PROJECT SUMMARY/ABSTRACT Multiple sclerosis (MS) is an immune-mediated neurodegenerative disease of the central nervous system that causes localized damage to myelin, resulting in loss of function, disability, and reduced quality of life. Although disease-modifying drugs can help reduce the frequency of relapses and onset of new symptoms, this approach is insufficient for optimal recovery from existing symptoms. One potential approach to overcome functional impairments related to existing motor deficits is through development of therapeutic strategies that induce neuroplasticity. The objective of this proposal is to investigate the potential of a novel therapeutic intervention — Acute Intermittent Hypoxia (AIH) — that has shown significant promise to enhance neuroplasticity in persons with spinal cord injury but has not yet been studied in MS. AIH constitutes a brief, repeated reduction in oxygen concentration which stimulates the serotonergic pathway and enhances activity of serotonin receptors. This results in increased synthesis of plasticity-related proteins that potentiate synaptic transmission and drive plasticity. We hypothesize that a repeated AIH protocol will improve voluntary limb function in individuals with MS. We also hypothesize that AIH will induce sustained changes in neural activity within the central nervous system, which contribute to therapeutic plasticity. We test this hypothesis using a double-blind, sham-controlled and crossover trial in MS patients with established motor deficits and controlled relapse activity who are administered mild doses of intermittent hypoxia (or sham hypoxia) for five days. We examine the resulting effects by quantifying changes in strength, function and walking performance immediately and 1-week post-intervention. We also use advanced functional magnetic resonance imaging techniques to measure changes in neural activation during voluntary ankle flexion and intrinsic connectivity in the somatomotor cortices at rest, which have both shown plasticity-related changes during successful motor rehabilitation strategies. Additional clinical MRI scans at enrollment and 1-week post-intervention will be monitored for radiologic signs of new disease activity as part of participant safety monitoring. This proposal will determine the extent to which priming the central nervous system with an approach known to induce plasticity improves function in MS, and provide evidence of the neural mechanisms driving these therapeutic effects. The insights gained from this work will inform the development of more effective therapies combining daily AIH with task specific training for improvement of function and quality of life in individuals with MS.