Objective: 1) To assess fMRI-based functional connectivity (FC) anomalies in early multiple sclerosis (MS), 2) To determine the relation between FC changes and structural brain damage due to disease progression 3) To study the association between FC changes and cognitive and physical disability. Methods: Structural MRI and resting-state fMRI were acquired from 76 early relapsing-remitting MS patients at baseline (average disease duration 71.7 months {+/-} 63) and after five years. Ninety-four healthy controls (HCs) matched for age and sex were included at baseline. Independent component analysis (ICA) and network modelling were used to measure FC. FC variation was related to expanded disability status scale and neuropsychological outcomes. Brain and lesion volumes were quantified using standard methods. We used the 25 independent components obtained from ICA to estimate the longitudinal stability of the brain connectome as a proxy for functional reorganization over time. Results: The MS subjects were clinically and cognitively stable. Compared to HCs, FC abnormalities were detected within networks and in single connections in patients with early MS at baseline. Over time, FC was relatively invariable, but changes in FC were associated with progression of brain atrophy ({rho}= 0.39, p = .06). No significant relationship with clinical and cognitive measures or lesion load was detected. Conclusion: Patients with MS showed evidence of altered FC in the early stages of the disease. Over time, changes in FC seem to be related to a progression of brain atrophy, which are known to precede changes in clinical and cognitive functioning.

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