New Protocol to Study Brain Stimulation With Virtual Reality in MS

A newly published study protocol in PLOS ONE outlines a rigorous effort to evaluate whether combining anodal transcranial direct current stimulation (A-tDCS) with virtual reality-based exergame training can improve cognitive dysfunction in patients with multiple sclerosis (MS), a population in which cognitive impairment (CI) affects an estimated 40% to 82% of individuals.¹ The randomized, double-blind, prospective trial is designed to assess both short-term and sustained cognitive effects of this combined neurorehabilitation strategy.

CI in multiple sclerosis is associated with deficits in attention, processing speed, working memory, visuospatial function, and executive control, which can substantially compromise activities of daily living, employment, and quality of life.² Current therapies have not consistently demonstrated benefit for cognitive outcomes, positioning rehabilitation as the primary intervention. Prior studies of cognitive training, transcranial stimulation, and virtual reality (VR) alone have shown mixed and often modest effects, prompting interest in multimodal strategies that may leverage complementary neuroplastic mechanisms.^3,4

The 2-year study will enroll 80 patients with multiple sclerosis and objectively confirmed CI across 3 sites in Genoa, Italy.¹ All participants will undergo a 2-week cognitive rehabilitation program consisting of 10 1-hour sessions delivered 5 days per week using a virtual reality exergame platform. The system integrates motor and cognitive exercises with adjustable difficulty to individualize treatment. The experimental group will also receive concurrent A-tDCS over the left dorsolateral prefrontal cortex during each training session, while the control group will receive sham stimulation at the same site. Both participants and neuropsychological assessors will remain blinded to treatment allocation.

Cognitive outcomes will be assessed using the Brief International Cognitive Assessment for Multiple Sclerosis battery and the Paced Auditory Serial Addition Test at baseline, immediately after the intervention, and at 1- and 6-month follow-up to evaluate whether therapeutic benefits persist over time. Secondary outcomes will encompass quality of life, with patient-reported outcomes assessed, including depression and fatigue, using validated instruments specific to MS populations.

The results of this study may help clarify whether neuromodulation can meaningfully augment functional cognitive recovery rather than produce only short-lived performance gains. Sustained cognitive benefits at 6 months would be particularly meaningful in a disease characterized by progressive neurodegeneration and limited restorative options. "Our results may contribute to refining this knowledge, clarifying the neural mechanisms underlying CI in MS, and possibly pointing to new therapeutic targets," the authors suggest.

Virtual reality-based exergames offer advantages beyond traditional cognitive rehabilitation by increasing patient engagement and motivation, potentially enhancing treatment adherence. Evidence from systematic reviews shows that virtual reality works across multiple neurological conditions, and, specifically in MS, studies have found meaningful gains in attention, visuospatial abilities, executive function, and the speed at which patients process information.[5]

Combining A-tDCS with VR rehabilitation is a new approach, but one that makes sense based on what researchers understand about how the brain responds to these interventions. Anodal stimulation encourages the brain to form new connections through the same processes involved in long-term potentiation, while simultaneously activating broader areas of the cortex. Investigators report that they "anticipate that the combined, simultaneous (on-line) use of A-tDCS and exergames will outperform VR alone (with sham stimulation) in both efficacy and persistence of effects. If confirmed, these findings would strengthen the rationale for implementing integrated neurotechnological protocols in MS rehabilitation, providing protocols that can be translated into everyday rehabilitation settings."

The study has enrolled participants since September 2024, with completion expected by January 2026. Data collection should conclude by July 2026, with final analysis anticipated by September 2026.

References

1. Vestito L, Schenone C, Casazza F, et al. Impact of anodal tDCS and virtual reality on cognitive dysfunction in patients with multiple sclerosis: protocol of a double blind, randomized, prospective, controlled study. PLoS One. 2025;20(12):e0337405. doi:10.1371/journal.pone.0337405

2. Schmidt R, Starke A, Bednarz N, Then Bergh F. Effect of impairment on health-related quality of life in people with multiple sclerosis: association of functional systems and EQ-5D-5L index values in a cross-sectional study. Qual Life Res. 2025;34(6):1773-1781. doi:10.1007/s11136-025-03928-9

3. Mattioli F, Bellomi F, Stampatori C, Capra R, Miniussi C. Neuroenhancement through cognitive training and anodal tDCS in multiple sclerosis. Mult Scler. 2016;22(2):222-30. doi:10.1177/1352458515587597

4. Grigorescu C, Chalah MA, Lefaucheur JP, Kümpfel T, Padberg F, Ayache SS, Palm U. Effects of transcranial direct current stimulation on information processing speed, working memory, attention, and social cognition in multiple sclerosis. Front Neurol. 2020;11:545377. doi:10.3389/fneur.2020.545377

5. Maggio MG, Russo M, Cuzzola MF, et al. Virtual reality in multiple sclerosis rehabilitation: A review on cognitive and motor outcomes. J Clin Neurosci. 2019;65:106-111. doi:10.1016/j.jocn.2019.03.017