Abstract
Paralysis, loss of gait function, and reduced mobility are devastating and life-altering consequences of spinal cord injury (SCI) that not only reduce quality of life, but have dangerous and costly medical co-morbidities, and for societies reduce productivity and increase health care burdens. Although rodent studies have identified numerous promising therapies, the failure to validate these treatments in resource-intensive and time-consuming clinical trials shows the urgent need for effective translational models and pipelines in SCI research. One approach with significant therapeutic potential is neuromodulation. Recent advances in the application of neuromodulation to patients with chronic, motor complete SCI have allowed scientists to restore voluntary leg movements, stepping, standing, and even brief episodes of assisted overground ambulation.
In this study, we developed a large animal model of neuromodulation and SCI using the Yucatan micropig, which has multiple translational advantages and relevant similarities to the human nervous system. We used this model to characterize and investigate the effects on gait of deep brain stimulation (DBS) of the mesencephalic locomotor region (MLR), a midbrain target that is a known control center for gait in many species, and lumbar epidural stimulation (ES), a current experimental therapy being researched to address multiple functional losses in SCI. We found that MLR DBS is capable of initiating and augmenting locomotion in uninjured animals, and that stimulation frequency controls locomotor output. We also identified optimal stimulation sites centered in a specific component of the MLR, the cuneiform nucleus. In animals with incomplete T10 injury, we found that MLR DBS and lumbar ES enhanced functional gait parameters, including measures of gait speed, weight bearing, and limb coordination. Finally, we present a preliminary translation of our MLR DBS animal research into a Parkinson's disease patient with gait dysfunction.