The relationship between cerebellar functional connectivity alterations and hand dexterity impairment in multiple sclerosis

Background and purpose: Altered cerebellar resting-state functional connectivity (FC) may contribute to hand motor impairment in People with Multiple Sclerosis (PwMS). We aimed to assess whether: 1. FC abnormalities of the sensorimotor and cognitive cerebellum (smCb, cCb) are associated with impaired hand dexterity; 2. these alterations contribute to impaired hand dexterity beyond structural brain and spinal cord damage. Methods: Six hundred and sixty-seven subjects from the Italian Neuroimaging Network Initiative database were included: two hundred forty-eight PwMS with impaired (iPwMS) and two hundred forty-eight with preserved hand dexterity (pPwMS), and one hundred seventy-one healthy controls (HC). We obtained measures of white matter lesion load, cortical, deep gray matter and cerebellar volumes, and C2-C3 spinal cord area. Cerebellar FC of the smCb and cCb was evaluated using voxel-wise seed-based analyses. Group comparisons were performed using ANCOVA models, with and without adjusting for global and regional structural measures. Results: Compared to HC and pPwMS, iPwMS showed widespread FC reductions of both smCb and cCb in several cortical, subcortical, and cerebellar regions (p < 0.05, FDR-corrected), whereas pPwMS did not differ significantly from HC. After adjusting for structural measures, FC reductions in iPwMS persisted, although to a lesser extent, particularly in cortical and cerebellar regions. Conclusion: Cerebellar FC reductions involving both sensorimotor and cognitive domains are robustly associated with impaired hand dexterity in PwMS and remain significant even after controlling for brain and spinal cord structural damage. This suggests that cerebellar FC alterations are a key, only partly structure-dependent contributor to dexterity impairment, highlighting cerebellar connectivity as a promising target for motor rehabilitation in MS.