INTRODUCTION: Upper limb (UL) impairment is common in people with multiple sclerosis (pwMS), and functional recovery of the UL is a key rehabilitation goal. Technology-based approaches, like virtual reality (VR), are increasingly promising. While most VR environments are task-oriented, our clinical approach integrates neuroproprioceptive 'facilitation and inhibition' (NFI) principles. To advance this, we developed immersive VR software based on NFI principles targeting UL function and sit-to-stand ability. This study aims to evaluate the effectiveness of this VR therapy compared with conventional NFI-based physical therapy in pwMS. Our study uniquely applies advanced imaging techniques, along with biological molecular assessments, to explore adaptive processes induced by VR rehabilitation. METHODS AND ANALYSIS: This double-arm, randomised, assessor-blinded, controlled trial runs over 2 months (1 hour, 2 times per week). PwMS with mild to severe disability will receive either VR therapy or real-world physical therapy. Primary outcomes include the nine-hole peg test, box and block test, handgrip strength, tremor and five times sit-to-stand test. Secondary measures include the Multiple Sclerosis Impact Scale, the 5-level EQ-5D questionnaire and kinematic analysis. Adaptive processes will be monitored using imaging techniques (functional MRI and tractography), molecular genetic methods (long non-coding RNAs) and immune system markers (leukocytes, dendritic cells). The International Classification of Functioning, Disability and Health brief set for MS will map the bio-psycho-social context of participants. ETHICS AND DISSEMINATION: This project and its amendments were approved by the Ethics Committee of the Institute for Clinical and Experimental Medicine and Thomayer Hospital (1983/21+4772/21 (G-21-02) and the Ethics Committee of Kralovske Vinohrady University Hospital (EK-VP/38/0/2021) in Prague, Czechia (with single enrolment). The findings of this project will be disseminated through scientific publications, conferences, professional networks, public engagement, educational materials and stakeholder briefings to ensure a broad impact across clinical, academic and public domains. TRIAL REGISTRATION NUMBER: clinicaltrials.gov (NCT04807738).

• Keywords
• Functional Magnetic Resonance Imaging, IMMUNOLOGY, Multiple sclerosis, Neuroradiology, REHABILITATION MEDICINE, Virtual Reality,
• MeSH
• Adult MeSH
• Double-Blind Method MeSH
• Upper Extremity * physiopathology   MeSH
• Quality of Life * MeSH
• Humans MeSH
• Magnetic Resonance Imaging * methods   MeSH
• Posture MeSH
• Randomized Controlled Trials as Topic MeSH
• Multiple Sclerosis * diagnostic imaging   MeSH
• Hand Strength MeSH
• Physical Therapy Modalities * MeSH
• Virtual Reality Exposure Therapy methods   MeSH
• Virtual Reality MeSH
• Check Tag
• Adult MeSH
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Clinical Trial Protocol MeSH

• Keywords
• data report, fMRI, multiple sclerosis, neurorehabilitation, open access,
• Publication type
• Journal Article MeSH