Neuroanatomical Correlates of Disrupted Fear Learning in Acutely Traumatized Individuals

Abstract

Background: Posttraumatic stress disorder (PTSD) is associated with altered gray matter volume (GMV) in brain regions critical for threat processing. However, whether variability in brain structure relates to extinction learning in recently traumatized individuals is unclear. Further, limited research has investigated whether the interaction between brain structure and extinction relates to PTSD symptom development. We investigated subcortical brain regions critical for extinction learning processes (amygdala, hippocampus, and thalamus) and the relationship between GMV and threat-related psychophysiology (measured by fear-potentiated startle; FPS) to elucidate how extinction learning and GMV interact to impact PTSD symptom development. Methods: 99 civilians underwent a fear conditioning procedure two weeks after trauma exposure as part of a larger, multisite Emergency Department study. T1-weighted magnetic resonance images of the brain were also acquired. Participants completed the PTSD Checklist for DSM-5 (PCL-5) and Brief Dissociative Experiences Scale (DES-B) at two- and eight-weeks post-trauma. Multiple regressions were completed to investigate the relationships between FPS, subcortical GMV, and later PTSD symptom development, while controlling for intracranial volume, age, and site effects. Results: No significant relationships emerged between FPS during late extinction learning and GMV. However, we observed an interaction between thalamus GMV and late extinction FPS to the CS+ related to PCL-5 scores at two (β=0.246, p=0.027) and eight (β=0.275, p=0.014) weeks post-trauma. Greater thalamus GMV and increased FPS to the CS+ during late extinction were associated with higher PCL-5 scores. However, with decreasing thalamic GMV, better fear extinction predicted increasingly worse PCL-5 scores. A similar thalamic GMV-FPS interaction also predicted dissociation symptoms (2-week β=0.244, p=0.025; 8-week: β=0.270, p=0.014) and depressive symptoms (2-week: β=0.281, p=0.011; 8-week: β=0.267, p=0.020) following trauma exposure. Conclusion: PTSD, dissociation, and depression symptom severity were predicted by the interaction of thalamic GMV and FPS to the CS+ during late extinction. The thalamus is critical for sensory signal integration and relay to other regions to determine behavior, with recent literature showing its importance in fear extinction. The present data suggest that similar presentations of posttraumatic dysfunction may have different brain-behavior interactions in regions implicated in extinction learning. Further, these results provide initial evidence that combined multimodal assessments in the acute phase following trauma exposure may aid in identifying individuals susceptible to adverse posttraumatic outcomes. Future research would benefit from further consideration of the distinct phenotypes that may clarify vulnerability for adverse posttraumatic outcomes.