Impacts of Dalfampridine on Interhemispheric Relationships in MS

Background: Multiple sclerosis (MS) is a chronic, degenerative condition associated with inflammation and demyelination of the central nervous system (CNS). While most treatments target the suspected autoimmune and inflammatory process, there is growing interest in the development of treatments that directly impact axonal function and the electrophysiological consequences of the disease with respect to slowed or blocked neuronal conduction.

Objectives: This project evaluated biomarkers that reflect the functional integrity of the CNS through exploration of physiological activity within and between key brain regions supporting sensory, motor, and cognitive abilities. The project also sought to assess the impact of extended-release dalfampridine, a potassium-channel blocker, on interhemispheric functional relationships mediated through the corpus callosum.

Methods: Ten patients with MS (ages 25-65) participated in a battery of visual-motor, cognitive, and neuroimaging tests. They were evaluated by structural MRI and fMRI; dual magnetoencephalography (MEG)/electroencephalography (EEG) in resting state and during performance of a visual-motor interhemispheric integration (IHIT) task; cognitive assessments (CANTAB); and neurological examination to stage an EDSS score and measure Timed 25’ Walking Speed. Patients were enrolled before beginning treatment with dalfampridine for gait dysfunction. They were tested before treatment (Baseline), after 14-21 days on drug, and again after 7-14 days without drug (Washout).

Results: Compared to neurotypical controls, MS patients at Baseline showed significant deficits in interhemispheric conduction as measured by visual-motor reaction times, MEG/EEG timing and coherence data, and fractional anisotropy (FA) values for the corpus callosum (p < 0.01 for all). For a subset of patients, dalfampridine improved function between hemispheres (indexed by visual-motor and electrophysiological reaction times), but changes in DTI were not seen. Dalfampridine-induced improvements in IHIT did not reflect changes in FA (p > 0.1), but at both Baseline and Washout there was an association between increased interhemispheric coherence and the efficiency of IHIT as measured by visual-motor reaction times. Patients with greater abnormalities at Baseline tended to show greater positive responses to dalfampridine than patients whose initial findings were closer to normal limits.

Conclusions: Patients with MS show significant structural and functional impairments in interhemispheric relationships. For some, dalfampridine leads to functional improvement. The data suggest that simple visual-motor measures, which can be done in a clinician's office, can serve as surrogates for complex functional measures of interhemispheric connectivity. Future studies will explore more cognitive and real-world correlates of improvements in interhemispheric communication across the corpus callosum.