This is a double-blind, parallel, randomized, sham-controlled pilot study evaluating the safety, feasibility, and efficacy of Gamma Sensory Stimulation (GSS) delivered via a Virtual Reality (VR) headset in individuals with Multiple Sclerosis (MS) who experience moderate to severe fatigue. Participants will be randomized (1:1) to 4 weeks of active GSS or sham stimulation, followed by a 4-week post-treatment follow-up. The primary objective is to determine whether GSS reduces fatigue, measured by the Modified Fatigue Impact Scale (MFIS). Secondary outcomes include additional fatigue scales, cognitive performance, quality-of-life measures, tolerability and safety.

Gamma Sensory Stimulation (GSS) is a non-invasive audiovisual neuromodulation method that delivers synchronized 40 Hz stimulation to engage gamma-band neural oscillations. Gamma-frequency activity is implicated in cognitive processing and large-scale network coordination, which may be disrupted in people with Multiple Sclerosis (MS), particularly in those experiencing fatigue. Prior research suggests that gamma-frequency entrainment may modulate neural network activity and support functional outcomes.

This single-center, double-blind, randomized, sham-controlled pilot study investigates whether 4 weeks of GSS delivered through an immersive Virtual Reality (VR) system can reduce fatigue in individuals with MS. Participants with moderate to severe fatigue will be randomized in a 1:1 ratio to receive either active GSS or sham stimulation embedded in matched VR content. The intervention consists of 16 in-lab stimulation sessions delivered over 4 weeks (4 sessions per week). Each session includes 30 minutes of active stimulation within a standardized VR experience.

The primary endpoint is the change in Modified Fatigue Impact Scale (MFIS) total score from baseline to End of Treatment (Week 4). Secondary endpoints include changes from baseline to End of Treatment (Week 4) and follow-up (Week 8) in additional validated fatigue measures (Fatigue Severity Scale, Visual Analogue Scale for Mental Fatigue, PROMIS Fatigue), cognitive performance assessed by the Symbol Digit Modalities Test (SDMT), quality-of-life measures (Neuro-QoL Fatigue), and the rate of change in Daily Fatigue Severity (DFS) across the treatment period. Exploratory outcomes include MFIS subscale scores, variability in daily fatigue ratings, embedded cognitive task performance during stimulation, and treatment acceptability.

Safety and tolerability will be assessed through monitoring of adverse events, session attendance, and retention. Electroencephalography (EEG) will be collected at baseline and at End of Treatment (Week 4) for exploratory characterization of neural responses to gamma-frequency stimulation.

This pilot investigation aims to generate preliminary safety, feasibility, and efficacy data to inform future multisite studies evaluating VR-based GSS as a potential at-home therapeutic approach for MS-related fatigue.

Inclusion Criteria:

1. Be between 18 to 65 years of age (inclusive) on the day of signing informed consent.

2. Have MS (McDonald criteria 2017) with Modified Fatigue Impact Scale (MFIS) score greater than 33 OR fatigue greater than 4 (out of 7) on the Fatigue Severity Scale (FSS).

3. Sufficient hearing and vision.

4. Any type of disease modifying therapy is allowed and should be stable in the last 3 months.

5. Not having received corticosteroids the previous month.

6. Each subject must sign the informed consent form, in accordance with local requirements, after the scope and nature of the investigation have been explained to the subject, and before Screening assessments.

7. Based on the investigator's judgment, the subject should:

   1. Be able to speak, read, and understand the language of the trial staff and the informed consent form;
   2. Possess the ability to respond verbally to questions, follow instructions, and complete study assessments;
   3. Be able to adhere to the stimulation protocol and visit schedules.

8. Women of child-bearing potential* must have a negative urine pregnancy test before the inclusion in the study and agree to use highly effective contraceptive methods during the study. Highly effective contraceptive methods will include intrauterine device, implant, patch or pill, bilateral tubal occlusion, vasectomized partner and sexual abstinence.

Exclusion Criteria:

1. Any condition or therapy impairing trial participation and assessments.
2. The presence of a relapse or use of IV steroids for any reason 3 months prior to screening visit.
3. Severe systemic diseases or history of cancer or hereditary familiar cancer.
4. Clinically relevant concomitant disease: cardiac, gastrointestinal, hepatic, pulmonary, neurological, renal or other major disease.
5. A history of seizure or epilepsy.
6. Pregnant or breastfeeding women.
7. Drug or alcohol abuse.
8. Patients with active systemic bacterial, viral or fungal infections, or known to have uncontrolled AIDS or to be HIV-positive but not receiving anti-retroviral therapy based on medical history or available clinical information at screening.
9. Dementia or severe psychiatric, cognitive or behavioral problems or other comorbidity that may interfere with the compliance to the protocol.
10. Any other clinically relevant medical or surgical condition, which, in the opinion of the investigator, would put the subject at risk by participating in the study.
11. Participation in other experimental studies within the previous 90 days prior to screening visit.
12. Patients having a pacemaker or other metal implants.

This study collects pseudonymized clinical, behavioral, and EEG data that are subject to GDPR and local data protection regulations. Because the dataset contains sensitive information that cannot be fully de-identified, individual-level data will not be made publicly available. Aggregate results may be shared in publications or upon reasonable request to the sponsor.

Participants, care providers, treating investigators, and outcome assessors are blinded to treatment allocation. Active and sham stimulation are delivered through identical virtual reality content and session procedures, and no perceptual cues are provided that would allow participants or study staff to distinguish between treatment conditions. Device configuration (active or sham mode) is preset by unblinded technical personnel who are not involved in participant interaction, clinical assessments, or data analysis.