Multiple sclerosis (MS) features extensive connectivity changes, but how structural and functional connectivity relate, and whether this relation could be a useful biomarker for cognitive impairment in MS is unclear. This study included 79 MS patients and 40 healthy controls (HCs). Patients were classified as cognitively impaired (CI) or cognitively preserved (CP). Structural connectivity was determined using diffusion MRI and functional connectivity using resting-state magnetoencephalography (MEG) data (theta, alpha1, and alpha2 bands). Structure-function coupling was assessed by correlating modalities, and further explored in frequency bands that significantly correlated with whole-brain structural connectivity. Functional correlates of short- and long-range structural connections (based on tract length) were then specifically assessed. Receiving operating curve analyses were performed on coupling values to identify biomarker potential. Only the theta band showed significant correlations between whole-brain structural and functional connectivity (rho = −0.26, p = 0.023, only in MS). Long-range structure-function coupling was stronger in CI patients compared to HCs (p = 0.005). Short-range coupling showed no group differences. Structure-function coupling was not a significant classifier of cognitive impairment for any tract length (short-range area under the curve (AUC) = 0.498, p = 0.976, long-range AUC = 0.611, p = 0.095). Long-range structure-function coupling was stronger in CI MS compared to HCs, but more research is needed to further explore this measure as biomarkers in MS.

Cognitive impairment in multiple sclerosis (MS) is common and related to structural and functional connectivity. However, it remains unclear whether the interplay (coupling) between structural and functional connectivity could be a biomarker of MS-related cognitive impairment. This study investigated the cognitive relevance of structure-function coupling in 79 MS patients and 40 healthy controls using diffusion MRI and magnetoencephalography. Results show that coupling was stronger in cognitively impaired MS patients compared to controls, but only when considering long-distance connections. Nonetheless, classifier analyses indicated only weak biomarker potential in terms of sensitivity and specificity. Future studies should include additional operationalization of coupling as well as longitudinal and regional or network level data.

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Equal contribution.

Competing Interests: The authors have declared that no competing interests exist.

Handling Editor: Olaf Sporns

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