Intrusive Traumatic Re-Experiencing Domain (ITRED) – Functional Connectivity Feature Classification by the ENIGMA PTSD Consortium

Background Intrusive Traumatic Re-Experiencing Domain (ITRED) was recently introduced as a novel perspective on posttraumatic psychopathology, proposing to focus research of posttraumatic stress disorder (PTSD) on the unique symptoms of intrusive and involuntary re-experiencing of the trauma, namely, intrusive memories, nightmares, and flashbacks. The aim of the present study was to explore ITRED from a neural network connectivity perspective. Methods Data was collected from nine sites taking part in the ENIGMA-PTSD Consortium (n=584) and included itemized PTSD symptoms scores and resting-state functional connectivity (rsFC) data. We assessed the utility of rsFC in classifying PTSD, ITRED-only (no PTSD diagnosis), and Trauma-exposed (TE)-only (no PTSD or ITRED) groups using a machine learning approach, examining well-known networks implicated in PTSD. Random forest classification model was built on a training set using cross-validation (CV), and the averaged CV model performance for classification was evaluated using area-under-the-curve (AUC). The model was tested using a fully independent portion of the data (test dataset), and the test AUC was evaluated. Results RsFC signatures differentiated TE-only participants from PTSD and from ITRED-only participants at about 60% accuracy. Conversely, rsFC signatures did not differentiate PTSD from ITRED-only individuals (45% accuracy). Common features differentiating TE-only participants from PTSD and from ITRED-only participants mainly involved default mode network-related pathways. Some unique features, such as connectivity within the frontal-parietal network, differentiated TE-only participants from one group (PTSD or ITRED-only), but to a lesser extent from the other. Conclusion Neural network connectivity supports ITRED as a novel neurobiologically-based approach to classifying post-trauma psychopathology

Intranasal Oxytocin Administration Dampens Amygdala Reactivity towards Emotional Faces in Male and Female PTSD Patients

Post-traumatic stress disorder (PTSD) is a disabling psychiatric disorder. As a substantial part of PTSD patients responds poorly to currently available psychotherapies, pharmacological interventions boosting treatment response are needed. Because of its anxiolytic and pro-social properties, the neuropeptide oxytocin (OT) has been proposed as promising strategy for treatment augmentation in PTSD. As a first step to investigate the therapeutic potential of OT in PTSD, we conducted a double-blind, placebo-controlled, cross-over functional MRI study examining OT administration effects (40 IU) on amygdala reactivity toward emotional faces in unmedicated male and female police officers with (n=37, 21 males) and without (n=40, 20 males) PTSD. Trauma-exposed controls were matched to PTSD patients based on age, sex, years of service and educational level. Under placebo, the expected valence-dependent amygdala reactivity (ie, greater activity toward fearful-angry faces compared with happy-neutral faces) was absent in PTSD patients. OT administration dampened amygdala reactivity toward all emotional faces in male and female PTSD patients, but enhanced amygdala reactivity in healthy male and female trauma-exposed controls, independent of sex and stimulus valence. In PTSD patients, greater anxiety prior to scanning and amygdala reactivity during the placebo session were associated with greater reduction of amygdala reactivity after OT administration. Taken together, our results indicate presumably beneficial neurobiological effects of OT administration in male and female PTSD patients. Future studies should investigate OT administration in clinical settings to fully appreciate its therapeutic potentia

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