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.

Drug-facilitated sexual assault, impaired trauma memory, and implications for mental health treatment.

Background: Sexual assault (SA) is a highly prevalent global public health problem and a robust predictor of posttraumatic stress disorder (PTSD), substance use disorder (SUD), and suicidality. A large percentage are drug or alcohol facilitated (DFSA), impairing trauma memory and affecting the application of evidence-based treatments. Despite these problems, few have investigated DFSA-specific mental health (MH) needs. Objective: Goals of this study were (1) to identify psychological sequelae characterizing DFSA towards explaining why symptoms have been treatment-refractory, comparing survivors with involuntary substance ingestion (forced, covert: DFSA-I), voluntary ingestion (DFSA-V), and non-DFSA; and (2) to determine how impaired trauma memory relates to the development of PTSD and depression symptoms. Method: Data from a retrospective chart review of 74 adults receiving SA MH services at an outpatient trauma center are presented. The sample includes a 2-year cohort seen acutely at an urban rape treatment center. The study is one of the first to examine therapy records beyond case studies for DFSA. Logistic, Poisson, and negative binomial regression analyses of quantitative data and qualitative thematic analysis of trauma cognitions and treatment foci were conducted. Results: DFSA-V had five times greater odds of SUD, and notable substance-related self-blame compared to DFSA-I. DFSA-I had prominent relationship distress and self-blame for missing danger of perpetrator drugging. Survivors with impaired trauma memory had significantly fewer hyper-arousal and overall PTSD symptoms, and specifically less hypervigilance. No differences were found in re-experiencing symptoms. Conclusion: Impaired trauma memory is common in DFSA and is associated with fewer baseline hyper-arousal and overall PTS. Despite this, DFSA issues including re-experiencing symptoms that are particularly distressing without the ability to cognitively connect the intrusions contribute to increased treatment needs. Impaired memory limits the application of evidence-based treatments, and collectively these findings call for the development of trauma-specific treatment protocols to enhance recovery for DFSA survivors. HIGHLIGHTS: Survivors of drug-facilitated sexual assault have prominent PTSD including reexperiencing, though trauma memory may not be encoded. • Those absent trauma memory have less hyperarousal, but DFSA complications explain why it is treatment refractory and inform treatment development.

Antecedentes: La agresión sexual (AS) es un problema de salud pública mundial de alta prevalencia y es un sólido predictor del trastorno de estrés postraumático (TEPT), del trastorno por uso de sustancias (TUS) y de suicidalidad. Un gran porcentaje de AS son facilitadas por drogas o alcohol (ASFDA), deteriorando la memoria del trauma y afectando la aplicación de tratamientos basados en la evidencia. A pesar de estos problemas, pocos han investigado las necesidades de salud mental (SM) específicas de los ASFDA.Objetivo: Los objetivos de este estudio fueron; primero, identificar las secuelas psicológicas que caracterizan a las ASFDA para explicar por qué los síntomas han sido refractarios al tratamiento. Para ello, se comparó a sobrevivientes a una ingestión involuntaria de sustancias (forzada, encubierta: ASFDA-I), a una ingestión voluntaria (ASFDA-V), y a una AS no-ASFDA; y, segundo; determinar cómo el deterioro de la memoria del trauma se relaciona con el desarrollo de síntomas del TEPT y depresión.Método: Se presentan los datos de una revisión retrospectiva de las historias clínicas de 74 adultos que recibieron servicios de SM por AS en un centro de trauma para pacientes ambulatorios. La muestra incluye a una cohorte de 2 años en donde los casos de AS fueron vistos de forma aguda en un centro urbano de tratamiento para violación. El estudio es uno de los primeros, más allá de los estudios de casos, en examinar los registros de terapia por ASFDA. Se realizaron análisis de regresión logística, Poisson y binomial negativa de datos cuantitativos y un análisis temático cualitativo de las cogniciones del trauma y los puntos clave del tratamiento.Resultados: Los ASFDA-V tuvieron cinco veces más probabilidades de TUS y de un notable sentimiento de culpa relacionado con las sustancias comparado con los ASFDA-I. Las ASFDA tenían problemas de relación importantes y sentimientos de culpa por haber pasado por alto el peligro de que el agresor se drogara. Los sobrevivientes con deterioro de la memoria traumática tuvieron significativamente menos síntomas de hiperactivación y del TEPT en general y, específicamente, menos hipervigilancia. No se encontraron diferencias en los síntomas de reexperimentación.Conclusión: El deterioro de la memoria traumática es común en las ASFDA y se asocia con menos hiperactivación de base y síntomas postraumáticos en general. A pesar de esto, los problemas de los ASFDA incluyen a los síntomas de reexperimentación que son particularmente angustiantes y que restan la capacidad de conectar cognitivamente las intrusiones, por lo que contribuyen a aumentar las necesidades de tratamiento. El deterioro de la memoria limita la aplicación de tratamientos basados en la evidencia y, en conjunto, estos hallazgos exigen el desarrollo de protocolos de tratamiento específicos para trauma para mejorar la recuperación de los sobrevivientes a las ASFDA.

Ventromedial and insular cortical volume moderates the relationship between BDNF Val66Met and threat sensitivity.

While the BDNF Val66Met polymorphism has been linked to various trauma and anxiety - related psychiatric disorders, limited focus has been on the neural structures that might modulate its relationship with objective measures of threat sensitivity. Therefore, we assessed whether there was an interaction of Val66Met polymorphism with brain area volumes previously associated with anxiety and PTSD, such as the ventromedial prefrontal cortex (vmPFC), insular cortex (IC), and dorsal and ventral anterior cingulate cortices (dACC and vACC), in predicting fear-potentiated psychophysiological response in a clinical sample of Veterans. 110 participants engaged in a fear-potentiated acoustic startle paradigm and provided genetic and imaging data. Fear conditions included no, ambiguous, and high threat conditions (shock). Psychophysiological response measures included electromyogram (EMG), skin conductance response (SCR), and heart rate (HR). PTSD status, trauma history, and demographics were also assessed. There was an interaction of Met allele carrier status with vmPFC, IC, dACC, and vACC volumes for predicting SCR (p < 0.001 for all regions). However, only vmPFC and IC significantly moderated the relationship between Val66Met and psychophysiological response (SCR). The Val66met polymorphism may increase susceptibility to PTSD and anxiety disorders via an interaction with reduced vmPFC and IC volume. Future research should examine whether these relationships might be associated with a differential course of illness longitudinally or response to treatments.

Impulsivity as a multifactorial construct and its relationship to PTSD severity and threat sensitivity.

Changes to the DSM-5's conceptualization of posttraumatic stress disorder (PTSD) highlight the importance of impulsivity within the context of PTSD-related arousal dysregulation. While the relationship between PTSD and threat sensitivity is well defined, how they relate to impulsivity remains understudied. We examined the relationship between PTSD symptom severity, threat sensitivity, and impulsivity. 124 participants completed the PTSD Checklist (PCL-C) and the Barratt Impulsiveness Scale 11th ed (BIS-11). BIS-11 items were separated to define cognitive and behavioral impulsivity subdomains. A trauma-exposed subsample of 39 participants were also exposed to no, ambiguous, and high threat conditions in a threat-enhanced acoustic startle paradigm with psychophysiological response as the outcome variable. PTSD severity was significantly associated with greater overall impulsivity and behavioral impulsivity. Greater overall impulsivity and both cognitive and behavioral impulsivity subdomains were significantly associated with psychophysiological magnitudes across threat conditions in the traumatized subsample. Our results suggest PTSD severity may linked to behavioral impulsivity and both cognitive and behavioral impulsivity are associated with threat sensitivity and hyperarousal. Assessing impulsivity within the context of PTSD, particularly in terms of its cognitive and behavioral subdomains, may provide important, clinically relevant information.

Child abuse interacts with hippocampal and corpus callosum volume on psychophysiological response to startling auditory stimuli in a sample of veterans.

Child abuse (CA), which is linked to posttraumatic stress disorder (PTSD), has been associated with a reduction in both hippocampal and corpus callosum (CC) volume. However, few studies have explored these relationships on psychophysiological variables related to trauma exposure. Therefore, we assessed whether the interaction between CA and hippocampal and CC volume were associated with enhanced fear potentiated psychophysiological response patterns in a sample of Veterans. 147 Veteran participants who were part of a larger study of Gulf War Illness were exposed to startling sounds in no, ambiguous, and high threat conditions and also provided MRI data. The Clinician Administered PTSD Scale and Trauma History Questionnaire were used to measure PTSD and CA respectively. Psychophysiological response was measured by EMG, SCR, and heart rate. Repeated-measures mixed linear models were used to assess the significance of CA by neural structure interactions. CA interacted with both hippocampal and CC volume on psychophysiological response magnitudes, where participants with CA and smaller hippocampal volume had greater EMG (p < 0.01) and SCR (p < 0.05) magnitudes across trials and over threat conditions. Participants with CA and smaller CC volume had greater SCR magnitudes across trials and over threat conditions (p < 0.01). Hippocampal and genu volume mediated CA and psychophysiological response magnitude. CA may impact psychophysiological response via a reduction in hippocampal and CC volume. Volumetric reduction in these structures may indicate a neurofunctional, CA-related increase in threat sensitivity, which could portend increased PTSD susceptibility and adverse interpersonal and social consequences across the lifespan.

Association among anterior cingulate cortex volume, psychophysiological response, and PTSD diagnosis in a Veteran sample.

Posttraumatic stress disorder (PTSD) is associated with fear response system dysregulation. Research has shown that the anterior cingulate cortex (ACC) may modulate the fear response and that individuals with PTSD have abnormalities in ACC structure and functioning. Our objective was to assess whether ACC volume moderates the relationship between PTSD and fear-potentiated psychophysiological response in a sample of Gulf War Veterans. 142 Veteran participants who were associated with a larger study associated with Gulf War Illness were exposed to no threat, ambiguous threat, and high threat conditions in a fear conditioned startle response paradigm and also provided MRI imaging data. PTSD was assessed using the Clinician Administered PTSD Scale (CAPS). Decreased caudal ACC volume predicted greater psychophysiological responses with a slower habituation of psychophysiological magnitudes across trials (p < 0.001). PTSD diagnosis interacted significantly with both caudal and rostral ACC volumes on psychophysiological response magnitudes, where participants with PTSD and smaller rostral and caudal ACC volumes had greater psychophysiological magnitudes across trials (p < 0.05 and p < 0.001, respectively) and threat conditions (p < 0.05 and p < 0.005). Our results suggest that ACC volume may moderate both threat sensitivity and threat response via impaired habituation in individuals who have been exposed to traumatic events. More research is needed to assess whether ACC size and these associated response patterns are due to neurological processes resulting from trauma exposure or if they are indicative of a premorbid risk for PTSD subsequent to trauma exposure.

The interaction of BDNF Val66Met, PTSD, and child abuse on psychophysiological reactivity and HPA axis function in a sample of Gulf War Veterans.

INTRODUCTION: While the BDNF Val66Met polymorphism has been linked to various psychological disorders, limited focus has been on its relationship to posttraumatic stress disorder (PTSD) and early traumas such as child abuse. Therefore, we assessed whether Val66Met was associated with fear potentiated psychophysiological response and HPA axis dysfunction and whether PTSD status or child abuse history moderated these outcomes in a sample of Veterans. METHODS: 226 and 173 participants engaged in a fear potentiated acoustic startle paradigm and a dexamethasone suppression test (DST) respectively. Fear conditions included no, ambiguous, and high threat conditions. Psychophysiological response measures included electromyogram (EMG), skin conductance response (SCR), and heart rate. The Clinician Administered PTSD Scale (CAPS) and the Trauma History Questionnaire (THQ) were used to assess PTSD status and child abuse history respectively. RESULTS: Met allele carriers exhibited greater SCR magnitudes in the no and ambiguous threat conditions (p < 0.01 and p < 0.05 respectively). Met carriers with PTSD exhibited greater physiological response magnitudes in the ambiguous (SCR, p < 0.001) and high threat conditions (SCR and heart rate, both p ≤ 0.005). Met carrier survivors of child abuse exhibited blunted heart rate magnitudes in the high threat condition (p < 0.01). Met allele carries with PTSD also exhibited greater percent cortisol suppression (p < 0.005). LIMITATIONS: Limitations included small sample size and the cross-sectional nature of the data. CONCLUSIONS: The Val66met may impact PTSD susceptibility differentially via enhanced threat sensitivity and HPA axis dysregulation. Child abuse may moderate Val66Met's impact on threat reactivity. Future research should explore how neuronal mechanisms might mediate this risk.

The effects of early trauma and the FKBP5 gene on PTSD and the HPA axis in a clinical sample of Gulf War veterans.

Previous research indicates that interactions between FKBP5 single nucleotide polymorphisms (SNPs) and child abuse are associated with posttraumatic stress disorder (PTSD) in adulthood. We examined the relationship between the T-allele of the rs1360780 FKBP5 SNP and child abuse on PTSD and the HPA axis in a clinical sample of Gulf War veterans. Genotyping was completed on 266 veterans and 174 veterans additionally participated in a low dose dexamethasone suppression test (DST). The CAPS was used to determine PTSD status and the THQ was used to determine child abuse operationalized as either childhood physical or sexual abuse. Hierarchical regression models were used to assess FKBP5 × child abuse interactions on PTSD, basal cortisol levels, and post DST cortisol levels. The FKBP5 risk allele and child abuse were separately associated with PTSD diagnosis. The risk allele was also associated with significantly lower cortisol levels at baseline. However, no significant FKBP5 × child abuse interaction on PTSD diagnosis, basal cortisol levels, or greater cortisol suppression was observed. Our results suggest that FKBP5 may be a viable biomarker for PTSD. Nonetheless, further work will be required to reconcile our findings with previous reports of an FKBP5 × child abuse interaction on posttraumatic stress response.

The relationship between childhood abuse and violent victimization in homeless and marginally housed women: The role of dissociation as a potential mediator.

OBJECTIVE: Previous studies have established a link between childhood abuse and dissociation. Other work has shown childhood abuse increases the likelihood of violent victimization in adulthood. Although it has been posited that dissociation may mediate childhood abuse and adult violent victimization, research investigating this hypothesis is sparse, particularly for extremely vulnerable populations such as homeless and unstably housed individuals. investigated the relationship between childhood abuse and dissociation on violent victimization in a cohort of homeless and unstably housed women. We also assessed whether dissociation mediated childhood abuse and violent victimization in this sample. METHOD: Participants were asked at an initial assessment and a 6-month follow-up to report any physical or sexual violence experienced in the previous 6 months. Questionnaires recording history of specific types of childhood abuse, dissociation, and other factors were also recorded at the initial assessment. RESULTS: Hierarchical logistic regression models revealed that childhood sexual abuse (Odds ratio [OR] = 3.10, p < .01) and severe dissociation (OR = 1.99, p < .01) were significantly associated with recent physical violence, and childhood sexual abuse (OR = 3.88, p < .01) and dissociation (OR = 1.87, p < .05) were also associated with recent sexual violence. Dissociation mediated neither childhood abuse on recent physical violence or recent sexual violence. CONCLUSION: Developing approaches that effectively identify and treat dissociation as a part of an overall framework of trauma-informed care in homeless and unstably housed women may be an effective way to decrease future physical violence in this vulnerable population. (PsycINFO Database Record

Effects of FVB/NJ and C57Bl/6J strain backgrounds on mammary tumor phenotype in inducible nitric oxide synthase deficient mice.

The ability to genetically manipulate mice has led to rapid progress in our understanding of the roles of different gene products in human disease. Transgenic mice have often been created in the FVB/NJ (FVB) strain due to its high fecundity, while gene-targeted mice have been developed in the 129/SvJ-C57Bl/6J strains due to the capacity of 129/SvJ embryonic stem cells to facilitate germline transmission. Gene-targeted mice are commonly backcrossed into the C57Bl/6J (B6) background for comparison with existing data. Genetic modifiers have been shown to modulate mammary tumor latency in mouse models of breast cancer and it is commonly known that the FVB strain is susceptible to mammary tumors while the B6 strain is more resistant. Since gene-targeted mice in the B6 background are frequently bred into the polyomavirus middle T (PyMT) mouse model of breast cancer in the FVB strain, we have sought to understand the impact of the different genetic backgrounds on the resulting phenotype. We bred mice deficient in the inducible nitric oxide synthase (iNOS) until they were congenic in the PyMT model in the FVB and B6 strains. Our results reveal that the large difference in mean tumor latencies in the two backgrounds of 53 and 92 days respectively affect the ability to discern smaller differences in latency due to the Nos2 genetic mutation. Furthermore, the longer latency in the B6 strain enables a more detailed analysis of tumor formation indicating that individual tumor development is not stoichastic, but is initiated in the #1 glands and proceeds in early and late phases. NO production affects tumors that develop early suggesting an association of iNOS-induced NO with a more aggressive tumor phenotype, consistent with human clinical data positively correlating iNOS expression with breast cancer progression. An examination of lung metastases, which are significantly reduced in PyMT/iNOS-/- mice compared with PyMT/iNOS+/+ mice only in the B6 background, is concordant with these findings. Our data suggest that PyMT in the B6 background provides a useful model for the study of inflammation-induced breast cancer.