Focusing on neural mechanisms of exercise training benefits in multiple sclerosis.

Exercise training (ET) should be a mainstay of comprehensive care in multiple sclerosis (MS), yet there is reluctance regarding its implementation among healthcare providers. This reluctance has its roots in the lack of evidence from randomized controlled trials (RCTs) that provide a neurobiological mechanism for beneficial outcomes. We argue that ET training is efficacious for improving mobility and cognitive dysfunction as hallmark consequences of MS, and propose an experimental medicine framework for guiding research focusing on CNS mechanisms-of-action for ET benefits. The framework establishes three hierarchical pathways as preconditions for applying a mediation framework in a fourth pathway for fully testing mechanistic research questions using a RCT. This paper describes the conceptual basis of the pathways, and then reviews the existing evidence within the pathways of the framework for ET effects on the CNS, mobility, and cognition in MS. Lastly, this paper discusses future directions and challenges for testing the pathways of the framework for advancing the evidence regarding CNS mechanisms of ET benefits in this population. Our objective is guiding the field toward evidence that facilitates the prescription and promotion of ET as a neurorestorative approach within MS clinical practice.