Repetitive Transcranial Magnetic Stimulation to alleviate Fatigue in Multiple Sclerosis – study protocol for a randomized sham-controlled double-blinded clinical trial

Sofus Nygaard^1*Mads A.J. Madsen^1,2Vanessa Wiggermann¹Chiara Cabras¹Lasse Christiansen¹Alena Svatkova³Henrik Lundell¹Helene Højsgaard Chow⁴Jeppe Romme Christensen⁴Morten Blinkenberg⁴Finn Sellebjerg^4,5Hartwig Roman Siebner^1,5,6*

• ¹Department of Radiology and Nuclear Medicine, Danish Research Centre for Magnetic Resonance, Hvidovre Hospital, Hvidovre, Denmark
• ²MS Center Amsterdam, Amsterdam UMC Locatie VUmc Afdeling Anatomie & Neurowetenschappen, Amsterdam, Netherlands
• ³Department of Radiology and Nuclear Medicine, Hvidovre Hospital, Hvidovre, Denmark
• ⁴Rigshospitalet Dansk Multipel Sklerose Center, Glostrup, Denmark
• ⁵Faculty of Health and Medical Sciences, Department of Clinical Medicine, Kobenhavns Universitet, Copenhagen, Denmark
• ⁶Department of Neurology, Bispebjerg Hospital, Copenhagen, Denmark

Background: Fatigue is a common and disabling symptom in multiple sclerosis (MS), quantifiable by patient reported outcome instruments such as the Fatigue Scale for Motor and Cognitive Functions (FSMC). The pathophysiology of fatigue remains poorly understood, and effective treatments are limited. Emerging evidence implicates disrupted excitation–inhibition balance in the premotor cortex as a potential culprit of fatigue in MS. Converging evidence now show that such network imbalance can be modulated with repetitive transcranial magnetic stimulation (TMS). The efficacy of premotor rTMS retuning excitation-inhibition balance, thus improving MS-related fatigue, has yet to be examined in a clinical trial. Methods: This randomized, double-blinded, sham-controlled, parallel-group trial investigates the efficacy of premotor TMS in treating fatigue in MS. Fifty-eight patients with MS will receive either active or sham TMS targeting the left dorsal premotor cortex (PMd). On five consecutive days, participants will undergo 30-minute sessions using a novel low-frequency (0.72 Hz) paired-pulse repetitive TMS protocol with an interstimulus interval of 33 ms. The primary endpoint is the change in FSMC score six days post-intervention. Secondary outcomes include additional fatigue assessments and quantification of regional γ-aminobutyric acid (GABA) and glutamate concentrations of the targeted PMd, via ultra-high-field (7T) magnetic resonance spectroscopy. We hypothesize that active treatment will result in greater fatigue reduction than sham treatment and correlate positively with an increase in regional GABA in the stimulated premotor region. Exploratory endpoints include structural and functional connectivity changes assessed with 7T resonance imaging and motor cortical excitability changes measured with TMS. Discussion: This study will assess the feasibility and efficacy of a novel low-frequency paired-pulse TMS protocol for fatigue in MS. Repeated neurophysiological measurements of cortical excitation–inhibition balance will yield mechanistic insights and guide future repetitive TMS trials targeting MS-related fatigue. Trial registration: Prospectively pre-registered at www.clinicaltrials.gov with ID NCT06569550. Published August 12th, 2024