Functional Connectivity Alterations of the Central Autonomic Network in Multiple Sclerosis

BACKGROUND AND OBJECTIVES: Autonomic dysfunction is common in multiple sclerosis (MS), and autonomic symptoms are independent contributors to MS fatigue. Aerobic training (AT) has been shown to reduce fatigue severity and to promote functional network reorganization in MS. We explored resting-state (RS) functional connectivity (FC) of the central autonomic network (CAN) in MS, its relationship with fatigue severity, and its modifications after AT vs non-AT. METHODS: Seventy-five patients with MS (38 with relapsing-remitting [RR] and 37 with progressive [P]) underwent 3T RS functional MRI at baseline and at the end of AT (24 training sessions, 2-3 times per week for 2-3 months) or non-AT of equivalent duration. Sixty-seven matched healthy controls (HCs) served as a reference for baseline RS FC. At both visits, all patients were assessed using the Modified Fatigue Impact Scale (MFIS). Seed-based RS FC used core CAN modulatory regions: left/right ventromedial prefrontal cortex (vmPFC), mid-cingulate cortex (MCC), amygdala, hypothalamus, and anterior and posterior insula. RESULTS: < 0.001, significant time-by-treatment interaction vs non-AT), with more prominent changes in patients with RRMS compared with patients with PMS. No correlations were found between longitudinal RS FC modifications and concomitant fatigue changes. DISCUSSION: CAN dysregulation is present in MS, with distinct RS FC abnormalities characterizing patients with RRMS and PMS and correlating with fatigue severity. AT modulates CAN RS FC, particularly in patients with RRMS.