Increased functional network connectivity following cognitive rehabilitation in progressive multiple sclerosis with moderate to severe disabilty: findings from the CogEx study

Background: Functional neuroplasticity likely occurs following cognitive rehabilitation (CR) and aerobic exercise (EX) in progressive multiple sclerosis (PMS). We explored network resting state (RS) functional connectivity (FC) changes and associations with cognitive measure modifications in CogEx study participants. Methods: Patients with PMS were randomly assigned to four groups and underwent 12 weeks of treatment with a combination of CR and EX or sham therapies. Cognitive and fMRI assessments were performed at baseline, immediately post-intervention (week-12) and 6 months post-intervention (month-9). RS FC within the main cognitive brain networks was extracted and compared between groups at whole-network and voxel-wise levels and correlated with cognitive changes. Results: We included 87 PMS patients with moderate-to-severe disability (Expanded Disability Status Scale score 4.0–6.5). There were no differences in whole-network RS FC between the four groups. When comparing patients performing CR vs CR-S, we found increased salience (p = 0.01) and default-mode network (p = 0.02) RS FC at week-12, and increased left (p = 0.05) and right frontoparietal network (p = 0.04) RS FC at month-9 in CR compared with CR-S groups. Increased default-mode network RS FC correlated weakly with increased verbal memory in CR (rho = 0.27, p = 0.06). At voxel-wise level, we found increased RS FC in most analyzed networks in CR groups (p < 0.001, uncorrected) and decreased RS FC in CR-S groups at week-12 (p < 0.05, family-wise error corrected). Conclusions: CR modulated RS FC in cognitive networks of patients with PMS, suggesting treatment-related functional plasticity of large-scale networks even in late, disabling MS phases. These network-level changes may reflect neural processes that support cognitive improvement following CR.