Matthew C. Tresch - US grants

[unreadable] DESCRIPTION (provided by applicant): Movement results from the complex interplay between neural and musculoskeletal systems. Whether investigating motor control in healthy subjects or following injury, both systems must be considered in order to interpret the function, or dysfunction, of movement. Our long term research goal is to investigate this interplay, providing insights into the mechanisms and strategies underlying biological motor control in health and disease. In the research proposed here, we will examine the production of locomotion in the rat, examining both its neural control and its biomechanics. Although the rat is being used increasingly to study motor control and the consequences of injury, many features of its behavior and biomechanics are unknown. We will evaluate a specific hypothesis about biological motor control: that motor systems produce movement through the flexible combination of a small number of muscle groups, or muscle synergies. We propose that the muscles within each such group are not arbitrary but are adapted to the biomechanics of the motor system. Our specific aims are to 1) Evaluate, using novel computational analyses, whether the patterns of muscle activations recorded during locomotion in freely behaving rats can be well described as the combination of muscle synergies; 2) Develop a biomechanical model of the hindlimb musculoskeletal system of the rat to be used in interpreting the identified muscle synergies; 3) Use this model to examine the biomechanical actions of identified synergies and to assess whether complex behaviors can be produced by combination of muscle synergies. The research proposed here thus serves two simultaneous purposes, both of potential relevance to public health. First, by testing this specific hypothesis of the production of complex movement by a mammal, this research will provide insights to motor control in other mammals, including humans. Second, by providing basic information and powerful computational tools for the analysis of motor control in the rat, this research will greatly increase our basic understanding of this important model system. Based on this understanding, we can better evaluate the effects of injury in this system and can more readily develop strategies of rehabilitation and regeneration, strategies which might then be translated into clinical settings. [unreadable] [unreadable]

DESCRIPTION (provided by applicant): The control of every movement, whether it is a basic reflex or a sophisticated skill, is highly complex, involving the control of muscles distributed throughout the limb and body. This complexity is present whether movements are produced naturally by the nervous system or artificially by rehabilitation engineers for the restoration of movement following motor impairments. Understanding the neural strategies used to overcome these complexities can therefore potentially provide new advances in our ability to restore movement following injury. We take this approach in the proposed research, attempting to translate insights derived from basic experimental and theoretical research in order to improve strategies used to restore motor function. The experiments performed in this research are based on two recently proposed principles for the simplification of biological motor control. The first principle suggests that the nervous system uses muscle synergies to reduce the number of variables that need to be specified in the production of movements. In this hypothesis, each such 'synergy'controls the activation of a small group of muscles, with complex movements produced by flexibly combining multiple synergies. The second principle suggests that the nervous system exploits the intrinsic dynamics of the limb in order to increase the efficiency of motor control. In this hypothesis, the properties of the muscles and skeleton allow certain motor commands to be particularly effective in producing movements. In this proposal, we combine these two principles in order to develop a novel strategy for the restoration of motor function following injury. In particular, we will develop and evaluate a controller based on muscles synergies which are designed to exploit the intrinsic dynamics of the limb. We have shown in simulation work that this hypothesis is capable of producing a wide range of movement efficiently and effectively. The proposed experiments will extend this simulation work and evaluate this strategy directly by using it to reanimate a paralyzed limb. Specifically, this research will 1) use experimental measurements of the musculoskeletal dynamics to identify a low dimensional representation of the rat hindlimb, 2) identify a set of muscle synergies which controls the intrinsic dynamics of the rat hindlimb, 3) then finally use these synergies to produce movements in a paralyzed limb. This research will therefore directly test whether this strategy of using muscle synergies to exploit intrinsic limb dynamics is capable of restoring motor function following injury. This work will take recent novel theoretical research and translate it to an experimental situation with direct clinical relevance. The results of this research therefore have the potential to significantly advance clinical applications using control strategies to restore movement in patients with motor impairments. PUBLIC HEALTH RELEVANCE: The research in this proposal will evaluate a novel strategy for restoring motor function following paralysis. This strategy will greatly simplify the control of limb movements using functional electrical stimulation, increasing the efficiency and efficacy of rehabilitation strategies. The experiments to be performed in this research therefore have the potential to significantly advance clinical applications for the restoration of function in patients with motor impairments.

DESCRIPTION (provided by applicant): Sarcomere lengths are one of the main determinants of how a muscle contributes to behavior. Whether a muscle functions primarily for movement stabilization or for power generation is strongly influenced by the sarcomere lengths over which that muscle operates. Moreover, alterations in sarcomere properties contribute to muscle damage following injury. Although investigators have used a variety of methods to measure sarcomere lengths, the ability to measure these lengths in situ and how they vary when the limb is moved or when the muscle is active, remains a fundamental challenge. The research in this proposal will develop a promising new technique, two photon microscopy, to measure sarcomere lengths in muscles in situ. This technique will allow us to characterize sarcomere length variations across muscles, limb configurations, and activation patterns. Importantly, it also will allow us to begin characterizing how these measures change following exercise related muscle damage. This technique has several potential advantages over current techniques of characterizing sarcomere lengths of muscles. First, it can measure sarcomere lengths without disturbing muscle fibers, so sarcomere lengths can be measured in an intact muscle. Second, sarcomere lengths can be measured in functioning muscles, so that effects of activation can be directly evaluated. Such measurements are impossible with current techniques of measuring sarcomere lengths. Third, multiple sarcomere length measurements can be made quickly and repeatedly, so that we can examine sarcomere operating ranges directly without resorting to extrapolation. This repeatability also allows us to visualize the development of muscle damage during exercise related activity in situ; e.g. tracking sarcomere properties in the same muscle as damage is progressively induced through eccentric contractions. Finally, we will perform these measurements in an in vivo preparation that we have recently developed for measuring muscle actions, so that we will be able to measure both sarcomere lengths and muscle actions in situ. The ability to collect these measurements together in the same preparation will give us unprecedented insight into the function of a muscle and how it contributes to behavior. We have three specific aims in this proposal. First, we will measure the operating range of sarcomeres across a large number of muscles in the rat hindlimb, to determine the relationship between sarcomere lengths and hypothesized muscle functions. Second, we will measure the change in sarcomere operating ranges after muscle activation, to determine the degree to which neural control alters sarcomere operating ranges. Finally, we will image sarcomeres during the development of muscle damage induced by eccentric contractions. If successful, this research has the potential to directly address these fundamental issues of muscle function and disease, demonstrating the potential power of two photon microscopy in studies of muscle function. PUBLIC HEALTH RELEVANCE: The experiments described in this proposal will develop an innovative technique for making in situ measurements of sarcomeres in muscles. The force produced by a muscle is critically determined by these sarcomere lengths and yet these lengths can be difficult to measure in living tissue. We will use two photon microscopy to measure these sarcomere lengths in living muscle, characterizing directly how these micro scale muscle properties contribute to macro scale aspects of muscle function. We will also examine sarcomere properties during the induction of muscle damage from exercise related activity, providing new insights into the structural substrate underlying injury.

DESCRIPTION (provided by applicant): Most motor control studies consider how the CNS controls task level variables, examining, for example, how the CNS produces the joint torques necessary to achieve behaviors such as locomotion. In this context, it is the set of torques produced by a muscle that determines its activation by the CNS. However, this focus on task performance ignores the control of another critical set of variables, those characterizing the state of internal joint structures such as ligaments and articular cartilage (i.e. ligament strainsor bone contact forces). Failure to regulate these internal joint variables can have significant consequences to health both in the short term (e.g. ligament rupture, joint dislocation) and in the long term (e.g. chronic joint pain, arthritis). The CNS should therefore consider both task performance and internal joint variables when determining muscle activations. How internal joint variables might be incorporated into motor control strategies, however, is poorly understood. The overall goal of the experiments described in this proposal is to evaluate these issues, examining the control of internal joint variables by the CNS. We will examine these issues using an animal model, focusing on the control of the knee joint by quadriceps muscles in the rat. The specific anatomy of the rat knee allows for a clear separation between the effects of quadriceps muscles on task performance variables (joint torques) and internal joint variables (mediolateral patellar forces). Using this model we can therefore make strong predictions about how the control of internal joint variables should be reflected in muscle activations across a range of behavioral conditions. We will perform three sets of related experiments. In Aim 1 we will characterize the mechanical actions of quadriceps muscles on task performance and internal joint variables. We hypothesize that quadriceps muscles will produce similar knee joint torques but distinct mediolateral patellar forces. In Aim 2, we will examine whether the neural control of quadriceps reflects the regulation of internal joint variables. We first hypothesize that in intact animals, the correlation in the variability of EMGs reflects the balancing of mediolateral patellar forces. Further, we hypothesize that following selective muscle paralysis or perturbations of patellar forces, long term adaptations in muscle activations will improve the control of internal joint variables. In Aim 3 we will examine the role of joint afferents in the control of internal jont variables. We hypothesize that joint afferents are not used for rapid feedback control of muscle activations but are used to guide long term adaptations of muscle activations following perturbations to internal joint variables. These experiments provide a systematic analysis of the role of internal joint variables in the neural control of behavior, using a range of techniques in conceptually simple and tractable experimental model. The results of these experiments have the potential to significantly impact motor control, both in our basic understanding of motor control and in clinical applications that seek to restore function after injury.

Despite the  long-­term promise  of  stem-­cell  and  other biological  approaches,  current options to  improve  function  following  spinal  cord  injury  (SCI)  remain  quite  limited.  However,  brain  machine  interfaces  (BMIs)  that  use  cortical  activity  to  drive  functional  electrical  stimulation  (FES)  of  muscles  or  the  spinal  cord  have  great  promise  not  only  for  the  restoration  of  motor  ability  when  using  the  BMI,  but  also  for  improved  functional  rehabilitation so that their performance is improved when the BMI is removed. The overall goal of our research  is to identify strategies that maximize both of these potential strengths of cortically-­controlled FES.   A system using cortical activity to drive stimulation of individual muscles might maximize the restoration  of motor function: by enabling users to vary the amplitude and timing of individual muscles, movements can  potentially be adapted as necessary to achieve task demands. Alternate strategies of producing movement,  such as activation of muscle groups or of sites in the spinal cord producing limb flexion or extension, will  reduce the range of possible movements. Although these strategies might be simpler to learn after SCI than  control of individual muscles, they clearly limit the level of motor function that can be restored.  In order to achieve the greatest functional rehabilitation, however, spinal stimulation might be a more  promising strategy than muscle stimulation. Repeated spinal stimulation might maintain the function of spinal  pathways involved in the production of movement and enable restoration of connections from descending  systems through associative plasticity. Conversely, since muscle stimulation does not activate spinal pathways  to produce movement, it might produce less functional rehabilitation.  There is therefore a potential tradeoff between muscle and spinal stimulation: muscle stimulation enables  high  levels  of  motor  ability  but  might  limit  functional  rehabilitation,  while  spinal  stimulation  might  enhance  rehabilitation  but  limit  flexibility.  Our  research  will  investigate  this  tradeoff,  with  the  goal  of  designing  a  hybrid  system  that  combines  spinal and  muscle  stimulation  to achieve high  levels  of  both  motor  ability  and  functional  rehabilitation.  We  will  perform  these  experiments  in  rats,  implanting  electrodes  in  the  cortex  to  record  neural  activity  and  in  the  spinal  cord  and  muscles  to  produce  movements.  We  will  then  train  rats  to  use  these  systems  after  SCI, evaluating  whether  they  can  improve  motor ability and  functional  rehabilitation.  In  Aim 1,  we will  evaluate  whether animals can produce high levels of motor ability with a system using cortical activity to control activation  of  individual  muscles.  In  Aim  2,  we  will  evaluate  whether  animals  using  cortical  activity  to  control  activation  of  spinal stimulation have better functional rehabilitation. Finally, in Aim 3 we will evaluate whether a hybrid system  that  controls  activation  of  both  muscle  and  spinal  stimulation,  exploits  the  advantages  of  each  approach  to  produce movement, resulting in high levels of both motor ability and of functional rehabilitation.