From Neural Control of Movement to Treatments for Spinal Cord Injury

Project Summary/Abstract Over the last 15 years, our NINDS-funded research has focused on understanding transmission in descending motor pathways and spinal cord networks during motor behaviors in humans with and without spinal cord injury (SCI), with the long-term goal of maximizing the activity of spared pathway connections to enhance recovery potential. Our studies revealed that in people with SCI, corticospinal and reticulospinal systems contribute differentially to muscle weakness and functionally relevant behaviors, such as fine and gross grasping manipulations, compared with control subjects. Imbalanced contributions from these descending motor systems were found when spasticity and muscle spasms were present, providing light for the mechanisms of hyperreflexia following SCI. Motoneuron responsiveness to corticospinal, reticulospinal, and afferent input decreased in a task- dependent manner. Our research group pioneered the use of spike-timing dependent plasticity in the corticospinal pathway, from basic proof-of-principle studies on Hebbian plasticity to randomized placebo controlled clinical trials showing that plasticity at corticospinal-motoneuronal synapses improves exercise- mediated recovery after chronic incomplete SCI. In this application, we request to consolidate two ongoing NINDS-funded proposals that focus on the control of voluntary movement (R01NS090622) and spasticity and muscle spasms (R01NS100810). We will leverage our existing knowledge to produce new research that challenges the existing paradigm by integrating information across residual networks in the subacute and chronic phases of SCI and focuses on understanding: a) transmission in a widespread set of spared descending motor pathways and spinal circuits, b) hyperreflexia in these spared systems, and c) neuroplasticity-based therapies. Our research protocol will build on our past successes using cutting-edge neurophysiological, neuroimaging, and behavioral tools. We will employ more advanced spinal cord imaging methodologies, high-density surface electromyography recordings, and new physiological examinations using multidimensional behavioral tools to enhance our understanding of residual connections in humans with subacute and chronic SCI. Successful completion of this research will increase our understanding of the neural control of movement and symptoms, including spasticity and muscle spasms, in other neurological disorders (i.e., stroke, multiple sclerosis, and ALS). This research also may provide new avenues for treatments and assessment of humans with SCI and other neurological disorders.