A conserved gastropod withdrawal circuit in Biomphalaria glabrata, an intermediate host for schistosomiasis.

Neuronal signals mediated by the biogenic amine serotonin (5-HT) underlie critical survival strategies across the animal kingdom. This investigation examined serotonin-like immunoreactive neurons in the cerebral ganglion of the panpulmonate snail Biomphalaria glabrata, a major intermediate host for the trematode parasite Schistosoma mansoni. Five neurons comprising the cerebral serotonergic F (CeSF) cluster of B. glabrata shared morphological characteristics with neurons that contribute to withdrawal behaviors in numerous heterobranch species. The largest member of this group, designated CeSF-1, projected an axon to the tentacle, a major site of threat detection. Intracellular recordings demonstrated repetitive activity and electrical coupling between the bilateral CeSF-1 cells. In semi-intact preparations, the CeSF-1 cells were not responsive to cutaneous stimuli but did respond to photic stimuli. A large FMRF-NH2-like immunoreactive neuron, termed C2, was also located on the dorsal surface of each cerebral hemiganglion near the origin of the tentacular nerve. C2 and CeSF-1 received coincident bouts of inhibitory synaptic input. Moreover, in the presence of 5-HT they both fired rhythmically and in phase. As the CeSF and C2 cells of Biomphalaria share fundamental properties with neurons that participate in withdrawal responses in Nudipleura and Euopisthobranchia, our observations support the proposal that features of this circuit are conserved in the Panpulmonata.NEW & NOTEWORTHY Neuronal signals mediated by the biogenic amine serotonin underlie critical survival strategies across the animal kingdom. This investigation identified a group of serotonergic cells in the panpulmonate snail Biomphalaria glabrata that appear to be homologous to neurons that mediate withdrawal responses in other gastropod taxa. It is proposed that an ancient withdrawal circuit has been highly conserved in three major gastropod lineages.

Associations of alcohol and cannabis use with change in posttraumatic stress disorder and depression symptoms over time in recently trauma-exposed individuals.

BACKGROUND: Several hypotheses may explain the association between substance use, posttraumatic stress disorder (PTSD), and depression. However, few studies have utilized a large multisite dataset to understand this complex relationship. Our study assessed the relationship between alcohol and cannabis use trajectories and PTSD and depression symptoms across 3 months in recently trauma-exposed civilians. METHODS: In total, 1618 (1037 female) participants provided self-report data on past 30-day alcohol and cannabis use and PTSD and depression symptoms during their emergency department (baseline) visit. We reassessed participant's substance use and clinical symptoms 2, 8, and 12 weeks posttrauma. Latent class mixture modeling determined alcohol and cannabis use trajectories in the sample. Changes in PTSD and depression symptoms were assessed across alcohol and cannabis use trajectories via a mixed-model repeated-measures analysis of variance. RESULTS: Three trajectory classes (low, high, increasing use) provided the best model fit for alcohol and cannabis use. The low alcohol use class exhibited lower PTSD symptoms at baseline than the high use class; the low cannabis use class exhibited lower PTSD and depression symptoms at baseline than the high and increasing use classes; these symptoms greatly increased at week 8 and declined at week 12. Participants who already use alcohol and cannabis exhibited greater PTSD and depression symptoms at baseline that increased at week 8 with a decrease in symptoms at week 12. CONCLUSIONS: Our findings suggest that alcohol and cannabis use trajectories are associated with the intensity of posttrauma psychopathology. These findings could potentially inform the timing of therapeutic strategies.

Longitudinal study of traumatic-stress related cellular and cognitive aging.

Traumatic stress is associated with both accelerated epigenetic age and increased risk for dementia. Accelerated epigenetic age might link symptoms of traumatic stress to dementia-associated biomarkers, such as amyloid-beta (Aß) proteins, neurofilament light (NFL), and inflammatory molecules. We tested this hypothesis using longitudinal data obtained from 214 trauma-exposed military veterans (85 % male, mean age at baseline: 53 years, 75 % White) who were assessed twice over the course of an average of 5.6 years. Cross-lagged panel mediation models evaluated measures of lifetime posttraumatic stress disorder and internalizing and externalizing comorbidity (assessed at Time 1; T1) in association with T1 epigenetic age (per the GrimAge algorithm) and T1 plasma markers of neuropathology along with bidirectional temporal paths between T1 and T2 epigenetic age and the plasma markers. Results revealed that a measure of externalizing comorbidity was associated with accelerated epigenetic age (ß = 0.30, p <.01), which in turn, was associated with subsequent increases in Aß-40 (ß = 0.20, p <.001), Aß-42 (ß = 0.18, p <.001), and interleukin-6 (ß = 0.18, p <.01). T1 advanced epigenetic age and the T1 neuropathology biomarkers NFL and glial fibrillary acidic protein predicted worse performance on T2 neurocognitive tasks assessing working memory, executive/attentional control, and/or verbal memory (ps = 0.03 to 0.009). Results suggest that advanced GrimAge is predictive of subsequent increases in neuropathology and inflammatory biomarkers as well as worse cognitive function, highlighting the clinical significance of this biomarker with respect to cognitive aging and brain health over time. The finding that advanced GrimAge mediated the association between psychiatric comorbidity and future neuropathology is important for understanding potential pathways to neurodegeneration and early identification of those at greatest risk.

African ancestry GWAS of dementia in a large military cohort identifies significant risk loci.

While genome wide association studies (GWASs) of Alzheimer's Disease (AD) in European (EUR) ancestry cohorts have identified approximately 83 potentially independent AD risk loci, progress in non-European populations has lagged. In this study, data from the Million Veteran Program (MVP), a biobank which includes genetic data from more than 650,000 US Veteran participants, was used to examine dementia genetics in an African descent (AFR) cohort. A GWAS of Alzheimer's disease and related dementias (ADRD), an expanded AD phenotype including dementias such as vascular and non-specific dementia that included 4012 cases and 18,435 controls age 60+ in AFR MVP participants was performed. A proxy dementia GWAS based on survey-reported parental AD or dementia (n = 4385 maternal cases, 2256 paternal cases, and 45,970 controls) was also performed. These two GWASs were meta-analyzed, and then subsequently compared and meta-analyzed with the results from a previous AFR AD GWAS from the Alzheimer's Disease Genetics Consortium (ADGC). A meta-analysis of common variants across the MVP ADRD and proxy GWASs yielded GWAS significant associations in the region of APOE (p = 2.48 × 10-101), in ROBO1 (rs11919682, p = 1.63 × 10-8), and RNA RP11-340A13.2 (rs148433063, p = 8.56 × 10-9). The MVP/ADGC meta-analysis yielded additional significant SNPs near known AD risk genes TREM2 (rs73427293, p = 2.95 × 10-9), CD2AP (rs7738720, p = 1.14 × 10-9), and ABCA7 (rs73505251, p = 3.26 × 10-10), although the peak variants observed in these genes differed from those previously reported in EUR and AFR cohorts. Of the genes in or near suggestive or genome-wide significant associated variants, nine (CDA, SH2D5, DCBLD1, EML6, GOPC, ABCA7, ROS1, TMCO4, and TREM2) were differentially expressed in the brains of AD cases and controls. This represents the largest AFR GWAS of AD and dementia, finding non-APOE GWAS-significant common SNPs associated with dementia. Increasing representation of AFR participants is an important priority in genetic studies and may lead to increased insight into AD pathophysiology and reduce health disparities.

Structural inequities contribute to racial/ethnic differences in neurophysiological tone, but not threat reactivity, after trauma exposure.

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.

Internal capsule microstructure mediates the relationship between childhood maltreatment and PTSD following adulthood trauma exposure.

Childhood trauma is a known risk factor for trauma and stress-related disorders in adulthood. However, limited research has investigated the impact of childhood trauma on brain structure linked to later posttraumatic dysfunction. We investigated the effect of childhood trauma on white matter microstructure after recent trauma and its relationship with future posttraumatic dysfunction among trauma-exposed adult participants (n = 202) recruited from emergency departments as part of the AURORA Study. Participants completed self-report scales assessing prior childhood maltreatment within 2-weeks in addition to assessments of PTSD, depression, anxiety, and dissociation symptoms within 6-months of their traumatic event. Fractional anisotropy (FA) obtained from diffusion tensor imaging (DTI) collected at 2-weeks and 6-months was used to index white matter microstructure. Childhood maltreatment load predicted 6-month PTSD symptoms (b = 1.75, SE = 0.78, 95% CI = [0.20, 3.29]) and inversely varied with FA in the bilateral internal capsule (IC) at 2-weeks (p = 0.0294, FDR corrected) and 6-months (p = 0.0238, FDR corrected). We observed a significant indirect effect of childhood maltreatment load on 6-month PTSD symptoms through 2-week IC microstructure (b = 0.37, Boot SE = 0.18, 95% CI = [0.05, 0.76]) that fully mediated the effect of childhood maltreatment load on PCL-5 scores (b = 1.37, SE = 0.79, 95% CI = [-0.18, 2.93]). IC microstructure did not mediate relationships between childhood maltreatment and depressive, anxiety, or dissociative symptomatology. Our findings suggest a unique role for IC microstructure as a stable neural pathway between childhood trauma and future PTSD symptoms following recent trauma. Notably, our work did not support roles of white matter tracts previously found to vary with PTSD symptoms and childhood trauma exposure, including the cingulum bundle, uncinate fasciculus, and corpus callosum. Given the IC contains sensory fibers linked to perception and motor control, childhood maltreatment might impact the neural circuits that relay and process threat-related inputs and responses to trauma.

MMPI-2-RF Profiles of Treatment-Seeking Veterans in a VA Pain Clinic and Associations with Markers of Physical Performance.

Chronic pain is a debilitating condition for many military Veterans and is associated with posttraumatic stress disorder (PTSD). This study examined the Minnesota Multiphasic Personality Inventory-2-Restructured Form (MMPI-2-RF) in 144 Veterans (88.2% male, mean age = 57.95 years) recruited from a VA outpatient pain clinic and associations with self-reported pain severity, pain-related interference in daily activities, prescription opioid use, and objective metrics of physical performance on tasks impacted by pain (walking, stair climbing, grip strength, indexed by a single latent variable). Among the cohort with valid responses on the MMPI-2-RF (n = 117) and probable PTSD, mean Somatic Complaints (RC1) and Ideas of Persecution (RC6) scores were clinically elevated. All MMPI-2-RF scales were more strongly correlated with self-reported pain interference than severity. Regressions revealed associations between self-rated pain interference (but not pain or PTSD severity) and physical performance scores (ß = .36, p = .001). MMPI-2-RF overreporting Validity and Higher-Order scales contributed incremental variance in predicting physical performance, including Infrequent Psychopathology Responses (ß = .33, p = .002). PTSD severity was associated with prescription opioid use when accounting for the effects of over-reported somatic and cognitive symptoms (odds ratio 1.05, p ≤ .025). Results highlight the role of symptom overreporting and perceptions of functional impairment to observable behaviors among individuals with chronic pain.

Hippocampal Threat Reactivity Interacts with Physiological Arousal to Predict PTSD Symptoms.

Hippocampal 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 functional magnetic resonance imaging (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, due to increases in fear-potentiated arousal.Significance StatementAlterations 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 non-trauma 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.

Derivation and Validation of a Brief Emergency Department-Based Prediction Tool for Posttraumatic Stress After Motor Vehicle Collision.

STUDY OBJECTIVE: To derive and initially validate a brief bedside clinical decision support tool that identifies emergency department (ED) patients at high risk of substantial, persistent posttraumatic stress symptoms after a motor vehicle collision. METHODS: Derivation (n=1,282, 19 ED sites) and validation (n=282, 11 separate ED sites) data were obtained from adults prospectively enrolled in the Advancing Understanding of RecOvery afteR traumA study who were discharged from the ED after motor vehicle collision-related trauma. The primary outcome was substantial posttraumatic stress symptoms at 3 months (Posttraumatic Stress Disorder Checklist for Diagnostic and Statistical Manual of Mental Disorders-5 ≥38). Logistic regression derivation models were evaluated for discriminative ability using the area under the curve and the accuracy of predicted risk probabilities (Brier score). Candidate posttraumatic stress predictors assessed in these models (n=265) spanned a range of sociodemographic, baseline health, peritraumatic, and mechanistic domains. The final model selection was based on performance and ease of administration. RESULTS: Significant 3-month posttraumatic stress symptoms were common in the derivation (27%) and validation (26%) cohort. The area under the curve and Brier score of the final 8-question tool were 0.82 and 0.14 in the derivation cohort and 0.76 and 0.17 in the validation cohort. CONCLUSION: This simple 8-question tool demonstrates promise to risk-stratify individuals with substantial posttraumatic stress symptoms who are discharged to home after a motor vehicle collision. Both external validation of this instrument, and work to further develop more accurate tools, are needed. Such tools might benefit public health by enabling the conduct of preventive intervention trials and assisting the growing number of EDs that provide services to trauma survivors aimed at promoting psychological recovery.

Alzheimer's disease and related dementias among aging veterans: Examining gene-by-environment interactions with post-traumatic stress disorder and traumatic brain injury.

INTRODUCTION: Post-traumatic stress disorder (PTSD) and traumatic brain injury (TBI) confer risk for Alzheimer's disease and related dementias (ADRD). METHODS: This study from the Million Veteran Program (MVP) evaluated the impact of apolipoprotein E (APOE) ε4, PTSD, and TBI on ADRD prevalence in veteran cohorts of European ancestry (EA; n = 11,112 ADRD cases, 170,361 controls) and African ancestry (AA; n = 1443 ADRD cases, 16,191 controls). Additive-scale interactions were estimated using the relative excess risk due to interaction (RERI) statistic. RESULTS: PTSD, TBI, and APOE ε4 showed strong main-effect associations with ADRD. RERI analysis revealed significant additive APOE ε4 interactions with PTSD and TBI in the EA cohort and TBI in the AA cohort. These additive interactions indicate that ADRD prevalence associated with PTSD and TBI increased with the number of inherited APOE ε4 alleles. DISCUSSION: PTSD and TBI history will be an important part of interpreting the results of ADRD genetic testing and doing accurate ADRD risk assessment.

Socio-demographic and trauma-related predictors of PTSD within 8 weeks of a motor vehicle collision in the AURORA study.

This is the initial report of results from the AURORA multisite longitudinal study of adverse post-traumatic neuropsychiatric sequelae (APNS) among participants seeking emergency department (ED) treatment in the aftermath of a traumatic life experience. We focus on n = 666 participants presenting to EDs following a motor vehicle collision (MVC) and examine associations of participant socio-demographic and participant-reported MVC characteristics with 8-week posttraumatic stress disorder (PTSD) adjusting for pre-MVC PTSD and mediated by peritraumatic symptoms and 2-week acute stress disorder (ASD). Peritraumatic Symptoms, ASD, and PTSD were assessed with self-report scales. Eight-week PTSD prevalence was relatively high (42.0%) and positively associated with participant sex (female), low socioeconomic status (education and income), and several self-report indicators of MVC severity. Most of these associations were entirely mediated by peritraumatic symptoms and, to a lesser degree, ASD, suggesting that the first 2 weeks after trauma may be a uniquely important time period for intervening to prevent and reduce risk of PTSD. This observation, coupled with substantial variation in the relative strength of mediating pathways across predictors, raises the possibility of diverse and potentially complex underlying biological and psychological processes that remain to be elucidated with more in-depth analyses of the rich and evolving AURORA data.

PTSD, major depression, and advanced transcriptomic age in brain tissue.

BACKGROUND: Psychiatric disorders have been associated with advanced epigenetic age in DNA methylation, yet this relationship has not been studied in the brain transcriptome. We examined transcriptomic age using an RNA-based algorithm recently developed by Ren and Kuan ("RNAAgeCalc") and the associations between posttraumatic stress disorder (PTSD), major depressive disorder (MDD), and alcohol use disorder with age-adjusted RNA age ("RNA age residuals") in three brain regions: dorsolateral prefrontal cortex, ventromedial prefrontal cortex (vmPFC), and motor cortex. METHODS: RNA sequencing was used to measure gene expression in postmortem brain tissue from the VA National PTSD Brain Bank (n = 94; 59% male). RESULTS: Linear models revealed that diagnoses of PTSD and/or MDD were positively associated with RNA age residuals in vmPFC only (p-adj = 0.012). Three genes in the RNAAgeCalc algorithm (KCNJ16, HYAL2, and CEBPB) were also differentially expressed in association with PTSD/MDD in vmPFC (p-adj = 6.45E-05 to 0.02). Enrichment analysis revealed that inflammatory and immune-related pathways were overrepresented (p-adj < 0.05) among the 43 genes in RNAAgeCalc that were also at least nominally associated with PTSD/MDD in vmPFC relative to the 448 RNAAgeCalc genes. Endothelial and mural cells were negatively associated with RNA age residuals in vmPFC (both p-adj = 0.028) and with PTSD/MDD (both p-adj = 0.017). CONCLUSIONS: Results highlight the importance of inflammation and immune system dysregulation in the link between psychopathology and accelerated cellular aging and raise the possibility that blood-brain barrier degradation may play an important role in stress-related accelerated brain aging.

Methylation of the AIM2 gene: An epigenetic mediator of PTSD-related inflammation and neuropathology plasma biomarkers.

BACKGROUND: Posttraumatic stress disorder (PTSD) is associated with inflammation and various forms of chronic disease. The Absent in Melanoma 2 (AIM2) gene has been implicated in mechanisms of inflammation and anxiety, and methylation at a particular locus in this gene (cg10636246) has previously been shown to influence the association between PTSD and elevated C-reactive protein levels in blood. METHOD: We tested if this association might extend to other indicators of inflammation and to plasma-based measures of neuropathology in a cohort of post-9/11 US military veterans. Using a Bayesian approach, mediation models were tested cross-sectionally (n = 478) and longitudinally (n = 298). Peripheral markers of inflammation and neuropathology were measured with ultra-sensitive Single Molecule Array (Simoa®) technology. RESULTS: Analyses revealed indirect effects of PTSD symptom severity on peripheral indices of both inflammation (interleukin [IL]6, IL-10, tumor necrosis factor-α; indirect standardized [std.] ß range = 0.018-0.023, all p-values adjusted for multiple testing [padj ] < 0.05) and neuropathology (neurofilament light [NFL]; indirect std. ß = -0.018, padj = 0.02) via AIM2 methylation. This indirect effect was also evident when predicting IL-10 at a follow-up assessment (indirect std. ß = -0.018, padj = 0.04) controlling for baseline IL-10. CONCLUSIONS: Given that AIM2 methylation mediated the association between PTSD symptoms and multiple inflammatory and neuropathology markers, our results suggest that AIM2 methylation may offer clinical utility for indexing risk for adverse health outcomes associated with these peripheral indices of inflammation and neuropathology. Results also suggest a possible shared etiology underlying the frequent co-occurrence of inflammation and neuropathology.

Prior histories of posttraumatic stress disorder and major depression and their onset and course in the three months after a motor vehicle collision in the AURORA study.

BACKGROUND: A better understanding of the extent to which prior occurrences of posttraumatic stress disorder (PTSD) and major depressive episode (MDE) predict psychopathological reactions to subsequent traumas might be useful in targeting posttraumatic preventive interventions. METHODS: Data come from 1306 patients presenting to 29 U.S. emergency departments (EDs) after a motor vehicle collision (MVC) in the advancing understanding of recovery after trauma study. Patients completed self-reports in the ED and 2-weeks, 8-weeks, and 3-months post-MVC. Associations of pre-MVC probable PTSD and probable MDE histories with subsequent 3-months post-MVC probable PTSD and probable MDE were examined along with mediation through intervening peritraumatic, 2-, and 8-week disorders. RESULTS: 27.6% of patients had 3-month post-MVC probable PTSD and/or MDE. Pre-MVC lifetime histories of these disorders were not only significant (relative risk = 2.6-7.4) but were dominant (63.1% population attributable risk proportion [PARP]) predictors of this 3-month outcome, with 46.6% prevalence of the outcome among patients with pre-MVC disorder histories versus 9.9% among those without such histories. The associations of pre-MVC lifetime disorders with the 3-month outcome were mediated largely by 2- and 8-week probable PTSD and MDE (PARP decreasing to 22.8% with controls for these intervening disorders). Decomposition showed that pre-MVC lifetime histories predicted both onset and persistence of these intervening disorders as well as the higher conditional prevalence of the 3-month outcome in the presence of these intervening disorders. CONCLUSIONS: Assessments of pre-MVC PTSD and MDE histories and follow-ups at 2 and 8 weeks could help target early interventions for psychopathological reactions to MVCs.

Premorbid traumatic stress and veteran responses to the COVID-19 pandemic.

The COVID-19 pandemic has had unprecedented effects on lifestyle stability and physical and mental health. We examined the impact of preexisting posttraumatic stress disorder (PTSD), alcohol use disorder (AUD), and depression on biopsychosocial responses to the pandemic, including psychiatric symptoms, COVID-19 exposure, and housing/financial stability, among 101 U.S. military veterans enrolled in a longitudinal study of PTSD, a population of particular interest given veterans' trauma histories and defense-readiness training. Participants (83.2% male, 79.2% White, Mage  = 59.28 years) completed prepandemic, clinician-administered psychiatric diagnostic interviews and a phone-based assessment between May and September 2020 using a new measure, the Rapid Assessment of COVID-19-Related Experiences (RACE), which was used to assess pandemic responses and its effects on mental and physical health; COVID-19 diagnosis and testing were also extracted from electronic medical records. Multivariate regressions showed that, controlling for demographic characteristics, prepandemic PTSD, ß = .332; p = .003, and AUD symptoms, ß = .228; p = .028, were associated with increased pandemic-related PTSD symptoms. Prepandemic AUD was associated with increased substance use during the pandemic, ß = .391; p < .001, and higher rates of self-reported or medical record-based COVID-19 diagnosis, ß = .264; p = .019. Minority race was associated with pandemic-related housing/financial instability, ß = -.372; p < .001, raising concerns of population inequities. The results suggest that preexisting PTSD and AUD are markers for adverse pandemic-related psychiatric outcomes and COVID-19 illness. These findings carry implications for the importance of targeting prevention and treatment efforts for the highest-risk individuals.

PTSD is associated with increased DNA methylation across regions of HLA-DPB1 and SPATC1L.

Posttraumatic stress disorder (PTSD) is characterized by intrusive thoughts, avoidance, negative alterations in cognitions and mood, and arousal symptoms that adversely affect mental and physical health. Recent evidence links changes in DNA methylation of CpG cites to PTSD. Since clusters of proximal CpGs share similar methylation signatures, identification of PTSD-associated differentially methylated regions (DMRs) may elucidate the pathways defining differential risk and resilience of PTSD. Here we aimed to identify epigenetic differences associated with PTSD. DNA methylation data profiled from blood samples using the MethylationEPIC BeadChip were used to perform a DMR analysis in 187 PTSD cases and 367 trauma-exposed controls from the Grady Trauma Project (GTP). DMRs were assessed with R package bumphunter. We identified two regions that associate with PTSD after multiple test correction. These regions were in the gene body of HLA-DPB1 and in the promoter of SPATC1L. The DMR in HLA-DPB1 was associated with PTSD in an independent cohort. Both DMRs included CpGs whose methylation associated with nearby sequence variation (meQTL) and that associated with expression of their respective genes (eQTM). This study supports an emerging literature linking PTSD risk to genetic and epigenetic variation in the HLA region.

The AURORA Study: a longitudinal, multimodal library of brain biology and function after traumatic stress exposure.

Adverse posttraumatic neuropsychiatric sequelae (APNS) are common among civilian trauma survivors and military veterans. These APNS, as traditionally classified, include posttraumatic stress, postconcussion syndrome, depression, and regional or widespread pain. Traditional classifications have come to hamper scientific progress because they artificially fragment APNS into siloed, syndromic diagnoses unmoored to discrete components of brain functioning and studied in isolation. These limitations in classification and ontology slow the discovery of pathophysiologic mechanisms, biobehavioral markers, risk prediction tools, and preventive/treatment interventions. Progress in overcoming these limitations has been challenging because such progress would require studies that both evaluate a broad spectrum of posttraumatic sequelae (to overcome fragmentation) and also perform in-depth biobehavioral evaluation (to index sequelae to domains of brain function). This article summarizes the methods of the Advancing Understanding of RecOvery afteR traumA (AURORA) Study. AURORA conducts a large-scale (n = 5000 target sample) in-depth assessment of APNS development using a state-of-the-art battery of self-report, neurocognitive, physiologic, digital phenotyping, psychophysical, neuroimaging, and genomic assessments, beginning in the early aftermath of trauma and continuing for 1 year. The goals of AURORA are to achieve improved phenotypes, prediction tools, and understanding of molecular mechanisms to inform the future development and testing of preventive and treatment interventions.

Biochemical and apoptotic changes in the nervous and ovotestis tissues of Biomphalaria alexandrina following infection with Schistosoma mansoni.

Infection with trematodes produces physiological and behavioural changes in intermediate snail hosts. One response to infection is parasitic castration, in which energy required for reproduction of the host is thought to be redirected to promote development and multiplication of the parasite. This study investigated some reproductive and biochemical parameters in the nervous (CNS) and ovotestis (OT) tissues of Biomphalaria alexandrina during the course of Schistosoma mansoni infection. Antioxidant and oxidative stress parameters including catalase (CAT), nitric oxide (NO) and lipid peroxidation (MDA) were measured. Levels of steroid hormones, including testosterone, progesterone and estradiol, were also assessed. Finally, flow cytometry was used to compare measures of apoptosis between control snails and those shedding cercariae by examining mitochondrial membrane potential with the stain 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimi-dazolylcarbocyanine iodide (JC-1) and poly(ADP-ribose) polymerase (PARP). Infection with S. mansoni caused a 47.7% reduction in the net reproductive rate (Ro) of B. alexandrina. CAT activity was increased in the CNS at 21 days post infection (dpi) but by 28 dpi it was reduced below control values. Also, CAT activity increased significantly in the OT at 14, 21 and 28 dpi. In CNS tissues, NO levels were reduced at 7 dpi, increased at 14 and 21 dpi, and reduced again at 28 dpi. The overall level of lipid peroxidation gradually increased during the course of infection to reach its highest levels at 28 dpi. Steroid hormone measurements showed that concentrations of testosterone and estradiol were reduced in the CNS tissues at 28 dpi, while those of progesterone were slightly increased in the CNS and OT tissues. The percentage of cells that positively stained with JC-1was significantly increased in CNS and OT tissues of infected snails while the percentage of cells positively stained with PARP was decreased compared to controls. Together, these findings indicate that infection initiates diverse biochemical and hormonal changes leading to loss of cells responsible for egg laying and reproduction in B. alexandrina.

Localization of keyhole limpet hemocyanin-like immunoreactivity in the nervous system of Biomphalaria alexandrina.

Recent years have led to increased effort to describe and understand the peripheral nervous system and its influence on central mechanisms and behavior in gastropod molluscs. This study revealed that an antibody raised against keyhole limpet hemocyanin (KLH) cross-reacts with an antigen(s) found extensively in both the central and the peripheral nervous systems of Biomphalaria alexandrina. The results revealed KLH-like immunoreactive (LIR) neurons in the cerebral, pedal, buccal, left pleural, right parietal, and visceral ganglion within the CNS with fibers projecting throughout all the peripheral nerves. Numerous KLH-LIR peripheral sensory neurons located in the foot, lips, tentacles, mantle, esophagus, and penis exhibited a bipolar morphology with long tortuous dendrites. KLH-LIR cells were also present in the eye and statocyst, thus suggesting the labeling of multiple sensory modalities/cell types. KLH-LIR cells did not co-localize with tyrosine hydroxylase (TH)-LIR cells, which have previously been described in this and other gastropods. The results thus provide descriptions of thousands of peripheral sensory neurons, not previously described in detail. Future research should seek to pair sensory modalities with peripheral cell type and attempt to further elucidate the nature of KLH-like reactivity. These findings also emphasize the need for caution when analyzing results obtained through use of antibodies raised against haptens conjugated to carrier proteins, suggesting the need for stringent controls to help limit potential confounds caused by cross-reactivity. In addition, this study is the first to describe neuronal cross-reactivity with KLH in Biomphalaria, which could provide a substrate for host-parasite interactions with a parasitic trematode, Schistosoma.

Posttraumatic psychopathology and the pace of the epigenetic clock: a longitudinal investigation.

BACKGROUND: Posttraumatic stress disorder (PTSD) and stress/trauma exposure are cross-sectionally associated with advanced DNA methylation age relative to chronological age. However, longitudinal inquiry and examination of associations between advanced DNA methylation age and a broader range of psychiatric disorders is lacking. The aim of this study was to examine if PTSD, depression, generalized anxiety, and alcohol-use disorders predicted acceleration of DNA methylation age over time (i.e. an increasing pace, or rate of advancement, of the epigenetic clock). METHODS: Genome-wide DNA methylation and a comprehensive set of psychiatric symptoms and diagnoses were assessed in 179 Iraq/Afghanistan war veterans who completed two assessments over the course of approximately 2 years. Two DNA methylation age indices (Horvath and Hannum), each a weighted index of an array of genome-wide DNA methylation probes, were quantified. The pace of the epigenetic clock was operationalized as change in DNA methylation age as a function of time between assessments. RESULTS: Analyses revealed that alcohol-use disorders (p = 0.001) and PTSD avoidance and numbing symptoms (p = 0.02) at Time 1 were associated with an increasing pace of the epigenetic clock over time, per the Horvath (but not the Hannum) index of cellular aging. CONCLUSIONS: This is the first study to suggest that posttraumatic psychopathology is longitudinally associated with a quickened pace of the epigenetic clock. Results raise the possibility that accelerated cellular aging is a common biological consequence of stress-related psychopathology, which carries implications for identifying mechanisms of stress-related cellular aging and developing interventions to slow its pace.