Investigating Functional Network Abnormalities and Associations With Disability in Multiple Sclerosis

Abstract

Background and Objectives:In multiple sclerosis (MS), functional networks undergo continuous reconfiguration and topography changes over the disease course. Here, we aimed to investigate functional networks topography abnormalities in MS and their association with disease phenotype, clinical and cognitive disability, and structural MRI damage.Methods:This is a multi-centre cross-sectional study. Enrolled subjects performed MRI, neurological and neuropsychological assessment. Network topography was assessed on resting state fMRI data using degree centrality, which counted the number of functional connections of each grey matter voxel with the rest of the brain. SPM12 age-, sex-, scanner-, framewise displacement and grey matter volume adjusted ANOVA and multivariable regressions were employed (p<0.05, family-wise error [FWE] corrected).Results:We enrolled 971 patients with MS (624 females; mean age=43.1 ±11.8 years; 47 clinically isolated syndrome [CIS], 704 relapsing-remitting [RRMS], 145 secondary progressive [SPMS] and 75 primary progressive [PPMS]) and 330 healthy controls (186 females; mean age=41.2 ± 13.3 years). Patients with MS showed reduced centrality in the salience and sensorimotor networks as well as increased centrality in the default mode network vs controls (p<0.05, FWE). Abnormal centrality was already found in CIS vs controls and in RRMS vs CIS (p<0.001, uncorrected); however it became more severe in SPMS vs RRMS (p<0.05, FWE) and in PPMS vs controls (p<0.001, uncorrected). Cognitively impaired patients (39%) showed reduced centrality in the salience network and increased centrality in the default mode network vs cognitively preserved patients (p<0.001, conjunction analysis). More severe disability correlated with increased centrality in the right precuneus (r=0.18, p<0.05 FWE). Higher T2 lesion volume and brain/grey matter atrophy were associated with reduced centrality in the bilateral insula and cerebellum (r=range -0.17/-0.15 and 0.26/0.28, respectively; p<0.05, FWE). Higher brain/grey matter atrophy was also associated with increased centrality in the default mode network (r=range -0.31/-0.22, p<0.05, FWE).Discussion:Patients with MS presented with reduced centrality in the salience and primary sensorimotor networks and increased centrality in the default mode network. Centrality abnormalities were specific for different disease phenotypes and associated with clinical and cognitive disability, hence suggesting that voxel-wise centrality analysis may reflect pathological substrates underpinning disability accrual.