Therapeutic exercise in multiple sclerosis: Mechanisms of neuroprotection, modality-specific benefits, and...

Exercise represents a foundational disease-modifying therapy for multiple sclerosis (MS), engaging interconnected biological pathways including brain-derived neurotrophic factor (BDNF)-mediated neuroprotection, pro-inflammatory cytokine reduction (IL-6, TNF-α), oligodendrocyte precursor stimulation for remyelination, and metabolic optimization. This comprehensive review synthesizes evidence from 103 studies on exercise modalities and technology-enhanced delivery systems. Analysis reveals that appropriately prescribed exercise significantly improves health-related quality of life (HRQoL; Surface Under the Cumulative Ranking Curve [SUCRA] 87 % for sensorimotor training), reduces fatigue (Effect Size [ES] = -4.34), enhances mobility (+25.56 m on the 6-minute walk test [6MWT]), and confers neuroprotective benefits. Aerobic exercise optimizes cardiorespiratory function, resistance training best reduces fatigue, while mind-body practices improve mental HRQoL. Critically, emerging technologies-including robotic exoskeletons (27.3 m 6MWT improvement), adaptive virtual reality (VR) (41 % greater adherence), and AI-driven telerehabilitation (88 % retention) - overcome historical barriers of heat sensitivity, fatigue, and accessibility. Precision frameworks must account for sex-specific responses, with women showing greater fatigue/HRQoL improvements and men exhibiting superior strength gains. Limitations include clinical heterogeneity, underrepresentation of progressive MS, and technology access disparities. The evidence supports structured exercise as essential across disease stages, with recommended implementation through biomarker-integrated prescription. Future research should prioritize exercise-disease-modifying therapy [DMT] synergies, validation of gender-specific protocols, and real-world artificial intelligence (AI) prescription models.