2026 Theses Doctoral

Development and Clinical Translation of Focused Ultrasound Peripheral Neuromodulation for Chronic Pain Treatment

McCune, Erica P.

Chronic pain affects an estimated 20.4% of adults within the United States and hundreds of millions worldwide. Patients experiencing chronic pain have severe quality of life degradation and an urgent need for treatment, contributing to a rise in clinical visits and the prescription, and potential abuse, of drugs such as opioids. Chronic pain, however, is notoriously difficult to treat. Many current treatments are only moderately effective or have severe drawbacks, such as systemic side effects, being invasive, or not having the necessary precision or depth penetration to target pain circuits. Evidence shows that chronic pain is linked to hyperexcitability in unmyelinated peripheral pain neurons (C-nociceptors) in both neuropathic and nociceptive pain. This suggests that a therapy targeted to specific neurons in the peripheral nervous system (PNS) may be highly effective in chronic pain treatment. Focused ultrasound (FUS) is a technique of non-invasively focusing high frequency acoustic pressure waves to a spot deep within the body, with transmission through solid structures such as bone and soft tissue and spatial resolutions on the order of millimeters. FUS has been shown to provide localized PNS stimulation and may be an ideal candidate for targeted pain treatment. Thus, this dissertation seeks to further develop FUS as a peripheral neuromodulatory tool and implement FUS treatments of chronic pain first in animals and then translate it to human neuropathic pain.

In this dissertation, we first explore the underlying mechanisms and effective parameters for peripheral neuromodulation in an animal model through sciatic nerve stimulation. Baseline tissue temperature was shown to affect both cavitation and displacement in vivo, with greater inertial cavitation and tissue displacement occurring with warmer tissue. Next, FUS parameters such as sonication pressure, center frequency, and sonication location along the nerve were explored to elucidate those contributing most to successful motor activation. Compound muscle action potentials were more readily induced with center frequencies between 2.8 and 3.1 MHz and corresponded with smaller regions of displacement localized to the nerve itself. Displacement was found to correlate with the compound muscle action potential amplitude rather than cavitation.

After exploration of peripheral FUS neuromodulation parameters and bioeffects, protocols for successful long-term suppression of chronic nociceptive and neuropathic pain were developed in an in vivo murine model. First, a FUS parametric space exploration was conducted to determine the optimal FUS parameter set that provided maximum pain reduction. This parameter set was then applied to a complete Freund's adjuvant model of chronic nociceptive pain and a spared nerve injury model of neuropathic pain. A single treatment of FUS was found to improve von Frey withdrawal thresholds for up to 5 days post-sonication compared to positive control mice. FUS-induced analgesia was compared to that of standard-of-care pharmaceuticals. Sonication performed every 5 days provided sustained pain relief across multiple weeks, illustrating possible clinical sonication schemes for long-term relief. Maximum analgesia in the FUS-sonicated mice was produced when peak nerve relaxations of at least 30 µm occurred, demonstrating the value of displacement-guidance in FUS therapies.

Finally, in the last aim of this dissertation, these findings were translated to the clinic where peripheral FUS neuromodulation was used to modulate both somatosensation and pain in healthy and neuropathic human populations. Median nerve FUS was shown to reduce somatosensory-evoked potentials (SSEP) as measured by electroencephalography in both healthy and carpal tunnel syndrome (CTS) patients, with SSEP reductions strongly correlating with the cumulative median nerve displacement. Pain was additionally reduced by an average of 40.6% in CTS subjects. Bi-weekly sonication in CTS subjects over the course of 8 weeks was found to relieve sensory symptoms, including pain, numbness, and tingling. Finally, weekly sonication was administered in patients with chronic neuropathic pain resulting from neurofibromatosis type 1. Peripheral FUS neuromodulation was shown to improve both pain interference and quality of life indicators.

This dissertation represents a substantial step forward in displacement-guided peripheral FUS neuromodulation, demonstrating the capability of this treatment to be implemented as an analgesic for chronic pain and the parameters which should be tuned for its efficacy.