Intra-amygdala circuits of sleep disruption-induced anxiety in female mice.

Combining mouse genetics, electrophysiology, and behavioral training and testing, we explored how sleep disruption may affect the function of anxiety-controlling circuits, focusing on projections from the basolateral nucleus of the amygdala (BLA) to CRF-positive cells in the lateral division of the central amygdala (CeL). We found in Crh-IRES-Cre::Ai14(tdTomato) reporter female mice that 6 hours of sleep disruption during their non-active (light) cycle may be anxiogenic. Notably, the AMPAR/NMDAR EPSC amplitude ratio at the BLA inputs to CRF-CeL cells (CRF CeL ), assessed with whole-cell recordings in ex vivo experiments, was enhanced in slices from sleep-disrupted mice, whereas paired-pulse ratio (PPR) of the EPSCs induced by two closely spaced presynaptic stimuli remained unchanged. These findings indicate that sleep disruption-associated synaptic enhancements in glutamatergic projections from the BLA to CRF-CeL neurons may be postsynaptically expressed. We found also that the excitation/inhibition (E/I) ratio in the BLA to CRF CeL inputs was increased in sleep-disrupted mice, suggesting that the functional efficiency of excitation in BLA inputs to CRF CeL cells has increased following sleep disruption, thus resulting in their enhanced activation. The latter could be translated into enhanced anxiogenesis as activation of CRF cells in the CeL was shown to promote anxiety-like behaviors.

Acute sleep deprivation reduces fear memories in male and female mice.

Sleep problems are a prominent feature of mental health conditions including post-traumatic stress disorder (PTSD). Despite its potential importance, the role of sleep in the development of and/or recovery from trauma-related illnesses is not understood. Interestingly, there are reports that sleep deprivation immediately after a traumatic experience can reduce fear memories, an effect that could be utilized therapeutically in humans. While the mechanisms of this effect are not completely understood, one possible explanation for these findings is that immediate sleep deprivation interferes with consolidation of fear memories, rendering them weaker and more sensitive to intervention. Here, we allowed fear-conditioned mice to sleep immediately after fear conditioning during a time frame (18 hr) that includes and extends beyond periods typically associated with memory consolidation before subjecting them to 6 hr of sleep deprivation. Mice deprived of sleep with this delayed regimen showed dramatic reductions in fear during tests conducted immediately after sleep deprivation, as well as 24 hr later. This sleep deprivation regimen also increased levels of mRNA encoding brain-derived neurotrophic factor (BDNF), a molecule implicated in neuroplasticity, in the basolateral amygdala (BLA), a brain area implicated in fear and its extinction. These findings raise the possibility that the effects of our delayed sleep deprivation regimen are not due to disruption of memory consolidation, but instead are caused by BDNF-mediated neuroadaptations within the BLA that actively suppress expression of fear. Treatments that safely reduce expression of fear memories would have considerable therapeutic potential in the treatment of conditions triggered by trauma.

Systems biology dissection of PTSD and MDD across brain regions, cell types, and blood.

The molecular pathology of stress-related disorders remains elusive. Our brain multiregion, multiomic study of posttraumatic stress disorder (PTSD) and major depressive disorder (MDD) included the central nucleus of the amygdala, hippocampal dentate gyrus, and medial prefrontal cortex (mPFC). Genes and exons within the mPFC carried most disease signals replicated across two independent cohorts. Pathways pointed to immune function, neuronal and synaptic regulation, and stress hormones. Multiomic factor and gene network analyses provided the underlying genomic structure. Single nucleus RNA sequencing in dorsolateral PFC revealed dysregulated (stress-related) signals in neuronal and non-neuronal cell types. Analyses of brain-blood intersections in >50,000 UK Biobank participants were conducted along with fine-mapping of the results of PTSD and MDD genome-wide association studies to distinguish risk from disease processes. Our data suggest shared and distinct molecular pathology in both disorders and propose potential therapeutic targets and biomarkers.

Circulating PACAP levels are associated with altered imaging measures of entorhinal cortex neurite density in posttraumatic stress disorder.

Introduction: Pituitary adenylate cyclase-activating polypeptide (PACAP) regulates plasticity in brain systems underlying arousal and memory and is associated with posttraumatic stress disorder (PTSD). Research in animal models suggests that PACAP modulates entorhinal cortex (EC) input to the hippocampus, contributing to impaired contextual fear conditioning. In PTSD, PACAP is associated with higher activity of the amygdala to threat stimuli and lower functional connectivity of the amygdala and hippocampus. However, PACAP-affiliated structural alterations of these regions have not been investigated in PTSD. Here, we examined whether peripheral PACAP levels were associated with neuronal morphology of the amygdala and hippocampus (primary analyses), and EC (secondary) using Neurite Orientation Dispersion and Density Imaging.Methods: Sixty-four (44 female) adults (19 to 54 years old) with DSM-5 Criterion A trauma exposure completed the Clinician-Administered PTSD Scale (CAPS-5), a blood draw, and magnetic resonance imaging. PACAP38 radioimmunoassay was performed and T1-weighted and multi-shell diffusion-weighted images were acquired. Neurite Density Index (NDI) and Orientation Dispersion Index (ODI) were quantified in the amygdala, hippocampus, and EC. CAPS-5 total score and anxious arousal score were used to test for clinical associations with brain structure.Results: Higher PACAP levels were associated with greater EC NDI (ß = 0.0099, q = 0.032) and lower EC ODI (ß = -0.0073, q = 0.047), and not hippocampal or amygdala measures. Neither EC NDI nor ODI was associated with clinical measures.Conclusions: Circulating PACAP levels were associated with altered neuronal density of the EC but not the hippocampus or amygdala. These findings strengthen evidence that PACAP may impact arousal-associated memory circuits in PTSD.

PACAP was associated with altered entorhinal cortex neurite density in PTSD.PACAP was not associated with altered neurite density in amygdala or hippocampus.PACAP may impact arousal-associated memory circuits.

Effects of genetically predicted posttraumatic stress disorder on autoimmune phenotypes.

Observational studies suggest that posttraumatic stress disorder (PTSD) increases risk for various autoimmune diseases. Insights into shared biology and causal relationships between these diseases may inform intervention approaches to PTSD and co-morbid autoimmune conditions. We investigated the shared genetic contributions and causal relationships between PTSD, 18 autoimmune diseases, and 3 immune/inflammatory biomarkers. Univariate MiXeR was used to contrast the genetic architectures of phenotypes. Genetic correlations were estimated using linkage disequilibrium score regression. Bi-directional, two-sample Mendelian randomization (MR) was performed using independent, genome-wide significant single nucleotide polymorphisms; inverse variance weighted and weighted median MR estimates were evaluated. Sensitivity analyses for uncorrelated (MR PRESSO) and correlated horizontal pleiotropy (CAUSE) were also performed. PTSD was considerably more polygenic (10,863 influential variants) than autoimmune diseases (median 255 influential variants). However, PTSD evidenced significant genetic correlation with nine autoimmune diseases and three inflammatory biomarkers. PTSD had putative causal effects on autoimmune thyroid disease (p = 0.00009) and C-reactive protein (CRP) (p = 4.3 × 10-7). Inferences were not substantially altered by sensitivity analyses. Additionally, the PTSD-autoimmune thyroid disease association remained significant in multivariable MR analysis adjusted for genetically predicted inflammatory biomarkers as potential mechanistic pathway variables. No autoimmune disease had a significant causal effect on PTSD (all p values > 0.05). Although causal effect models were supported for associations of PTSD with CRP, shared pleiotropy was adequate to explain a putative causal effect of CRP on PTSD (p = 0.18). In summary, our results suggest a significant genetic overlap between PTSD, autoimmune diseases, and biomarkers of inflammation. PTSD has a putative causal effect on autoimmune thyroid disease, consistent with existing epidemiologic evidence. A previously reported causal effect of CRP on PTSD is potentially confounded by shared genetics. Together, results highlight the nuanced links between PTSD, autoimmune disorders, and associated inflammatory signatures, and suggest the importance of targeting related pathways to protect against disease and disability.

Focal clusters of peri-synaptic matrix contribute to activity-dependent plasticity and memory in mice.

Recent findings show that effective integration of novel information in the brain requires coordinated processes of homo- and heterosynaptic plasticity. In this work, we hypothesize that activity-dependent remodeling of the peri-synaptic extracellular matrix (ECM) contributes to these processes. We show that clusters of the peri-synaptic ECM, recognized by CS56 antibody, emerge in response to sensory stimuli, showing temporal and spatial coincidence with dendritic spine plasticity. Using CS56 co-immunoprecipitation of synaptosomal proteins, we identify several molecules involved in Ca2+ signaling, vesicle cycling, and AMPA-receptor exocytosis, thus suggesting a role in long-term potentiation (LTP). Finally, we show that, in the CA1 hippocampal region, the attenuation of CS56 glycoepitopes, through the depletion of versican as one of its main carriers, impairs LTP and object location memory in mice. These findings show that activity-dependent remodeling of the peri-synaptic ECM regulates the induction and consolidation of LTP, contributing to hippocampal-dependent memory.

The neurophysiological consequences of racism-related stressors in Black Americans.

Racism-related stressors, from experiences of both implicit and explicit racial discrimination to systemic socioeconomic disadvantage, have a cumulative impact on Black Americans' health. The present narrative review synthesizes peripheral (neuroendocrine and inflammation markers), psychophysiological (heart-rate variability, skin conductance), and neuroimaging (structural and functional) findings that demonstrate unique associations with racism-related stress. Emerging evidence reveals how racism-related stressors contribute to differential physiological and neural responses and may have distinct impacts on regions involved with threat and social processing. Ultimately, the neurophysiological effects of racism-related stress may confer biological susceptibility to stress and trauma-related disorders. We note critical gaps in the literature on the neurophysiological impact of racism-related stress and outline additional research that is needed on the multifactorial interactions between racism and mental health. A clearer understanding of the interactions between racism-related stress, neurophysiology, and stress- and trauma-related disorders is critical for preventative efforts, biomarker discovery, and selection of effective clinical treatments for Black Americans.

SKA2 regulated hyperactive secretory autophagy drives neuroinflammation-induced neurodegeneration.

High levels of proinflammatory cytokines induce neurotoxicity and catalyze inflammation-driven neurodegeneration, but the specific release mechanisms from microglia remain elusive. Here we show that secretory autophagy (SA), a non-lytic modality of autophagy for secretion of vesicular cargo, regulates neuroinflammation-mediated neurodegeneration via SKA2 and FKBP5 signaling. SKA2 inhibits SA-dependent IL-1ß release by counteracting FKBP5 function. Hippocampal Ska2 knockdown in male mice hyperactivates SA resulting in neuroinflammation, subsequent neurodegeneration and complete hippocampal atrophy within six weeks. The hyperactivation of SA increases IL-1ß release, contributing to an inflammatory feed-forward vicious cycle including NLRP3-inflammasome activation and Gasdermin D-mediated neurotoxicity, which ultimately drives neurodegeneration. Results from protein expression and co-immunoprecipitation analyses of male and female postmortem human brains demonstrate that SA is hyperactivated in Alzheimer's disease. Overall, our findings suggest that SKA2-regulated, hyperactive SA facilitates neuroinflammation and is linked to Alzheimer's disease, providing mechanistic insight into the biology of neuroinflammation.

Children of trauma survivors: Influences of parental posttraumatic stress and child-perceived parenting.

BACKGROUND: Research has established a negative association between parental posttraumatic stress symptoms (PTSS), including subthreshold symptoms, and child physical and behavioral health outcomes. Such intergenerational transmission of risk has multiple possible mechanisms, including lack of positive parenting, increased negative parenting, shared environmental and contextual risks, and potential biological components such as shared genetics or even transmission of epigenetic risk. METHOD: This study examined 93 parent-child dyads (n = 171 participants total) from a mixed Urban-Suburban US metropolitan area to investigate the relations between parental PTSS and child-perceived parenting and child PTSS. We sought to examine interactions between parental PTSS and parenting on child PTSS. RESULTS: We found an association between parent and child PTSS, consistent with prior literature showing increased risk for children of trauma survivors. Interestingly, we found effects of positive parenting on diminished child PTSS symptoms only in parents without PTSS, whereas the effect of positive parenting on buffering child symptoms was absent in parents with PTSS. LIMITATIONS: The present findings are tempered by the use of self-report data to assess parent and child PTSS, which is not as reliable as clinician assessment of symptoms. Further, the use of survey data limits what is known about the extent of trauma exposure in parents and children, and different measures were used to assess PTSS in parents and kids, which limits comparability of these reported symptoms. DISCUSSION: Limitations notwithstanding, findings suggest joint attention paid to parenting practices and to a parent's recovery, even from subthreshold symptoms of PTSS, as two different but important ways to support trauma survivor parents in their efforts to most optimally parent and protect their children from intergenerational risk.

Brain dynamics reflecting an intra-network brain state is associated with increased posttraumatic stress symptoms in the early aftermath of trauma.

This study examines the association between brain dynamic functional network connectivity (dFNC) and current/future posttraumatic stress (PTS) symptom severity, and the impact of sex on this relationship. By analyzing 275 participants' dFNC data obtained ~2 weeks after trauma exposure, we noted that brain dynamics of an inter-network brain state link negatively with current (r=-0.179, pcorrected= 0.021) and future (r=-0.166, pcorrected= 0.029) PTS symptom severity. Also, dynamics of an intra-network brain state correlated with future symptom intensity (r = 0.192, pcorrected = 0.021). We additionally observed that the association between the network dynamics of the inter-network brain state with symptom severity is more pronounced in females (r=-0.244, pcorrected = 0.014). Our findings highlight a potential link between brain network dynamics in the aftermath of trauma with current and future PTSD outcomes, with a stronger protective effect of inter-network brain states against symptom severity in females, underscoring the importance of sex differences.

Sex Differences in Response Inhibition-Related Neural Predictors of Posttraumatic Stress Disorder in Civilians With Recent Trauma.

BACKGROUND: Females are more likely to develop posttraumatic stress disorder (PTSD) than males. Impaired inhibition has been identified as a mechanism for PTSD development, but studies on potential sex differences in this neurobiological mechanism and how it relates to PTSD severity and progression are relatively rare. Here, we examined sex differences in neural activation during response inhibition and PTSD following recent trauma. METHODS: Participants (n = 205, 138 female sex assigned at birth) were recruited from emergency departments within 72 hours of a traumatic event. PTSD symptoms were assessed 2 weeks and 6 months posttrauma. A Go/NoGo task was performed 2 weeks posttrauma in a 3T magnetic resonance imaging scanner to measure neural activity during response inhibition in the ventromedial prefrontal cortex, right inferior frontal gyrus, and bilateral hippocampus. General linear models were used to examine the interaction effect of sex on the relationship between our regions of interest and the whole brain, PTSD symptoms at 6 months, and symptom progression between 2 weeks and 6 months. RESULTS: Lower response inhibition-related ventromedial prefrontal cortex activation 2 weeks posttrauma predicted more PTSD symptoms at 6 months in females but not in males, while greater response inhibition-related right inferior frontal gyrus activation predicted lower PTSD symptom progression in males but not females. Whole-brain interaction effects were observed in the medial temporal gyrus and left precentral gyrus. CONCLUSIONS: There are sex differences in the relationship between inhibition-related brain activation and PTSD symptom severity and progression. These findings suggest that sex differences should be assessed in future PTSD studies and reveal potential targets for sex-specific interventions.

Genetic risk for hospitalization of African American patients with severe mental illness reveals HLA loci.

Background: Mood disorders such as major depressive and bipolar disorders, along with posttraumatic stress disorder (PTSD), schizophrenia (SCZ), and other psychotic disorders, constitute serious mental illnesses (SMI) and often lead to inpatient psychiatric care for adults. Risk factors associated with increased hospitalization rate in SMI (H-SMI) are largely unknown but likely involve a combination of genetic, environmental, and socio-behavioral factors. We performed a genome-wide association study in an African American cohort to identify possible genes associated with hospitalization due to SMI (H-SMI). Methods: Patients hospitalized for psychiatric disorders (H-SMI; n=690) were compared with demographically matched controls (n=4467). Quality control and imputation of genome-wide data were performed following the Psychiatric Genetic Consortium (PGC)-PTSD guidelines. Imputation of the Human Leukocyte Antigen (HLA) locus was performed using the HIBAG package. Results: Genome-wide association analysis revealed a genome-wide significant association at 6p22.1 locus in the ubiquitin D (UBD/FAT10) gene (rs362514, p=9.43x10-9) and around the HLA locus. Heritability of H-SMI (14.6%) was comparable to other psychiatric disorders (4% to 45%). We observed a nominally significant association with 2 HLA alleles: HLA-A*23:01 (OR=1.04, p=2.3x10-3) and HLA-C*06:02 (OR=1.04, p=1.5x10-3). Two other genes (VSP13D and TSPAN9), possibly associated with immune response, were found to be associated with H-SMI using gene-based analyses. Conclusion: We observed a strong association between H-SMI and a locus that has been consistently and strongly associated with SCZ in multiple studies (6p21.32-p22.1), possibly indicating an involvement of the immune system and the immune response in the development of severe transdiagnostic SMI.

Blood-based DNA methylation and exposure risk scores predict PTSD with high accuracy in military and civilian cohorts.

Background: Incorporating genomic data into risk prediction has become an increasingly useful approach for rapid identification of individuals most at risk for complex disorders such as PTSD. Our goal was to develop and validate Methylation Risk Scores (MRS) using machine learning to distinguish individuals who have PTSD from those who do not. Methods: Elastic Net was used to develop three risk score models using a discovery dataset (n = 1226; 314 cases, 912 controls) comprised of 5 diverse cohorts with available blood-derived DNA methylation (DNAm) measured on the Illumina Epic BeadChip. The first risk score, exposure and methylation risk score (eMRS) used cumulative and childhood trauma exposure and DNAm variables; the second, methylation-only risk score (MoRS) was based solely on DNAm data; the third, methylation-only risk scores with adjusted exposure variables (MoRSAE) utilized DNAm data adjusted for the two exposure variables. The potential of these risk scores to predict future PTSD based on pre-deployment data was also assessed. External validation of risk scores was conducted in four independent cohorts. Results: The eMRS model showed the highest accuracy (92%), precision (91%), recall (87%), and f1-score (89%) in classifying PTSD using 3730 features. While still highly accurate, the MoRS (accuracy = 89%) using 3728 features and MoRSAE (accuracy = 84%) using 4150 features showed a decline in classification power. eMRS significantly predicted PTSD in one of the four independent cohorts, the BEAR cohort (beta = 0.6839, p-0.003), but not in the remaining three cohorts. Pre-deployment risk scores from all models (eMRS, beta = 1.92; MoRS, beta = 1.99 and MoRSAE, beta = 1.77) displayed a significant (p < 0.001) predictive power for post-deployment PTSD. Conclusion: Results, especially those from the eMRS, reinforce earlier findings that methylation and trauma are interconnected and can be leveraged to increase the correct classification of those with vs. without PTSD. Moreover, our models can potentially be a valuable tool in predicting the future risk of developing PTSD. As more data become available, including additional molecular, environmental, and psychosocial factors in these scores may enhance their accuracy in predicting the condition and, relatedly, improve their performance in independent cohorts.

Smaller total and subregional cerebellar volumes in posttraumatic stress disorder: a mega-analysis by the ENIGMA-PGC PTSD workgroup.

Although the cerebellum contributes to higher-order cognitive and emotional functions relevant to posttraumatic stress disorder (PTSD), prior research on cerebellar volume in PTSD is scant, particularly when considering subregions that differentially map on to motor, cognitive, and affective functions. In a sample of 4215 adults (PTSD n = 1642; Control n = 2573) across 40 sites from the ENIGMA-PGC PTSD working group, we employed a new state-of-the-art deep-learning based approach for automatic cerebellar parcellation to obtain volumetric estimates for the total cerebellum and 28 subregions. Linear mixed effects models controlling for age, gender, intracranial volume, and site were used to compare cerebellum volumes in PTSD compared to healthy controls (88% trauma-exposed). PTSD was associated with significant grey and white matter reductions of the cerebellum. Compared to controls, people with PTSD demonstrated smaller total cerebellum volume, as well as reduced volume in subregions primarily within the posterior lobe (lobule VIIB, crus II), vermis (VI, VIII), flocculonodular lobe (lobule X), and corpus medullare (all p-FDR < 0.05). Effects of PTSD on volume were consistent, and generally more robust, when examining symptom severity rather than diagnostic status. These findings implicate regionally specific cerebellar volumetric differences in the pathophysiology of PTSD. The cerebellum appears to play an important role in higher-order cognitive and emotional processes, far beyond its historical association with vestibulomotor function. Further examination of the cerebellum in trauma-related psychopathology will help to clarify how cerebellar structure and function may disrupt cognitive and affective processes at the center of translational models for PTSD.

Single nuclei transcriptomics in human and non-human primate striatum in opioid use disorder.

In brain, the striatum is a heterogenous region involved in reward and goal-directed behaviors. Striatal dysfunction is linked to psychiatric disorders, including opioid use disorder (OUD). Striatal subregions are divided based on neuroanatomy, each with unique roles in OUD. In OUD, the dorsal striatum is involved in altered reward processing, formation of habits, and development of negative affect during withdrawal. Using single nuclei RNA-sequencing, we identified both canonical (e.g., dopamine receptor subtype) and less abundant cell populations (e.g., interneurons) in human dorsal striatum. Pathways related to neurodegeneration, interferon response, and DNA damage were significantly enriched in striatal neurons of individuals with OUD. DNA damage markers were also elevated in striatal neurons of opioid-exposed rhesus macaques. Sex-specific molecular differences in glial cell subtypes associated with chronic stress were found in OUD, particularly female individuals. Together, we describe different cell types in human dorsal striatum and identify cell type-specific alterations in OUD.

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.

Sensory alterations in post-traumatic stress disorder.

PTSD is characterized by difficulties in accurately evaluating the threat value of sensory stimuli. While the role of canonical fear and threat neural circuitry in this ability has been well studied, recent lines of evidence suggest a need to include more emphasis on sensory processing in the conceptualization of PTSD symptomology. Specifically, studies have demonstrated a strong association between variability in sensory processing regions and the severity of PTSD symptoms. In this review, we summarize recent findings that underscore the importance of sensory processing in PTSD, in addition to the structural and functional characteristics of associated sensory brain regions. First, we discuss the link between PTSD and various behavioral aspects of sensory processing. This is followed by a discussion of recent findings that link PTSD to variability in the structure of both gray and white matter in sensory brain regions. We then delve into how brain activity (measured with task-based and resting-state functional imaging) in sensory regions informs our understanding of PTSD symptomology.

Training for Lasting Change: Trauma-Informed Training Results in Improved and Sustained Individual and Organizational Knowledge, Attitudes, and Policies.

Objective: Trauma-informed care (TIC) trainings seek to improve individual and organizational recognition and care to individuals who have experienced trauma. However, whether TIC trainings result in long-term changes to an organization's policies and practices remains unclear. This article describes the effectiveness of a workshop designed to train professionals across disciplines in understanding and implementing TIC in their work and workplace.Methods: Between July 2021 and May 2022, participants completed a 2-day (approximately 12 hours) training in TIC that included didactics on cultural responsivity, the biological effects of trauma, the components of TIC, and how to deploy TIC within their organization. Prior to the training, participants completed a previously validated survey, the Survey for Trauma-Informed Systems Change, which evaluated their pre-training (T0) competency in TIC and the level of TIC within their organization. Within 48 hours following the training, participants completed a post-survey (T1). To evaluate the longer-term impact of the training, participants repeated the post-survey at 6 months post-training (T2).Results: Over a 1-year period, 598 individuals (78% women, 20% men; mean age = 45.5 years) received training in TIC. There was a significant increase between the T0 survey and the T1 post-survey in self-assessed knowledge and attitudes; systemwide knowledge and attitudes; training, support, interaction, and environment; and awareness of cultural background at work (P values < .001), but not safety and acceptance at work (P = .06). Open-ended qualitative responses on the T2 survey, which probed what specific policies and/or practices had been modified within the participant's organization, revealed improvement in several key themes (training, policy, and communication).Conclusions: This unique trauma-informed didactic training resulted isn persistent quantitative and qualitative change within individuals and organizations. Most notably, the training yielded greater confidence in utilizing TIC practices and systemic change at the organizational level. The results suggest that a 2-day training in TIC can transform organizational training, policy, and communications.

Prior Sexual Trauma Exposure Impacts Posttraumatic Dysfunction and Neural Circuitry Following a Recent Traumatic Event in the AURORA Study.

Background: Prior sexual trauma (ST) is associated with greater risk for posttraumatic stress disorder after a subsequent traumatic event; however, the underlying neurobiological mechanisms remain opaque. We investigated longitudinal posttraumatic dysfunction and amygdala functional dynamics following admission to an emergency department for new primarily nonsexual trauma in participants with and without previous ST. Methods: Participants (N = 2178) were recruited following acute trauma exposure (primarily motor vehicle collision). A subset (n = 242) completed magnetic resonance imaging that included a fearful faces task and a resting-state scan 2 weeks after the trauma. We investigated associations between prior ST and several dimensions of posttraumatic symptoms over 6 months. We further assessed amygdala activation and connectivity differences between groups with or without prior ST. Results: Prior ST was associated with greater posttraumatic depression (F1,1120 = 28.35, p = 1.22 × 10-7, ηp2 = 0.06), anxiety (F1,1113 = 17.43, p = 3.21 × 10-5, ηp2 = 0.05), and posttraumatic stress disorder (F1,1027 = 11.34, p = 7.85 × 10-4, ηp2 = 0.04) severity and more maladaptive beliefs about pain (F1,1113 = 8.51, p = .004, ηp2 = 0.02) but was not related to amygdala reactivity to fearful versus neutral faces (all ps > .05). A secondary analysis revealed an interaction between ST and lifetime trauma load on the left amygdala to visual cortex connectivity (peak Z value: -4.41, corrected p < .02). Conclusions: Findings suggest that prior ST is associated with heightened posttraumatic dysfunction following a new trauma exposure but not increased amygdala activity. In addition, ST may interact with lifetime trauma load to alter neural circuitry in visual processing regions following acute trauma exposure. Further research should probe the relationship between trauma type and visual circuitry in the acute aftermath of trauma.

Circulating PACAP levels are associated with altered imaging measures of entorhinal cortex neurite density in posttraumatic stress disorder.

Background: Pituitary adenylate cyclase-activating polypeptide (PACAP) regulates plasticity in brain systems underlying arousal and memory and is associated with posttraumatic stress disorder (PTSD). Research in animal models suggests that PACAP modulates entorhinal cortex (EC) input to the hippocampus, contributing to impaired contextual fear conditioning. In PTSD, PACAP is associated with higher activity of the amygdala to threat stimuli and lower functional connectivity of the amygdala and hippocampus. However, PACAP-affiliated structural alterations of these regions have not been reported. Here, we examined whether peripheral PACAP levels were associated with neuronal morphology of the amygdala and hippocampus (primary analysis), and EC (secondary analysis) using Neurite Orientation Dispersion and Density Imaging. Methods: Sixty-four (44 female) adults (19 to 54 years old) with DSM-5 Criterion A trauma exposure completed the Clinician-Administered PTSD Scale (CAPS-5), a blood draw, and magnetic resonance imaging. PACAP38 radioimmunoassay was performed and T1-weighted and multi-shell diffusion- weighted images were acquired. Neurite Density Index (NDI) and Orientation Dispersion Index (ODI) were quantified in the amygdala, hippocampus, and EC. CAPS-5 total score and anxious arousal score were used to test for clinical associations with brain structure. Results: Higher PACAP levels in blood were associated with greater EC NDI (ß=0.31, q=0.034) and lower EC ODI (ß=-0.30, q=0.042) and not hippocampal or amygdala measures. Neither EC NDI nor ODI was associated with clinical measures. Conclusions: Circulating PACAP levels were associated with altered neuronal density of the EC but not hippocampus or amygdala. These findings strengthen evidence that PACAP may impact arousal- associated memory circuits.