Cognitive impairment is prevalent, disabling, and poorly-managed among the 1 million Americans living with
multiple sclerosis (MS). Indeed, 67% of adults with MS demonstrate cognitive impairment, particularly slowed
cognitive processing speed (CPS), and this is associated with worse fatigue, depression, anxiety, 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, and QOL. Importantly, 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 further 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 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 280 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 are self-report measures of fatigue, depression, anxiety, and QOL; the tertiary
outcome is accelerometry as a 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
outcome data on 3 occasions over a 12-month period (i.e., pre-intervention, immediately post-intervention, and
6-month follow-up). The outcome data 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. The proposed research is further consistent with the National
Center for Medical Rehabilitation Research’s mission of fostering the development of scientific knowledge for
enhancing the health, productivity, independence, and QOL.