Ventral Attention Network Connectivity Differentiates Radiologically Isolated Syndrome from Multiple Sclerosis: A Longitudinal Resting-State fMRI Study

BACKGROUND AND PURPOSE: Radiologically isolated syndrome (RIS) entails incidental MS-like MRI lesions. Longitudinal fMRI could clarify brain-symptom links; however, no longitudinal resting-state fMRI studies in RIS existed until now. The goal was to compare 14-month clinical, neuropsychological, and resting-state functional connectivity (FC) trajectories in RIS, MS, and healthy controls (HC), and relate FC change to fatigue. MATERIALS AND METHODS: Nineteen patients with RIS, 20 with MS, and 22 HC completed baseline and 14-month assessments (fatigue, neuropsychology) and 3T MRI (resting-state fMRI, 3D T1, FLAIR). FC within canonical networks and VAN seed-to-voxel connectivity were tested in the CONN toolbox using repeated-measures ANOVA with family-wise error (FWE) correction for multiple comparisons. Regression analyses examined associations between longitudinal changes in FC and changes in fatigue; receiver operating characteristic curves evaluated the ability of longitudinal FC measures to distinguish between groups. RESULTS: < .05). Greater increases in within-VAN and VAN-thalamus/caudate connectivity over time were associated with reductions in fatigue. A composite VAN metric differentiated RIS from MS (area under the curve = 0.919). Lesion volumes were unchanged. CONCLUSIONS: RIS and MS exhibit divergent, VAN-centered FC trajectories paralleling fatigue evolution. VAN-based longitudinal FC metrics may provide sensitive, noninvasive biomarkers that complement lesion measures in early MS.