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June 8, 2026Open Access

The constrained brain in multiple sclerosis: Cognitive impairment is related to network-specific coupling of structural and functional connectivity

MBM BetAmsterdam Neuroscience MDMaureen van DamLeiden University TBTommy AA BroedersAmsterdam Neuroscience

Key Points

This research aims to explore the relationship between structural and functional connectivity in multiple sclerosis (MS) and cognitive impairment.
Classified 266 people with MS into cognitively impaired (CI) or preserved cognitive abilities (CP) groups based on cognitive tests.
Compared whole-brain, within-network, and between-network structural-functional connectivity (SC-FC) and its dynamics (dSC-FC).
Used diffusion-weighted and functional magnetic resonance imaging to derive SC-FC metrics.
Cognitively impaired individuals showed higher SC-FC in dorsal attention and somatomotor networks (p ≤ 0.006 and p ≤ 0.024, respectively).
Higher dSC-FC was observed within the visual network and deep grey matter (p ≤ 0.003; p ≤ 0.006).
SC-FC from the dorsal attention network predicted cognitive status (β = 0.069, OR = 1.072 [95% CI = 1.009–1.139], p = 0.025).

Abstract

Background Cognitive impairment in multiple sclerosis (MS) is related to abnormal structural and functional brain network changes. As both modalities have mostly been studied separately, structure connectivity-function coupling (SC-FC) may elucidate how function is constrained by structure. Objectives We examine how changes in SC-FC and its dynamics SC-FC (dSC-FC) may underlie MS-related cognitive impairment. Methods We classified 266 people with MS (PwMS) as cognitively impaired (CI; z −1.5 on ≥2/7 abilities). Derived from diffusion-weighted and functional magnetic resonance imaging, SC-FC reflected the correlation coefficient between structural and functional connectivity, while dSC-FC reflected its variability. Whole-brain, within-network, and between-network (d)SC-FC were compared between 95 HC, 197 CP, and 69 CI. Results Compared to CP and HC, CI showed higher SC-FC for connections extending from the dorsal attention (DAN; p ≤ 0.006) and somatomotor networks ( p ≤ 0.024), and higher dSC-FC within the visual network ( p ≤ 0.003) and deep grey matter ( p ≤ 0.006). SC-FC in connections extending from the DAN predicted CP/CI status in PwMS ( β = 0.069, OR = 1.072 95% CI = 1.009–1.139, p = 0.025). Conclusions In MS-related CI, deterioration of structural pathways is paired with loss of functional strength in connections extending from the DAN. This may hinder DAN-mediated stimulus selection, possibly contributing to CI.

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