This proposal responds to PAR-21-315 Blueprint MedTech Translator and aims to translate a next-generation noninvasive neuromodulation system that supports a device-based strategy for non-addictive pain treatments. Specifically, we have developed an integrated magnetic resonance (MR) image-guided focused ultrasound (MRgFUS) stimulation system for targeted and high precision modulation of deep brain regions with real-time targeting feedback and functional monitoring by fMRI. Although there are several devices available on the market to treat pain, their efficacy is limited by imprecise targeting resulting from insufficient mechanistic data about “device-able” targets, and from lack of feedback of effects to modulate the therapy. Reversible FUS stimulation under MRI guidance (MRgFUS) combines the dual neuromodulation capacity of low frequency focal ultrasound with simultaneous monitoring of neuromodulation in action using fMRI. MRgFUS overcomes the limitations of existing pain-treatment devices and has great potential to improve patient outcomes through FUS and MRI technologies that enable targeting and control. Our group has developed an MRgFUS system for non-human primate (NHP) use and successfully modulated neural activity in the brain regions responsible for nociceptive information processing validated by fMRI. As part of previously funded work, we have scaled the device to function with a human skull, and here we propose to translate this early-stage technology into a new non-addictive pain therapy. We have designed the human device to use FUS to stimulate pain targets (thalamic nuclei, ACC, and PAG/PVG) that are currently used in clinical pain treatments with the ability to validate the location of stimulation and to monitor brain activity using blood oxygenation level dependent fMRI. Our experimental plan navigates barriers to deploying FUS, including 1) optimizing MR-based methods to visualize the ultrasound beam with high precision while using safe ultrasound exposure to the brain, 2) assessing device safety in non-human primates, and 3) obtaining regulatory approval for use of the proposed device for a first-in-human trial of high precision MRgFUS in patients with medically-refractory essential tremor and intractable chronic central post-stroke pain. The UG3-phase is designed to prepare the device for human use and has quantitative go/no-go milestones for establishing safe use of high precision MRgFUS in humans with regulatory approval. Successful completion of the UG3 milestones will place this groundbreaking technology into the hands of treating physicians and lead to the first clinical trial of high precision MRgFUS neuromodulation in patients with movement disorders and chronic pain. The proposed work will deliver a system that overcomes technical barriers in transcranial ultrasound and is ready for pilot clinical trials in various pain management applications.

In the clinical management of chronic pain there is an unmet need for a device-based nonaddictive and noninvasive pain relief treatment. This proposal responds to PA-21-315 Blueprint MedTech Translator, and aims to translate a novel integrated magnetic resonance (MR) image-guided focused ultrasound (MRgFUS) neuromodulation system, which has built-in real-time targeting feedback and functional monitoring capacity for pain relief for patients with chronic central post-stroke pain. We have demonstrated feasibility and safety of our novel MRgFUS neuromodulation system in relevant experimental models and propose a plan for the safe translation and testing of this system in humans.