Project Summary The objective of the proposed project is to continue the laboratory’s development of 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. Here we will extend study of a novel application of electrical stimulation for rehabilitation of forelimb motor deficits in a rat model of cervical 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. Previous data demonstrated the effectiveness of multi-channel, intraspinal stimulation triggered by activity of forelimb muscles to improve motor performance in rats with chronic SCI. Specific Aim 1 seeks to complete the characterization of the interplay between stimulation and physical rehabilitation in order to establish principles for combining the therapies. Specific Aim 2 will examine possible causes underlying dramatic differences in recovery in female and male rats treated with the closed-loop stimulation. Specific Aim 3 will determine if activity-dependent epidural stimulation, a much less invasive and easier to translate to clinical practice approach than intraspinal stimulation, is as effective in facilitating recovery.