The role of cerebellar functional connectivity in upper limb impairment in Multiple Sclerosis

Background and purpose: The cerebellum, frequently affected in People with Multiple Sclerosis (PwMS), plays a fundamental role in motor control, as well as contributes to a range of cognitive functions. Alterations in cerebellar functional connectivity (FC) are thought to contribute to upper limb motor impairment, that can be assessed through 9-Hole Peg Test (9HPT). However, the extent and functional relevance of cerebellar FC alterations underlying upper limb motor impairment are not yet fully understood. The aim of this study was to assess: 1. Whether FC abnormalities of the sensori-motor and cognitive cerebellum (smCb and cCb) are associated with impaired upper limb dexterity; 2. Whether such FC alterations contribute to upper limb dysfunction, beyond structural brain damage. Methods: A total of 667 subjects were selected from the Italian Neuroimaging Network Initiative (INNI) database. There were 248 PwMS with impaired 9HPT performance (iPwMS), 248 PwMS with preserved dexterity (pPwMS), and 171 healthy controls (HC). From multimodal 3 T MRI data we obtained measures of T2-lesion volume (T2-LV), cortical and deep grey matter volumes (caudate, putamen, and thalamus), cerebellar volumes, and spinal cord area at the C2–C3 level. Resting-state FC of the smCb and cCb was evaluated using voxel-wise seed-based analyses. Group comparisons were performed using ANCOVA models, adjusting for age, sex, and global brain volume in Model 1, for peripheral GM and global brain volumes, total thalamic and cerebellar volumes, and C2–C3 area as covariates of no interest in Model 2. Results: FC of both smCb and cCb was reduced in PwMS relative to HC. Post hoc analysis using Model 1 indicated lower FC in iPwMS compared with both pPwMS and HC. After adjusting for global and regional structural measures in Model 2, significant differences persisted (albeit at a lower extent) between iPwMS and both groups, whereas FC in pPwMS did not differ from HC. Conclusion: Alterations in cerebellar FC represent a prominent correlate of upper limb disability in pwMS. The role of cerebellar FC reductions in upper limb impairment is at least primary and not merely dependent on the brain structural damage. The involvement of both smCb and cCb suggests that fine motor impairment may reflect widespread cerebellar dysfunction extending beyond purely motor regions, supporting the role of cerebellar connectivity as a potential biomarker of motor disability and a target for rehabilitative interventions in MS.