2015 — 2019 |
Guest, James David Noga, Brian Ronald |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Gait Ignition After Sci @ University of Miami School of Medicine
? DESCRIPTION (provided by applicant): Deep brain stimulation (DBS) is an effective, relatively safe, reversible, and adjustable treatment modality for medically-refractory movement disorders. It has had little application in persons with spinal cord injury (SCI), even though a significant percentage of new and chronic injuries are classified as motor incomplete and have spared connections. Recent work in our laboratory has pointed to a potential target for locomotor control after partial SCI. This is the mesencephalic locomotor region or MLR, a major coordinating center for activation of both locomotor command and descending modulatory pathways. Based on our studies, DBS of the MLR (mlrDBS) enhances neurotransmission along descending pathways innervating locomotor-generating neurons of the spinal cord. Furthermore, mlrDBS produces immediate and highly significant improvements in gait, locomotor speed and endurance in animals with mild and clinically relevant mid-thoracic contusion (moderate and severe) injuries. To achieve maximal clinical benefit from DBS and to minimize potential adverse effects, DBS electrodes need to be placed precisely into the target structure and the stimulation parameters must be optimized. This is especially important for its use after SCI since pathways responsible for generating locomotion are compromised and clinical benefit will depend upon utilizing the surviving pathways to the fullest extent possible. Unfortunately, there is great controversy concerning the anatomical location of the optimal site for mlrDBS in humans, indicating the importance of large animal testing to minimize the probability of negative or suboptimal clinical results, collateral damage to structures surrounding the MLR, as well as unwanted clinical side effects from stimulation. As part of our long-term goal of developing and optimizing treatments for SCI paralysis, the overall objective of this application is to determine the therapeutic potential of mlrDBS to improve walking following anatomically incomplete, acute and chronic SCI in a large animal model. We hypothesize that locomotion may be facilitated in either acute or chronic stages of injury. We shall pursue the following specific aims: In Aim 1, we propose to first identify and characterize the MLR in uninjured animals, establishing optimal stimulation sites and parameters of stimulation for controlling locomotor responses. In Aim 2, we will assess the ability of mlrDBS to enhance locomotor performance following acute and chronic incomplete thoracic SCI once optimal location and stimulation parameters have been established. The study will provide testing of this novel application of DBS in a large animal preclinical setting, to establish efficacy and to delimi the potential benefits of this procedure as a rehabilitation strategy for differing grades of injur. We expect this work to lead to a Phase 1 clinical study and establish a baseline for future work concerning combinatorial strategies utilizing supplementary transmitter replacement in combination with locomotor training and functional electrical stimulation.
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2020 |
Guest, James David |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Can Spinal Cord Epidural Stimulation Increase the Efficacy of Midbrain Excitation of Locomotor Circuits? @ University of Miami School of Medicine
Project summary Spinal cord injury (SCI) interrupts motor control pathways between supraspinal and spinal sensorimotor networks. This disruption results in impairment of gait and sensation, chronic decreased quality of life (QOL), and numerous medical complications. In human studies of chronic SCI, lumbar electrical epidural stimulation (EES) based rehabilitation has allowed weight-bearing and unprecedented voluntary stepping in motor complete patients. These results establish that even severe complete SCIs have intact axons spared through the injury site. EES activates dorsal sensory roots to raise excitability of residual intact locomotor circuitry in the spinal cord. This allows otherwise silent descending inputs to become effective, permitting voluntary motion. Although impressive, ES based rehabilitation has not been adequate to restore balanced independent gait in the community setting. If applied during subacute rehabilitation, a period of increased neuroplasticity, this strategy may engender a greater level of permanent recovery. To address inadequate supraspinal drive we will use deep brain stimulation (DBS) of the mesencephalic locomotor region (MLR) to ?overdrive? the stepping initiation center. We have previously developed protocols for MLR DBS and EES in a porcine contusion SCI model but have not combined them. In this project with 2:1 treatment:controls, we propose testing DBS and ES, together with developing a closed-loop perturbation and response protocol, to provide feedback driven stability and balance during weight supported stepping. In Aim 1, Yucatan minipigs with severe T9 SCI will be implanted with both MLR DBS and lumbar ES electrodes and undergo intensive rehabilitation for 3 months. In Aim 2 we test to what extent postural correction can be achieved by asymmetric modification of stimulus parameters in response to a posterior pelvic mounted inertial measurement unit coupled to a PID controller. Primary outcome measures include extent recovery of locomotion, time-walked testing, capacity to achieve unassisted weight support and structural plasticity of the reticulospinal tract. Measures will be acquired using state of the art kinematic analysis and telemetry-electromyography. In histological analysis after neuroanatomical tracing we determine if MLR- DBS causes axonal structural plasticity. Our aims align with the NIBIB mission statement by testing a multidisciplinary bioengineering approach in a clinically relevant and translational paraplegia model. ES and DBS technology has been applied in other clinical conditions including neuropathic pain and Parkinson?s disease. Thus, if successful, the translational path would be accelerated. The combined neuromodulation and rehabilitative intervention is relevant to public health, as it may fundamentally improve recovery from SCI and render subacute neurorehabilitation more effective allowing allow community-setting ambulation, supplanting wheelchair use and increasing QOL for individuals with SCI.
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