Neuromodulatory Pathways Required for Targeted Plasticity Therapy

Targeted plasticity therapy (TPT) utilizes vagus nerve stimulation (VNS) paired with physical rehabilitation to direct plasticity and promote recovery. Pre-clinical trials in stroke, spinal cord injury, traumatic brain injury, and peripheral nerve injury models show improved functional recovery after VNS-pairing when compared to physical rehabilitation alone. Pairing VNS with motor movements in neurologically intact animals leads to expansion of task-specific cortical representations. Precise timing of VNS is required to drive plasticity and functional recovery. VNS engages pro-plasticity neuromodulators, but there is no direct evidence that they mediate VNS effects. Acute responses to VNS in key neuromodulatory centers are also unknown.

This dissertation work aims to elucidate the neuromodulatory pathways required for VNS directed plasticity underlying TPT. A reliable preparation driving expansion of proximal forelimb representation in rats after one week of VNS pairing on a lever-press task is used in two experiments. Targeted neurotoxins selectively deplete cholinergic, noradrenergic, and serotonergic innervation of the cortex in experimental animals, testing the necessity of each key neuromodulatory pathway to VNS effects. Intracortical microstimulation reveal cortical representations to compare across groups. The third experiment characterizes locus coeruleus (LC) responses to parametric variation of VNS. It uses acute VNS cuff implants and standard LC recording techniques to elucidate phasic response characteristics to a wide range of VNS intensity, pulse width, and frequency.

The results of this dissertation replicate previous findings that VNS drives robust plasticity in the motor cortex following VNS-movement pairings. Cholinergic, noradrenergic, and serotonergic depletion each block the effects of VNS. The cortical depletion of acetylcholine was complete, while noradrenergic and serotonergic lesions were confined to the experimental hemisphere. This result suggests that each neuromodulator system uniquely contributes to VNS-directed plasticity and TPT. Recordings from the LC reveal rapid phasic activity in response to VNS. Increases in intensity and pulse width monotonically increase LC activation. Alterations in stimulation frequency do not influence total driven activity, but allow for temporal shaping of the response. These results make substantial contributions to elucidating the mechanisms, resoundingly confirming the neuromodulatory basis for TPT and VNS-directed plasticity. They can help guide clinical considerations in terms of patient selection based on pharmacological profiles. Additionally, they contribute to efforts to optimize stimulation parameters by elucidating responses characteristics in a key neuromodulatory center.