Predicting aggressive behaviors: Examining unique and interactive roles of PTSD and emotion dysregulation in a minority sample.

Aggression is a costly public health problem with severe and multi-faceted negative consequences and thus, identifying factors that contribute to aggression, particularly in understudied populations, is necessary to develop more effective interventions to reduce the public health cost of aggression. The goal this study was to test whether difficulties regulating emotions moderated the association between posttraumatic stress disorder (PTSD) symptoms and aggression in a community sample of predominantly Black females with high levels of trauma exposure. Furthermore, we explored unique relations between PTSD symptom clusters and distinct subscales of difficulties regulating emotions and aggression. The sample included 601 community participants recruited from an urban public hospital. Symptoms were assessed using self-report measures including the Difficulties in Emotion Regulation Scale (DERS) and Behavioral Questionnaire-Short. Regression analyses were conducted using PTSD symptoms and total DERS to test their interaction as predictors for aggression (using BQ-Short). We found that higher levels of PTSD arousal symptoms and difficulty controlling impulses when upset were positively related to aggression. We also conducted an exploratory analysis to examine the association between PTSD symptom clusters using the Alternative Symptom Clusters hybrid model. The results suggest that some PTSD symptoms (externalizing behavior) and some emotion dysregulation processes (difficulties controlling impulses when upset), relate to aggression in independent, rather than multiplicative ways. These results offer insights for new directions of research that focuses on the independent association between specific emotion dysregulation processes and PTSD symptoms on aggression.

Neurophysiological changes associated with vibroacoustically-augmented breath-focused mindfulness for dissociation: targeting interoception and attention.

BACKGROUND: Dissociative symptoms can emerge after trauma and interfere with attentional control and interoception; disruptions to these processes are barriers to mind-body interventions such as breath-focused mindfulness (BFM). To overcome these barriers, we tested the use of an exteroceptive augmentation to BFM, using vibrations equivalent to the amplitude of the auditory waveform of the actual breath, delivered via a wearable subwoofer in real time (VBFM). We tested whether this device enhanced interoceptive processes, attentional control and autonomic regulation in trauma-exposed women with dissociative symptoms. METHODS: 65 women, majority (82%) Black American, aged 18-65 completed self-report measures of interoception and 6 BFM sessions, during which electrocardiographic recordings were taken to derive high-frequency heart rate variability (HRV) estimates. A subset (n = 31) of participants completed functional MRI at pre- and post-intervention, during which they were administered an affective attentional control task. RESULTS: Compared to those who received BFM only, women who received VBFM demonstrated greater increases in interoception, particularly their ability to trust body signals, increased sustained attention, as well as increased connectivity between nodes of emotion processing and interoceptive networks. Intervention condition moderated the relationship between interoception change and dissociation change, as well as the relationship between dissociation and HRV change. CONCLUSIONS: Vibration feedback during breath focus yielded greater improvements in interoception, sustained attention and increased connectivity of emotion processing and interoceptive networks. Augmenting BFM with vibration appears to have considerable effects on interoception, attention and autonomic regulation; it could be used as a monotherapy or to address trauma treatment barriers.

The PedBE clock accurately estimates DNA methylation age in pediatric buccal cells.

The development of biological markers of aging has primarily focused on adult samples. Epigenetic clocks are a promising tool for measuring biological age that show impressive accuracy across most tissues and age ranges. In adults, deviations from the DNA methylation (DNAm) age prediction are correlated with several age-related phenotypes, such as mortality and frailty. In children, however, fewer such associations have been made, possibly because DNAm changes are more dynamic in pediatric populations as compared to adults. To address this gap, we aimed to develop a highly accurate, noninvasive, biological measure of age specific to pediatric samples using buccal epithelial cell DNAm. We gathered 1,721 genome-wide DNAm profiles from 11 different cohorts of typically developing individuals aged 0 to 20 y old. Elastic net penalized regression was used to select 94 CpG sites from a training dataset (n = 1,032), with performance assessed in a separate test dataset (n = 689). DNAm at these 94 CpG sites was highly predictive of age in the test cohort (median absolute error = 0.35 y). The Pediatric-Buccal-Epigenetic (PedBE) clock was characterized in additional cohorts, showcasing the accuracy in longitudinal data, the performance in nonbuccal tissues and adult age ranges, and the association with obstetric outcomes. The PedBE tool for measuring biological age in children might help in understanding the environmental and contextual factors that shape the DNA methylome during child development, and how it, in turn, might relate to child health and disease.

Epigenetic upregulation of FKBP5 by aging and stress contributes to NF-κB-driven inflammation and cardiovascular risk.

Aging and psychosocial stress are associated with increased inflammation and disease risk, but the underlying molecular mechanisms are unclear. Because both aging and stress are also associated with lasting epigenetic changes, a plausible hypothesis is that stress along the lifespan could confer disease risk through epigenetic effects on molecules involved in inflammatory processes. Here, by combining large-scale analyses in human cohorts with experiments in cells, we report that FKBP5, a protein implicated in stress physiology, contributes to these relations. Across independent human cohorts (total n > 3,000), aging synergized with stress-related phenotypes, measured with childhood trauma and major depression questionnaires, to epigenetically up-regulate FKBP5 expression. These age/stress-related epigenetic effects were recapitulated in a cellular model of replicative senescence, whereby we exposed replicating human fibroblasts to stress (glucocorticoid) hormones. Unbiased genome-wide analyses in human blood linked higher FKBP5 mRNA with a proinflammatory profile and altered NF-κB-related gene networks. Accordingly, experiments in immune cells showed that higher FKBP5 promotes inflammation by strengthening the interactions of NF-κB regulatory kinases, whereas opposing FKBP5 either by genetic deletion (CRISPR/Cas9-mediated) or selective pharmacological inhibition prevented the effects on NF-κB. Further, the age/stress-related epigenetic signature enhanced FKBP5 response to NF-κB through a positive feedback loop and was present in individuals with a history of acute myocardial infarction, a disease state linked to peripheral inflammation. These findings suggest that aging/stress-driven FKBP5-NF-κB signaling mediates inflammation, potentially contributing to cardiovascular risk, and may thus point to novel biomarker and treatment possibilities.

Associations of maternal emotion regulation with child white matter connectivity in Black American mother-child dyads.

Parental emotion regulation plays a major role in parent-child interactions, and in turn, neural plasticity in children, particularly during sensitive developmental periods. However, little is known about how parental emotion dysregulation is associated with variation in children's brain structure, which was the goal of this study. Forty-five Black American mother-child dyads were recruited from an intergenerational trauma study; emotion regulation in mothers and their children (age 8-13 years) was assessed. Diffusion-weighted images were collected in children; deterministic tractography was used to reconstruct pathways of relevance to emotion regulation. Metrics of white matter connectivity [fractional anisotropy (FA), mean diffusivity (MD)] were extracted for pathways. Socio-economic variables were also included in statistical models. Maternal emotion dysregulation was the strongest predictor of child fornix MD (r = .35, p = .001), indicating that more severe emotion dysregulation in mothers corresponded with lower fornix connectivity in children. Maternal impulsivity was a strong predictor of child fornix MD (r = .51, p < .001). Maternal emotion dysregulation may adversely influence connectivity of the child.s fornix, a hippocampal-striatal pathway implicated in reward processes; these associations remained even after accounting for other socio-environmental factors. Dysregulated maternal emotions may uniquely impact children's adaptation to trauma/stress by affecting networks that support appetitive processing.

Measures of adult psychological resilience following early-life adversity: how congruent are different measures?

BACKGROUND: Psychological resilience - positive psychological adaptation in the context of adversity - is defined and measured in multiple ways across disciplines. However, little is known about whether definitions capture the same underlying construct and/or share similar correlates. This study examined the congruence of different resilience measures and associations with sociodemographic factors and body mass index (BMI), a key health indicator. METHODS: In a cross-sectional sample of 1429 African American adults exposed to child maltreatment, we derived four resilience measures: a self-report scale assessing resiliency (perceived trait resilience); a binary variable defining resilience as low depression and posttraumatic stress (absence of distress); a binary variable defining resilience as low distress and high positive affect (absence of distress plus positive functioning); and a continuous variable reflecting individuals' deviation from distress levels predicted by maltreatment severity (relative resilience). Associations between resilience measures, sociodemographic factors, and BMI were assessed using correlations and regressions. RESULTS: Resilience measures were weakly-to-moderately correlated (0.27-0.69), though similarly patterned across sociodemographic factors. Women showed higher relative resilience, but lower perceived trait resilience than men. Only measures incorporating positive affect or resiliency perceptions were associated with BMI: individuals classified as resilient by absence of distress plus positive functioning had lower BMI than non-resilient (ß = -2.10, p = 0.026), as did those with higher perceived trait resilience (ß = -0.63, p = 0.046). CONCLUSION: Relatively low congruence between resilience measures suggests studies will yield divergent findings about predictors, prevalence, and consequences of resilience. Efforts to clearly define resilience are needed to better understand resilience and inform intervention and prevention efforts.

Important Correlates of Purpose in Life Identified Through a Machine Learning Approach.

OBJECTIVE: A wealth of evidence has linked purpose in life (PiL) to better mental and physical health and healthy aging. Here, the authors aimed to determine important correlates of PiL using a machine learning approach. METHODS: Participants were recruited from retirement communities by the Rush Memory and Aging Project and assessed for childhood experience, adulthood sociodemographic factors (e.g., education, income, marital status), lifestyle and health behavior (e.g., cognitively stimulating activities, exercise, social activities, social network size), psychological factors (e.g., depression, loneliness, perceived discrimination, perceived social support), personality traits (e.g., PiL, harm avoidance), and medical conditions. Elastic Net was implemented to identify important correlates of PiL. RESULTS: A total of 1,839 participants were included in our analysis. Among the 23 variables provided to Elastic Net, 10 were identified as important correlates of PiL. In order of decreasing effect size, factors associated with lower PiL were loneliness, harm avoidance, older age, and depressive symptoms, while those associated with greater PiL were perceived social support, more social activities, more years of education, higher income, intact late-life cognitive performance, and more middle-age cognitive activities. CONCLUSION: Our findings identify potentially important modifiable factors as targets for intervention strategies to enhance PiL.

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

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

Psychometric Properties of the Personality Inventory for DSM-5-Brief Form in a Community Sample with High Rates of Trauma Exposure.

In the current study, we used a sample of predominantly African-American women with high rates of trauma exposure (N = 434) to examine psychometric properties of the Personality Inventory for DSM-5-Brief Form (PID-5-BF). We compared model fit between a model with five correlated latent factors and a higher-order model in which the five latent factors were used to estimate a single "general pathology" factor. Additionally, we computed estimates of internal consistency and domain interrelations and examined indices of convergent/discriminant validity of the PID-5-BF domains by examining their relations to relevant criterion variables. The expected five-factor structure demonstrated good fit indices in a confirmatory factor analysis, and the more parsimonious, higher-order model was retained. Within this higher-order model, the first-order factors accounted for more variance in the criterion variables than the general pathology factor in most instances. The PID-5-BF domains were highly interrelated (rs = .38 to .66), and convergent/discriminant validity of the domains varied: Negative Affectivity and Detachment generally showed the hypothesized pattern of relations with external criteria, while Antagonism and Disinhibition displayed less consistent and discriminant relations. Results are discussed in terms of the costs and benefits of using brief pathological trait measures in samples characterized by high levels of psychopathology.

Features of Childhood Maltreatment and Resilience Capacity in Adulthood: Results from a Large Community-Based Sample.

Childhood maltreatment is consistently associated with poor outcomes. However, few epidemiological studies have examined the association between childhood maltreatment and adult resilience capacity, defined as one's perceived ability to cope successfully with challenges. This study aimed to determine associations between adult resilience capacity and specific types and features of childhood maltreatment. Participants were African American adults recruited from a public urban hospital in Atlanta, GA (N = 1,962) between 2005 and 2013. Childhood maltreatment, including witnessing domestic violence or physical, emotional, and sexual abuse, was assessed retrospectively using the Traumatic Events Inventory. Perceived resilience capacity was assessed using the Connor-Davidson Resilience Scale. Linear regressions were performed assessing the association between resilience capacity and childhood maltreatment exposure in general, as well as specific dimensions of exposure, including type, co-occurrence, and developmental timing, adjusting for covariates. Participants exposed to any maltreatment reported lower resilience capacity than unexposed peers, B = -0.38, SE = 0.04, p < .001. All maltreatment types were negatively associated with resilience capacity, even after adjusting for other lifetime trauma exposure. Only emotional abuse remained significantly associated with resilience capacity after accounting for current psychological distress, B = -0.11, SE = 0.05, p = .022. Maltreatment co-occurrence followed an inverse dose-response relationship with resilience capacity: For each additional maltreatment type, scores decreased by 0.18 units (SD = 0.02), p < .001. Finally, the developmental timing of maltreatment did not reveal any differential influences on resilience capacity. The results suggest that childhood emotional abuse and co-occurrence of maltreatment types may be particularly deleterious to adult resilience capacity.

The differential effects of PTSD, MDD, and dissociation on CRP in trauma-exposed women.

OBJECTIVE: C-reactive protein (CRP), a marker of systemic inflammation, has been associated with psychiatric disorders including major depressive disorder (MDD) and post-traumatic stress disorder (PTSD). Some research suggests that exposure to trauma can trigger increased activity in the inflammatory system. Dissociation is associated with chronic trauma exposure and may be an important factor in understanding the risk for psychiatric outcomes associated with inflammation. The main objective of the current study was to understand how CRP was related to trauma, dissociation, PTSD and MDD in a sample of 55 traumatized African American women with type 2 diabetes mellitus recruited from an urban hospital. METHOD: High sensitivity CRP (hsCRP) was assayed through blood samples; psychiatric disorders were assessed with structured clinical interviews, dissociation was assessed with the Multiscale Dissociation Inventory, and exposure to trauma in childhood and adulthood was assessed with the Childhood Trauma Questionnaire and the Traumatic Events Inventory, respectively. RESULTS: Correlational results showed a significant association between higher concentrations of hsCRP and child abuse (p < 0.05), overall dissociation severity (p < 0.001), and PTSD symptoms (p < 0.01). ANOVA results showed significantly higher levels of hsCRP in those with current MDD, current PTSD, and remitted PTSD. A hierarchical linear regression model demonstrated a significant association between dissociation symptoms and greater hsCRP levels independent of childhood abuse, PTSD, and MDD (R2∆ = 0.11, p = 0.001) and independent of emotion dysregulation (p < 0.05). CONCLUSION: These findings suggest that dissociation symptoms among those with a history of trauma may be particularly associated with higher levels of inflammation.

Problematic alcohol use associates with sodium channel and clathrin linker 1 (SCLT1) in trauma-exposed populations.

Excessive alcohol use is extremely prevalent in the United States, particularly among trauma-exposed individuals. While several studies have examined genetic influences on alcohol use and related problems, this has not been studied in the context of trauma-exposed populations. We report results from a genome-wide association study of alcohol consumption and associated problems as measured by the alcohol use disorders identification test (AUDIT) in a trauma-exposed cohort. Results indicate a genome-wide significant association between total AUDIT score and rs1433375 [N = 1036, P = 2.61 × 10-8 (dominant model), P = 7.76 × 10-8 (additive model)], an intergenic single-nucleotide polymorphism located 323 kb upstream of the sodium channel and clathrin linker 1 (SCLT1) at 4q28. rs1433375 was also significant in a meta-analysis of two similar, but independent, cohorts (N = 1394, P = 0.0004), the Marine Resiliency Study and Systems Biology PTSD Biomarkers Consortium. Functional analysis indicated that rs1433375 was associated with SCLT1 gene expression and cortical-cerebellar functional connectivity measured via resting state functional magnetic resonance imaging. Together, findings suggest a role for sodium channel regulation and cerebellar functioning in alcohol use behavior. Identifying mechanisms underlying risk for problematic alcohol use in trauma-exposed populations is critical for future treatment and prevention efforts.

Post-traumatic stress disorder is associated with PACAP and the PAC1 receptor.

Pituitary adenylate cyclase-activating polypeptide (PACAP) is known to broadly regulate the cellular stress response. In contrast, it is unclear if the PACAP-PAC1 receptor pathway has a role in human psychological stress responses, such as post-traumatic stress disorder (PTSD). Here we find, in heavily traumatized subjects, a sex-specific association of PACAP blood levels with fear physiology, PTSD diagnosis and symptoms in females. We examined 44 single nucleotide polymorphisms (SNPs) spanning the PACAP (encoded by ADCYAP1) and PAC1 (encoded by ADCYAP1R1) genes, demonstrating a sex-specific association with PTSD. A single SNP in a putative oestrogen response element within ADCYAP1R1, rs2267735, predicts PTSD diagnosis and symptoms in females only. This SNP also associates with fear discrimination and with ADCYAP1R1 messenger RNA expression in human brain. Methylation of ADCYAP1R1 in peripheral blood is also associated with PTSD. Complementing these human data, ADCYAP1R1 mRNA is induced with fear conditioning or oestrogen replacement in rodent models. These data suggest that perturbations in the PACAP-PAC1 pathway are involved in abnormal stress responses underlying PTSD. These sex-specific effects may occur via oestrogen regulation of ADCYAP1R1. PACAP levels and ADCYAP1R1 SNPs may serve as useful biomarkers to further our mechanistic understanding of PTSD.

Gene × Environment Determinants of Stress- and Anxiety-Related Disorders.

The burgeoning field of gene-by-environment (G×E) interactions has revealed fascinating biological insights, particularly in the realm of stress-, anxiety-, and depression-related disorders. In this review we present an integrated view of the study of G×E interactions in stress and anxiety disorders, including the evolution of genetic association studies from genetic epidemiology to contemporary large-scale genome-wide association studies and G×E studies. We convey the importance of consortia efforts and collaboration to gain the large sample sizes needed to move the field forward. Finally, we discuss several robust and well-reproduced G×E interactions and demonstrate how epidemiological identification of G×E interactions has naturally led to a plethora of basic research elucidating the mechanisms of high-impact genetic variants.

PACAP receptor gene polymorphism impacts fear responses in the amygdala and hippocampus.

We have recently found higher circulating levels of pituitary adenylate cyclase-activating polypeptide (PACAP) associated with posttraumatic stress disorder (PTSD) symptoms in a highly traumatized cohort of women but not men. Furthermore, a single nucleotide polymorphism in the PACAP receptor gene ADCYAP1R1, adenylate cyclase activating polypeptide 1 receptor type 1, was associated with individual differences in PTSD symptoms and psychophysiological markers of fear and anxiety. The current study outlines an investigation of individual differences in brain function associated with ADCYAP1R1 genotype. Forty-nine women who had experienced moderate to high levels of lifetime trauma participated in a functional MRI task involving passive viewing of threatening and neutral face stimuli. Analyses focused on the amygdala and hippocampus, regions that play central roles in the pathophysiology of PTSD and are known to have high densities of PACAP receptors. The risk genotype was associated with increased reactivity of the amygdala and hippocampus to threat stimuli and decreased functional connectivity between the amygdala and hippocampus. The findings indicate that the PACAP system modulates medial temporal lobe function in humans. Individual differences in ADCYAP1R1 genotype may contribute to dysregulated fear circuitry known to play a central role in PTSD and other anxiety disorders.

Maternal emotion dysregulation, parenting stress, and child physiological anxiety during dark-enhanced startle.

Maternal emotion dysregulation (ED) plays a crucial role in the development of psychopathology in children. The current study aimed to investigate parenting stress as a mediator of the relationship between maternal emotion dysregulation and child startle potentiation, with child sex as a moderator. Mothers were interviewed to obtain self-report of maternal ED and parenting stress and child's dark-enhanced startle (DES) response was measured using electromyographic recordings of the eye-blink muscle during the delivery of acoustic probes. We found that maternal ED was positively correlated with both her parenting stress and her child's DES. A bootstrap analysis yielded a full mediation of the association between ED and child DES via parenting stress. Child sex was not a significant moderator of these relationships. These results suggest that maternal ED has important consequences for the intergenerational transmission of risk and also highlight the interaction of behavioral and biological mechanisms of risk.

Associations Between Posttraumatic Stress Disorder, Emotion Dysregulation, and Alcohol Dependence Symptoms Among Inner City Females.

OBJECTIVE: The purpose of this study was to examine how emotion dysregulation (ED) might help explain the relationship between posttraumatic stress disorder (PTSD) and alcohol dependence (AD) symptoms in females. METHOD: Participants included 260 women from primary, diabetes, and gynecological clinics of an urban public hospital. This is a primarily African American sample (96.9%), including individuals reporting exposure to at least 1 traumatic event. We examined the associations and predictability patterns between severity of PTSD symptoms, ED, and AD symptoms. RESULTS: Using linear regression analyses, PTSD avoidance and numbing symptoms and ED were significant predictors of AD symptoms. When looking at specific dimensions of ED, one's inability to engage in goal-directed behavior under strong emotional influences showed a full indirect effect on the relationship between PTSD avoidance and numbing symptoms and AD symptoms. CONCLUSION: Our findings suggest that having poor emotion regulation skills may help explain why females with PTSD become dependent on alcohol.

Kernel Approach for Modeling Interaction Effects in Genetic Association Studies of Complex Quantitative Traits.

The etiology of complex traits likely involves the effects of genetic and environmental factors, along with complicated interaction effects between them. Consequently, there has been interest in applying genetic association tests of complex traits that account for potential modification of the genetic effect in the presence of an environmental factor. One can perform such an analysis using a joint test of gene and gene-environment interaction. An optimal joint test would be one that remains powerful under a variety of models ranging from those of strong gene-environment interaction effect to those of little or no gene-environment interaction effect. To fill this demand, we have extended a kernel machine based approach for association mapping of multiple SNPs to consider joint tests of gene and gene-environment interaction. The kernel-based approach for joint testing is promising, because it incorporates linkage disequilibrium information from multiple SNPs simultaneously in analysis and permits flexible modeling of interaction effects. Using simulated data, we show that our kernel machine approach typically outperforms the traditional joint test under strong gene-environment interaction models and further outperforms the traditional main-effect association test under models of weak or no gene-environment interaction effects. We illustrate our test using genome-wide association data from the Grady Trauma Project, a cohort of highly traumatized, at-risk individuals, which has previously been investigated for interaction effects.

CHILDHOOD MALTREATMENT PREDICTS REDUCED INHIBITION-RELATED ACTIVITY IN THE ROSTRAL ANTERIOR CINGULATE IN PTSD, BUT NOT TRAUMA-EXPOSED CONTROLS.

BACKGROUND: A deficit in the ability to inhibit fear has been proposed as a biomarker of posttraumatic stress disorder (PTSD). Previous research indicates that individuals with PTSD show reduced inhibition-related activation in rostral anterior cingulate cortex (rACC). The goal of the current study was to investigate differential influences of an early environmental risk factor for PTSD-childhood maltreatment-on inhibition-related brain function in individuals with PTSD versus trauma-exposed controls. METHODS: Individuals with PTSD (n = 37) and trauma-exposed controls (n = 53) were recruited from the primary care waiting rooms of an urban public hospital in Atlanta, GA. Participants completed an inhibition task during fMRI, and reported childhood and adult traumatic experiences. The groups were matched for adult and child trauma load. RESULTS: We observed an interaction between childhood maltreatment severity and PTSD status in the rACC (P < .05, corrected), such that maltreatment was negatively associated with inhibition-related rACC activation in the PTSD group, but did not influence rACC activation in the TC group. Rostral ACC activation was associated with inhibition-related task performance in the TC group but not the PTSD group, suggesting a possible contribution to stress resilience. CONCLUSIONS: Findings highlight individual differences in neural function following childhood trauma, and point to inhibition-related activation in rostral ACC as a risk factor for PTSD.

STRUCTURAL AND FUNCTIONAL CONNECTIVITY IN POSTTRAUMATIC STRESS DISORDER: ASSOCIATIONS WITH FKBP5.

BACKGROUND: The integrity of connections between the hippocampus and the anterior cingulate cortex (ACC) is critical for adaptive cognitive and emotional processing; these connections may be compromised in posttraumatic stress disorder (PTSD). However, there is a lack of PTSD research that combines structural and functional connectivity data, and no studies have examined whether abnormal ACC-hippocampal connectivity is associated with genetic variability, particularly for polymorphisms of a gene that has been previously associated with PTSD, FKBP5. This was the goal of the present study. METHODS: Fifty-four women with and without PTSD underwent diffusion tensor imaging and resting-state MRI. Probabilistic tractography was used to examine ACC-hippocampal structural connectivity; mean fractional anisotropy (FA) values were extracted from connectivity streamlines, which represent the cingulum bundle. Genotype data were collected for a single nucleotide polymorphism (SNP) of FKBP5, rs1360780. RESULTS: Participants with PTSD demonstrated poorer structural connectivity (lower cingulum FA) compared to traumatized controls (F1, 50 = 6.77, P < .05). An interaction of FKBP5 genotype and diagnostic group was also observed (F1, 37 = 4.52, P = .04), indicating lower cingulum FA in carriers of two risk alleles for this SNP, compared to other diagnostic and genotype groups. Carriers of two FKBP5 risk alleles also demonstrated poorer hippocampus-ACC connectivity at rest (P < .05). When cingulum FA was used a regressor in a brain-wide, seed-based regression analysis, significant associations were found between the hippocampus and dorsal regions of the ACC (P < .05). CONCLUSIONS: Individuals with PTSD demonstrated compromised structural connectivity of the hippocampus-ACC pathway. Altered hippocampus-ACC connectivity may represent a highly salient intermediate neural phenotype for PTSD.