Human Cytomegalovirus Oncoprotection across Diverse Populations, Tumor Histologies, and Age Groups: The Relevance for Prospective Vaccinal Therapy.

The oncogenicity of the human cytomegalovirus (CMV) is currently being widely debated. Most recently, mounting clinical evidence suggests an anti-cancer effect via CMV-induced T cell-mediated tumor destruction. However, the data were mostly obtained from single-center studies and in vitro experiments. Broad geographic coverage is required to offer a global perspective. Our study examined the correlation between country-specific CMV seroprevalence (across 73 countries) and the age-standardized incidence rate (of 34 invasive tumors). The populations studied were stratified according to decadal age periods as the immunologic effects of CMV seropositivity may depend upon age at initial infection. The International Agency for Research on Cancer of the World Health Organization (IARC WHO) database was used. The multivariate linear regression analysis revealed a worldwide inverse correlation between CMV seroprevalence and the incidences of 62.8% tumors. Notably, this inverse link persists for all cancers combined (Spearman's ρ = -0.732, p < 0.001; ß = -0.482, p < 0.001, adjusted R2 = 0.737). An antithetical and significant correlation was also observed in particular age groups for the vast majority of tumors. Our results corroborate the conclusions of previous studies and indicate that this oncopreventive phenomenon holds true on a global scale. It applies to a wide spectrum of cancer histologies, additionally supporting the idea of a common underlying mechanism-CMV-stimulated T cell tumor targeting. Although these results further advance the notion of CMV-based therapies, in-depth investigation of host-virus interactions is still warranted.

Prospective Measurement of Skin Conductance Response during Trauma Interview Predicts Future PTSD Severity in Trauma Exposed Children.

Previous cross-sectional studies have shown that sympathetic nervous system (SNS) arousal is positively associated with posttraumatic stress disorder (PTSD) symptoms in children with trauma exposure. One of the ways that SNS activity is measured is through skin conductance response (SCR), which has been shown to predict future PTSD severity in adults. In this study, we explored the utility of a novel, low-cost mobile SCR device, eSense, to predict future PTSD symptom severity in trauma exposed children. We recruited children (N=43, age 9 years at initial visit) for a longitudinal study in which SCR was recorded at baseline visit, and PTSD symptoms were assessed two years later. Results indicated an interaction between SCR and trauma exposure, such that children with lower trauma exposure who demonstrated greater SCR reported higher PTSD severity two years later. This association remained significant even after controlling for baseline PTSD symptoms. Children with higher levels of trauma exposure did not show this association, potentially due to ceiling effects of PTSD symptoms. Together these findings suggest the utility of SCR as a biomarker for predicting trauma related disorders in children, and that it may be a valuable tool in clinical interventions targeting sympathetic arousal.

Significance of Cytomegalovirus gB Genotypes in Adult Patients Undergoing Hematopoietic Stem Cell Transplantation: Insights from a Single-Centre Investigation.

INTRODUCTION: Cytomegalovirus (CMV) infection is a major clinical issue after allogeneic hematopoietic stem cell transplantation (HSCT). The CMV envelope glycoproteins are key in viral pathogenesis; the glycoprotein B (gB) encoded by the UL55 gene might be an important determinant of viral virulence and disease severity marker in patients treated with allogeneic HSCT. Our aim was to investigate the molecular diversity of CMV gB and inquire into the associations between UL55 gene variations and clinical manifestations in adult patients treated with allogeneic HSCT. RESULTS: The most prevalent genotypes were gB1 and gB4 (11/27, 40.7%). Patients with genotype gB1 infection had earlier platelet engraftment (p < 0.033) and less frequent minimal/measurable residual disease post HSCT than those without this genotype. Patients with gB4 glycoprotein infection had a significantly lower CD4+/CD8+ ratio at D90 (p < 0.026). Interestingly, patients with gB5 glycoprotein infection had shorter overall survival from base condition diagnosis (p < 0.042), as well as shorter overall survival after HSCT (p < 0.036). Acute GvHD was noted more frequently in those with mixed-genotype infection (p = 0.047). MATERIAL AND METHODS: The study included fifty-nine adult patients treated with allogeneic HSCT. Peripheral venous blood was sampled typically per week, with detection of CMV performed by quantitative real-time PCR. Multiplex nested PCR was used to determine specific gB genotypes, which were then statistically compared vis-à-vis specific clinical variables. CONCLUSIONS: Our study points to variations in the viral UL55 locus imparting both beneficial (earlier platelet engraftment, less frequent MRD post HSCT) and adverse effects (shorter overall survival, more frequent acute GvHD, less frequent 100% chimerism at day 90) to the transplanted host. Comprehensive molecular investigations are necessary to validate this apparent duality, as the potential benefits of CMV could perhaps be utilized for the benefit of the patient in the future.

Sex differences in response inhibition-related neural predictors of PTSD in recent trauma-exposed civilians.

BACKGROUND: Females are more likely to develop posttraumatic stress disorder (PTSD) than males. Impaired inhibition has been identified as mechanism for PTSD development, but studies on the potential sex differences of this neurobiological mechanism and how it relates to PTSD severity and progression are sparse. 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 post-trauma. A Go/NoGo task was performed 2-weeks post-trauma in a 3T MRI scanner to measure neural activity during response inhibition in the ventromedial prefrontal cortex (vmPFC), right inferior frontal gyrus (rIFG), and the bilateral hippocampus. General Linear models were used to examine the interaction effect of sex on the relationship between our regions of interest (ROIs) and the whole brain, and PTSD symptoms at 6-months, and symptom progression between 2-weeks and 6-months. RESULTS: Lower response-inhibition-related vmPFC activation 2-weeks post-trauma predicted more PTSD symptoms at 6-months in females but not in males, while greater response-inhibition-related rIFG 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.

HIV Interacts with Posttraumatic Stress Disorder to Impact Fear Psychophysiology in Trauma-Exposed Black Women.

Background: The prevalence of posttraumatic stress disorder (PTSD) among people living with HIV (PLWH) is higher than in the general population and can impact health behaviors. The influence of HIV on PTSD psychophysiology requires further investigation due to implications for the treatment of PTSD in PLWH. Objective: Utilizing fear-potentiated startle (FPS), we aimed to interrogate the influence of PTSD and HIV on fear responses. Materials and Methods: Women (18-65 years of age) recruited from the Women's Interagency HIV Study in Atlanta, GA (n = 70, 26 without HIV and 44 with HIV), provided informed consent and completed a semistructured interview to assess trauma exposure and PTSD symptom severity. Participants also underwent an FPS paradigm to assess fear acquisition and extinction: Psychophysiological indices that measure how individuals learn new fear and then subsequently attempt to suppress this fear. Results: Women with PTSD, who did not have HIV, exhibited a greater startle response compared to women without PTSD or HIV during late acquisition to both the danger cue, reinforced conditioned stimulus (CS+, p = 0.013)), and the safety cue, non-reinforced conditioned stimulus (CS-, p = 0.046)), whereas women living with HIV (WLH) and PTSD demonstrated blunted fear responses compared to women with PTSD only. During extinction, WLH comorbid with PTSD exhibited an increased fear response during the extinction period in comparison to all other groups (p = 0.023). Women without PTSD demonstrated a reduction in the fear response during extinction regardless of HIV status. Conclusion: Our findings indicate that HIV further modifies fear psychophysiology in WLH with comorbid PTSD, highlighting the importance of considering HIV status in conjunction with PTSD treatment.

Post-traumatic stress and future substance use outcomes: leveraging antecedent factors to stratify risk.

Background: Post-traumatic stress disorder (PTSD) and substance use (tobacco, alcohol, and cannabis) are highly comorbid. Many factors affect this relationship, including sociodemographic and psychosocial characteristics, other prior traumas, and physical health. However, few prior studies have investigated this prospectively, examining new substance use and the extent to which a wide range of factors may modify the relationship to PTSD. Methods: The Advancing Understanding of RecOvery afteR traumA (AURORA) study is a prospective cohort of adults presenting at emergency departments (N = 2,943). Participants self-reported PTSD symptoms and the frequency and quantity of tobacco, alcohol, and cannabis use at six total timepoints. We assessed the associations of PTSD and future substance use, lagged by one timepoint, using the Poisson generalized estimating equations. We also stratified by incident and prevalent substance use and generated causal forests to identify the most important effect modifiers of this relationship out of 128 potential variables. Results: At baseline, 37.3% (N = 1,099) of participants reported likely PTSD. PTSD was associated with tobacco frequency (incidence rate ratio (IRR): 1.003, 95% CI: 1.00, 1.01, p = 0.02) and quantity (IRR: 1.01, 95% CI: 1.001, 1.01, p = 0.01), and alcohol frequency (IRR: 1.002, 95% CI: 1.00, 1.004, p = 0.03) and quantity (IRR: 1.003, 95% CI: 1.001, 1.01, p = 0.001), but not with cannabis use. There were slight differences in incident compared to prevalent tobacco frequency and quantity of use; prevalent tobacco frequency and quantity were associated with PTSD symptoms, while incident tobacco frequency and quantity were not. Using causal forests, lifetime worst use of cigarettes, overall self-rated physical health, and prior childhood trauma were major moderators of the relationship between PTSD symptoms and the three substances investigated. Conclusion: PTSD symptoms were highly associated with tobacco and alcohol use, while the association with prospective cannabis use is not clear. Findings suggest that understanding the different risk stratification that occurs can aid in tailoring interventions to populations at greatest risk to best mitigate the comorbidity between PTSD symptoms and future substance use outcomes. We demonstrate that this is particularly salient for tobacco use and, to some extent, alcohol use, while cannabis is less likely to be impacted by PTSD symptoms across the strata.

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.

Resting heart rate associations with violence exposure and posttraumatic stress symptoms: sex differences in children.

BACKGROUND: Traumatic events experienced in childhood can lead to increased risk of cardiovascular disorders in adulthood. Black Americans are disproportionately affected, as they are at increased risk for experiencing childhood trauma and cardiovascular diseases in adulthood. One of the hypothesized mechanisms of this association is through long-lasting dysregulation of the autonomic nervous system, a hallmark physiological biomarker of posttraumatic stress disorder (PTSD), which is twice as prevalent in women compared to men. METHODS: Ninety-one, majority Black American children, aged 9 were recruited to be a part of our longitudinal study of child development at research centers in Atlanta, GA and Detroit, MI. Resting HR was measured through a electrocardiogram (ECG) recording using the Biopac MP150. Self-report measures of violence exposure and PTSD symptoms were administered by research staff. RESULTS: Children with more violence exposure reported increased PTSS as well as lower resting HR. Regression analysis showed evidence of sex modifying this relationship, (B = -0.64, p < 0.05), such that the association between resting HR and PTSS was stronger in girls than in boys. In our exploratory analysis with standard clinical cutoffs of resting HR, the normative HR group was found to significantly moderate the relationship between violence exposure and PTSS in boys, (B = -2.14, p < 0.01), but not girls (B = -0.94, p = 0.27). CONCLUSION: In our sample of primarily Black urban children, we found that violence exposure was associated with slower, more adult-like HR, that girls showed greater PTSS associated with slower HR while boys did not, and that girls with lower than normative HR showed significantly higher PTSS compared to girls with normative HR. Our sample's demonstration of psychological consequences in addition to the physiological implications could provide new information about a psychobiological sequelae of violence exposure.

Experiencing traumatic events in childhood can lead to increased risk of heart disease in adulthood. One of the ways this might happen is through long-lasting changes of the autonomic nervous system. This system is dysregulated in posttraumatic stress disorder (PTSD), which is twice as common in women compared to men. We explored whether resting heart rate (HR), a measure of autonomic functioning was associated with violence exposure in children, and whether this relationship was different in boys and girls. We also explored whether categorizing our sample into resting HR groups based off standardized norms for HR predicted differing relationships between violence exposure and posttraumatic stress symptoms (PTSS). Because childhood trauma and heart disease impact Black Americans at greater rates, we recruited our sample of 92 nine-year-old children from research centers in Atlanta, GA and Detroit, MI. We measured their resting HR, exposure to violence, and PTSS. We found that violence exposure was associated with lower HR overall, that girls showed greater PTSS associated with lower HR when compared to boys, and that boys with lower than normative HR showed a stronger association between violence exposure and PTSS compared to boys with normative HR. Future studies should examine potential mechanisms underlying this sex difference to best understand the long-term cardiovascular consequences for sex-related health disparities. Specifically, longitudinal studies may be able to help researchers understand how reduced HR during adolescents might lead to future cardiovascular disease and psychopathology.

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.

Acupuncture for Combat-Related Posttraumatic Stress Disorder: A Randomized Clinical Trial.

Importance: Current interventions for posttraumatic stress disorder (PTSD) are efficacious, yet effectiveness may be limited by adverse effects and high withdrawal rates. Acupuncture is an emerging intervention with positive preliminary data for PTSD. Objective: To compare verum acupuncture with sham acupuncture (minimal needling) on clinical and physiological outcomes. Design, Setting, and Participants: This was a 2-arm, parallel-group, prospective blinded randomized clinical trial hypothesizing superiority of verum to sham acupuncture. The study was conducted at a single outpatient-based site, the Tibor Rubin VA Medical Center in Long Beach, California, with recruitment from April 2018 to May 2022, followed by a 15-week treatment period. Following exclusion for characteristics that are known PTSD treatment confounds, might affect biological assessment, indicate past nonadherence or treatment resistance, or indicate risk of harm, 93 treatment-seeking combat veterans with PTSD aged 18 to 55 years were allocated to group by adaptive randomization and 71 participants completed the intervention protocols. Interventions: Verum and sham were provided as 1-hour sessions, twice weekly, and participants were given 15 weeks to complete up to 24 sessions. Main Outcomes and Measures: The primary outcome was pretreatment to posttreatment change in PTSD symptom severity on the Clinician-Administered PTSD Scale-5 (CAPS-5). The secondary outcome was pretreatment to posttreatment change in fear-conditioned extinction, assessed by fear-potentiated startle response. Outcomes were assessed at pretreatment, midtreatment, and posttreatment. General linear models comparing within- and between-group were analyzed in both intention-to-treat (ITT) and treatment-completed models. Results: A total of 85 male and 8 female veterans (mean [SD] age, 39.2 [8.5] years) were randomized. There was a large treatment effect of verum (Cohen d, 1.17), a moderate effect of sham (d, 0.67), and a moderate between-group effect favoring verum (mean [SD] Δ, 7.1 [11.8]; t90 = 2.87, d, 0.63; P = .005) in the intention-to-treat analysis. The effect pattern was similar in the treatment-completed analysis: verum d, 1.53; sham d, 0.86; between-group mean (SD) Δ, 7.4 (11.7); t69 = 2.64; d, 0.63; P = .01). There was a significant pretreatment to posttreatment reduction of fear-potentiated startle during extinction (ie, better fear extinction) in the verum but not the sham group and a significant correlation (r = 0.31) between symptom reduction and fear extinction. Withdrawal rates were low. Conclusions and Relevance: The acupuncture intervention used in this study was clinically efficacious and favorably affected the psychobiology of PTSD in combat veterans. These data build on extant literature and suggest that clinical implementation of acupuncture for PTSD, along with further research about comparative efficacy, durability, and mechanisms of effects, is warranted. Trial Registration: ClinicalTrials.gov Identifier: NCT02869646.

Humoral and Cellular Immune Response after Three Doses of Sinopharm [Vero Cell]-Inactivated COVID-19 Vaccine in Combination with SARS-CoV-2 Infection Leads to Hybrid Immunity.

BACKGROUND: Several vaccines against COVID-19 have been developed and licensed to enhance the immune response against SARS-CoV-2. Similarly, previous infection with SARS-CoV-2 has been shown to provide significant protection against severe infection and hospitalization. METHODS: We investigated the effect of three doses of the Sinopharm vaccine and SARS-CoV-2 infection on the specific immune response in 103 volunteers, measuring neutralizing antibodies, anti-S1 IgG, anti-RBD IgM, anti-N IgM, anti-N IgG antibodies, and INF γ. RESULTS: Our results showed that the presence of cardiovascular diseases increased the level of anti-N-IgG antibodies, while endocrinological diseases decreased the level of neutralizing antibodies and anti-N IgG antibodies, suggesting that these diseases alter the effect of vaccine-induced immunity. In addition, there was a significant decrease in anti-S1 IgG levels at 6 months and in anti-N IgG levels 18 months post-infection, while neutralizing antibodies and INF γ levels were constant at 3, 6, and 18 months post-infection. CONCLUSIONS: Our results confirm the emergence of hybrid immunity, which is the strongest and most durable compared to natural immunity or vaccine-induced immunity. Significant positive correlations were found between humoral and cellular immunity markers: neutralizing antibodies, anti-S1 IgG and anti-N IgG antibodies, and INF γ, indicating a unique coordinated response specific to COVID-19.

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.

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.

Association between dimensions of trauma-related psychopathology and asthma in trauma-exposed women.

Introduction: Exposure to traumatic events and stressful life experiences are associated with a wide range of adverse mental and physical health outcomes. Studies have found post-traumatic stress disorder (PTSD), depression, and anxiety sensitivity occurrence to be common in addition to inflammatory diseases like asthma, especially in women. Moreover, overlapping neurobiological mechanisms have been linked to both PTSD and asthma. Methods: In the current study, n = 508 women reported on presence of lifetime asthma diagnosis and symptoms of trauma-related psychopathology including PTSD and depression. A separate group of female participants (n = 64) reported on asthma, PTSD, depression and anxiety sensitivity, and underwent functional MRI scans during a fearful faces task, and their anterior insula responses were analyzed. Results: Overall, PTSD and depression severity were significantly higher in those with asthma versus those without asthma. There was a positive association between anterior insula response to social threat cues and depression symptoms only among individuals without a lifetime presence of asthma. Discussion: These findings provide continued evidence on the interactions between stress, neural mechanisms involved in interoception and salience detection, and trauma-related psychopathology.

White matter predictors of PTSD: Testing different machine learning models in a sample of Black American women.

BACKGROUND: Machine learning neuroimaging studies of posttraumatic stress disorder (PTSD) show promise for identifying neurobiological signatures of PTSD. However, studies to date, have largely evaluated a single machine learning approach, and few studies have examined white matter microstructure as a predictor of PTSD. Further, individuals from minoritized racial groups, specifically, Black individuals, who experience disproportionate trauma frequency, and have relatively higher rates of PTSD, have been underrepresented in these studies. We used four different machine learning models to test white matter microstructure classifiers of PTSD in a sample of trauma-exposed Black American women with and without PTSD. METHOD: Participants included 45 Black women with PTSD and 89 trauma-exposed controls recruited from an ongoing trauma study. Current PTSD presence was estimated using the Clinician-Administered PTSD Scale. Average fractional anisotropy of 53 white matter tracts served as input features. Additional exploratory analysis incorporated estimates of interpersonal and structural racism exposure. Classification models included linear support vector machine, radial basis function support vector machine, multilayer perceptron, and random forest. RESULTS: Performance varied notably between models. With white matter features along, linear support vector machine demonstrated the best model fit and reached an average AUC = 0.643. Inclusion of estimates of exposure to racism increased linear support vector machine performance (AUC = 0.808). CONCLUSIONS: White matter microstructure had limited ability to predict PTSD presence in this sample. These results may indicate that the relationship between white matter microstructure and PTSD may be nuanced across race and gender spectrums.

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.

Neighborhood Disadvantage and Neural Correlates of Threat and Reward Processing in Survivors of Recent Trauma.

Importance: Differences in neighborhood socioeconomic characteristics are important considerations in understanding differences in risk vs resilience in mental health. Neighborhood disadvantage is associated with alterations in the function and structure of threat neurocircuitry. Objective: To investigate associations of neighborhood disadvantage with white and gray matter and neural reactivity to positive and negative stimuli in the context of trauma exposure. Design, Setting, and Participants: In this cross-sectional study, survivors of trauma who completed sociodemographic and posttraumatic symptom assessments and neuroimaging were recruited as part of the Advancing Understanding of Recovery After Trauma (AURORA) study between September 2017 and June 2021. Data analysis was performed from October 25, 2022, to February 15, 2023. Exposure: Neighborhood disadvantage was measured with the Area Deprivation Index (ADI) for each participant home address. Main Outcomes and Measures: Participants completed separate threat and reward tasks during functional magnetic resonance imaging. Diffusion-weighted and high-resolution structural images were also collected. Linear models assessed the association of ADI with reactivity, microstructure, and macrostructure of a priori regions of interest after adjusting for income, lifetime trauma, sex at birth, and age. A moderated-mediation model tested whether ADI was associated with neural activity via microstructural changes and if this was modulated by PTSD symptoms. Results: A total of 280 participants (183 females [65.4%]; mean [SD] age, 35.39 [13.29] years) completed the threat task and 244 participants (156 females [63.9%]; mean [SD] age, 35.10 [13.26] years) completed the reward task. Higher ADI (per 1-unit increase) was associated with greater insula (t274 = 3.20; ß = 0.20; corrected P = .008) and anterior cingulate cortex (ACC; t274 = 2.56; ß = 0.16; corrected P = .04) threat-related activity after considering covariates, but ADI was not associated with reward reactivity. Greater disadvantage was also associated with altered microstructure of the cingulum bundle (t274 = 3.48; ß = 0.21; corrected P = .001) and gray matter morphology of the ACC (cortical thickness: t273 = -2.29; ß = -0.13; corrected P = .02; surface area: t273 = 2.53; ß = 0.13; corrected P = .02). The moderated-mediation model revealed that ADI was associated with ACC threat reactivity via cingulum microstructural changes (index of moderated mediation = -0.02). However, this mediation was only present in individuals with greater PTSD symptom severity (at the mean: ß = -0.17; standard error = 0.06, t= -2.28; P = .007; at 1 SD above the mean: ß = -0.28; standard error = 0.08; t = -3.35; P < .001). Conclusions and Relevance: In this study, neighborhood disadvantage was associated with neurobiology that supports threat processing, revealing associations of neighborhood disadvantage with neural susceptibility for PTSD and suggesting how altered structure-function associations may complicate symptoms. Future work should investigate specific components of neighborhood disadvantage that may be associated with these outcomes.

Getting Better with Age? A Review of Psychophysiological Studies of Fear Extinction Learning Across Development.

A critical developmental task is learning what constitutes reliable threat and safety signals in the environment. In humans, atypical fear learning processes are implicated in many mental health conditions, particularly fear and anxiety disorders, pointing to the potential for laboratory measures of fear learning to facilitate early identification of at-risk individuals. This chapter reviews studies of fear learning and extinction learning that incorporate peripheral measures of psychophysiological response and include a developmental sample. Broadly, these studies indicate substantial consistency in differential learning and extinction across development, as assessed with multiple paradigms, across physiological indices. Importantly, though, response coherence across measures (e.g., physiological, neural, and behavioral) was inconsistent across studies. There was also less consistency in results from studies that probed associations between anxiety and fear learning processes. These mixed findings highlight the need for additional examination of when and why there is variability, both across development and in relation to individual differences factors, including mental health, childhood adversity, and sex. In addition, there remains a need for studies that test for developmental change in extinction recall learning and whether stimulus type impacts learning across development. Longitudinal studies designed to address these questions could provide novel insight into the developmental trajectory of fear learning and extinction.

Intergenerational Transmission of Depression: Examining the Roles of Racism and Trauma Among Black Mothers and Youth.

OBJECTIVE: Racism is a multifaceted system of oppression that disproportionately harms Black mothers and children across the lifespan. Despite reliable evidence that racism is associated with worse mental health outcomes (eg, increased depressive symptoms), less is known about potential intergenerational effects of Black mothers' experiences of racism on children's mental health, as well as how traumatic experiences influence these pathways. In this cross-sectional quantitative study, we aimed (1) to replicate the finding that maternal experiences of racism are associated with both maternal and child depression; (2) to identify whether maternal experiences of racism are indirectly associated with child depression via the effect of maternal depression; and (3) to test whether the indirect effect of racism on child depression via maternal depression is conditioned on maternal trauma. METHOD: Black mothers and their children (N = 148 dyads) were recruited from an urban hospital and were interviewed about their experiences of racism, trauma, and mental health symptoms. The mothers' average age was 35.16 years (SD = 8.75) and the children's average age was 10.03 years (SD = 1.51). RESULTS: First, we found that maternal experiences of racism were associated with more severe maternal depression (r = 0.37, p < .01) as well as more severe child depression (r = 0.19, p = .02). Second, we found that maternal experiences of racism were indirectly associated with child depression through the effect of maternal depression (ab = 0.76, 95% CI = 0.26, 1.37). Third, we found that maternal trauma exposure moderated this indirect effect such that, at relatively lower levels of maternal trauma exposure, the indirect effect of maternal experiences of racism on child depression was nonsignificant (ωlow = -0.05, 95% CI = -0.50, 0.45), whereas at relatively higher levels of maternal trauma exposure, the indirect effect of maternal experiences of racism on child depression was statistically significant (ωhigh= .65, 95% CI = 0.21, 1.15). CONCLUSION: These findings suggest that the indirect effect of maternal experiences of racism on child depression through the effect of maternal depression depends on the degree of maternal trauma exposure. This study advances the literature by shedding light on key processes that can explain the intergenerational effects of racism as well as contextual factors that can exacerbate racism's downstream consequences across generations.

Intergenerational transmission of trauma: A biological perspective.

This commentary is based on an invited panel for the 2022 International Society of Traumatic Stress Studies (ISTSS) annual meeting entitled "Perspective Discourses On…Intergenerational Transmission of Trauma: A Biological Perspective." This was a new format introduced by ISTSS to facilitate discussion around timely topics. This session included scholars from different backgrounds (e.g., epidemiology, neuroscience, environmental health) who shared their approaches to understanding the biological bases of the intergenerational transmission of trauma. Specifically, the panel presented information about putative direct and indirect mechanisms of transmission, including epigenetic and environmental factors, and pointed to behavioral and neurobiological outcomes in offspring. This commentary synthesizes some of the current knowledge gained by these different approaches and identifies key areas to advance in future work.