Understanding Fatigue in Multiple Sclerosis to Build Smarter Physical Therapy Exercise Programs

Fatigue represents one of the most disabling and least understood symptoms of multiple sclerosis. It is multifactorial, involving both central and peripheral mechanisms that compromise muscle performance and functional endurance. For many patients, fatigue limits daily activities for patients. It also hinders their capacity to participate fully in therapeutic exercise, which is the same intervention known to improve strength, mobility and quality of life. Despite its clinical significance, little is known about the rate at which muscle force declines in people with MS during repeated or sustained activity.

Why Quantifying Fatigue Matters

This knowledge gap has practical consequences: Physical therapy exercise prescriptions to increase strength and power output in neurologic rehabilitation are often adapted from musculoskeletal protocols designed for individuals without central nervous system disease. While these regimens emphasize repeated sets to build strength and endurance, clinicians frequently encounter patients with MS who cannot tolerate the same exercise volume. The inability to quantify how quickly force production deteriorates leaves physical therapists relying primarily on perceived exertion or functional observation. As a result, exercise intensity may be set too low to drive adaptation or too high to sustain engagement.

Study Design and Objectives

To address this, my colleagues in the Department of Physical Medicine and Rehabilitation at Rush and I are initiating a controlled study to characterize the pattern and rate of muscle fatigue in people with MS. The study, entitled Strength and Force Changes During Repeated Muscle Contractions and Functional Tasks in People with Multiple Sclerosis, began enrollment in November 2025; participants include adults with MS who are 18 to 60 years of age.

The study will quantify changes in maximal voluntary isometric contraction (MVIC), peak joint torque, overall body system power output per body weight and concentric and eccentric ground force impulse. These measures will be collected using dynamometry during isolated muscle contractions and through novel marker less motion capture techniques during the standardized functional exercise task of a sit to stand closely reflects daily movement. By examining both controlled and functional fatigue paradigms, we aim to capture differences between physiologic muscle fatigue and the perception of exertion that often dominates self-reported symptom scales.

Defining Objective Markers of Fatigue

We hypothesize that this study may clarify how neuromuscular fatigue evolves over time and how it differs between individuals with MS and healthy controls. It also gives us the opportunity to identify early objective markers, such as a defined percentage drop in joint and or body system force variables over time, that could serve as practical indicators for adjusting therapeutic workload. The inclusion of a healthy control group will provide normative data against which disease-related changes can be interpreted, allowing the team to separate fatigue attributable to normal muscular physiology from that driven by demyelination or impaired central drive.

Translating Research to Clinical Practice

Beyond its immediate findings, the study reflects a broader effort within rehabilitation science to move toward quantitative, biomarker-based approaches to exercise dosing. Similar to how advanced neuroimaging metrics have refined understanding of disease progression in MS, objective physiologic measures can inform individualized rehabilitation plans. For clinicians, the ability to predict when a patient will experience performance decline could guide rest intervals, resistance levels and session frequency with far greater precision than subjective fatigue reporting alone.

Data generated from this work will also have implications for clinical trial design and therapeutic development. Quantitative fatigue profiles could serve as secondary outcome measures in studies evaluating pharmacologic or behavioral interventions aimed at improving endurance or neuromuscular efficiency. Within the clinical setting, these measures could be integrated into routine assessments to track progress and adjust interventions dynamically.

Rush’s Commitment to Translational Rehabilitation Research

Rush’s Brain Health Program provides an ideal environment for this research, integrating multidisciplinary expertise in neurology and physical medicine and rehabilitation. The program’s infrastructure supports rapid translation of findings from the laboratory to the therapy gym, where individualized, evidence-based interventions can be implemented immediately. As data collection progresses, we plan to analyze within-subject and between-group variance to model predictors of early fatigue onset, recovery patterns and correlations with disease subtype and disability status.

Toward a More Precise Model of Exercise Prescription

Fatigue remains one of the most common reasons people with MS disengage from exercise programs, yet exercise remains one of the most powerful tools available to preserve function. Defining the physiologic limits of effort will help clinicians prescribe the right intensity, frequency and progression for each individual, which will be strong enough to promote adaptation but calibrated to sustain participation over time. Through this work, we aim to close the gap between research and clinical care, advancing a precision-based approach to rehabilitation that improves safety, efficiency and long-term outcomes for people living with multiple sclerosis.