Functional Connectivity at Rest and During Cognitive Processing in Multiple Sclerosis: A Pilot Magnetoencephalography Study and Systematic Review

Background/Objectives: Cognitive impairment and neurological dysfunction in Multiple Sclerosis are increasingly understood as consequences of altered brain network connectivity. Magnetoencephalography offers high temporal resolution for investigating functional connectivity patterns, which may underlie various clinical symptoms. This exploratory pilot study aims to characterize preliminary FC patterns at rest and during cognitive processing in MS patients with a high fatigue burden compared with healthy controls using MEG, complemented by a systematic review of existing MEG literature in MS. Methods: In this pilot study, MEG was utilized to investigate connectivity in MS patients and HCs. Data were acquired during resting-state and a digitized version of the Symbol Digit Modalities Test. A systematic review was also conducted following PRISMA guidelines to synthesize the current evidence on frequency-specific MEG connectivity in MS. Results: MS patients exhibited a connectivity pattern paralleling the directionality of neuronal slowing, described in the spectral power MS literature, during resting-state, characterized by reduced interhemispheric coherence in alpha and beta bands alongside region-specific increases in frontal–parietal and parietal–occipital alpha coherence, reflecting a bidirectional spatial reorganization. Conversely, during the SDMT task, the MS group demonstrated significant compensatory recruitment with increased coherence in theta and gamma bands (specifically in frontal and striatal circuits). The systematic review of 44 MEG studies corroborated these findings, highlighting a consistent trend of frequency-dependent dysconnectivity that aligns with clinical load and disease pathology. Conclusions: We found that in MS, network alterations are state-dependent, shifting from reduced connectivity at rest to increased coherence during cognitive effort. These preliminary findings suggest that MEG-based connectivity may serve as a functional neuroimaging biomarker of underlying network reorganization, for monitoring early cognitive disease progression in MS.