Tracking remyelination in a model of multiple sclerosis: Visual evoked potentials reveal therapeutic effect from brain stimulation and exercise

Visual evoked potentials (VEPs) represent an accurate, fast, and cost-effective diagnostic tool to evaluate visual function in multiple sclerosis (MS), and its use in preclinical research can support longitudinal monitoring of treatments effects with implications for translational purposes. Anodal transcranial direct current stimulation (tDCS) and physical exercise (PE) are known to exert neuromodulatory effects on the central nervous system, increasing brain activity, promoting plasticity and remyelination. To improve our understanding of the effects of tDCS and PE on demyelination/remyelination processes and refine its therapeutic use in MS, VEPs were employed to monitor the mouse visual pathway during cuprizone (CPZ) demyelination including before and after therapeutic interventions. In CPZ-fed mice, VEP latency delays were associated with MBP loss in the dorsolateral geniculate nucleus (dLGN) confirming VEP as a biomarker of demyelination in the subcortical visual pathway. Combination of anodal tDCS and PE showed a strong beneficial effect on VEP latency during CPZ demyelination. Both VEP latency and behavioural motor function improvements were stronger after combined protocols, highlighting the potential of this multimodal approach in demyelinating conditions. Differential and synergistic contribution by anodal tDCS and PE was associated with reduced microglia/macrophage levels whilst effects on myelin by the first, and reduced cell death and BDNF protein were driven by the second. VEPs efficiency to detect modulation of visual function by brain stimulation and physical activity, strongly correlated with myelin changes in the visual pathway, providing a potent platform for the translatability of preclinical findings to the clinic.