To understand control strategies employed by the central nervous system (CNS) control movement or force generation in a limb, a seven degree of freedom cat hindlimb was modeled. In this study, the biomechanical constraints affecting force generation for balance and postural control were investigated. Due to the redundancies at the muscular and joint levels in the musculoskeletal system, even the muscle coordination pattern to statically produce a certain amount of force/torque at the ground is not straightforward. A 3D musculoskeletal model of the cat hindlimb was created from cat cadaver measurements using Software for Interactive Musculoskeletal Systems (SIMM, Musculographics, Inc.). Six kinematic degrees of freedom and 31 individual hindlimb muscles were modeled. The moment arms of the muscles were extracted from the software model to be used in a linear transformation between muscle activation, and end effector force and moment. The Jacobian matrix that establishes the relationship between joint torques and end effector wrench was calculated. Maximal muscle forces were estimated from the literature. A feasible set of forces that can be generated at the toe was constructed using combination of maximally activated muscle excitations. Because the endpoint torque is typically small in a cat, an optimization algorithm was also performed to maximize the force generation at the end effector while constraining the magnitude of the endpoint torque. The results are compared with the measured force magnitude and direction data from an acute cat hindlimb preparation for different postures. This static model is applicable for understanding muscle coordination during postural responses to small balance perturbations.

Thesis (Ph. D.)--University of Missouri--Columbia, 2001. / "May 2001." Typescript. Vita. Includes bibliographical references (leaves 141-150). Also available on the Internet.

Clinical evidence indicates a higher incidence of peripheral arterial occlusive disease and associated likelihood of critical limb ischemia in women, as well as worse prognosis and decreased survival post myocardial infarction. Therefore, understanding the possible differences in underlying vascular compensation mechanisms is crucial. With arterial occlusions, necrosis and tissue injury can be naturally mitigated by the collateral circulation, improving patient prognosis. Previous sex-comparison studies describing differences in vascular remodeling are inconsistent. Therefore, the aim of this study was to describe the effect of arterial occlusion on collateral remodeling in healthy male and healthy reproductive-stage female mice. At 7 days following femoral artery ligation in C57Bl/6 and BALB/c mice, there were no sex-related differences in functional ambulatory recovery. There were no sex-related differences in mechanoadaption indicators in the collateral stem- vascular smooth muscle cell (VSMC) length and overlap, with the exception of longer smooth muscle cells in male C57Bl/6 mice, VSMC lengths 329 ± 19 verses 288 ± 13 μm, male and female. Collateral midzone luminal and abluminal diameters, as well as wall thicknesses were not different between sexes. As comprehensive sex-specific differences were not captured in our specific investigation of arteriogenesis, an evaluation of microvascular remodeling in the ischemic zone and collateral vasodilation would be of interest, as would evaluating arteriogenesis following oophorectomy with estrogen depletion. The determination of any underlying mechanistic sex-specific differences could be the foundation for which targeted therapeutics are developed, which will be crucial for closing the prognosis gap between men and women in the global treatment of peripheral arterial occlusive disease.

Functional hyperemia and arteriolar vasodilation are impaired with chronic ischemia. We sought to examine the impact of chronic ischemia on collateral artery function. For this we used two hindlimb ischemia models to dissect the impact of different repair processes on collateral function. Ligation of the femoral artery increases shear stress in the muscular branch and results in outward remodeling and arteriogenesis. In contrast, resection of the femoral artery proximal to the muscular branch induces blood flow divergence and neutral remodeling along with expectedly greater hypoxia and inflammation. On day 14 after each surgery the diameter of the muscular branch was measured using sidestream dark field (SDF) imaging before and after gracilis muscle stimulation. A slight, but not statistically significant, impairment in functional vasodilation was observed in ligated mice (69±10% average diameter increase compared to 74±7% average diameter increase). Resected mice exhibited slightly (not statistically significant) enhanced collateral artery functional vasodilation (104±16% average diameter increase) but were also refractory to the restoration of resting vascular tone following the cessation of stimulation. Outward remodeling did not significantly impair vascular function, whereas neutral remodeling and tissue hypoxia induced impaired vascular tone.

Although people can typically maintain balance on moving trains, or press the appropriate button on an elevator with little conscious effort, the apparent ease of these sensorimotor tasks is courtesy of neural mechanisms that continuously interpret many sensory input signals to activate muscles throughout the body. The overall hypothesis of this work is that motor behaviors emerge from the interacting constraints and features of the nervous and musculoskeletal systems. The nervous system may simplify the control problem by recruiting muscles in groups called muscle synergies rather than individually. Because muscles cannot be recruited individually, muscle synergies may represent a neural constraint on behavior. However, the constraints of the musculoskeletal system and environment may also contribute to determining motor behaviors, and so must be considered in order to identify and interpret muscle synergies. Here, I integrated techniques from musculoskeletal modeling, control systems engineering, and data analysis to identify neural and biomechanical constraints that determine the muscle activity and ground reaction forces during the automatic postural response (APR) in cats. First, I quantified the musculoskeletal constraints on force production during postural tasks in a detailed, 3D musculoskeletal model of the cat hindlimb. I demonstrated that biomechanical constraints on force production in the isolated hindlimb do not uniquely determine the characteristic patterns of force activity observed during the APR. However, when I constrained the muscles in the model to activate in a few muscle synergies based on experimental data, the force production capability drastically changed, exhibiting a characteristic rotation with the limb axis as the limb posture was varied that closely matched experimental data. Finally, after extending the musculoskeletal model to be quadrupedal, I simulated the optimal feedforward control of individual muscles or muscle synergies to regulate the center of mass (CoM) during the postural task. I demonstrated that both muscle synergy control and optimal muscle control reproduced the characteristic force patterns observed during postural tasks. These results are consistent with the hypothesis that the nervous system may use a low-dimension control scheme based on muscle synergies to approximate the optimal motor solution for the postural task given the constraints of the musculoskeletal system. One primary contribution of this work was to demonstrate that the influences of biomechanical mechanisms in determining motor behaviors may be unclear in reduced models, a factor that may need to be considered in other studies of motor control. The biomechanical constraints on force production in the isolated hindlimb did not predict the stereotypical forces observed during the APR unless a muscle synergy organization was imposed, suggesting that neural constraints were critical in resolving musculoskeletal redundancy during the postural task. However, when the model was extended to represent the quadrupedal system in the context of the task, the optimal control of the musculoskeletal system predicted experimental force patterns in the absence of neural constraints. A second primary contribution of this work was to test predictions concerning muscle synergies developed in theoretical neuromechanical models in the context of a natural behavior, suggesting that these concepts may be generally useful for understanding motor control. It has previously been shown in abstract neuromechanical models that low-dimension motor solutions such as muscle synergies can emerge from the optimal control of individual muscles. This work demonstrates for the first time that low-dimension motor solutions can emerge from optimal muscle control in the context of a natural behavior and a realistic musculoskeletal model. This work also represents the first explicit comparison of muscle synergy control and optimal muscle control during a natural behavior. It demonstrates that an explicit low-dimension control scheme based on muscle synergies is competent for performance of the postural task across biomechanical conditions, and in fact, may approximate the motor solution predicted by optimal muscle control. This work advances our understanding how the constraints and features of the nervous and musculoskeletal systems interact to produce motor behaviors. In the future, this understanding may inform improved clinical interventions, prosthetic applications, and the general design of distributed, hierarchal systems.

Extended periods of mechanical unloading are known to be detrimental to bone health. Astronauts who spend months in microgravity aboard the International Space Station (ISS) are at particular risk. It is anticipated that NASA will not drastically increase the size of the astronaut corps, and this will mean increased likelihood of repeat missions for more astronauts. Thus, it is important to better understand the effects that prolonged, multiple bouts of unloading have on bone. This study utilized the hindlimb unloaded (HU) rat model to examine bone loss and recovery for single and double unloading bouts. Adult male Sprague-Dawley rats (6 months old) were randomized into the following groups: baseline (sacrificed at 6 months), 1HU7 (unloaded for 1 month, weight-bearing recovery for 3 months), 2HU10 (unloaded for 1 month, recovered for 2 months, unloaded for another month, and then recovered 2 months), 1HU10 (normal cage activity until 1 month HU ending at month 10, 2 month recovery followed), and aging controls (remained ambulatory throughout experiment). Every month (28 days), animals were terminated and the left femurs were excised, resulting in n=15 per group for each time point. Mineral and geometric properties were measured using peripheral quantitative computed tomography (pQCT) at the distal femur metaphysis, and quasi-static reduced platen compression (RPC) was used to estimate the mechanical properties of cancellous bone. Strength indices based on pQCT parameters were calculated as predictors of mechanical properties. Bone mass properties decreased due to HU and recovered within 2-3 months post-HU. A combination of increased periosteal apposition and endocortical resorption also occurred during HU. The initial HU bout suppressed normal age-related increases in mechanical properties and recovered within 1-2 months. Cancellous compressive strength index (CSI) most closely matched changes in mechanical properties. A second HU bout after two months recovery had a less detrimental effect on pQCT parameters but a greater negative impact on mechanical properties, when compared to pre-HU values. The opposite is true for mechanical properties if loss is characterized relative to aging controls. Recovery after the second HU period did not appear to be significantly affected by a previous bout of HU.

Mechanical unloading has deleterious effects on the musculoskeletal system and results in significant reductions in bone density, mass, and strength, which do not fully recover even years after returning to weightbearing. For example, the rate of bone loss in microgravity is 10-fold more rapid than the rate of loss seen in elderly Caucasian females, the population group most predisposed to osteoporosis. This raises concern with individuals who are exposed to multiple bed rest periods or crewmembers who make repeated missions. Exercise offers a way to reduce or reverse these effects. Dual-energy X-ray absorptiometry (DXA) densitometry and bone mineral density (BMD) alone are generally insufficient for capturing the complex changes in bone mass, structure, and integrity and not an accurate predictor of fracture risk. Therefore, it is essential to measure the mechanical properties of bone tissue directly using animal models. The hindlimb unloaded (HU) rat model is a well-established ground-based analog for studying bone response to disuse and effects of spaceflight. The current study is one of the very few that has measured longitudinally densitometric and mechanical properties of bone after repeated simulated microgravity and long-term recovery at multiple anatomic sites in skeletally mature rats. The specific aims were to characterize 1) loss and recovery dynamics of bone following a period of unloading, 2) bone response after a second exposure to 28 days of HU, following an initial 28 days of HU and a recovery period equal to twice the duration of initial exposure, and 3) effects of resistance exercise during recovery period following an initial HU exposure and its effects on a subsequent exposure. In general, our data showed that bone response to unloading and recovery is site-specific. More specifically, we found that: 1) the rat proximal tibia metaphysis modeled the loss and discordant recovery dynamics as seen in the International Space Station (ISS) crewmembers proximal femur better than the rat femoral neck; 2) the initial exposure to HU has minimal effect on the subsequent HU exposure, and detrimental effects of the second HU exposure were milder than the initial due to reduced mechanosensitivity of the bone; 3) exercise significantly enhanced recovery following the initial HU exposure, and losses during the second exposure were not affected by exercise in most cases.

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