Childhood Trauma and COMT Genotype Interact to Increase Hippocampal Activation in Resilient Individuals

Both childhood trauma and a functional COMT genetic polymorphism have been associated with PTSD and depression; however, it is still unclear whether the two interact and how this interaction relates to long-term risk or resilience. Imaging and genotype data were collected on 73 highly traumatized women. DNA extracted from saliva was used to determine COMT genotype (Val/Val, n=38, Met carriers, n=35). Functional MRI data were collected during a Go/NoGo task to investigate the neurocircuitry underlying response inhibition. Self-report measures of adult and childhood trauma exposure, PTSD and depression symptom severity, and resilience were collected. Childhood trauma was found to interact with COMT genotype to impact inhibition-related hippocampal activation. In Met carriers, more childhood trauma was associated with decreased hippocampal activation, whereas in the Val/Val group childhood trauma was related to increased hippocampal activation. Second, hippocampal activation correlated negatively with PTSD and depression symptoms, and positively with trait resilience. Moreover, hippocampal activation mediated the relationship between childhood trauma and psychiatric risk or resilience in the Val/Val, but not in the Met-carrier group. These data reveal a potential mechanism by which childhood trauma and COMT genotype interact to increase risk for trauma-related psychopathology or resilience. Hippocampal recruitment during inhibition may improve the ability to use contextual information to guide behavior, thereby enhancing resilience in trauma-exposed individuals. This finding may contribute to early identification of individuals at risk, and suggests a mechanism that can be targeted in future studies aiming to prevent or limit negative outcomes

Episodic memory after trauma exposure: Medial temporal lobe function is positively related to re-experiencing and inversely related to negative affect symptoms

Hippocampal structure is particularly sensitive to trauma and other stressors. However, previous findings linking hippocampal function with trauma-related psychopathology have been mixed. Heterogeneity in psychological responses to trauma has not been considered with respect to hippocampal function and may contribute to mixed findings. To address these issues, we examined associations between data-driven symptom dimensions and episodic memory formation, a key function of the hippocampus, in a trauma-exposed sample. Symptom dimensions were defined using principal components analysis (PCA) in 3881 trauma-exposed African-American women recruited from primary care waiting rooms of a large urban hospital. Hippocampal and amygdala function were subsequently investigated in an fMRI study of episodic memory formation in a subset of 54 women. Participants viewed scenes with neutral, negative, and positive content during fMRI, and completed a delayed cued recall task. PCA analysis produced five symptom dimensions interpreted as reflecting negative affect, somatic symptoms, re-experiencing, hyper-arousal, and numbing. Re-experiencing was the only symptom type associated with hippocampal function, predicting increased memory encoding-related activation in the hippocampus as well as the amygdala. In contrast, the negative affect component predicted lower amygdala activation for subsequently recalled scenes, and lower functional coupling with other important memory-related regions including the precuneus, inferior frontal gyrus, and occipital cortex. Symptom dimensions were not related to hippocampal volume. The fMRI findings for re-experiencing versus negative affect parallel differences in behavioral memory phenomena in PTSD versus MDD, and highlight a need for more complex models of trauma-related pathology

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; β = 0.20; corrected P = .008) and anterior cingulate cortex (ACC; t274 = 2.56; β = 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; β = 0.21; corrected P = .001) and gray matter morphology of the ACC (cortical thickness: t273 = -2.29; β = -0.13; corrected P = .02; surface area: t273 = 2.53; β = 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: β = -0.17; standard error = 0.06, t= -2.28; P = .007; at 1 SD above the mean: β = -0.28; standard error = 0.08; t = -3.35; P \u3c .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

Individual prediction of psychotherapy outcome in posttraumatic stress disorder using neuroimaging data

Trauma-focused psychotherapy is the first-line treatment for posttraumatic stress disorder (PTSD) but 30–50% of patients do not benefit sufficiently. We investigated whether structural and resting-state functional magnetic resonance imaging (MRI/rs-fMRI) data could distinguish between treatment responders and non-responders on the group and individual level. Forty-four male veterans with PTSD underwent baseline scanning followed by trauma-focused psychotherapy. Voxel-wise gray matter volumes were extracted from the structural MRI data and resting-state networks (RSNs) were calculated from rs-fMRI data using independent component analysis. Data were used to detect differences between responders and non-responders on the group level using permutation testing, and the single-subject level using Gaussian process classification with cross-validation. A RSN centered on the bilateral superior frontal gyrus differed between responders and non-responder groups (PFWE < 0.05) while a RSN centered on the pre-supplementary motor area distinguished between responders and non-responders on an individual-level with 81.4% accuracy (P < 0.001, 84.8% sensitivity, 78% specificity and AUC of 0.93). No significant single-subject classification or group differences were observed for gray matter volume. This proof-of-concept study demonstrates the feasibility of using rs-fMRI to develop neuroimaging biomarkers for treatment response, which could enable personalized treatment of patients with PTSD

Individual prediction of psychotherapy outcome in posttraumatic stress disorder using neuroimaging data

Trauma-focused psychotherapy is the first-line treatment for posttraumatic stress disorder (PTSD) but 30–50% of patients do not benefit sufficiently. We investigated whether structural and resting-state functional magnetic resonance imaging (MRI/rs-fMRI) data could distinguish between treatment responders and non-responders on the group and individual level. Forty-four male veterans with PTSD underwent baseline scanning followed by trauma-focused psychotherapy. Voxel-wise gray matter volumes were extracted from the structural MRI data and resting-state networks (RSNs) were calculated from rs-fMRI data using independent component analysis. Data were used to detect differences between responders and non-responders on the group level using permutation testing, and the single-subject level using Gaussian process classification with cross-validation. A RSN centered on the bilateral superior frontal gyrus differed between responders and non-responder groups (PFWE < 0.05) while a RSN centered on the pre-supplementary motor area distinguished between responders and non-responders on an individual-level with 81.4% accuracy (P < 0.001, 84.8% sensitivity, 78% specificity and AUC of 0.93). No significant single-subject classification or group differences were observed for gray matter volume. This proof-of-concept study demonstrates the feasibility of using rs-fMRI to develop neuroimaging biomarkers for treatment response, which could enable personalized treatment of patients with PTSD

fMRI data of PTSD patients with and without comorbid Major Depressive Disorder

<p>Patients were male veterans recruited from the Military Mental Health Care Center, the Netherlands. MDD_diagnosis = current depressive episode (1=yes, 0=no), CAPS_TOTAL_B = total scores from CAPS cluster B symptoms, CAPS_TOTAL_C = total scores from CAPS cluster C symptoms, CAPS_TOTAL_D = total scores from CAPS cluster D symptoms, MASQ_NA = negative affect scores, MASQ_PA = positive affect scores, MASQ_SA = somatic anxiety scores, RSFC=resting state functional connectivity, Hip = hippocampus, ACC= anterior cingulate cortex, sg= subgenual, Thal = thalamus, SSRI = current use of selective serotonin reuptake inhibitor (0=no, 1=yes), BENZO = current use of benzodiazepines (0=no, 1=yes), SARI = current use of serotonin antagonist and reuptake inhibitor (0=no, 1=yes), ISCED = international standard classification of education. Handedness presents right-handedness as 0, left-handedness as 2 and ambidexterity as 3. The code 9999 represents a missing value.</p

Neural correlates and structural markers of emotion dysregulation in traumatized civilians

Abstract Emotion dysregulation (ED) reflects deficits in understanding and managing negative emotions and may serve as a transdiagnostic mechanism of risk for trauma-related psychiatric disorders. Therefore, understanding neurobiological substrates of ED in traumatized individuals is critical. The present study examined associations between ED and baseline structural differences and patterns of functional activity during an emotional task in a sample of African American women (n = 136) recruited from an urban hospital. Participants engaged in a structural magnetic resonance imaging (MRI) session. A subsample (n = 92) also viewed emotional face stimuli during functional MRI. ED was related to greater dorsal anterior cingulate cortex (dACC) surface area (Pcorr < 0.05) and increased dorsomedial prefrontal cortex (dmPFC) and ventromedial PFC activation to fearful stimuli (Pcorr < 0.05), independent of the trauma and psychiatric symptoms. DMPFC activation was also associated with posttraumatic stress disorder and depression symptoms. Mediation analyses showed a significant mediation effect of ED on the relation between dmPFC activation and psychiatric symptoms. These findings are important since dACC and dmPFC play central roles in fear expression and attention to emotional stimuli. Future longitudinal research is needed to help solidify a model of risk for how such neural substrates may be impacted by traumatic experiences to create ED