Ultrasound and Computational Modeling Reveal Complex Relationships between Muscle Size, Quality, and Strength in Patients with Neuromuscular Diseases

Author: ORCID icon orcid.org/0000-0001-9381-2152
McCrady, Allison, Biomedical Engineering - School of Engineering and Applied Science, University of Virginia
Blemker, Silvia, EN-Biomed Engr Dept, University of Virginia

Skeletal muscle is essential to all activities, powering all human movements such as walking, drinking, and even driving a powered wheelchair. In neuromuscular diseases (NMDs) such as Duchenne muscular dystrophy (DMD), facioscapulohumeral muscular dystrophy (FSHD), and spinal muscular atrophy (SMA), muscles degenerate over time, contributing to progressive loss of function. Despite therapeutic advances, clinical assessments remain unchanged and highly participative and subjective, emphasizing the need for objective biomarkers sensitive to subtle changes across disease stages. Previous research established links between muscle structure and function, but in diseased muscles, factors like tissue loss, neurogenic dysfunction, fibrosis, and fatty infiltration disrupt this relationship, challenging the direct correlation between changes in tissue quality and strength alterations, thereby highlighting the inadequacy of measuring skeletal muscle tissue quality alone to predict subtle functional changes. My thesis leverages ultrasound imaging and finite element modeling to uncover the complex relationship between muscle size, quality, and strength in patients with NMDs.
First, I utilized ultrasound imaging to quantify the size and quality of elbow flexor muscles in patients with DMD and SMA as well as healthy controls. From these measurements, I developed a multi-variable estimate of muscle strength that accounted for 65% of the variation in torque production. Next, I longitudinally tracked these patients over three years to analyze dynamic changes in elbow flexor muscle size, quality, and their correlation with strength variations. I revealed that size and quality are not directly linked and are both necessary to estimate strength from ultrasound measurements. Finally, I developed a pipeline to rapidly generate subject specific finite element models, incorporating heterogeneous distributions of fat within muscle to examine its impact on strength. The study found that fat at location within muscle volume significantly influenced force generation, particularly noting a pronounced force decline with middle-region fatty infiltration compared to distal and proximal regions. Overall, my work identified structural and qualitative changes in skeletal muscle in NMDs, established a foundation for a multivariable ultrasound-based biomarker of patient function, and elucidated the impact of regional fat infiltration heterogeneity on muscle mechanics, thus advancing understanding of NMD impacts, enhancing clinical assessments, and improving clinical trial design to transform care for patients with these diseases.

PHD (Doctor of Philosophy)
skeletal muscle, ultrasound, finite element analysis, neuromuscular disease, muscle function and strength
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