The proposed course of study is designed to develop the candidate as a rehabilitation clinician-investigator by providing training in both laboratory and clinical investigation of recovery and enhancement of locomotion following spinal cord injury (SCI).The plan combines the basic science environment provided by the Department of Anatomy and Neurobiology at Medical College of Pennsylvania (MCP) with the clinical environment at Thomas Jefferson University (TJU) and the Regional Spinal Cord Injury Center of the Delaware Valley. Training at MCP will include weekly seminars and journal clubs relating to neural development and plasticity and basic mechanisms underlying recovery, graduate courses in statistics, neuropharmacology and cell and molecular neurobiology, and intensive laboratory experience. Training at TJU will include monthly seminars on neurobiological issues that relate to recovery and rehabilitation after CNS injuries and biostatistics, and clinical research experience. Traumatic SCI results in significant mobility limitations. Mobility is the major prognostic concern of most patients and their families in the acute postinjury period and is a critical factor in maintaining an individual's health and independence. Efforts to enhance recovery following complete transection of the spinal cord have demonstrated improved locomotion in neonatal rats that have had fetal spinal cord transplanted into the lesion site, although the recovery remains incomplete. The locomotor pattern is influenced by the balance between activatory and inactivatory influences and pharmacologic intervention to modulate these influences may further enhance this recovery. The first set of experiments of this project, which will be performed at MCP, will evaluate whether antagonists of inhibitory neurotransmitters enhance locomotor function in spinal rats (Specific Aim 1) and whether these same agents act synergistically with embryonic spinal cord transplants (Specific Aim 2). Spasticity, a common problem in SCI patients, appears to be due to an imbalance between excitatory and inhibitory influences. The second set of experiments, to be performed on patients at TJU, will investigate the impact of varying degrees of spasticity on gait (Specific Aim 3) and whether intrathecal baclofen, a GABA-B receptor agonist, improves aspects of gait in SCI patients with spasticity. (Specific Aim 4). This program should provide the candidate with the skills to investigate clinical rehabilitation research questions with a background of basic research methodologies in order to apply these skills to develop treatments that will enhance locomotor recovery following SCI.
