Multimodal Analysis of Secondary Cerebellar Alterations after Pediatric Traumatic Brain Injury

Abstract While traditionally ignored as a region purely responsible for motor function, the cerebellum is increasingly being appreciated for its contributions to higher order functions through various cerebro-cerebellar networks. Traumatic brain injury (TBI) research generally focuses on the cerebrum, in part because acute pathology is not found in the cerebellum as often. Acute pathology is an important predictor of outcome, but neural disruption also evolves over time in ways that have implications for daily-life functioning. Here we examine these changes in a multi-modal, multi-cohort study. Combining 12 datasets from the Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Pediatric msTBI (moderate-severe TBI) working group, we measured volume of the total cerebellum and 17 subregions using a state-of-the-art, deep learning-based approach for automated parcellation in 598 children and adolescents with or without TBI (msTBI; n = 314 | non-TBI; n = 284; age M = 14.0 ± 3.1 years). Further, we investigated brain-behavior relations between cerebellar volumes and a measure of executive functioning (i.e., Behavioral Rating Inventory of Executive Function [BRIEF]). In a subsample with longitudinal data, we then assessed whether late changes in cerebellar volume were associated with early white matter microstructural organization using diffusion tensor imaging (DTI). Significantly smaller total cerebellar volume was observed in the msTBI group (Cohen’s d = −0.37). In addition, lower regional cerebellar volume was found in posterior lobe regions including crus II, lobule VIIB, lobule VIIIB, vermis VII, and IX (Cohen’s d range = −0.22 to −0.43). Smaller cerebellum volumes were associated with more parent-reported executive function problems. These alterations were primarily driven by participants in the chronic phase of injury (> 6 months). In a subset of participants with longitudinal data (n = 80), we found evidence of altered growth in total cerebellum volume, with younger msTBI participants showing secondary degeneration in the form of volume reductions, and older participants showing disrupted development reflected in slower growth rates. Changes in total cerebellum volume over time were also associated with white matter microstructural organization in the first weeks and months post-injury, such that poorer white matter organization in the first months post-injury was associated with decreases in volume longitudinally. Pediatric msTBI was characterized by smaller cerebellar volumes, primarily in the posterior lobe and vermis. The course of these alterations, along with group differences in longitudinal volume changes as well as injury-specific associations between DTI measures and volume changes, is suggestive of secondary cerebellar atrophy, possibly related to supra-tentorial lesions, and/or disruption in cerebellar structural and functional circuits. Moreover, evidence for robust brain-behavior relationships underscore the potential cognitive and behavioral consequences of cerebellar disruption during a critical period of brain development.