Structural and Functional Architecture of Cortico-Cerebellar Systems in Posttraumatic Stress Disorder and Trauma

ABSTRACT The cerebellum shares rich anatomical connections with prefrontal and limbic areas and participates in processes well beyond motor coordination. Recent evidence on the role of the cerebellum in fear learning and memory, coupled with established findings of posttraumatic stress disorder (PTSD)-associated abnormalities in threat detection and processing, suggest the cerebellum may play a significant role in the pathophysiology of PTSD. Smaller whole cerebellar and cerebellar subregion volumes have been observed in adults and children with PTSD. However, sparse knowledge of cerebellar activation and functional connectivity differences in PTSD need to be addressed with large, rigorous, and reproducible characterizations of the cerebellum in PTSD, and its potential as a treatment target. Widespread connectivity of the cerebellum with stress related regions (e.g. amygdala, hippocampus, periaqueductal gray) make it vulnerable to traumatic stress and disruption by brain-mediated stress responses via cortico-cerebellar circuits. We hypothesize these connections are highly relevant to PTSD neurobiology. Our overarching goal is to study cerebellar subregion connectivity (structural and functional) to cortical regions, subcortical regions, and canonical resting-state networks implicated in PTSD. We will analyze existing neuroimaging and clinical data in > 1,887 samples of PTSD cases and trauma-exposed controls from 25 international cohorts shared with the ENIGMA-PTSD Consortium workgroup. Aim 1 will investigate the influence of PTSD, trauma exposure, and PTSD symptom clusters on the functional connectivity of cerebellar subregions to cortical regions and subcortical regions. Aim 2 will examine the structural covariance and structure-function coupling of cortico-ponto-cerebellar tracts, cortical regions, and subcortical regions with cerebellar subregions. Aim 3 will investigate differential effects of PTSD on task-positive networks (ventral attention, fronto-parietal), task-negative networks (default mode, dorsal attention), the putative balance between task-positive and task-negative networks, and other canonical resting-state networks. Aim 4 will explore cerebellar subregion activation and connectivity in response to threat stimuli in PTSD and trauma exposure. The proposed research may pay a central role in developing neuromodulatory therapeutics for PTSD. Cortico-cerebellar paired associative stimulation may be deployed in the future with a paradigm to enhance feedback and feedforward cortico-cerebellar connections involved in threat processing, particularly threat stimuli that evoke a fight or flight response.