Effects of cognitive rehabilitation and exercise on brain structure in progressive multiple sclerosis: results from the CogEx trial

Background: We previously showed increased cortical grey matter (GM) volume in CogEx trial participants who performed cognitive rehabilitation (CR). Here, we explore combined CR and aerobic exercise (EX) effects on regional changes in brain volumes and white matter (WM) integrity. Methods: Seventy-three patients were randomized into four groups receiving a combination of CR and EX or their sham versions: CR + EX, CR + EX-sham, EX + CR-sham, and CR-sham + EX-sham. A diagnosis of progressive multiple sclerosis (PMS) and impaired information processing speed were required for inclusion. Participants attended a 12-week intervention twice/week. Assessments were performed at baseline, week-12 (W12), and nine months post-baseline (M9). Structural MRI scans were acquired with a standardized protocol, and voxelwise variations of brain volumes and WM fractional anisotropy (FA) were analyzed. Results: Baseline regional brain volumes and WM FA were comparable between groups. Voxelwise analyses at W12 and M9 revealed generalized volume reductions in all groups. We found different patterns of volumetric changes in the left inferior temporal gyrus between CR + EX and CR-sham + EX-sham, and in the right cerebellum crus II between EX + CR-sham and CR + EX-sham. WM FA values remained stable throughout the trial and no longitudinal between-group differences were found. Conclusions: Our analysis showed a decrease in brain volumes and limited effects of the combined CR + EX intervention, indicating that the previously found cortical GM increase was not superimposable at voxel level. Methodological and sampling differences between the studies could explain these discrepancies. In few cognitively relevant areas, the combined CR interventions might have affected patterns of volume changes, while EX modified cerebellar motor regions. Clinical trial registration: The main trial was registered on ClinicalTrials.gov (NCT03679468; registration date: 20 Sep 2018).