T Richard Nichols - US grants

The body's reaction to mechanical disturbance is determined in part by the resultant stiffness of the joints. The long-term goals of this research are to understand the reflex and brainstem mechanisms which determine joint stiffness and which may function abnormally in disorders of movement. The stiffness of a joint depends upon the muscular stiffness of its agonists and antagonists. Muscular stiffness can, in turn, be partitioned into a component due to the mechanical properties of muscle and reflex component. The reflex component receives contributions from the same muscle synergists by way of autogenetic reflexes and from antagonists by way of non-antogenetic pathways. The analysis of reflex function proposed here is based on methods of evaluating these contributions to muscular stiffness. Mechanical measurements will be made on ankle flexors and extensors in decerebrate cats with intact midbrain structures. Net muscular stiffness will be calculated from measurements of changes in force in response to ramp length changes (K=dF/dL). Mechanical components will be estimated from the responses of electrically stimulated muscles and subtracted from net stiffness to give the reflex component. The magnitude of the reflex component of stiffness is an index of the net strength of transmission in the reflex pathways. Its measurement will be used to test the following hypotheses. 1) That the stretch reflex linearizes the mechanical properties of muscle or, equivalently, regulates its stiffness will be tested by studying muscles individually. 2) The hypothesis that Golgi tendon organs participate with muscle spindles in stiffness regulation will be tested by evaluating force feedback. 3) That the reflex component of a muscle in an intact joint system receives a contribution from non-autogenetic reflexes will be tested by comparing the result of stretching a muscle alone with the result of stretching the muscle and releasing its antagonist. 4) That signals from the brainstem can change or reset regulated stiffness by modulating transmission in reflex pathways will be tested by attempting to modulate stiffness using microstimulation of brainstem areas. If the regulated stiffness of a muscle can be reset, then the hypothesis that the strength of transmission in spinal reflexes is invariant and that resultant joint stiffness can be varied only by cocontraction would not be supported. If resetting exists, then some motor disorders may result from abnormalities of reflex function as well as from abnormal patterns of excitation of motoneuron pools.

The long-term goals of this project are to understand spinal reflex mechanisms that regulate the mechanical properties of muscle and interjoint coordination. Most studies of the mechanical actions of spinal reflexes have focused on autogenic, or stretch, reflexes. A muscle, however, also receives powerful reflex inputs from other muscles in the joint and limb (Heterogenic reflexes). Although the synaptic connectivity of heterogenic reflexes has been studied extensively, the mechanical actions of these pathways have received little attention. The decerebrate preparation will be used to evaluate the organization of autogenic and heterogenic reflexes of knee and ankle musculature under a variety of states of activation. Measurement of heterogenic actions between two muscles will be achieved by applying mechanical inputs independently to the freed tendons and measuring the force responses. A functional and quantitative map of reflexes appropriate for modellingg will be obtained. The rules by which autogenic and heterogenic inputs are integrated in the spinal cord, receptor mechanisms and pharmacology of heterogenic pathways, and the effect of stimulating supraspinal strutures on the organization of spinal pathways will also be studied. The predictions from these measurements will be tested by applying perturbations to the intact, instrumented limbs of decerebrate animals with intact muscle attachments and feedback from cutaneous and joint receptors. Malfunction of heterogenic reflexes may be an important component of motor disorders such as spasticity. Knowledge about heterogenic reflex organization is needed to understand these motor disorders and to suggest improved diagnostic methods.

The goal of the Program Project Grant is to discover the manner in which coordinated movement results from interactions between the musculoskeletal system and neural circuits in the spinal cord. The purpose of this project is to investigate the role of proprioceptive pathways in mediating intermuscular and interjoint coordination during multi-directional movements. Experiments will be performed on freely moving cats and decerebrate preparations. The patterns of recruitment of key output elements which act at the ankle, including both whole muscles and compartments, will be observed in normal animals during sagittal plane locomotion and turning movements. In terminal experiments, the organization of proprioceptive pathways interconnecting these key output elements will be investigated in the decerebrate state. Proprioceptive feedback from these output elements, but not motor output, will be rendered ineffective by the process of self-reinnervation, and the effects of this procedure on coordination and reflex organization evaluated. The importance of feedback in coordinating postural muscles in the cat hindlimb will be tested by severing the tendons of selected weight-bearing muscles. If intact muscles with similar actions but different patterns of usage assume the activity patterns of the tenotomized muscles, then the hypothesis will be supported if strong intermuscular reflexes develop from and to the intact muscles. The experiments proposed here and elsewhere in this Program Project Grant are intended to help revise and extend current models of spinal cord function in motor control. These advances will lead to more comprehensive diagnoses and new treatments for motor disorders.

biomedical equipment; electrophysiology; biomedical facility;

The long-term goal of this project is to understand the consequences of the loss of short-latency proprioceptive feedback for motor coordination during locomotion and targeted reaching. Self-reinnervation of muscle following transection of the nerve can lead to a permanent loss of effective proprioceptive feedback. Peripheral nerve injury can also lead to a long-term disruption of dexterity or motor coordination, even after regrowth of the nerve. The central hypothesis for this project is that sensory feedback from muscle prioprioceptors provides ongoing regulation of coordination and during voluntary motor behavior, and that the loss of this feedback leads to permanent deficits in motor coordination. This hypothesis will be tested by using the method of self- reinnervation to remove effective feedback from selected muscles in the cat and evaluating the motor performance of these animals following the restoration of motor power. The intermuscular distribution of proprioceptive feedback from muscle spindle receptors and Golgi tendon organs will first be determined. Actions of these pathways will be measured by stretching individual muscles or perturbing the forelimb in decerebrate animals and then measuring the resulting force or electromyographic responses. These data will be used to determine the most important sources of sensory feedback. Motor deficits resulting from loss of this feedback will be evaluated in otherwise intact animals by causing the self-reinnervation of selected muscles that supply critical feedback to other muscles in the forelimb. Animals will be filmed during locomotion on ramp surfaces or during targeted reaching movements. Based on similar studies using the hindlimb, the removal of effective feedback is expected to produce a loss of interjoint coordination down a ramp and difficulty in terminating movements of the forelimb. The ability of these animals to compensate for these deficits will be evaluated by long-term experience on the behavioral task. This project will constitute an evaluation of the role of sensory feedback from muscles on the coordination of voluntary movements and of the mechanisms underlying the loss of coordination following peripheral nerve injury.

[unreadable] DESCRIPTION (provided by applicant): The scant quantified knowledge base within the profession of prosthetics and orthotics (P&O) is due to a fundamental lack of research skills among clinical practitioners and educators within the profession. It is estimated that approximately 11% of individuals in the P&O profession possess a master's degree and less than 1% (about a dozen individuals) possess a terminal academic degree, i.e. a PhD (1). The only way to address the disconnect between clinically relevant basic science, and applied engineering research in P&O is to make a concerted effort to produce competent researchers who are sensitive to the clinical needs of the consumer requiring a prosthesis or orthosis as part of a comprehensive treatment plan of rehabilitative care. It is this need that provides the motivation for this training grant application. In direct response to the profession's own recommendation (AERTI Report, Appendix C) to pursue the formulation of graduate training programs, a PhD training program focused in prosthetics and orthotics in the School of Applied Physiology at the [unreadable] Georgia Institute of Technology is proposed. Twenty-five academic faculty from ten separate schools at three separate Universities and 21 clinical faculty from the general Atlanta area will be engaged in a unique program of advanced research and education training. The purpose of the proposed program is to prepare independent scientists through predoctoral, interdisciplinary research training in the rehabilitation priority, specifically rehabilitation related to prosthetics and orthotics, of the movement sciences. The objective of this training program is to provide an advanced theoretical basis in the biomechanics and neural control of movement for the skills required in rehabilitation research in the field of prosthetics and orthotics. Uniquely, Georgia Tech is in a position to advance the profession of prosthetics and orthotics in acquiring research skills and new knowledge through the integration of the only entry level masters degree program in P&O in the US and a PhD training program rich in integrated research in the biomechanics and neural control of movement. A flexible curriculum with a series of required and elective classes is presented to accommodate basic undergraduate preparation in engineering and the life sciences as well as pre- and post- professional applicants in the field. The plan of study lasts from 4-5 years culminating in a PhD degree from the Georgia Institute of Technology focused in prosthetics and/or orthotics. [unreadable] [unreadable] [unreadable]

Abstract Following transaction and surgical repair of a muscle nerve in the cat, motor and sensory axons gradually reinnervate the muscle over the course of 6-9 months, but the sensory information is permanently blocked from accessing the parent muscle. It has been shown in patients that such nerve injuries result in permanent loss of dexterity, suggesting an important role for sensory feedback from muscles in motor coordination. In previous cycles of this program project, it was shown that one year after animals received transection and repair of the nerves to the triceps surae muscles the animals exhibited a loss of ankle joint stiffness that resulted in a pronounced ankle joint yield when the animals walked down a ramp but not up the ramp. These findings are consistent with the directional properties of length feedback. In the last grant cycle, it was found that the pronounced yield following reinnervation was absent or much reduced if the animals underwent treadmill training for 12 months following the transection and repair, even though the stretch reflex remained absent. We now propose three new investigations. The first is to elucidate the manner in which the animal was able to compensate for the loss of directionally-specific feedback. Second, we plan to investigate the possibility that systematic training on ramp walking itself might provide a means of restoring local feedback to muscles. Third, we wish to understand the contributions of a second receptor, the Golgi tendon organ that provides force-related feedback to muscles in the limb. We will address these questions using a combination of experiments and computer simulations. Experiments in the cat will be used to address the mechanisms underlying adaptations to the loss of muscle force and sensory feedback. Computer simulations will be used to understand how peripheral nerve injury and adaptations to this injury result in changes in global coordination of the joints of the limb. Finally, we will use ramp training in an attempt to restore local sensory feedback. These experiments will test the extent to which an animal can use an alternative pattern of muscle recruitment to compensate for the deficits from peripheral nerve injuries and provide additional insight into the specific roles of sensory information from muscle spindles and Golgi tendon organs. Finally, we will attempt to employ a therapy to restore the normal mechanisms of motor coordination.

PROJECT SUMMARY (See instructions): Tendon transfer surgery is a common procedure to treat paralysis or paresis resulting from spinal cord injury, cerebral palsy or other neurological disorders. The tendon of a functioning muscle, sometimes even a direct antagonist, is sewn into the tendon of the weakened muscle to improve motor function in the desired direction. The recovery of motor function from these procedures can be limited and learning new motor patterns can be difficult. It is therefore important to develop quantitative assessment tools to measure the success of surgical manipulation of the musculoskeletal system and to track the progress of rehabilitation of individuals with injury to the peripheral motor apparatus. One such approach is the measurement of limb stiffness using robotic technology. This approach can potentially detect changes in musculoskeletal organization such as occurs with tendon transfer or fasciotomy as well as changes in proprioceptive circuits in the spinal cord and brainstem resulting from neurological disease. Stiffness measurements will be made on the hindlimbs of decerebrate cats after tendon transfer, fasciotomy and muscle reinnervation in order to establish the relationship between the manipulation of the motor system and the emergent mechanical properties. These measurements will then be used to evaluate adaptations of the motor system to the manipulation after a survival period. This approach can be readily adapted for use with human subjects, and potentially constitutes a powerful diagnostic tool. Among the several possible reasons for a less than satisfactory outcome of tendon transfer surgery, and one that appears not to have been considered until now, is that the relationships between the natural patterns of activation of the muscle and the mechanical feedback from the muscle are altered. This mismatch, rather than contributing to the retraining of muscular activation patterns, could result in suppression or reorganization of proprioceptive circuits. The proposed experiments have been designed to test the hypothesis that the altered timing of sensory information could limit recovery of function following tendon transfer. These experiments will utilize measurements of limb stiffness as well as evaluations of individual proprioceptive pathways in decerebrate cats.

DESCRIPTION (provided by applicant): There is a pressing need for an increase in the number of scientists and clinicians in the profession of prosthetics and orthotics with advanced degrees to pursue research and direct the associated clinical education programs. In view of the rise of terroristic warfare, increases in the incidence of diabetes and obesity, and the aging population, the shortage of basic and translational research is limiting critical advances in this field. The purpose of this application is to request a renewal of a successful predoctoral training grant designed to ameliorate the research base of prosthetics and orthotics. In this training program, competent researchers are being trained in the clinically relevant physiological sciences and engineering. The trainees are exposed to the clinical practice of prosthetics and orthotics to better inform the research and to develop sensitivity to the needs of the patients. The students are also educated in the responsible conduct of research and biomedical medical ethics in a problem-based setting. Twenty-three faculty members from basic science and clinical departments and centers from Georgia Institute of Technology, Emory University and Georgia State University and the Shepherd Center constitute the training faculty for this program, which is based in the School of Applied Physiology at Georgia Tech. The School provides a unique setting for this program given that the focus of interest is on movement science. The faculty investigates mechanisms of motor control from molecular through systems and behavioral levels using physiological and engineering approaches. The School is also the home of the first entry-level masters level degree program in prosthetics and orthotics in the United States. The trainees work closely with the students and faculty of this clinical masters program to ensure the clinical relevance of the training. The program includes a core curriculum in physiology, neuroscience and biomechanics, and a seminar in which problems in contemporary rehabilitation sciences are discussed. Courses in rehabilitation related science and technology have been developed with faculty members in the Division of Physical Therapy at Emory. The program is flexible in accommodating students with different backgrounds and different research goals. The program of study lasts from 4-6 years and culminates in the PhD degree from The Georgia Institute of Technology with a focus in prosthetics and orthotics