Fatigue in multiple sclerosis: The contribution of resting-state functional connectivity reorganization

Objectives: To investigate resting-state functional connectivity (RS-FC) of the default-mode network (DMN) and of sensorimotor network (SMN) network in relapsing remitting (RR) multiple sclerosis (MS) patients with fatigue (F) and without fatigue(NF). Methods: In all, 59 RRMS patients and 29 healthy controls (HC) underwent magnetic resonance imaging (MRI) protocol including resting-state fMRI (RS-fMRI). Functional connectivity of the DMN and SMN was evaluated by independent component analysis (ICA). A linear regression analysis was performed to explore whether fatigue was mainly driven by changes observed in the DMN or in the SMN. Regional gray matter atrophy was assessed by voxel-based morphometry (VBM). Results: Compared to HC, F-MS patients showed a stronger RS-FC in the posterior cingulate cortex (PCC) and a reduced RS-FC in the anterior cingulated cortex (ACC) of the DMN. F-MS patients, compared to NF-MS patients, revealed (1) an increased RS-FC in the PCC and a reduced RS-FC in the ACC of the DMN and (2) an increased RS-FC in the primary motor cortex and in the supplementary motor cortex of the SMN. The regression analysis suggested that fatigue is mainly driven by RS-FC changes of the DMN. Conclusions: Fatigue in RRMS is mainly associated to a functional rearrangement of non-motor RS networks.