Multiple sclerosis (MS) is a degenerative disease process that disrupts the transmission
of nerve impulses, resulting in a range of neurological signs and symptoms.
Walking-related impairment is one of the most common symptoms, reported to affect more
than 90% of people with MS. The leading non-pharmacological intervention for
walking-related deficits in people with MS is rehabilitation, such as physical therapy.
Rehabilitation is believed to restore function through experience-dependent
neuroplasticity. There is strong evidence that physical therapy can improve
mobility-related function in people with MS, and emerging evidence that motor-relearning
approaches to rehabilitation may be associated with changes in brain structure and
function that correlate with improvements in functional performance. The leading
pharmacological intervention for walking-related deficits in people with MS is
dalfampridine. Dalfampridine improves motor function by increasing nerve conduction
through demyelinated axons, however, dalfampridine alone is not likely to generate
neuroplastic changes needed for lasting benefits, because neural plasticity requires
salient and task-specific practice with high repetition at adequate intensity, as well as
complex environments that stimulate opportunities for movement to facilitate synthesis of
neurotrophic factors. Indeed, the treatment effects of dalfampridine are reversed as soon
as the treatment was discontinued. However, it is possible that improved nerve conduction
velocity provided by dalfampridine may accelerate neuroplasticity generated from
rehabilitation. Yet, combining dalfampridine with concurrent rehabilitation has never
been studied. The objective of the proposed study is to test our central hypothesis that
providing a motor-relearning physical therapy intervention in combination with
dalfampridine will produce superior gains to either intervention alone in mobility
through augmented neuroplasticity.
Aim 1 will determine if dalfampridine can augment the effects of physical therapy in
restoring function in people with MS by comparing the combined intervention to physical
therapy without dalfampridine. Aim 2 will explore the comparative effectiveness between
the combined intervention with dalfampridine alone, and between physical therapy alone
and dalfampridine alone. In Aim 3, the investigators will investigate mechanisms of
treatment effects by evaluating functional connectivity before and after each
intervention arm. Exploratory Aim 4 will examine whether there are specific clinical and
personal factors associated with treatment responsiveness to each type of treatment. The
primary efficacy outcome will be percent change from baseline in Timed 25-Foot Walk to
enable direct comparison to previous dalfampridine studies. A range of secondary and
tertiary clinical outcomes, both objective and self-reported, will examine restoration of
function (objective and perceived) beyond just walking speed.
The investigators will enroll 48 participants with MS-related mobility deficits and EDSS
≤6.5. In the first treatment phase, all participants will receive 6 weeks of
dalfampridine treatment to assess the effects of this treatment and determine individual
responder status for stratified randomization in phase 2. Following 2-week dalfampridine
washout and new off-drug baseline assessment, stratified randomization will allocate
participants to either 6 weeks of physical therapy with resumed dalfampridine or 6 weeks
of physical therapy without dalfampridine. Outcomes will be reassessed after the physical
therapy treatment phase. This project tests a novel combination of two traditional
interventions to improve mobility in people with MS, with specific aims that investigate
both restoration of function and mechanisms of treatment effects using brain imaging
outcomes. These two leading, yet distinct approaches for improving mobility in people
with MS, may have complementary mechanisms of action leading to enhanced outcomes when
combined. The findings generated by this research will inform the design of further
studies exploring longer-term outcomes and disease progression trajectories associated
with the interventions found to be most effective and tolerable for individuals with MS
in this stage of the research.