Functional connectivity changes are associated with disability progression in multiple sclerosis: a longitudinal fMRI study

Background: Resting-state functional connectivity (FC) alterations in people with multiple sclerosis (PwMS) have been hypothesized to reflect either adaptive or maladaptive plasticity. Investigating FC longitudinal evolution and its relationship with disability progression can help clarify this issue. This study examined 5-year FC changes in pwMS and their clinical relevance. Methods: From the Italian Neuroimaging Network Initiative database, we included 156 pwMS with two clinical visits and 3T-MRI scans acquired on the same scanner 4–6 years apart. Clinical/neuropsychological visits included the Expanded Disability Status Scale (EDSS), Nine-Hole Peg Test (9HPT), Timed 25-Foot Walk Test (T25FWT), Paced Auditory Serial Addition Test (PASAT3), and Symbol Digit Modalities Test (SDMT). One hundred fifty-six age- and sex-matched healthy subjects (HS) with baseline MRI and the same tests were also included. Based on the EDSS, pwMS were divided into three groups: low disability (0–1.5; N = 78), mild disability (2–3.5; N = 50), and high disability (≥ 4; N = 28). Resting-state networks (RSNs) were identified using independent component analysis. Baseline and longitudinal FC changes were correlated with baseline and follow-up clinical/neuropsychological measures. Results: At baseline, the low-disability group showed significantly higher FC in all RSNs (FDR-corrected p < 0.05) compared to HS, which correlated with better baseline scores (SDMT, T25FWT) and less worsening at follow-up (PASAT3, 9HPT). The mild- and high-disability groups exhibited mixed FC abnormalities, with both higher and lower FC than HS in several RSNs. In the mild-disability group, higher FC was associated with worse baseline scores (SDMT, T25FWT) and greater clinical worsening (PASAT3, 9HPT, T25FWT). In the high-disability group, higher sensorimotor baseline FC correlated only with worse baseline 9HPT. Longitudinally, all RSNs showed FC increase in the low-disability group, but a FC decrease in the other groups. FC increases in the low-disability group generally correlated with better clinical outcome (T25FWT), while FC decreases in the mild-disability group correlated with clinical worsening (9HPT, T25FWT). Conclusions: FC increases appear to reflect compensatory mechanisms in low-disability pwMS, while in more disabled patients, FC alterations likely represent maladaptive responses. These findings support resting-state FC as a biomarker for monitoring disease progression and treatment response in MS.