Linking movement-related beta oscillations to cortical excitability, structural damage, and fatigue in multiple sclerosis

Abstract

[Abstract] Fatigue is one of the most disabling symptoms of multiple sclerosis (MS), yet its neurobiology remains unclear, and there are no objective biomarkers. Previous studies using electroencephalography alone have revealed altered movement-related beta Event-Related Desynchronization (ERD) and Synchronization (ERS) dynamics in fatigued patients, but without providing mechanistic insight. In this cross-sectional study, we combined electroencephalography with transcranial magnetic stimulation, structural magnetic resonance imaging with diffusion tensor imaging (DTI), and clinical measures to probe the mechanistic basis of movement-related beta modulation depth (ERS-ERD) and its link with fatigue. Based on the Fatigue Severity Scale score (FSS), we enrolled 41 relapsing-remitting MS patients, 19 with clinically significant fatigue, 22 without (aged 25-55 years, 25 females), alongside 18 age- and sex-matched healthy volunteers. Participants underwent neuropsychological assessment, blood sampling for inflammatory and neurodegeneration-related biomarkers, structural magnetic resonance imaging with DTI to assess grey and white matter integrity, transcranial magnetic stimulation to quantify cortical excitatory and inhibitory balance, and continuous electroencephalography during 300 cued pinch movements to characterize movement-related beta dynamics. Compared with non-fatigued patients and healthy volunteers, fatigued patients exhibited reduced beta peak ERD to ERS modulation (P < 0.001), especially in frontal regions. The modulation depth correlated with fatigue severity (ρ = -0.54, P = 0.0006), intracortical facilitation (ρ = 0.49, P = 0.0009), and caudate nucleus volume (ρ = 0.35, P = 0.010). A nested elastic-net logistic regression integrating demographic, clinical, structural, and functional markers showed robust held-out performance (mean Receiver Operating Characteristic-Area Under the Curve = 0.92, Precision Recall-Area Under the Curve = 0.83, accuracy = 0.89, Brier score = 0.10). Variables with the strongest protective association with fatigue were higher intracortical facilitation, better mental health, larger caudate volume, greater beta modulation over the frontal regions, and higher corticospinal tract and superior longitudinal fasciculus integrity. These findings support frontal beta modulation as a mechanistically grounded, non-invasive biomarker of central fatigue in multiple sclerosis and highlight its potential utility for clinical diagnosis and targeted therapeutic intervention.