Investigating a combination therapy of robot-driven rehabilitation techniques with viral delivery of brain-derived neurotrophic factor in treating adult spinal cord injury

Abstract

A complete spinal cord injury (SCI) disrupts the normal architecture of the central nervous system, resulting in severe and irreversible impairment of the healthy functions of the body. SCI physically interrupts the neural networks used to relay descending motor information from and ascending sensory information to supraspinal structures in the brain separating circuits in spinal cord from brain supervision and recruitment. Depending on the location of the injury, complete SCI can lead to paraplegia or quadriplegia. In the injured individual, the loss of autonomy and mobility can severely decrease quality of life, as well as negatively impact health outcomes. As a result, locomotor rehabilitation is an area of interest for research for its potential translational benefits in the clinic. In previous work in our lab studying the rat model for SCI, we have demonstrated the efficacy of robotic technology in the rehabilitation of adult rats transected as neonates (NTX), which are unique in their ability to produce autonomous stepping after complete SCI without intervention. Using robotic assistance at the pelvis in our trunk-based rehabilitation paradigm, we have significantly improved locomotor function in such animals. Viewing the NTX model, thus, as a signpost for what is possible in recovery when using our robot in animals that can step after SCI, we have also shown that our robot can be used to drive epidural stimulation (ES) in the rat transected as an adult (ATX) to promote stepping patterns and increase body weight support. Recently, the use of neurotrophins, such as brain-derived neurotrophic factor (BDNF) has been investigated as a means to induce stepping and locomotor behaviors in the ATX model to varying levels of success. We believe that there are potentially synergistic benefits to combining our robot rehabilitation techniques with the use of BDNF to rehabilitate ATX animals. This thesis addresses this idea in depth. We first investigated how BDNF and our robot-assisted treadmill training might interact in the ATX model. Next, we added robot-driven epidural stimulation to the treatment regimen to further understand how the therapies might interact in rehabilitation. Finally, to elucidate the mechanisms underlying locomotor recovery following injury, we used intracortical microstimulation (ICMS) to map the motor cortex of successfully rehabilitated animals. Our results suggest that BDNF and robot technologies can be combined successfully to provide robust stepping patterns, characterized by body weight support and plantar stepping in the ATX model for rats. Furthermore, we show that epidural stimulation can be used to mitigate pathological sequelae that come from BDNF use. Finally, our work shows how active stepping using BDNF and robot rehabilitation in the ATX model may induce significant reorganization of the trunk motor cortex, providing more clues to the relationship between the cortex and the spinal cord in motor control and muscle synergy development.%%%%Ph.D., Biomedical Engineering – Drexel…