Steve Perlmutter, Ph.D. - US grants

limb movement; neurophysiology; spinal nerves; interneurons; motor neurons; single cell analysis; neuroanatomy; afferent nerve; electromyography; Primates; microelectrodes;

DESCRIPTION (Adapted from the Applicant's Abstract): The proposed experiments are components of a research effort whose long-term objective is to understand the role played by the spinal cord in the control of voluntary movements of the primate arm. This goal includes a search for therapies or interventions that will overcome the motor deficits associated with central nervous system injury or disease. The proposed study advances these goals by elucidating the functional organization of spinal interneurons controlling forearm movements in the normal behaving monkey. A thorough understanding of normal spinal function is essential before studies of motor impairment and recovery following injury can be usefully interpreted. The specific aims of the project are: 1. How do descending and sensory signals interact at the level of individual spinal interneurons? 2. Do descending signals recruit subsets of functionally related spinal interneurons by activating them synchronously, and is this coupling of activity modified by sensory input? 3. Are individual motor units within a motor pool controlled independently by spinal interneurons and, if so, how are these interneurons selectively recruited by descending and afferent pathways? The activity of pairs of interneurons in the lower cervical spinal cord of monkeys will be recorded as they move their wrist and exert a power grip of the hand. Interneurons will be identified as having correlational linkages to arm muscles using spike-triggered averaging of electromyographic activity. The responses of interneurons to applied muscle stretch and cutaneous stimuli will be characterized when the muscles are relaxed, and during the preparation for and execution of movements. Cross-correlation histograms of the activity of pairs of interneurons will be calculated to detect synchronous firing in different phases of the movement. The activity of individual, type-identified motor units will be isolated and connections from interneurons detected with cross-correlations of their activity. Together, these studies will elucidate the role of interneuronal pathways in integrating descending and sensory signals to generate motor patterns and lay the foundation for future studies on the mechanisms of motor dysfunction and recovery from injury.

[unreadable] DESCRIPTION (provided by applicant): The proposed experiments are components of a research effort whose long-term objective is to understand the role played by the spinal cord in the control of voluntary movements of the primate arm. This goal includes a search for therapies or interventions that will overcome the motor deficits associated with spinal cord injury. The proposed study advances these goals by elucidating the functional organization of spinal interneurons controlling forearm movements in the normal, behaving monkey. A thorough understanding of normal spinal function is essential before studies of motor impairment and recovery following injury can be interpreted usefully. The specific aims of the project are: 1. What is the role of propriospinal interneurons located rostral to the cervical enlargement in the control of primate arm and hand movements? 2. How are motoneuron and interneuron excitability regulated during normal movements by inhibitory mechanisms in the spinal cord? 3. Is the normal activity of spinal motoneurons during voluntary movement dependent on the action of monoamines? The activity of cervical neurons will be recorded during voluntary reaching, isolated wrist movements, and cocontraction of flexor and extensor muscles of the wrist in the awake monkey. Inhibitory and neuromodulator inputs to spinal neurons will be manipulated with local iontophoresis of pharmacological agents that activate or block serotonin, noradrenaline, GABA or glycine receptors. Input and output connections of interneurons will be identified with spike-triggered averages of EMG and natural and electrical stimulation of peripheral afferents and descending pathways. These studies will elucidate the mechanisms by which the excitability of interneurons and motoneurons are controlled during voluntary movements and lay the foundation for future studies on the mechanisms of motor dysfunction and recovery from injury. [unreadable] [unreadable]

DESCRIPTION (provided by applicant): The proposed experiments will elucidate the integration of descending and sensory signals by interneuronal pathways in the cervical spinal cord of the behaving monkey. The long-term objective of the work is to understand the contribution of spinal cord circuits to the control of normal and impaired voluntary movements of the primate arm. Ultimately, the work will lead to a search for therapies and interventions that can overcome the motor deficits associated with spinal cord injury and stroke. The specific aims of the project examine two broad issues. First, what are the mechanisms by which spinal interneuronal pathways integrate descending and feedback information to regulate the amplitude and timing of wrist and hand muscle activity during voluntary movements? Second, how does information processing in spinal pathways adapt muscle activity to expected and unexpected mechanical conditions? The activity of interneurons in the C5-T1 spinal segments will be recorded in awake monkeys performing several voluntary motor tasks with different instructions and under different loading conditions. These behaviors will include ballistic and slow tracking movements of the wrist, power and precision grips of the hand, and a reach-and-grasp task. The connectivity of the neurons will be identified with spike-triggered averages of muscle activity, and natural and electrical stimulation of peripheral afferents and descending pathways. Mechanical perturbations will be applied to test for the contribution of specific feedback pathways to ongoing and compensatory muscle activity. Neurons in primary motor cortex will be studied under the same conditions. Comparison of cortical and spinal responses will explore the nature of corticospinal processing during execution of voluntary arm and hand movements. PUBLIC HEALTH RELEVANCE: The experiments will provide new insights into the contribution of the primate spinal cord to the generation of a varied repertoire of accurate and flexible movements of the arm and hand. This information is essential for understanding spinal mechanisms of motor impairment and recovery following central nervous system injury. The project will lay the foundation for future studies on possible therapies or interventions to improve recovery from stroke and spinal cord injury.

DESCRIPTION (provided by applicant): The objective of the proposed project is to develop a neuroprosthetic device that uses targeted, activity-dependent spinal stimulation to improve arm and hand motor recovery after cervical spinal cord injury (SCI). The project seeks to advance clinical practice through the use of brain-computer-interface technology to harness physiological mechanisms of neural plasticity. Motor deficits severely impact the quality of life of people with SCI, yet current treatments produce limited improvements in movement abilities. Recent clinical and experimental evidence suggests that electrical stimulation of the nervous system can be an effective therapy for a variety of neurological disorders. This preclinical project will evaluate novel application of electrical stimulation for rehabilitation of forelimb motor deficits in a rat model of SCI. The strategy is designed to enhance the function of spared neural pathways by directing Hebbian plasticity through targeted stimulation of volitionally activated neural circuits Results will lay the foundation for a future clinical trial using spinal stimulation in human subjets with SCI. Preliminary data demonstrate the effectiveness of one-channel, intraspinal stimulation triggered by activity of a forelimb muscle to improve motor performance in rats with chronic SCI. Specific Aim 1 seeks to optimize the one-channel intervention by exploring the use of electrocorticography signals to trigger stimulation rather than muscle activity, and of less invasive surface stimulation of the spinal cord. A new electrode technology will be deployed for cortical recording and surface stimulation. Specific Aim 2 will develop multi-channel stimulation to extend the capacity of the therapy. Specific Aim 3 will determine if the therapy can produce further recovery if introduced during the subacute phase of SCI. Specific Aim 4 begins an investigation of the mechanisms of action of the intervention to suggest refinements and combinatorial therapies to facilitate further recovery. Physiological and immunohistochemical approaches will be employed to identify reorganized descending and reflex pathways, effects on serotonin regulation of spinal excitability, and changes in the structure of spinal perineuronal nets that could promote synaptic plasticity.

Project Summary The objective of the proposed project is to develop a neuroprosthetic therapy that uses targeted, activity-dependent spinal stimulation to improve arm and hand motor recovery after cervical spinal cord injury (SCI). The project seeks to advance clinical practice through the use of brain-computer-interface technology to harness physiological mechanisms of neural plasticity. Motor deficits severely impact the quality of life of people with SCI, yet current treatments produce limited improvements in movement abilities. Recent clinical and experimental evidence suggests that electrical stimulation of the nervous system can be an effective therapy for a variety of neurological disorders. This preclinical project will evaluate a novel application of electrical stimulation for rehabilitation of forelimb motor deficits in a rat model of SCI. The strategy is designed to enhance the function of spared neural pathways by directing Hebbian plasticity through targeted stimulation of volitionally activated neural circuits. Results will lay the foundation for a future clinical trial using spinal stimulation in human subjects with SCI. Preliminary data demonstrate the effectiveness of one-channel, intraspinal stimulation triggered by activity of a forelimb muscle to improve motor performance in rats with chronic SCI. Specific Aim 1 seeks a) to develop a multi-channel intervention to enhance functional recovery and b) to characterize the interplay between stimulation and physical rehabilitation in order to establish principles for combining the therapies. Specific Aim 2 will determine the relative effectiveness of ECoG vs. EMG as a triggering signal for facilitating behavioral recovery. Specific Aim 3 begins an investigation of the mechanisms of action of the intervention to suggest refinements and combinatorial therapies to facilitate further recovery.

The proposed projects will investigate synaptic plasticity in the primate motor system, using a novel bidirectional brain-computer interface (BBCI). The BBCI records neural activity and uses a programmable computer chip to deliver activity-contingent stimuli in real time to nervous system sites during hours of free behavior. We will use the BBCI to produce spike timing-dependent plasticity through neurally-triggered and paired stimulation, which can strengthen physiological connections. The effects of the conditioning will be documented by changes in cortical connectivity, as measured by spike- and stimulus-triggered averages of cortical field potentials and correlational measures of spontaneous activity. We will attempt to generate plasticity with surface stimulation, which is less invasive than intracortical stimulation and would be easier to translate to clinical applications. To further investigate the neural elements mediating plasticity we will compare the conditioning effects produced by optogenetic stimulation of excitatory neurons with those produced by electrical stimulation at the same sites. Also, we will investigate for the first time whether the stimulation-induced plasticity can be prolonged through additional interventions and whether more than one pair of cortical sites can be simultaneously conditioned. Finally, we will investigate the influence of behavioral state, such as sleep and waking, on cortical connectivity and the efficacy of inducing plasticity. These studies will provide crucial evidence to inform clinical applications of closed-loop stimulation targeting neural plasticity. The results will advance development of novel therapies to improve recovery after stroke, traumatic brain injury and spinal cord injury.