ABSTRACT Background Functional neuroimaging studies have revealed complex and heterogeneous patterns of aberrant functional connectivity (FC) in multiple sclerosis (MS), yet it remains unclear how time-resolved FC relates to variance in clinical disease severity. Objectives To characterize brain activity in MS patients with time-resolved FC analysis and explore the relationship between disease severity, multi-domain impairments, and altered network dynamics. Methods Resting-state functional MRI data were acquired from 101 MS patients and 101 age- and sex-matched healthy controls (HC). Dynamic FC analysis identified five connectivity states that were compared between HC and patients with high vs. low disability. Results Patients with higher disease severity exhibited a more widespread spatiotemporal pattern of altered FC and spent more time in a high-connectivity, low-occurrence state compared to patients with lower disease severity and HC. Depressive symptom severity was positively related to functional dynamics on global and network scales in patients, while fatigue and motor impairment were inversely related to frontoparietal network connectivity with the basal ganglia. Conclusions Time-resolved FC analysis uncovered alterations in network dynamics and clinical correlations that remained undetected with a static account of brain activity. Such time-varying approaches are thus crucial for disentangling the relationship between brain dynamics, disease severity, and symptoms in MS.

Functional connectivity dynamics reflect disability and multi-domain clinical impairment in patients with relapsing-remitting multiple sclerosis