Ventral Attention Network Connectivity Differentiates Radiologically Isolated Syndrome from Multiple Sclerosis: A...

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.

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.

Fatigue increased in MS but was stable in RIS. VAN connectivity showed opposing trajectories (group × time; P < .001): RIS showed increased within-VAN connectivity and increased within-dorsal attention network connectivity versus HC, whereas MS showed decreased within-VAN connectivity. In MS, VAN connectivity increased with orbitofrontal and striatal regions and decreased with thalamus/caudate (FWE P < .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.

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.