Nearly 1 million individuals in the United States have multiple sclerosis, which causes fatigue and problems with walking. Fatigue and walking problems are poorly treated, but exercise training, particularly high-intensity walking exercise, may help. This provide insight into whether high-intensity walking exercise can improve fatigue and walking problems in people with multiple sclerosis, which could improve quality of life and reduce economic burden.

Multiple sclerosis (MS) is an immune-mediated, neurodegenerative disease of the central nervous system with a prevalence of nearly 1 million adults in the US. The pathophysiology of this disease results in two of the hallmark features of MS, namely symptomatic fatigue and walking impairment. These two features of MS are inter-related as symptomatic fatigue is often a driver of declines in walking and worsening of disability over time, and both compromise quality of life and independence. To date, fatigue and walking impairment are poorly managed through conventional disease modifying medications or rehabilitation therapy in MS.

One approach for improving fatigue and walking in MS is an appropriate dose of exercise training. Current recommendations of 30 min/day 2 days/week of low to moderate exercise training can improve symptomatic fatigue, aerobic capacity, strength, and walking endurance, and other symptoms in people with MS. This prescription is often delivered using moderate-intensity, continuous training (MCT) walking. However, improvements in fatigue and walking outcomes have been small, suggesting that MCT may not be the optimal approach. In people with stroke, high intensity, interval-based walking exercise has provided a greater stimulus than MCT for improving outcomes, but this approach has not been researched in MS.

There are a few field-wide limitations of research on exercise training, fatigue, and walking outcomes in MS. Often, researchers have (a) enrolled people with MS regardless of symptomatic fatigue and/or walking dysfunction, and this yields floor effects in outcomes and prevents conclusions on exercise as a treatment approach; (b) included people with mild disability, but not moderate or severe disability; and (c) applied exercise modalities not based on the principle of specificity (i.e., using walking training to improve fatigue and walking impairment). This project overcomes these field-wide limitations and compares effects of moderate and high intensity treadmill training on symptomatic fatigue and walking in people with MS with elevated fatigue and walking dysfunction.

Inclusion Criteria:

• Age ≥21 years
• Multiple sclerosis diagnosis
• Stable disease-modifying therapy (DMT) over the past 6 months
• Walking dysfunction (i.e., abnormal gait pattern, Expanded Disability Status Scale (EDSS) score of 4-6.5, and/or Patient-determined disease steps (PDDS) score of 3-6)
• Able to walk for 6 minutes at self-paced speed. Handheld assistive device is acceptable.
• Symptomatic fatigue (Fatigue Severity Score ≥ 4)

Exclusion Criteria:

• Adults unable to consent
• Pregnant women
• Prisoners
• Multiple sclerosis relapse within the last 30 days
• Other neurological disorders besides multiple sclerosis
• Cardiorespiratory or metabolic diseases (e.g., cardiac arrhythmia, uncontrolled hypertension or diabetes, chronic emphysema)
• Significant cognitive or communication impairment (Mini-Mental State Examination (MMSE)<21), which could impede the understanding of the purpose of procedures of the study or prevent the patient from performing the ankle-tracking task.
• Severe osteoporosis
• Failure to pass the graded exercise stress test
• Implanted cardiac pacemaker
• Metal implants in the head or face
• Unexplained, recurring headaches
• History of seizures or epilepsy
• Currently under medication that could increase motor excitability and lower seizure threshold
• Skull abnormalities or fractures
• Concussion within the last 6 months

All underlying data for this study will be deidentified and then will be shared.

All shared data will be made available at latest by the time of associated publication or at the end of the performance period, whichever comes first. As permitted by the relevant repositories, data will be made available in perpetuity, but at minimum for 10 years.

All data described above will be shared on UIC INDIGO and UIC Research Data Glacier, university institutional and data repositories. All shared data will be accessible via persistent unique identifiers (Digital Object Identifier [DOI]). DOIs will be referenced in any related publications.