Gene expression differences in PTSD are uniquely related to the intrusion symptom cluster: A transcriptome-wide analysis in military service members.

Posttraumatic stress disorder (PTSD) is associated with wide-spread immune dysregulation; however, little is known about the gene expression differences attributed to each PTSD symptom cluster. This is an important consideration when identifying diagnostic and treatment response markers in highly comorbid populations with mental and physical health conditions that share symptoms. To this aim, we utilized a transcriptome-wide analysis of differential gene expression in peripheral blood by comparing military service members: (1) with vs. without PTSD, (2) with high vs. low PTSD cluster symptom severity, and (3) with improved vs. not improved PTSD symptoms following 4-8 weeks of evidenced-based sleep treatment. Data were analyzed at a ±2.0-fold change magnitude with subsequent gene ontology-based pathway analysis. In participants with PTSD (n = 39), 89 differentially expressed genes were identified, and 94% were upregulated. In participants with high intrusion symptoms (n = 22), 1040 differentially expressed genes were identified, and 98% were upregulated. No differentially expressed genes were identified for the remaining two PTSD symptom clusters. Ten genes (C5orf24, RBAK, CREBZF, CD69, PMAIP1, AGL, ZNF644, ANKRD13C, ESCO1, and ZCCHC10) were upregulated in participants with PTSD and high intrusion symptoms at baseline and downregulated in participants with improved PTSD symptoms following treatment. Pathway analysis identified upregulated immune response systems and metabolic networks with a NF-kB hub, which were downregulated with symptom reduction. Molecular biomarkers implicated in intrusion symptoms and PTSD symptom improvement may inform the development of therapeutic targets for precise treatment of PTSD.

Entrapment in the military context: Factor structure and associations with suicidal thoughts and behaviors.

BACKGROUND: Improved understanding of how US service members transition from chronic/baseline to acute suicide risk is warranted. One such model, the Integrated Motivational Volitional Model of Suicide, posits entrapment as central to this process. However, entrapment has not been extensively investigated within military populations. METHODS: This study examines the factor structure, reliability, and predictive validity of the Entrapment Scale (E-Scale) within a military population. Exploratory structural equation modeling (SEM) and confirmatory factor analysis compared one- versus two-factor structures of the E-Scale. Autoregressive SEM assessed if E-Scale scores predicted suicidal ideation and suicide attempt likelihood at 6- and 12-month follow-up, and examined whether the impact of entrapment was moderated by social support (i.e., appraisal, tangible, and belonging). RESULTS: Results favored a two-factor solution (external and internal) of entrapment. The relationship between entrapment and suicide outcomes was moderated by perceived social support but in unexpected directions. Unexpectedly, social support strengthened the relationship between external entrapment and suicide outcomes for most models. Only tangible support moderated the relationship between internal entrapment (IE) and suicide outcomes as predicted. CONCLUSIONS: IE is linked with suicidal ideation in the short-term, whereas external entrapments relationship with suicide outcomes may reflect more persistent social challenges for military members.

Impact of the COVID-19 Pandemic on Indicators of Psychological Health and Suicidal Ideation Within an Active Duty U.S. Military Population.

INTRODUCTION: The COVID-19 pandemic has had a significant impact on the psychological health of individuals. The pandemic has contributed to increased anxiety, elevated rates of depression, and worsening suicidal ideation among civilians. Reported rates of burnout are also elevated as employees and employers adapted to ever-changing work environments, finding it increasingly difficult to maintain a work-life balance. The objective of this study is to determine how the COVID-19 pandemic impacted the psychological health and rates of suicidal ideation of active duty military personnel in the USA. MATERIALS AND METHODS: A total of 2055 military personnel and military-adjacent employees stationed at a U.S. Air Force base completed a self-report survey that was administered six times from January 2020 to December 2021. Validated scales assessed measures of psychological health and suicidal ideation. General Estimating Equations were used to examine how indicators of time and psychological health predicted suicidal ideation in a military population. RESULTS: Life satisfaction, happiness, feeling life is worthwhile, depression severity, and suicidal ideation did not statistically change across the six time points. Worry (P < .01) and depression (P < .001) did decrease significantly, while burnout (P = .01) significantly increased across these time points. Feeling life is worthwhile significantly predicted reduced suicidal ideation (B = -.19; SE = 0.05), while depression (B = 0.11; SE = 0.03), depression severity (B = 0.24; SE = 0.05), worry (B = 0.06; SE = 0.02), and burnout (B = 0.15; SE = 0.07) predicted increased suicidal ideation. CONCLUSIONS: The rates of depression and worry decreased throughout the pandemic for those in the study while rates of suicidal ideation remained constant, demonstrating the potential resilience of military personnel and military-adjacent employees in response to the COVID-19 pandemic. However, burnout increased and significantly predicted elevated rates of suicidal ideation, highlighting the importance of focusing on reducing workplace stressors for military personnel.

Intervening with Opioid-Exposed Newborns:: Modifying an Evidence-Based Parenting Intervention.

Background: Prenatal opioid exposure predisposes infants to adverse development of regulatory systems and jeopardizes their long-term health outcomes. While sensitive caregiving promotes healthy development of emotional and physiological regulation and may remediate risks associated with prenatal opioid exposure, mothers with opioid use disorder often experience unique challenges that make providing sensitive care difficult. Rationale: Empirically tested early interventions, such as the Attachment and Biobehavioral Catch-up (ABC) intervention, can positively impact children's development following adversity through promoting sensitive caregiving. ABC intervention targets correspond to those parenting behaviors that may be challenging for mothers with opioid use disorder (i.e., nurturing infants who may be difficult to soothe, responding sensitively to infants by following the child's lead with delight, and avoiding intrusive/frightening behavior), and have positive impacts on child development and regulation. However, given the unique challenges for infants and mothers impacted by opioid use, some adaptations may strategically address those vulnerabilities and thereby maximize the potential benefits for this population. Methods: The present paper describes modifications made to the ABC intervention for use with pregnant mothers in treatment for opioid use disorder. This modified intervention is currently being examined via a large scale randomized clinical trial (RCT) at the University of Delaware, and a case study is presented here to highlight considerations for working with mothers and infants impacted by opioid use and to exemplify ways that modified ABC addresses the needs of this population.

Effects of institutional rearing on children's diurnal cortisol production.

Young children living in institutional settings often show a range of deficits in social, physical, and cognitive functioning. Whereas the diurnal production of cortisol has been examined among post-institutionalized children in a number of investigations, studies of children continuing to live in institutions are limited. In this study, we assessed wake-up and bedtime cortisol among 73 children living in Russia, with 52 institutionally-reared (n = 31 at time 2), and 21 family-reared (n = 18 at time 2). Institutionally-reared children showed a blunter wake-up to bedtime slope than family-reared children at both time 1 and time 2, with significantly higher cortisol levels at bedtime. These findings highlight the deleterious effects of institutional care on children's developing neuroendocrine regulation.

Altered DNA Methylation Patterns Associated With Clinically Relevant Increases in PTSD Symptoms and PTSD Symptom Profiles in Military Personnel.

Military personnel experience posttraumatic stress disorder (PTSD), which is associated with differential DNA methylation across the whole genome. However, the relationship between these DNA methylation patterns and clinically relevant increases in PTSD severity is not yet clearly understood. The purpose of this study was to identify differences in DNA methylation associated with PTSD symptoms and investigate DNA methylation changes related to increases in the severity of PTSD in military personnel. In this pilot study, a cross-sectional comparison was made between military personnel with PTSD (n = 8) and combat-matched controls without PTSD (n = 6). Symptom measures were obtained, and genome-wide DNA methylation was measured using methylated DNA immunoprecipitation (MeDIP-seq) from whole blood samples at baseline and 3 months later. A longitudinal comparison measured DNA methylation changes in military personnel with clinically relevant increases in PTSD symptoms between time points (PTSD onset) and compared methylation patterns to controls with no clinical changes in PTSD. In military personnel with elevated PTSD symptoms 3 months following baseline, 119 genes exhibited reduced methylation and 8 genes exhibited increased methylation. Genes with reduced methylation in the PTSD-onset group relate to the canonical pathways of netrin signaling, Wnt/Ca+ pathway, and axonal guidance signaling. These gene pathways relate to neurological disorders, and the current findings suggest that these epigenetic changes potentially relate to PTSD symptomology. This study provides some novel insights into the role of epigenetic changes in PTSD symptoms and the progression of PTSD symptoms in military personnel.

Identification of mental states and interpersonal functioning in borderline personality disorder.

Atypical identification of mental states in the self and others has been proposed to underlie interpersonal difficulties in borderline personality disorder (BPD), yet no previous empirical research has directly examined associations between these constructs. We examine 3 mental state identification measures and their associations with experience-sampling measures of interpersonal functioning in participants with BPD relative to a healthy comparison (HC) group. We also included a clinical comparison group diagnosed with avoidant personality disorder (APD) to test the specificity of this constellation of difficulties to BPD. When categorizing blended emotional expressions, the BPD group identified anger at a lower threshold than did the HC and APD groups, but no group differences emerged in the threshold for identifying happiness. These results are consistent with enhanced social threat identification and not general negativity biases in BPD. The Reading the Mind in the Eyes Test (RMET) showed no group differences in general mental state identification abilities. Alexithymia scores were higher in both BPD and APD relative to the HC group, and difficulty identifying one's own emotions was higher in BPD compared to APD and HC. Within the BPD group, lower RMET scores were associated with lower anger identification thresholds and higher alexithymia scores. Moreover, lower anger identification thresholds, lower RMET scores, and higher alexithymia scores were all associated with greater levels of interpersonal difficulties in daily life. Research linking measures of mental state identification with experience-sampling measures of interpersonal functioning can help clarify the role of mental state identification in BPD symptoms. (PsycINFO Database Record

Circulating miRNA associated with posttraumatic stress disorder in a cohort of military combat veterans.

Posttraumatic stress disorder (PTSD) affects many returning combat veterans, but underlying biological mechanisms remain unclear. In order to compare circulating micro RNA (miRNA) of combat veterans with and without PTSD, peripheral blood from 24 subjects was collected following deployment, and isolated miRNA was sequenced. PTSD was associated with 8 differentially expressed miRNA. Pathway analysis shows that PTSD is related to the axon guidance and Wnt signaling pathways, which work together to support neuronal development through regulation of growth cones. PTSD is associated with miRNAs that regulate biological functions including neuronal activities, suggesting that they play a role in PTSD symptomatology.

Differential Gene Expression Associated with Meningeal Injury in Acute Mild Traumatic Brain Injury.

Injury to the meninges is not uncommon after traumatic brain injury (TBI), yet minimal research has been directed toward understanding the relevant biology. After a concussive event, the meninges are observed to abnormally enhance on post-contrast magnetic resonance imaging (MRI) in some patients, but not all. The aim of this work is to identify genes differentially expressed in patients with meningeal injury. Patients presenting to the emergency room with suspected TBI received a standard research MRI and blood draw within 48 h of injury. Two groups of patients were included: those with and without abnormal enhancement of the meninges on post-contrast MRI, both without other imaging findings. Groups were compared on microarray gene expression in peripheral blood samples using Affymetrix (Santa Clara, CA) and Partek Genomics Suite (Partek, Inc., St. Louis, MO) software (false discovery rate, <0.05). Forty patients were enrolled with a time from injury to MRI/blood draw of 16.8 h (interquartile range, 7.5-24.1). We observed 76 genes to be differentially expressed in patients with meningeal injury compared to those without, such as receptor for Fc fragment of IgA, multiple C2 domains, transmembrane 2, and G-protein-coupled receptor 27, which have been previously associated with initiating inflammatory mediators, phagocytosis, and other regulatory mechanisms. Post-contrast MRI is able to detect meningeal injury and has a unique biological signature observed through gene expression. These findings suggest that an acute inflammatory response occurs in response to injury to the meninges following a concussion.

Structural and functional alterations in the colonic microbiome of the rat in a model of stress induced irritable bowel syndrome.

Stress is known to perturb the microbiome and exacerbate irritable bowel syndrome (IBS) associated symptoms. Characterizing structural and functional changes in the microbiome is necessary to understand how alterations affect the biomolecular environment of the gut in IBS. Repeated water avoidance (WA) stress was used to induce IBS-like symptoms in rats. The colon-mucosa associated microbiome was characterized in 13 stressed and control animals by 16S sequencing. In silico analysis of the functional domains of microbial communities was done by inferring metagenomic profiles from 16S data. Microbial communities and functional profiles were compared between conditions. WA animals exhibited higher α-diversity and moderate divergence in community structure (ß-diversity) compared with controls. Specific clades and taxa were consistently and significantly modified in the WA animals. The WA microbiome was particularly enriched in Proteobacteria and depleted in several beneficial taxa. A decreased capacity in metabolic domains, including energy- and lipid-metabolism, and an increased capacity for fatty acid and sulfur metabolism was inferred for the WA microbiome. The stressed condition favored the proliferation of a greater diversity of microbes that appear to be functionally similar, resulting in a functionally poorer microbiome with implications for epithelial health. Taxa, with known beneficial effects, were found to be depleted, which supports their relevance as therapeutic agents to restore microbial health. Microbial sulfur metabolism may form a key component of visceral nerve sensitization pathways and is therefore of interest as a target metabolic domain in microbial ecological restoration.

Older Age Results in Differential Gene Expression after Mild Traumatic Brain Injury and Is Linked to Imaging Differences at Acute Follow-up.

Older age consistently relates to a lesser ability to fully recover from a traumatic brain injury (TBI); however, there is limited data to explicate the nature of age-related risks. This study was undertaken to determine the relationship of age on gene-activity following a TBI, and how this biomarker relates to changes in neuroimaging findings. A young group (between the ages of 19 and 35 years), and an old group (between the ages of 60 and 89 years) were compared on global gene-activity within 48 h following a TBI, and then at follow-up within 1-week. At each time-point, gene expression profiles, and imaging findings from both magnetic resonance imaging (MRI) and computed tomography were obtained and compared. The young group was found to have greater gene expression of inflammatory regulatory genes at 48 h and 1-week in genes such as basic leucine zipper transcription factor 2 (BACH2), leucine-rich repeat neuronal 3 (LRRN3), and lymphoid enhancer-binding factor 1 (LEF1) compared to the old group. In the old group, there was increased activity in genes within S100 family, including calcium binding protein P (S100P) and S100 calcium binding protein A8 (S100A8), which previous studies have linked to poor recovery from TBI. The old group also had reduced activity of the noggin (NOG) gene, which is a member of the transforming growth factor-ß superfamily and is linked to neurorecovery and neuroregeneration compared to the young group. We link these gene expression findings that were validated to neuroimaging, reporting that in the old group with a MRI finding of TBI-related damage, there was a lesser likelihood to then have a negative MRI finding at follow-up compared to the young group. Together, these data indicate that age impacts gene activity following a TBI, and suggest that this differential activity related to immune regulation and neurorecovery contributes to a lesser likelihood of neuronal recovery in older patients as indicated through neuroimaging.

Altered gene expression of the innate immune, neuroendocrine, and nuclear factor-kappa B (NF-κB) systems is associated with posttraumatic stress disorder in military personnel.

Whole transcriptome analysis provides an unbiased examination of biological activity, and likely, unique insight into the mechanisms underlying posttraumatic stress disorder (PTSD) and comorbid depression and traumatic brain injury. This study compared gene-expression profiles in military personnel with PTSD (n=28) and matched controls without PTSD (n=27) using HG-U133 Plus 2.0 microarrays (Affymetrix), which contain 54,675 probe sets representing more than 38,500 genes. Analysis of expression profiles revealed 203 differentially expressed genes in PTSD, of which 72% were upregulated. Using Partek Genomics Suite 6.6, differentially expressed transcription clusters were filtered based on a selection criterion of ≥1.5 relative fold change at a false discovery rate of ≤5%. Ingenuity Pathway Analysis (Qiagen) of the differentially expressed genes indicated a dysregulation of genes associated with the innate immune, neuroendocrine, and NF-κB systems. These findings provide novel insights that may lead to new pharmaceutical agents for PTSD treatments and help mitigate mental and physical comorbidity risk.