Cortico-subcortical functional connectivity modifications in fatigued ms patients treated with fampridine and amantadine.

Background Fatigue in multiple sclerosis (MS) is common and disabling; medication efficacy is still not fully proven. Aim of this study was to investigate four-week modifications of fatigue severity in 45 relapsing-remitting MS patients following different symptomatic treatments, and concomitant resting state (RS) functional connectivity (FC) changes. Methods Patients were randomly, blindly assigned to treatment with fampridine (n=15), amantadine (n=15) or placebo (n=15), and underwent clinical/3T RS fMRI at baseline (t0) and after four weeks (w4) of treatment. Fifteen healthy controls (HC) were also studied. Changes of modified fatigue impact scale (MFIS) and network RS FC were assessed. Results In MS, abnormalities of network RS FC at t0 did not differ between treatment groups and correlated with fatigue severity. At w4, global and subscore MFISs decreased in all groups, with no time-by-treatment interaction. At w4, all patient groups had changes of RS FC in several networks, with significant time-by-treatment interactions in basal ganglia, sensorimotor and default-mode networks in fampridine patients vs the other groups, and in fronto-parietal network in amantadine patients. In fampridine-group, RS FC changes correlated with concurrently decreased MFIS (r range=-0.75 to 0.74, p range=0.003-0.05). Conclusions Fatigue improved in all MS groups, independently from treatment. Concomitant RS FC modifications were located in sensorimotor, inferior frontal and subcortical regions for fampridine and amantadine patients, and in associative sensory cortices for placebo patients.