Combining pharmacological and non-invasive brain stimulation strategies to promote remyelination in multiple sclerosis

Remyelination in multiple sclerosis (MS) fails for several, partly overlapping reasons. The differentiation of oligodendrocyte precursor cells into myelin-producing oligodendrocytes is impaired both by intrinsic factors and by the surrounding lesion environment, which becomes increasingly inflammatory and senescent with age. Pharmacological strategies acting on a single target to promote oligodendrocyte lineage progression have been successful in animal models but have yet to produce meaningful clinical benefit in people with MS (pwMS). In this perspective paper, we argue that simultaneously targeting several of the mechanisms underlying this failure is a more promising route to repairing myelin lesions in pwMS. We outline how non-invasive brain stimulation (NIBS) might be leveraged to shift the glial microenvironment towards a pro-regenerative, remyelinating state, and how this can be paired with targeted pharmacological agents that enhance oligodendrocyte differentiation. We also discuss how the expected effect of such a combination may depend on age and lesion stage. This framework may offer a rational route beyond the translational failures of single-target remyelination therapies.