A Multisite and Multimodal Comparative Study of Cerebellar Connectome Between Multiple Sclerosis and Neuromyelitis Optica Spectrum Disorders

Abstract

The cerebellum has been increasingly recognized to play key roles in the pathology of multiple sclerosis (MS) and spectrum disorders (NMOSD), two main demyelinating diseases with similar clinical presentations. Despite accumulating evidence from neuroimaging research for cerebellar volumetric alterations in the diseases, however, there have been no network-based studies examining convergent and divergent alterations in cerebellar connectome between MS and NMOSD. This multisite and multimodal study examined common and specific alterations in within-cerebellar coordination and cerebello-cerebral communication between MS and NMOSD by retrospectively collecting structural and resting-state functional MRI data from 208 MS patients, 200 NMOSD patients and 228 healthy controls (HCs) in seven sites in China. Morphological brain networks were constructed by estimating interregional similarity in cortical thickness and functional brain networks were formed by calculating interregional temporal synchronization in functional signals. After identifying cerebellar modular architecture and based on prior cerebral cytoarchitectonic classification and functional partition, within-cerebellar and cerebello-cerebral morphological and functional connectivity were compared among the MS, NMOSD and HC groups. Five modules were identified within the cerebellum including Primary Motor A (PMA), Primary Motor B (PMB), Primary Non-Motor (PNM), Secondary Motor (SM) and Secondary Non-Motor (SNM) modules. Compared with the HCs, the MS and NMOSD patients exhibited both increases and decreases in within-cerebellar morphological connectivity that were mainly involved in the PMA, PMB and SNM. Particularly, the two patient groups showed a common altered pattern characterized by decreases between the PMA and SNM, both of which were more densely connected with the PMB. For cerebello-cerebral morphological connectivity, widespread reductions were found in both patient groups for the SM and SNM with almost all cerebral cytoarchitectonic classes and functional systems while increases were observed only in the NMOSD patients for the PMB with cerebral areas involving motor and sensory domains. With regard to cerebellar functional connectivity, fewer alterations were observed in the patients that were all characterized by reductions and were mainly involved in cerebello-cerebral interactions between cerebellar motor modules and cerebral association cortex and high-order networks, particularly in the NMOSD patients. Cerebellar connectivity-based classification achieved around 60% accuracies to distinguish the three groups to each other with morphological connectivity as predominant features for differentiating the patients from controls while functional connectivity for discriminating the two diseases. Altogether, this study characterizes common and specific circuit dysfunctions of the cerebellum between MS and NMOSD, which provide novel insights into shared and unique pathophysiologic mechanisms underlying the two diseases.