Faculty Bibliography

IMPORTANCE/UNASSIGNED:The weak link between subjective symptom-based diagnostics for posttraumatic psychopathology and objective neurobiological indices hinders the development of effective personalized treatments. OBJECTIVE/UNASSIGNED:To identify early neural networks associated with posttraumatic stress disorder (PTSD) development among recent trauma survivors. DESIGN, SETTING, AND PARTICIPANTS/UNASSIGNED:This prognostic study used data from the Neurobehavioral Moderators of Posttraumatic Disease Trajectories (NMPTDT) large-scale longitudinal neuroimaging dataset of recent trauma survivors. The NMPTDT study was conducted from January 20, 2015, to March 11, 2020, and included adult civilians who were admitted to a general hospital emergency department in Israel and screened for early PTSD symptoms indicative of chronic PTSD risk. Enrolled participants completed comprehensive clinical assessments and functional magnetic resonance imaging (fMRI) scans at 1, 6, and 14 months post trauma. Data were analyzed from September 2023 to March 2024. EXPOSURE/UNASSIGNED:Traumatic events included motor vehicle incidents, physical assaults, robberies, hostilities, electric shocks, fires, drownings, work accidents, terror attacks, or large-scale disasters. MAIN OUTCOMES AND MEASURES/UNASSIGNED:Connectome-based predictive modeling (CPM), a whole-brain machine learning approach, was applied to resting-state and task-based fMRI data collected at 1 month post trauma. The primary outcome measure was PTSD symptom severity across the 3 time points, assessed with the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5). Secondary outcomes included Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) (DSM-5) PTSD symptom clusters (intrusion, avoidance, negative alterations in mood and cognition, hyperarousal). RESULTS/UNASSIGNED:A total of 162 recent trauma survivors (mean [SD] age, 33.9 [11.5] years; 80 women [49.4%] and 82 men [50.6%]) were included at 1 month post trauma. Follow-up assessments were completed by 136 survivors (84.0%) at 6 months and by 133 survivors (82.1%) at 14 months post trauma. Among the 162 recent trauma survivors, CPM significantly predicted PTSD severity at 1 month (ρ = 0.18, P < .001) and 14 months (ρ = 0.24, P < .001) post trauma, but not at 6 months post trauma (ρ = 0.03, P = .39). The most predictive edges at 1 month included connections within and between the anterior default mode, motor sensory, and salience networks. These networks, with the additional contribution of the central executive and visual networks, were predictive of symptoms at 14 months. CPM predicted avoidance and negative alterations in mood and cognition at 1 month, but it predicted intrusion and hyperarousal symptoms at 14 months. CONCLUSIONS AND RELEVANCE/UNASSIGNED:In this prognostic study of recent trauma survivors, individual differences in large-scale neural networks shortly after trauma were associated with variability in PTSD symptom trajectories over the first year following trauma exposure. These findings suggest that CPM may identify potential targets for interventions.

At the 39th meeting of the International Society of Traumatic Stress Studies, four leading scientists and clinicians were invited to reflect on their careers, focusing on the biological mechanisms and markers of traumatic stress. Dr. Raul Andero has contributed to understanding how stress alters memory networks in the brain, influencing the development of novel treatments. Dr. Tanja Jovanovic has pioneered the measurement and mechanistic understanding of fear learning, bridging basic and clinical research. Dr. Murray B. Stein has scaled up clinical and lab observations to large populations, refining the field's understanding of traumatic stress. Dr. Arieh Y Shalev has shaped the definition of traumatic stress, pioneering the longitudinal investigation of stress and integrating advanced computational methods to identify individuals at risk. These panelists were asked to reflect on their initial problems, ambitions, concerns, and unexpected challenges, as well as the influence of their work, on new research trajectories. Their insights provide valuable lessons about the process and content of their work, and their pioneering efforts have significantly advanced our understanding of the biological mechanisms and markers of traumatic stress.

The recent worldwide surge of warfare and hostilities exposes increasingly large numbers of individuals to traumatic events, placing them at risk of developing posttraumatic stress disorder (PTSD) and challenging both clinicians and service delivery systems. This overview summarizes and updates the core knowledge of the genetic, molecular, and neural circuit features of the neurobiology of PTSD and advances in evidence-based psychotherapy, pharmacotherapy, neuromodulation, and digital treatments. While the complexity of the neurobiology and the biological and clinical heterogeneity of PTSD have challenged clinicians and researchers, there is an emerging consensus concerning the underlying mechanisms and approaches to diagnosis, treatment, and prevention of PTSD. This update addresses PTSD diagnosis, prevalence, course, risk factors, neurobiological mechanisms, current standard of care, and innovations in next-generation treatment and prevention strategies. It provides a comprehensive summary and concludes with areas of research for integrating advances in the neurobiology of the disorder with novel treatment and prevention targets.

BACKGROUND:Posttraumatic Stress Disorder (PTSD) has been associated with altered emotion processing and modulation in specific brain regions, i.e. amygdala, insula, medial prefrontal and anterior cingulate cortices. Functional alterations in these regions, recorded shortly after trauma exposure, may predict changes in PTSD symptoms. METHODS:Survivors (N=104) of a traumatic event, predominantly a motor vehicle accident, were included. Functional magnetic resonance imaging was used to assess brain activation one, six and 14 months after trauma exposure (T1, T2 and T3, respectively). Participants performed the Shifted Attention Emotional Appraisal Task (SEAT), which probes three affective processes: Implicit emotional processing (of emotional faces), emotion modulation by attention shifting (away from these faces), and emotion modulation by appraisal (of the participants' own emotional response to these faces). We defined regions-of-interest (ROIs) based on task-related activations, extracted beta-weights from these ROIs and submitted them to series of analyses to examine relationships between neural activation and PTSD severity over the three timepoints. RESULTS:At T1, a regression model containing activations in left dorsolateral prefrontal cortex, bilateral inferior frontal gyrus (IFG) and medial prefrontal cortex during emotion modulation by appraisal significantly predicted change in PTSD symptoms. Specifically, greater right IFG activation at T1 was associated with greater reduction in symptom severity (T1-T3). Exploratory analysis also found that activation of right IFG increased from T1 to T3. CONCLUSIONS:The results suggest that greater early activation during emotion appraisal in the right IFG, a region previously linked to cognitive control in PTSD, predicts recovery from post-trauma PTSD symptoms.

OBJECTIVE/UNASSIGNED:The weak link between subjective symptom-based diagnostic methods for posttraumatic psychopathology and objectively measured neurobiological indices forms a barrier to the development of effective personalized treatments. To overcome this problem, recent studies have aimed to stratify psychiatric disorders by identifying consistent subgroups based on objective neural markers. Along these lines, a promising 2021 study by Stevens et al. identified distinct brain-based biotypes associated with different longitudinal patterns of posttraumatic symptoms. Here, the authors conducted a conceptual nonexact replication of that study using a comparable data set from a multimodal longitudinal study of recent trauma survivors. METHODS/UNASSIGNED:A total of 130 participants (mean age, 33.61 years, SD=11.21; 48% women) admitted to a general hospital emergency department following trauma exposure underwent demographic, clinical, and neuroimaging assessments 1, 6, and 14 months after trauma. All analyses followed the pipeline outlined in the original study and were conducted in collaboration with its authors. RESULTS/UNASSIGNED:Task-based functional MRI conducted 1 month posttrauma was used to identify four clusters of individuals based on profiles of neural activity reflecting threat and reward reactivity. These clusters were not identical to the previously identified brain-based biotypes and were not associated with prospective symptoms of posttraumatic psychopathology. CONCLUSIONS/UNASSIGNED:Overall, these findings suggest that the original brain-based biotypes of trauma resilience and psychopathology may not generalize to other populations. Thus, caution is warranted when attempting to define subtypes of psychiatric vulnerability using neural indices before treatment implications can be fully realized. Additional replication studies are needed to identify more stable and generalizable neuroimaging-based biotypes of posttraumatic psychopathology.

The hippocampus and the amygdala play a central role in post-traumatic stress disorder (PTSD) pathogenesis. While alternations in volumes of both regions have been consistently observed in individuals with PTSD, it remains unknown whether these reflect pre-trauma vulnerability traits or acquired post-trauma consequences of the disorder. Here, we conducted a longitudinal panel study of adult civilian trauma survivors admitted to a general hospital emergency department (ED). One hundred eligible participants (mean age = 32.97 ± 10.97, n = 56 females) completed both clinical interviews and structural MRI scans at 1-, 6-, and 14-months after ED admission (alias T1, T2, and T3). While all participants met PTSD diagnosis at T1, only n = 29 still met PTSD diagnosis at T3 (a "non-Remission" Group), while n = 71 did not (a "Remission" Group). Bayesian multilevel modeling analysis showed robust evidence for smaller right hippocampus volume (P+ of ~0.014) and moderate evidence for larger left amygdala volume (P+ of ~0.870) at T1 in the "non-Remission" group, compared to the "Remission" group. Subregion analysis further demonstrated robust evidence for smaller volume in the subiculum and right CA1 hippocampal subregions (P+ of ~0.021-0.046) in the "non-Remission" group. No time-dependent volumetric changes (T1 to T2 to T3) were observed across all participants or between groups. Results support the "vulnerability trait" hypothesis, suggesting that lower initial volumes of specific hippocampus subregions are associated with non-remitting PTSD. The stable volume of all hippocampal and amygdala subregions does not support the idea of consequential, progressive, stress-related atrophy during the first critical year following trauma exposure.

Background: Reduced volume of the hippocampus (HC) has been repeatedly documented in Post-traumatic Stress Disorder (PTSD) patients, in whom it can represent either pre-traumatic vulnerability trait or post-exposure decay. Longitudinal brain volumetric studies of long-enough duration, proper timing, and reasonable attrition can inform that question. Here, we aimed to examine whether HC volume early after trauma is associated with the development of chronic PTSD, and whether there are time-dependent changes in HC volume during the first 14-months post-trauma.
Method(s): One hundred adult civilians, consecutively admitted to a medical center's emergency department following traumatic events, were screened for PTSD and underwent MRI scans at 1-, 6-, and 14-months post-trauma exposure (T1, T2, and T3, respectively). All participants met PTSD diagnosis at T1, as determined by a structured clinical interview using the Clinician-Administered PTSD Scale (CAPS). Cortical reconstruction and volumetric segmentation were performed using the FreeSurfer v7.1.0 image analysis suite.
Result(s): Out of the n=100 participants with PTSD at T1, n=29 participants still met PTSD diagnosis at T3 ('Persistent PTSD' group), while the other n=71 recovered by T3 ('Recovery' group). Bayesian multilevel (BML) analysis at T1 showed strong evidence for smaller right (but not left) HC volume in the 'Persistent PTSD' group (P+ = 0.014) compared to the 'Recovery' group. BML analysis examining change over time (T1, T2, and T3) showed no evidence for Time-by-Group interactions (right-HC: P+ = 0.406, left HC: P+ = 0.456).
Conclusion(s): HC volume remains stable among survivors of single traumatic events during the first 14-months following trauma exposure, whether they recover or develop chronic PTSD. A smaller initial volume of the right HC among the 'Persistent PTSD' group supports the above-mentioned 'vulnerability trait' hypothesis. Supported By: R01-MH-103287 from the National Institute of Mental Health (NIMH) Keywords: PT

Background: Post-traumatic stress disorder (PTSD) has been associated with neural alterations within emotion processing and modulation regions. Neurobiological processes following a traumatic event may predict either the recovery from or development of PTSD symptoms. We conducted this longitudinal study to understand the association between evolving PTSD symptoms and the neural processes among recent trauma survivors Methods: Ninety-eight trauma survivors (43 male; mean age (SD)= 33.36 (11.26) years) admitted to a general hospital emergency room following traumatic incidents were included. Functional magnetic resonance imaging (fMRI) was used to assess brain activation during the Shifted Attention Emotional Appraisal Task (SEAT) within 30 days (T1) following the trauma. We used CAPS-5 to assess symptoms severity at T1 (n=98), T2 (six months; n=82) and T3 (14 months; n=84) timepoints following the trauma.
Result(s): Neural activations during task conditions followed expected patterns. Specifically, we found activation of the bilateral insula and dACC and deactivation of bilateral dlPFC during implicit emotion processing; activation of bilateral dlPFC and deactivation of bilateral amygdala during emotion modulation by attention shifting; and activation of dlPFC, mPFC and bilateral IFG during emotion modulation by appraisal (all p<.050, FWE-corrected). During appraisal, combined activations in all five ROIs predicted change in symptoms (T1-T3), with a significant contribution of right IFG (all p<.050). There were no associations between other ROIs and other task conditions and CAPS.
Conclusion(s): These findings suggest that neural activation during emotion modulation within one month after the trauma could be used to predict PTSD symptom development over a 14-month period. (SA and JS: Equal contribution). Supported By: R01-MH-103287 Keywords: PTSD, Functional Neuroimaging, Implicit Emotion Processing, Emotion Modulation by Attention Shifting, Emotion Modulation by Appraisal
Copyright

Post-traumatic stress disorder (PTSD) is a protracted and debilitating consequence of traumatic events. Identifying early predictors of PTSD can inform the disorder's risk stratification and prevention. We used advanced computational models to evaluate the contribution of early neurocognitive performance measures to the accuracy of predicting chronic PTSD from demographics and early clinical features. We consecutively enrolled adult trauma survivors seen in a general hospital emergency department (ED) to a 14-month long prospective panel study. Extreme Gradient Boosting algorithm evaluated the incremental contribution to 14 months PTSD risk of demographic variables, 1-month clinical variables, and concurrent neurocognitive performance. The main outcome variable was PTSD diagnosis, 14 months after ED admission, obtained by trained clinicians using the Clinician-Administered PTSD Scale (CAPS). N = 138 trauma survivors (mean age = 34.25 ± 11.73, range = 18-64; n = 73 [53%] women) were evaluated 1 month after ED admission and followed for 14 months, at which time n = 33 (24%) met PTSD diagnosis. Demographics and clinical variables yielded a discriminatory accuracy of AUC = 0.68 in classifying PTSD diagnostic status. Adding neurocognitive functioning improved the discriminatory accuracy (AUC = 0.88); the largest contribution emanating from poorer cognitive flexibility, processing speed, motor coordination, controlled and sustained attention, emotional bias, and higher response inhibition, and recall memory. Impaired cognitive functioning 1-month after trauma exposure is a significant and independent risk factor for PTSD. Evaluating cognitive performance could improve early screening and prevention.