UNIVERSITY OF CALIFORNIA Los Angeles Applications of Quantitative Gait Analysis in the Assessment of Disease Progression in Duchenne Muscular Dystrophy A dissertation submitted in partial satisfaction of the requirements for the degree Doctor of Philosophy in Biomedical Engineering by Kent Robert Heberer 2016 © Copyright by Kent Robert Heberer 2016 ABSTRACT OF THE DISSERTATION Applications of Quantitative Gait Analysis in the Assessment of Disease Progression in Duchenne Muscular Dystrophy by Kent Robert Heberer Doctor of Philosophy in Biomedical Engineering University of California, Los Angeles 2016 Professor Eileen Greenan Fowler, Co-Chair Professor Alan Garfinkel, Co-Chair Duchenne muscular dystrophy (DMD) is a progressive X-linked genetic neuromuscular disorder that primarily affects males, is characterized by muscle atrophy, progressing proximally to distally, due to a lack of functional dystrophin protein, and currently has no cure. The focus of this work is gaining a biomechanical understanding of disease progression and compensatory strategies through quantitative gait analysis and musculoskeletal modeling. Gait deviations such as excessive trunk lean, excessive anterior pelvic tilt, reduced hip extensor moments, increased plantar flexion and plantar flexor moments have been observed for this population and are the result of progressive muscle weakness. Data obtained via quantitative gait analysis has the potential to be a sensitive outcome measure for clinical trials in young boys with DMD. This was explored by determining that joint moments about the hip were sensitive to improvement with a ii corticosteroid intervention in a group of young boys with DMD, as compared to a steroid-naïve group. The mechanical hypothesis of disease progression was explored through musculoskeletal modeling by calculating eccentric and concentric work performed by individual muscles during gait. Muscles that performed more eccentric work were generally those with a greater degree of involvement. Muscles with more involvement decreased work with disease progression. And there was an increase in work from distal muscles as the work from proximal muscles decreased. This laid groundwork towards linking two biomarkers of disease progression: muscle function during gait and fatty tissue infiltration as measured by imaging methods. Finally, Induced Acceleration Analysis was used to assess the efficacy of typical compensatory strategies that develop in response to proximal muscle weakness. To maintain ambulation, muscles must provide support and propulsion for the center of mass. With disease progression, the ability of proximal muscle decreases and contributions from distal muscles must increase to compensate. This work is the first study that uses quantitative gait analysis as an outcome measure for an intervention, and is the first study to use musculoskeletal modeling to analyze the biomechanics of gait in this population. iii The dissertation of Kent Robert Heberer is approved. Melissa Spencer Jacob Schmidt Alan Garfinkel, Committee Co-Chair Eileen Greenan Fowler, Committee Co-Chair University of California, Los Angeles 2016 iv This dissertation is dedicated to the children with DMD and their families. v Table of Contents Chapter 1. Introduction ................................................................................................................... 1 1.1. Duchenne Muscular Dystrophy ............................................................................................ 1 1.2. Randomized Clinical Trials .................................................................................................. 2 1.3. Multi-site Natural History Study .......................................................................................... 3 1.4. Quantitative Gait Analysis and Normative Gait .................................................................. 5 1.5. Normative Gait ..................................................................................................................... 7 1.6. Stance Phase of Gait ............................................................................................................. 9 1.7. Gait Analysis and Duchenne Muscular Dystrophy ............................................................ 10 1.8. Compensatory Gait Patterns in Duchenne Muscular Dystrophy........................................ 12 1.9. Musculoskeletal Modeling ................................................................................................. 14 1.10. Induced Acceleration Analysis ......................................................................................... 18 1.11. Significance of Study ....................................................................................................... 22 Chapter 2. Hip Kinetics During Gait as an Outcome Measure for Clinical Trials ....................... 25 2.1. Introduction ........................................................................................................................ 25 2.2. Methods .............................................................................................................................. 27 2.2.1. Study Population ......................................................................................................... 28 2.2.2. Gait Analysis ............................................................................................................... 29 2.2.3. Timed Functional Tests ............................................................................................... 29 2.2.4. Statistical Analysis ...................................................................................................... 29 2.3. Results ................................................................................................................................ 30 2.4. Discussion .......................................................................................................................... 37 2.5. Conclusions and Future Study ............................................................................................ 42 Chapter 3. Influence of Muscle Work on Disease Progression .................................................... 44 3.1. Introduction ........................................................................................................................ 44 3.2. Methods .............................................................................................................................. 48 3.2.1. Study Population ......................................................................................................... 48 3.2.2. Gait Assessment .......................................................................................................... 48 3.2.3. Musculoskeletal Modeling .......................................................................................... 49 3.2.4. Muscle Work Calculation ............................................................................................ 49 3.2.5. Quantification of Fat Fraction Rank ............................................................................ 50 3.3. Results ................................................................................................................................ 50 3.3.1. Spatial Temporal Parameters, Joint Kinematics, and Joint Kinetics ........................... 50 3.3.2. Simulation Residual and Reserve Actuators ............................................................... 53 3.3.3. Muscle Forces, Contraction Velocity, and Power ....................................................... 55 3.3.4. Muscle Work ............................................................................................................... 57 3.4. Discussion .......................................................................................................................... 60 3.4.1. Eccentric Muscle Work Relates to Fat Fraction Rank ................................................ 60 3.4.2. Compensatory Strategies Minimize Muscle Work...................................................... 61 3.4.3. Normalization Methods and Modeling Considerations ............................................... 64 3.5. Conclusions and Future Work ............................................................................................ 66 Chapter 4. Individual Muscle Contributions to Support and Propulsion ...................................... 67 4.1. Introduction ........................................................................................................................ 67 4.2. Methods .............................................................................................................................. 69 vi 4.2.1. Study Population ......................................................................................................... 69 4.2.2. Gait Assessment .......................................................................................................... 69 4.2.3. Musculoskeletal Modeling .......................................................................................... 69 4.2.4. Induced Acceleration Analysis .................................................................................... 70 4.3. Results ................................................................................................................................ 71 4.3.1. Overall Contributions .................................................................................................. 72 4.3.2.