Prior differences in previous trauma exposure primarily drive the observed racial/ethnic differences in posttrauma depression and anxiety following a recent trauma.

BACKGROUND: Racial and ethnic groups in the USA differ in the prevalence of posttraumatic stress disorder (PTSD). Recent research however has not observed consistent racial/ethnic differences in posttraumatic stress in the early aftermath of trauma, suggesting that such differences in chronic PTSD rates may be related to differences in recovery over time. METHODS: As part of the multisite, longitudinal AURORA study, we investigated racial/ethnic differences in PTSD and related outcomes within 3 months after trauma. Participants (n = 930) were recruited from emergency departments across the USA and provided periodic (2 weeks, 8 weeks, and 3 months after trauma) self-report assessments of PTSD, depression, dissociation, anxiety, and resilience. Linear models were completed to investigate racial/ethnic differences in posttraumatic dysfunction with subsequent follow-up models assessing potential effects of prior life stressors. RESULTS: Racial/ethnic groups did not differ in symptoms over time; however, Black participants showed reduced posttraumatic depression and anxiety symptoms overall compared to Hispanic participants and White participants. Racial/ethnic differences were not attenuated after accounting for differences in sociodemographic factors. However, racial/ethnic differences in depression and anxiety were no longer significant after accounting for greater prior trauma exposure and childhood emotional abuse in White participants. CONCLUSIONS: The present findings suggest prior differences in previous trauma exposure partially mediate the observed racial/ethnic differences in posttraumatic depression and anxiety symptoms following a recent trauma. Our findings further demonstrate that racial/ethnic groups show similar rates of symptom recovery over time. Future work utilizing longer time-scale data is needed to elucidate potential racial/ethnic differences in long-term symptom trajectories.

The Role of the Endocannabinoids 2-AG and Anandamide in Clinical Symptoms and Treatment Outcome in Veterans with PTSD.

Background: Although current treatments for Post-Traumatic Stress Disorder (PTSD) in war veterans are effective, unfortunately 30-50% still do not benefit from these treatments. Trauma-focused therapies, eg exposure therapy, are primarily based on extinction processes in which the endocannabinoid system (ECS) plays a significant role. Therefore, it can be hypothesized that poor treatment response on trauma-focused therapy due to extinction deficits may be associated with a poorly functioning ECS. The present study examined whether the endocannabinoids anandamide (AEA) and 2-arachidonylglycerol (2-AG) are associated with post-treatment symptom reduction. Methods: Blood plasma levels of AEA and 2-AG were determined in war veterans with a PTSD diagnosis (n = 54) and combat controls (n = 26) before and after a 6-8 month interval. During this period veterans with PTSD received trauma-focused therapy (eg cognitive behavioral therapy with exposure or eye-movement desensitization and reprocessing). Clinical symptoms were assessed before and after therapy with the Clinician Administered PTSD Scale (CAPS), State-Trait Anxiety Inventory (STAI) and Mood and Anxiety Symptom Questionnaire (MASQ). Results: Regression analysis demonstrated that pretreatment endocannabinoid levels were not predictive of PTSD symptom reduction. Additionally, baseline endocannabinoid levels did not differ between either PTSD and combat controls or between combat controls, treatment responders, and non-responders. Only cortisol levels significantly decreased over time from pre- to posttreatment (p = .041). Endocannabinoid levels were significantly lower in individuals who reported cannabis use during their lifetime, independent of PTSD diagnosis. Furthermore, correlation analysis revealed that pretreatment 2-AG levels in PTSD were positively correlated with anxious arousal (r = .354, p = .015) and negatively with avoidance symptoms (r = -.271, p = .048). Both posttreatment AEA and 2-AG were positively correlated with trait anxiety (AEA r = .459, p = .003; 2-AG r = .423, p = .006), anxious arousal (AEA r = .351, p = .024; 2-AG r = .311, p = .048) and general distress depression symptoms (AEA r = .414, p = .007; 2-AG r = .374, p = .016). Conclusion: Since endocannabinoids are mainly generated 'on demand', future work could benefit by investigating endocannabinoid circulation under both baseline and stressful conditions. In line with previous research cannabis use was associated with lower endocannabinoid levels. The correlation analysis between pre- and posttreatment endocannabinoid levels and pre- and posttreatment clinical symptomatology were exploratory analysis and should be replicated in future research.

Community Violence Exposure is Associated with Hippocampus-Insula Resting State Functional Connectivity in Urban Youth.

Our previous work has linked childhood violence exposure in Black youth to functional changes in the hippocampus, a brain region sensitive to stress. However, different contexts of violence exposure (e.g., community, home, school) may have differential effects on circuitry. We investigated the unique effect of community violence in predicting resting-state functional connectivity (rsFC) in the hippocampus. Fifty-two (26F) violence-exposed Black youth ages 8-15 performed resting-state functional neuroimaging scans while looking at a fixation cross for seven minutes with eyes open. Seed-based analyses were conducted to examine the association between total violence exposure and rsFC of the hippocampus to the whole brain. Follow-up hierarchical regression analysis were performed to specifically investigate community violence. Violence exposure was associated with higher hippocampus rsFC with a core node of the Default Mode Network (i.e., posterior cingulate cortex) and lower hippocampal rsFC with a core node of the Salience Network (i.e., insula). Community violence uniquely associated with lower hippocampus-insula rsFC, after controlling for home and school violence, sex and age. Age-related decreases in hippocampus-insula rsFC were also present in youth with lower violence exposure, but not in youth with higher violence exposure. This is one of the first studies to investigate the unique impact of community violence, above home and school violence, on threat circuitry. Our data suggest functional alterations in the hippocampus in violence-exposed youth, and that violence in the community may be a more salient form of threat exposure compared to other forms of violence experienced by youth.

Defining focal brain stimulation targets for PTSD using neuroimaging.

INTRODUCTION: Focal brain stimulation has potential as a treatment for posttraumatic stress disorder (PTSD). In this review, we aim to inform selection of focal brain stimulation targets for treating PTSD by examining studies of the functional neuroanatomy of PTSD and treatment response. We first briefly review data on brain stimulation interventions for PTSD. Although published data suggest good efficacy overall, the neurobiological rationale for each stimulation target is not always clear. METHODS: Therefore, we assess pre- and post-treatment (predominantly psychotherapy) functional neuroimaging studies in PTSD to determine which brain changes seem critical to treatment response. Results of these studies are presented within a previously proposed functional neural systems model of PTSD. RESULTS: While not completely consistent, research suggests that downregulating the fear learning and threat and salience detection circuits (i.e., amygdala, dorsal anterior cingulate cortex and insula) and upregulating the emotion regulation and executive function and contextual processing circuits (i.e., prefrontal cortical regions and hippocampus) may mediate PTSD treatment response. CONCLUSION: This literature review provides some justification for current focal brain stimulation targets. However, the examination of treatment effects on neural networks is limited, and studies that include the stimulation targets are lacking. Further, additional targets, such as the cingulate, medial prefrontal cortex, and inferior parietal lobe, may also be worth investigation, especially when considering how to achieve network level changes. Additional research combining PTSD treatment with functional neuroimaging will help move the field forward by identifying and validating novel targets, providing better rationale for specific treatment parameters and personalizing treatment for PTSD.

Pre-treatment cortisol awakening response predicts symptom reduction in posttraumatic stress disorder after treatment.

Dysfunction of the HPA-axis has frequently been found in the aftermath of trauma exposure with or without PTSD. Decreasing HPA-axis reactivity to different stress cues has been reported during PTSD treatment. The cortisol awakening response (CARi) is a well-validated, standardized measure of HPA-axis reactivity which can be easily acquired in the clinical setting. Whether CARi changes over time in traumatized individuals are specific to PTSD treatment is unknown. Furthermore, a possible role for the baseline CARi in predicting symptom reduction after treatment in PTSD has not been examined before. To answer these questions, a cohort study was conducted in which the awakening cortisol was measured in both PTSD (N=41) and non-PTSD (N=25) combat-exposed male subjects. Measurements took place at inclusion and 6-8 months after inclusion for both the PTSD and the non-PTSD group. During the 6-8 months interval, PTSD patients received trauma-focused focused psychotherapy, whereas non-PTSD patients received no treatment. We found a decrease in the CARi over time in both groups, suggesting it was not specific to PTSD or the effect of treatment. Therefore, caution is warranted when attributing diminished HPA-axis reactivity over time to effects of PTSD treatment. Second, CARi prior to treatment predicted PTSD symptom reduction (CAPS score change) after treatment, and accounted for 10% of the variance, even when adjusted for changes in depressive symptoms and medication use during the study period. A putative role emerges for CARi as a predictive biomarker of symptom reduction in male individuals with combat-related PTSD.

Choosing the polarity of the phase-encoding direction in diffusion MRI: Does it matter for group analysis?

Notorious for degrading diffusion MRI data quality are so-called susceptibility-induced off-resonance fields, which cause non-linear geometric image deformations. While acquiring additional data to correct for these distortions alleviates the adverse effects of this artifact drastically - e.g., by reversing the polarity of the phase-encoding (PE) direction - this strategy is often not an option due to scan time constraints. Especially in a clinical context, where patient comfort and safety are of paramount importance, acquisition specifications are preferred that minimize scan time, typically resulting in data obtained with only one PE direction. In this work, we investigated whether choosing a different polarity of the PE direction would affect the outcome of a specific clinical research study. To address this methodological question, fractional anisotropy (FA) estimates of FreeSurfer brain regions were obtained in civilian and combat controls, remitted posttraumatic stress disorder (PTSD) patients, and persistent PTSD patients before and after trauma-focused therapy and were compared between diffusion MRI data sets acquired with different polarities of the PE direction (posterior-to-anterior, PA and anterior-to-posterior, AP). Our results demonstrate that regional FA estimates differ on average in the order of 5% between AP and PA PE data. In addition, when comparing FA estimates between different subject groups for specific cingulum subdivisions, the conclusions for AP and PA PE data were not in agreement. These findings increase our understanding of how one of the most pronounced data artifacts in diffusion MRI can impact group analyses and should encourage users to be more cautious when interpreting and reporting study outcomes derived from data acquired along a single PE direction.

Functional network topology associated with posttraumatic stress disorder in veterans.

Posttraumatic stress disorder (PTSD) is a disabling disorder associated with resting state functional connectivity alterations. However, whether specific brain regions are altered in PTSD or whether the whole brain network organization differs remains unclear. PTSD can be treated with trauma-focused therapy, although only half of the patients recover after treatment. In order to better understand PTSD psychopathology our aim was to study resting state networks in PTSD before and after treatment. Resting state functional magnetic resonance images were obtained from veterans with PTSD (n = 50) and controls (combat and civilian controls; n = 54) to explore which network topology properties (degree and clustering coefficient) of which brain regions are associated with PTSD. Then, PTSD-associated brain regions were investigated before and after treatment. PTSD patients were subdivided in persistent (n = 22) and remitted PTSD patients (n = 17), and compared with combat controls (n = 22), who were also reassessed. Prior to treatment associations with PTSD were found for the degree of orbitofrontal, and temporoparietal brain regions, and for the clustering coefficient of the anterior cingulate cortex. No significant effects were found over the course of treatment. Our results are in line with previous resting state studies, showing resting state connectivity alterations in the salience network and default mode network in PTSD, and also highlight the importance of other brain regions. However, network metrics do not seem to change over the course of treatment. This study contributes to a better understanding of the psychopathology of PTSD.

Smaller hippocampal volume as a vulnerability factor for the persistence of post-traumatic stress disorder.

BACKGROUND: Smaller hippocampal volume has often been observed in patients with post-traumatic stress disorder (PTSD). However, there is no consensus whether this is a result of stress/trauma exposure, or constitutes a vulnerability factor for the development of PTSD. Second, it is unclear whether hippocampal volume normalizes with successful treatment of PTSD, or whether a smaller hippocampus is a risk factor for the persistence of PTSD. METHOD: Magnetic resonance imaging (MRI) scans and clinical interviews were collected from 47 war veterans with PTSD, 25 healthy war veterans (combat controls) and 25 healthy non-military controls. All veterans were scanned a second time with a 6- to 8-month interval, during which PTSD patients received trauma-focused therapy. Based on post-treatment PTSD symptoms, patients were divided into a PTSD group who was in remission (n = 22) and a group in whom PTSD symptoms persisted (n = 22). MRI data were analysed with Freesurfer. RESULTS: Smaller left hippocampal volume was observed in PTSD patients compared with both control groups. Hippocampal volume of the combat controls did not differ from healthy controls. Second, pre- and post-treatment analyses of the PTSD patients and combat controls revealed reduced (left) hippocampal volume only in the persistent patients at both time points. Importantly, hippocampal volume did not change with treatment. CONCLUSIONS: Our findings suggest that a smaller (left) hippocampus is not the result of stress/trauma exposure. Furthermore, hippocampal volume does not increase with successful treatment. Instead, we demonstrate for the first time that a smaller (left) hippocampus constitutes a risk factor for the persistence of PTSD.

Neural correlates of trauma-unrelated emotional processing in war veterans with PTSD.

BACKGROUND: Post-traumatic stress disorder (PTSD) is thought to be characterized by general heightened amygdala activation. However, this hypothesis is mainly based on specific studies presenting fear or trauma-related stimuli, hence, a thorough investigation of trauma-unrelated emotional processing in PTSD is needed. METHODS: In this study, 31 male medication-naive veterans with PTSD, 28 male control veterans (combat controls; CC) and 25 non-military men (healthy controls; HC) were included. Participants underwent functional MRI while trauma-unrelated neutral, negative and positive emotional pictures were presented. In addition to the group analyses, PTSD patients with and without major depressive disorder (MDD) were compared. RESULTS: All groups showed an increased amygdala response to negative and positive contrasts, but amygdala activation did not differ between groups. However, a heightened dorsal anterior cingulate cortex (dACC) response for negative contrasts was observed in PTSD patients compared to HC. The medial superior frontal gyrus was deactivated in the negative contrast in HC, but not in veterans. PTSD+MDD patients showed decreased subgenual ACC (sgACC) activation to all pictures compared to PTSD-MDD. CONCLUSION: Our findings do not support the hypothesis that increased amygdala activation in PTSD generalizes to trauma-unrelated emotional processing. Instead, the increased dACC response found in PTSD patients implicates an attentional bias that extends to trauma-unrelated negative stimuli. Only HC showed decreased medial superior frontal gyrus activation. Finally, decreased sgACC activation was related to MDD status within the PTSD group.