Improving Recovery Following Neurological Injury Utilizing Targeted Plasticity Therapy

Neurological injuries often cause permanent, significant impairments in motor and sensory function. Spinal cord injury affects 276,000 individuals in the United States and millions more worldwide, while 20 million American suffer from peripheral nerve related injuries. Both of these injuries commonly cause upper extremity motor and sensory dysfunction, which can persist for the rest of their lives. Currently, there are no consistently effective treatment options to restore sensorimotor function in patients suffering from these disabilities. In recent years, vagus nerve stimulation (VNS) paired with rehabilitation has emerged as a possible therapeutic intervention for treating motor and sensory dysfunction following a number of neurological injuries including ischemic stroke, hemorrhagic stroke, and traumatic brain injury. This dissertation works to further these findings by investigating new injury models and new modalities for restoring further function while simultaneously optimizing aspects of the therapy for more seamless translation to the clinic. We first describe how VNS paired with motor rehabilitation can be utilized to drive significant recovery in different models of spinal cord injury at the fifth cervical level. In the same study, we go on to demonstrate the importance of pairing VNS with neural activing driving the desired outcomes. Next, we vary the timing of VNS with the paired event in order to identify a synaptic eligibility trace of VNS which can be utilized to further optimize VNS pairings in the clinic. It was also discovered VNS paired with rehabilitation can drive plasticity in spared motor networks through the use of intracortical mapping and viral transsynaptic tract tracing. We investigated spinal cord injury at a lower level, C7, with a new bilateral injury model, and found that despite a loss in distal forelimb motor pools, VNS paired with rehabilitation was able to significantly enhance motor recovery. Generalization to similar but untrained tasks was also observed, further highlighting the potential for clinical translation. Next, we were able to demonstrate the use of VNS paired with sensory stimuli in order to restore sensory function following a model of chronic sensory loss in the forelimb, peripheral nerve injury. Not only did VNS paired with tactile rehabilitation drive significant enhancement of mechanosensory withdrawal thresholds, these VNS-mediated benefits were found to last for over two months. While generalization was not observed in a predominantly motor task, grip strength, it was observed in multiple sensorimotor functions including skilled forelimb placement, toe spread, and spontaneous forelimb use. The findings of this dissertation clearly demonstrate that VNS therapy paired with rehabilitation can significantly improve recovery of motor and sensory function following neurological injury. We demonstrate the first use of VNS therapy to treat dysfunction after spinal cord injury. We demonstrate the first preclinical use of VNS therapy to restore somatosensory function following peripheral nerve injury. Lastly, this dissertation demonstrates the clinical utility and massive potential for translation to improve both motor and sensory function following neurological injury.