5 expression in full Fkbp5 KO mice normalizes the HPA axis phenotype. Single-cell RNA sequencing revealed the cell-type-specific expression pattern of Fkbp5 in the PVN and showed that Fkbp5 expression is specifically upregulated in Crh neurons after stress. Finally, Crh-specific Fkbp5 overexpression alters Crh neuron activity, but only partially recapitulates the PVN-specific Fkbp5 overexpression phenotype. Together, the data establish the central and cell-type-specific importance of Fkbp5 in the PVN in shaping HPA axis regulation and the acute stress response.
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http://dx.doi.org/10.1038/s41380-021-01044-xDOI Listing
March 2021

Increasing the resolution and precision of psychiatric genome-wide association studies by re-imputing summary statistics using a large, diverse reference panel.

Am J Med Genet B Neuropsychiatr Genet 2021 01 11;186(1):16-27. Epub 2021 Feb 11.

Department of Psychiatry, Virginia Commonwealth University, Richmond, Virginia, USA.

Genotype imputation across populations of mixed ancestry is critical for optimal discovery in large-scale genome-wide association studies (GWAS). Methods for direct imputation of GWAS summary-statistics were previously shown to be practically as accurate as summary statistics produced after raw genotype imputation, while incurring orders of magnitude lower computational burden. Given that direct imputation needs a precise estimation of linkage-disequilibrium (LD) and that most of the methods using a small reference panel for example, ~2,500-subject coming from the 1000 Genome-Project, there is a great need for much larger and more diverse reference panels. To accurately estimate the LD needed for an exhaustive analysis of any cosmopolitan cohort, we developed DISTMIX2. DISTMIX2: (a) uses a much larger and more diverse reference panel compared to traditional reference panels, and (b) can estimate weights of ethnic-mixture based solely on Z-scores, when allele frequencies are not available. We applied DISTMIX2 to GWAS summary-statistics from the psychiatric genetic consortium (PGC). DISTMIX2 uncovered signals in numerous new regions, with most of these findings coming from the rarer variants. Rarer variants provide much sharper location for the signals compared with common variants, as the LD for rare variants extends over a lower distance than for common ones. For example, while the original PGC post-traumatic stress disorder GWAS found only 3 marginal signals for common variants, we now uncover a very strong signal for a rare variant in PKN2, a gene associated with neuronal and hippocampal development. Thus, DISTMIX2 provides a robust and fast (re)imputation approach for most psychiatric GWAS-studies.
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http://dx.doi.org/10.1002/ajmg.b.32834DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8247874PMC
January 2021

Combined effects of genotype and childhood adversity shape variability of DNA methylation across age.

Transl Psychiatry 2021 02 1;11(1):88. Epub 2021 Feb 1.

Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Kraepelinstr. 2-10, 80804, Munich, Germany.

Lasting effects of adversity, such as exposure to childhood adversity (CA) on disease risk, may be embedded via epigenetic mechanisms but findings from human studies investigating the main effects of such exposure on epigenetic measures, including DNA methylation (DNAm), are inconsistent. Studies in perinatal tissues indicate that variability of DNAm at birth is best explained by the joint effects of genotype and prenatal environment. Here, we extend these analyses to postnatal stressors. We investigated the contribution of CA, cis genotype (G), and their additive (G + CA) and interactive (G × CA) effects to DNAm variability in blood or saliva from five independent cohorts with a total sample size of 1074 ranging in age from childhood to late adulthood. Of these, 541 were exposed to CA, which was assessed retrospectively using self-reports or verified through social services and registries. For the majority of sites (over 50%) in the adult cohorts, variability in DNAm was best explained by G + CA or G × CA but almost never by CA alone. Across ages and tissues, 1672 DNAm sites showed consistency of the best model in all five cohorts, with G × CA interactions explaining most variance. The consistent G × CA sites mapped to genes enriched in brain-specific transcripts and Gene Ontology terms related to development and synaptic function. Interaction of CA with genotypes showed the strongest contribution to DNAm variability, with stable effects across cohorts in functionally relevant genes. This underscores the importance of including genotype in studies investigating the impact of environmental factors on epigenetic marks.
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http://dx.doi.org/10.1038/s41398-020-01147-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7851167PMC
February 2021

Classification and Prediction of Post-Trauma Outcomes Related to PTSD Using Circadian Rhythm Changes Measured via Wrist-Worn Research Watch in a Large Longitudinal Cohort.

IEEE J Biomed Health Inform 2021 08 6;25(8):2866-2876. Epub 2021 Aug 6.

Post-Traumatic Stress Disorder (PTSD) is a psychiatric condition resulting from threatening or horrifying events. We hypothesized that circadian rhythm changes, measured by a wrist-worn research watch are predictive of post-trauma outcomes.

Approach: 1618 post-trauma patients were enrolled after admission to emergency departments (ED). Three standardized questionnaires were administered at week eight to measure post-trauma outcomes related to PTSD, sleep disturbance, and pain interference with daily life. Pulse activity and movement data were captured from a research watch for eight weeks. Standard and novel movement and cardiovascular metrics that reflect circadian rhythms were derived using this data. These features were used to train different classifiers to predict the three outcomes derived from week-eight surveys. Clinical surveys administered at ED were also used as features in the baseline models.

Results: The highest cross-validated performance of research watch-based features was achieved for classifying participants with pain interference by a logistic regression model, with an area under the receiver operating characteristic curve (AUC) of 0.70. The ED survey-based model achieved an AUC of 0.77, and the fusion of research watch and ED survey metrics improved the AUC to 0.79.

Significance: This work represents the first attempt to predict and classify post-trauma symptoms from passive wearable data using machine learning approaches that leverage the circadian desynchrony in a potential PTSD population.
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http://dx.doi.org/10.1109/JBHI.2021.3053909DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8395207PMC
August 2021

Prognostic neuroimaging biomarkers of trauma-related psychopathology: resting-state fMRI shortly after trauma predicts future PTSD and depression symptoms in the AURORA study.

Neuropsychopharmacology 2021 06 21;46(7):1263-1271. Epub 2021 Jan 21.

Department of Emergency Medicine, Boston Medical Center, Boston, MA, USA.

Neurobiological markers of future susceptibility to posttraumatic stress disorder (PTSD) may facilitate identification of vulnerable individuals in the early aftermath of trauma. Variability in resting-state networks (RSNs), patterns of intrinsic functional connectivity across the brain, has previously been linked to PTSD, and may thus be informative of PTSD susceptibility. The present data are part of an initial analysis from the AURORA study, a longitudinal, multisite study of adverse neuropsychiatric sequalae. Magnetic resonance imaging (MRI) data from 109 recently (i.e., ~2 weeks) traumatized individuals were collected and PTSD and depression symptoms were assessed at 3 months post trauma. We assessed commonly reported RSNs including the default mode network (DMN), central executive network (CEN), and salience network (SN). We also identified a proposed arousal network (AN) composed of a priori brain regions important for PTSD: the amygdala, hippocampus, mamillary bodies, midbrain, and pons. Primary analyses assessed whether variability in functional connectivity at the 2-week imaging timepoint predicted 3-month PTSD symptom severity. Left dorsolateral prefrontal cortex (DLPFC) to AN connectivity at 2 weeks post trauma was negatively related to 3-month PTSD symptoms. Further, right inferior temporal gyrus (ITG) to DMN connectivity was positively related to 3-month PTSD symptoms. Both DLPFC-AN and ITG-DMN connectivity also predicted depression symptoms at 3 months. Our results suggest that, following trauma exposure, acutely assessed variability in RSN connectivity was associated with PTSD symptom severity approximately two and a half months later. However, these patterns may reflect general susceptibility to posttraumatic dysfunction as the imaging patterns were not linked to specific disorder symptoms, at least in the subacute/early chronic phase. The present data suggest that assessment of RSNs in the early aftermath of trauma may be informative of susceptibility to posttraumatic dysfunction, with future work needed to understand neural markers of long-term (e.g., 12 months post trauma) dysfunction. Furthermore, these findings are consistent with neural models suggesting that decreased top-down cortico-limbic regulation and increased network-mediated fear generalization may contribute to ongoing dysfunction in the aftermath of trauma.
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http://dx.doi.org/10.1038/s41386-020-00946-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8134491PMC
June 2021

Treatment Outcomes of Electroconvulsive Therapy for Depressed Patients With and Without Borderline Personality Disorder: A Retrospective Cohort Study.

J Clin Psychiatry 2021 01 19;82(2). Epub 2021 Jan 19.

McLean Hospital/Harvard Medical School, Belmont, Massachusetts, USA.

Background: Electroconvulsive therapy (ECT) is the gold-standard treatment for refractory depression. Borderline personality disorder (BPD) is generally considered a poor predictor of treatment response. We sought to assess symptom-severity outcomes among depressed patients with (BPD+) and without (BPD-) comorbid BPD undergoing acute phase ECT.

Methods: The study sample consisted of at least moderately depressed patients who received an acute course of ECT from January 2011 to December 2016 at an academic, freestanding psychiatric hospital. Participants completed a DSM-IV-validated BPD screening instrument at baseline. Measures of DSM-IV depressive symptom severity from the Quick Inventory of Depressive Symptomatology-Self Report (QIDS-SR) were taken serially on 4 occasions. Outcomes of interest comprised total QIDS-SR score trajectory, QIDS-SR suicidality subscore, and symptom cluster subscores posited to differentiate response among antidepressant treatments.

Results: Of the 693 individuals who met study inclusion criteria, 145 (20.9%) screened positive for BPD. Overall, ECT was associated with significant improvement of depressive symptoms (χ²₁ = 504.8, P < .0001). Despite differing from BPD- individuals on key baseline features, BPD+ individuals responded to ECT with similar improvement in overall depression severity (χ²₁ = 0.22, P = .64), suicidality (χ²₁ = 1.63, P = .20), and core emotional (χ²₁ = 0.63, P = .43), sleep (χ²₁ = 0.20, P = .65), and atypical (χ²₁ = 1.30, P = .25) symptoms after 15 treatments. Post hoc analysis indicated a slightly less robust overall response among the BPD+ group by the 15th treatment.

Conclusions: Acute course ECT benefits depressed patients with or without comorbid BPD, although patients with BPD may exhibit less pronounced improvement over time.
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http://dx.doi.org/10.4088/JCP.19m13202DOI Listing
January 2021

DSM-5 alternative model for personality disorders trait domains and PTSD symptoms in a sample of highly traumatized African American women and a prospective sample of trauma center patients.

Personal Disord 2021 Jan 14. Epub 2021 Jan 14.

Department of Psychiatry and Behavioral Sciences.

Posttraumatic stress disorder (PTSD) has a specified precipitant (i.e., trauma), and thus, is particularly well-suited to examine risk and maintenance factors for the development of the disorder. The alternative model of personality disorder (AMPD) is based, in part, on a dimensional trait model; previous research suggests that personality traits are related to PTSD symptoms. To date, there is little research examining this model with regard to PTSD symptoms, and such research could elucidate new strategies for identification and prevention. The present study investigates associations between AMPD traits and PTSD symptoms in a cross-sectional high-risk sample ( = 490; 100% female; 97.8% African American) and in a prospective, longitudinal sample of Level 1 trauma center patients ( = 185; 46.8% female; 72.5% African American). The Personality Inventory for Brief Form domains were significantly associated with PTSD total symptom severity and symptom clusters across both self-report and clinical interview measures. Personality Inventory for Negative Affectivity and Psychoticism emerged as significant predictors of concurrent PTSD. When prospectively predicting PTSD symptoms in the longitudinal cohort, Negative Affectivity and Psychoticism were significant predictors of PTSD symptom severity. These findings indicate how the AMPD pathological traits are associated with risk for stress-related disorders cross-sectionally and prospectively. (PsycInfo Database Record (c) 2021 APA, all rights reserved).
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http://dx.doi.org/10.1037/per0000477DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8277882PMC
January 2021

Posttraumatic cognitions predict distorted body perceptions in women with dissociative identity disorder.

J Psychiatr Res 2021 02 19;134:166-172. Epub 2020 Dec 19.

McLean Hospital, Belmont, MA, USA; Department of Psychiatry, Harvard Medical School, Boston, MA, USA. Electronic address:

Background: Dissociative identity disorder (DID) is a psychobiological syndrome associated with a history of exposure to childhood abuse and neglect. The consequences of these traumatic events often include a profound impact on the way individuals inhabit and experience their bodies. Despite this, there is a paucity of empirical research on the subject. The aim of this study was to systematically document the occurrence of distorted body perceptions in DID and examine childhood maltreatment, posttraumatic stress disorder (PTSD) symptom severity, and posttraumatic cognitions as predictors of distorted body perceptions in DID.

Methods: Participants were adult women with histories of childhood abuse and neglect and a current DID diagnosis receiving treatment at a psychiatric care facility. Data were obtained through a battery of self-report measures, including the Body Uneasiness Test, Childhood Trauma Questionnaire, PTSD Checklist for DMS-5, and Posttraumatic Cognitions Inventory.

Results: A series of unpaired t-tests documented elevated levels of weight phobia, body image concerns, body avoidance, compulsive self-monitoring, and depersonalization in DID compared to published non-clinical data on the Body Uneasiness Test. A series of multiple regression models including measures of childhood trauma, PTSD symptoms, and posttraumatic cognitions demonstrated that over and above childhood trauma and PTSD symptom severity, posttraumatic cognitions significantly predicted distorted body perceptions.

Conclusions: In a treatment-seeking sample of women with DID, distorted body perceptions were elevated. Furthermore, posttraumatic cognitive distortions significantly predicted distorted body perceptions when controlling for childhood maltreatment and PTSD symptom severity. This suggests that distorted cognitions are a key target for therapeutic intervention.
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http://dx.doi.org/10.1016/j.jpsychires.2020.12.053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7870557PMC
February 2021

Epigenetic biotypes of post-traumatic stress disorder in war-zone exposed veteran and active duty males.

Mol Psychiatry 2020 Dec 18. Epub 2020 Dec 18.

Medical Readiness Systems Biology, Walter Reed Army Institute for Research, Silver Spring, MD, USA.

Post-traumatic stress disorder (PTSD) is a heterogeneous condition evidenced by the absence of objective physiological measurements applicable to all who meet the criteria for the disorder as well as divergent responses to treatments. This study capitalized on biological diversity observed within the PTSD group observed following epigenome-wide analysis of a well-characterized Discovery cohort (N = 166) consisting of 83 male combat exposed veterans with PTSD, and 83 combat veterans without PTSD in order to identify patterns that might distinguish subtypes. Computational analysis of DNA methylation (DNAm) profiles identified two PTSD biotypes within the PTSD+ group, G1 and G2, associated with 34 clinical features that are associated with PTSD and PTSD comorbidities. The G2 biotype was associated with an increased PTSD risk and had higher polygenic risk scores and a greater methylation compared to the G1 biotype and healthy controls. The findings were validated at a 3-year follow-up (N = 59) of the same individuals as well as in two independent, veteran cohorts (N = 54 and N = 38), and an active duty cohort (N = 133). In some cases, for example Dopamine-PKA-CREB and GABA-PKC-CREB signaling pathways, the biotypes were oppositely dysregulated, suggesting that the biotypes were not simply a function of a dimensional relationship with symptom severity, but may represent distinct biological risk profiles underpinning PTSD. The identification of two novel distinct epigenetic biotypes for PTSD may have future utility in understanding biological and clinical heterogeneity in PTSD and potential applications in risk assessment for active duty military personnel under non-clinician-administered settings, and improvement of PTSD diagnostic markers.
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http://dx.doi.org/10.1038/s41380-020-00966-2DOI Listing
December 2020
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