Title: Focused Ultrasound Neuromodulation of the Peripheral Nervous System
Description: Recent evidence appears to indicate that neurons, responsible for our perception of the world around us, are not only electrically excitable, but may have mechanical triggers as well. This is well supported through the growing number of observations of focused ultrasound (FUS) perturbations of the neurons located in our central nervous system (CNS). However, while the CNS is largely responsible for turning electrical signals from the periphery into thoughts and understanding, less is known about the effect of which FUS has upon the peripheral signals themselves: our peripheral nervous system (PNS). Given the non-invasive nature of FUS - were it be discovered to influence neuronal signaling, FUS would become a powerful tool for therapy and medicine, especially in conditions involving pain. Thus, we ponder the question, "How can FUS modulate nerve activity and furthermore, what are the interactions on pain signaling?" In this dissertation, a road-map is described for translating insights acquired through pre-clinical study of ultrasound PNS stimulation to clinical investigation on neuropathic pain modulation in humans.

More specifically, methods and tools to study excitation of the sciatic nerve bundle and the dorsal root ganglia (DRG) were built and optimized in rodent models. In turn, these methods and findings enabled investigation into pain signaling and translation to human studies. Finally, FUS was shown to mitigate pain sensations in human patients with neuropathic pain. First, using a newly developed in vivo nerve displacement imaging technique, mechanical deformations of the nerve from FUS stimulation were noninvasively mapped in a two-dimensional plane centered at the sciatic nerve. Nerve displacements were positively correlated with downstream compound muscle activation from FUS sciatic nerve stimulation. Furthermore, by focusing ultrasound waves to the DRGs directly in an ex vivo preparation, additional parameters were identified to modulate spike transmission, effectively regulating high frequency signaling. Next, we investigated the feasibility translating FUS nerve stimulation to clinical studies.

We first looked at effects on upstream cortical activity and pain signaling from somatosensory stimuli using high-frequency functional ultrasound (fUS) imaging. FUS was shown to both stimulate somatosensation and suppress pain signaling in the cortex. Secondly, nerve displacement imaging was scaled-up for human investigation, essential for in-procedure localization and stimulation of the targeted nerve bundle. Using a combination of imaging and therapeutic excitation, simultaneous nerve targeting, stimulation, and monitoring was established at pressures required for stimulation. Lastly, clinical feasibility was investigated using previously optimized FUS pulse schemes and scaled-up neuromodulation technologies. Specifically, we applied simultaneous FUS to the median nerve and thermal stimulation to the corresponding dermatome in healthy human subjects. Furthermore, patients with robust and repeatable mechanically-assessed neuropathic pain were similarly stimulated with FUS to assess pain suppression.

Based on the findings presented herein, noninvasive FUS peripheral stimulation has the potential for radically shifting the traditional pharmaceutical paradigms in chronic and acute pain treatment by altering signals before being processed in the spinal cord and ultimately the brain. The studies outlined herein serve to elucidate mechanisms of FUS in the PNS, as well as provide the starting foundations for further development of FUS as an effective pain treatment.