Task-oriented virtual reality and brain functional plasticity in progressive multiple sclerosis: A randomized controlled trial on upper limb rehabilitation

Background: Motor rehabilitation effectiveness in progressive multiple sclerosis (PMS) remains uncertain. We assessed whether task-oriented (TO) rehabilitation, with or without non-immersive virtual reality, improves upper limb function in PMS and evaluated magnetic resonance imaging (MRI) changes related to motor performance. Methods: Eighty-one progressive multiple sclerosis patients on B-cell depleting therapy were randomized to task-oriented rehabilitation with virtual reality (TO-VR), TO rehabilitation, or passive mobilization (CG) for 8 weeks. Upper extremity performance was measured with the Nine-Hole Peg Test (9-HPT), Action Research Arm Test (ARAT), AbilHand Test (ABILHAND), and Manual Ability Measure-36 (MAM-36). Upper limb function, neurological status, and MRI were evaluated at baseline, after rehabilitation, and at 3 months. Results: Seventy-nine patients completed the study. No difference was observed in 9-HPT, but in the whole sample, ABILHAND improved post-treatment (p < 0.001), and ARAT improved on the left side (p = 0.014, false discovery rate adjusted p = 0.084). Additional gains appeared in several neurological tests. Brain volumes, morphometry, and diffusion indices were unchanged, while functional MRI showed increased connectivity post-treatment in TO-VR and TO groups, but not in CG. Connectivity changes were correlated, in particular, with clinical amelioration (ABILHAND) in both TO-VR (r = 0.54, p = 0.013) and TO groups (r = 0.50, p = 0.035). Conclusion: In PMS treated with high-efficacy therapy, TO rehabilitation, particularly when combined with VR, can improve motor function, inducing functional gains and plasticity in cerebral networks.