Cognitive impairment is prevalent, disabling, and poorly-managed among the 1 million Americans living with multiple sclerosis (MS). Indeed, 67% of adults with MS have cognitive impairment, particularly slowed cognitive processing speed (CPS), and this is associated with impaired learning and memory and worse fatigue, depression, anxiety, pain, and quality of life (QOL). This underscores the importance of identifying efficacious approaches for managing CPS impairment and its consequences among those with MS. There is merit in a remotely-delivered physical activity (PA) intervention for managing MS-related CPS dysfunction in MS. We have provided evidence from a pilot, randomized controlled trial (RCT) that an Internet-delivered PA intervention resulted in a clinically meaningful improvement in CPS among those with mild MS-related ambulatory disability; there were additional improvements in fatigue, depression, anxiety, pain, and QOL. The pilot RCT did not a priori recruit persons with MS who had objective CPS impairment nor examine sustainability of CPS changes over time, and it involved a waitlist control that did not account for the effects of attention and social contact. We leverage our experiences and preliminary results, and propose an appropriately-powered, Phase-II, RCT of a highly-developed and refined Internet-delivered PA intervention focusing on walking during ambulatory activities of daily living (steps/day) for yielding immediate and sustained improvements in remotely-assessed CPS among persons with mild MS-related ambulatory disability who demonstrate impaired CPS. The proposed study, if successful, will provide Class I evidence regarding the efficacy of a 6-month, Internet-delivered, PA intervention compared with an active control condition for improving important outcomes in 300 adults with MS who present with both mild MS ambulatory disability and impaired CPS. The primary outcome is the remotely-delivered Symbol Digit Modalities Test as a measure of CPS; the secondary outcomes include a remotely-delivered, objective measure of learning and memory and self-reports of fatigue, depression, anxiety, pain, and QOL; the tertiary outcome is accelerometry as an objective, device-based measure of PA. The conditions will be delivered by persons who are uninvolved in screening, recruitment, random assignment, and outcome assessment. We will collect outcomes on 3 occasions over a 12-month period (i.e., pre-intervention, immediately post-intervention, and 6-month follow-up). The outcomes will be collected using a blinded assessor. Data analyses will involve intent-to-treat principles, and mixed-effects models and logistic regression. The proposed research may yield "real-world" guidelines for free-living PA change that can be implemented for the treatment of CPS impairment in MS. Such an opportunity for rehabilitation of cognitive function using an approach with broad reach and scalability is paramount considering the prevalent, disabling, and poorly-managed nature of CPS impairment in MS and limited resources for its treatment.
