Fighting Fatigue in Multiple Sclerosis: A Comparative Study of Magnetic vs. Electrical Non-invasive Brain Stimulation

Multiple Sclerosis (MS) is a chronic neurological disease impacting 2.8 million individuals globally, with fatigue being its most debilitating symptom, reported by 75% of patients. Despite its prevalence, the pathophysiology of MS-related fatigue remains poorly understood, and current pharmacological treatments have limited effectiveness. This research addresses this critical gap by investigating two non-invasive brain stimulation (NIBS) techniquestranscranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS)as innovative, effective and scalable therapeutic approaches for MS fatigue.

The study employs a parallel, randomized, triple-blind, multicentric, sham-controlled design to assess and compare the short- and long-term efficacy of TMS and tDCS in addressing MS-related fatigue. 80 participants will be recruited from multiple centers in Spain and randomly assigned to one of four experimental groups: TMS, tDCS, Sham-TMS, Sham-tDCS. Each intervention will consist of 20 sessions, conducted daily from Monday to Friday, over 4 weeks. The left dorsolateral prefrontal cortex (DLPFC, F3 following the 10/20 system for EEG) was selected as the stimulation site based on its involvement in MS-related self-reported fatigue and in cognitive fatigability. For TMS experimental groups, intermittent theta-burst protocol (iTBS) will be used to increase the cortical excitability of the stimulated area. iTBS delivers a total of 600 pulses, organised into 50 Hz triplets repeated at 5 Hz, with 2second blocks of pulses, interleaved with 8 seconds of rest, repeated 20 times (total duration: 190s). The intensity of stimulation will be individually tailored based on the active motor threshold (aMT), setting it at 80% of the aMT. The sham stimulation will follow the same protocol, but using a sham coil (placebo). For tDCS experimental groups anodal tDCS will be applied (increasing cortical excitability) with the anode over the left DLPFC (F3), and the cathode over the contralateral supraorbital area. The intensity will be 2mA, and the duration of the stimulation will be 20min per session. For tDCS placebo condition, the sham option available on the device will be selected.

Primary outcomes include changes in fatigue levels measured through MS validated self-report scales (Modified Fatigue Impact Scale-MFIS; Fatigue Scale for Motor and Cognitive Functions-FSMC); secondary outcomes include depression (Beck Depression Inventory-II, BDI-II), quality of life (Multiple Sclerosis Quality of Life, MSQOL-54), functional independence (Functional Independence Measure, FIM), and cognitive fatigability (Symbol Digit Modalities Test, SDMT). All the outcomes will be assessed at baseline, at the end of the intervention, and six months after the end of the treatment (6 months follow-up).

This project promotes personalized precision medicine and innovative new treatment methods. This research is expected to expand scientific knowledge on NIBS efficacy in MS, establish evidence-based clinical practices, and set the foundation for cost-effective, patient-centered therapies. The study also addresses gender-specific responses to treatment, ensuring inclusive therapeutic strategies. Furthermore, it has the potential to benefit other neurological conditions characterized by fatigue, such as stroke, chronic fatigue syndrome or Parkinsons disease, showing significant social, clinical, and economic impact.