Progressive brain rich-club network disruption from clinically isolated syndrome towards multiple sclerosis

Objective: To investigate the rich-club organization in clinically isolated syndrome (CIS) and multiple sclerosis (MS), and to characterize its relationships with physical disabilities and cognitive impairments. Methods: We constructed high-resolution white matter (WM) structural networks in 41 CIS, 32 MS and 35 healthy controls (HCs) using diffusion MRI and deterministic tractography. Group differences in rich-club organization, global and local network metrics were investigated. The relationship between the altered network metrics, brain lesions and clinical variables including EDSS, MMSE, PASAT, disease duration were calculated. Additionally, reproducibility analysis was performed using different parcellation schemes. Results: Compared with HCs, MS patients exhibited a decreased strength in all types of connections (rich-club: p < 0.0001; feeder: p = 0.0004; and local: p = 0.0026). CIS patients showed intermediate values between MS patients and HCs and exhibited a decreased strength in feeder and local connections (feeder: p = 0.019; and local: p = 0.031) but not in rich-club connections. Compared with CIS patients, MS patients showed significant reductions in rich-club connections (p = 0.0004). The reduced strength of rich-club and feeder connections was correlated with cognitive impairments in the MS group. These results were independent of lesion distribution and reproducible across different brain parcellation schemes. Conclusion: The rich-club organization was disrupted in MS patients and relatively preserved in CIS. The disrupted rich-club connectivity was correlated with cognitive impairment in MS. These findings suggest that impaired rich-club connectivity is an essential feature of progressive structural network disruption, heralding the development of clinical disability in MS.