This randomized controlled trial (RCT) evaluates the effectiveness of virtual reality (VR) rehabilitation in improving cognitive, emotional, social, and motor functions in patients with neurological disorders (ABI, SCI, MS, PD). It investigates whether VR improves motor and cognitive functions more than traditional therapy, identifies neurophysiological changes (EEG, fNIRS, MRI), and assesses the integration of VR with NIBS or telerehabilitation. Conducted over three years at IRCCS Centro Neurolesi Bonino Pulejo, participants are randomly assigned to either a VR training group or an active control group receiving traditional rehabilitation. Procedures include baseline assessments (T0), 20 rehabilitation sessions over 8 weeks, post-intervention evaluations (T1), and a 3-month follow-up (T2). Primary outcomes measure motor and cognitive function (MoCA, MMSE, FIM, TUG, Berg Balance Scale), neurophysiological changes (EEG, MRI, fNIRS, motion analysis), and emotional/social function (Empathy Quotient, Hamilton Depression Scale).

This randomized controlled trial (RCT) aims to evaluate the effectiveness of virtual reality (VR) rehabilitation in improving cognitive, emotional, social, and motor functions in patients with neurological and neurodegenerative disorders (Acquired Brain Injuries, Spinal Cord Injuries, Multiple Sclerosis, and Parkinson's Disease). The study also explores neurophysiological changes and the potential benefits of combining VR with non-invasive brain stimulation (NIBS) and telerehabilitation.

Objectives:

Primary Objectives:

Assess the effectiveness of VR-based rehabilitation in enhancing cognitive and motor functions.

Identify neurophysiological changes (EEG, fNIRS, MRI) associated with functional recovery.

Secondary Objectives:

Identify behavioral and neurophysiological biomarkers predictive of rehabilitation outcomes.

Compare the effectiveness of different VR devices for rehabilitation. Evaluate the impact of VR telerehabilitation on recovery and continuity of care.

Explore the synergistic effects of VR combined with NIBS.

Methods:

Study Site: IRCCS Centro Neurolesi Bonino Pulejo. Duration: 3 years. Participants: 328 individuals with neurological disorders (18-75 years old).

Design:

Participants will be randomized into two groups:

VR Training Group: Engages in immersive VR-based rehabilitation. Active Control Group: Receives conventional therapy. Sessions: 20 sessions over 8 weeks (3 times per week).

Assessments at 3 time points:

T0 (Baseline): Neurological, neuropsychological, motor, and neurophysiological evaluations.

T1 (Post-intervention): Repeat assessments to measure immediate effects. T2 (Follow-up at 3 months): Evaluate the maintenance of improvements.

Assessments & Outcome Measures:

Cognitive Function: MoCA, MMSE, ACE-R, Rao's Battery. Motor Function: Functional Independence Measure (FIM), TUG, Tinetti Scale, Berg Balance Scale.

Neurophysiological Changes: EEG, fNIRS, MRI, eye-tracking, motion analysis, sEMG.

Emotional & Social Function: Short Empathy Quotient (EQ-short), Faux Pas Test, Hamilton Depression Scale.

Usability & Acceptance: System Usability Scale (SUS).

Expected Impact:

This study aims to advance personalized rehabilitation strategies, improve accessibility to innovative therapies (e.g., telerehabilitation), and optimize the use of VR-based interventions in clinical practice.

Inclusion Criteria:

• Age: 18 to 75 years
• Diagnosis:

Parkinson's Disease (PD) (MDS Clinical Diagnostic Criteria) Multiple Sclerosis (MS) (McDonald Criteria) Spinal Cord Injury (SCI) (ASIA Impairment Scale) Acquired Brain Injury (ABI) (WHO Criteria for Stroke)

• Education: Minimum of 5 years of formal education
• Cognitive and physical ability to engage in rehabilitation

Exclusion Criteria:

• Major psychiatric disorders (e.g., psychosis, severe depression, anxiety disorders)
• Severe medical conditions that impair participation
• Sensory or motor impairments preventing VR interaction
• Contraindications for MRI (e.g., pacemakers, incompatible implants)
• Pregnancy

IPD related to primary and secondary outcome measures will be shared. This includes data on cognitive performance, social cognition, neurophysiological parameters (EEG and MRI biomarkers), gait analysis, and eye movement metrics. Data will be made available to qualified researchers upon reasonable request, following ethical and legal guidelines to ensure participant confidentiality. Access will be provided through a secure platform for a limited period after the study's completion. Specific requests will be evaluated on a case-by-case basis, and approved researchers must agree to terms of use.

IPD and supporting documentation, including the Statistical Analysis Plan (SAP), will be available starting 6 months after the study's primary completion date. Access will be provided for 5 years from the initial availability date, ensuring adequate time for secondary analyses while maintaining relevance to ongoing research efforts.

Requests for access to Individual Participant Data (IPD) and supporting documentation will be evaluated by the study's data-sharing committee. Researchers must submit a proposal detailing their study objectives, statistical analysis plans, and ethical approval. Access will be granted for scientifically valid purposes, following a signed data use agreement. Requests should be directed to: mariagrazia.maggio@irccsme.it.

This study uses a single-blind design, where outcome assessors are masked to group assignments to reduce bias. Participants and therapists delivering the intervention are aware of the assignment due to the nature of the rehabilitation protocols, but the neuropsychological, motor, and neurophysiological evaluations (EEG, MRI, motion analysis) will be conducted by blinded assessors who do not know whether the participant belongs to the VR Training Group or the Active Control Group.