The Role of the Cerebellum in Multiple Sclerosis-Related Fatigue and Disability

Background: Fatigue is a prevalent and debilitating symptom in people with multiple sclerosis (pwMS), significantly impairing quality of life. While the cerebellum is traditionally associated with motor control, emerging evidence suggests its involvement in cognitive, emotional, and integrative functions. This study aimed to explore the relationship between fatigue components (physical, cognitive, and psychosocial), clinical disability, and cerebellar structural changes in pwMS acquired via magnetic resonance imaging (MRI). Methods: Participants of this cross-sectional study underwent clinical assessments for fatigue (Modified Fatigue Impact Scale) and disability (Expanded Disability Status Scale). Cerebellar volumes were measured using high-resolution MRI and voxel-based morphometry (VBM) to identify correlations between fatigue subdomains and specific cerebellar subregions. Statistical analyses included group comparisons and correlation tests. Results: Forty-four pwMS were included. Fatigued MS patients exhibited reduced sensorimotor cerebellar volumes compared to non-fatigued counterparts. Physical fatigue correlated negatively with sensorimotor cerebellum volume, while cognitive fatigue showed an inverse relationship with limbic cerebellum regions. Interestingly, psychosocial fatigue was positively associated with limbic cerebellum volume, contrary to initial hypotheses. Higher disability scores were linked to atrophy in cognitive and limbic cerebellar regions. Conclusions: The findings highlight the cerebellum's multifaceted role in MS-related fatigue, with distinct subregions contributing to physical, cognitive, and psychosocial fatigue components. These results underscore the cerebellum's critical function as a hub for motor, cognitive, and emotional integration. Future longitudinal studies incorporating objective measures and advanced imaging are essential to elucidate these relationships further and inform targeted therapeutic strategies for pwMS.