Low-intensity transcranial focused ultrasound suppresses pain by modulating pain processing brain circuits

There is an urgent and unmet clinical need to develop non-pharmacological interventions for chronic pain management due to the critical side effects of opioids. Low-intensity transcranial focused ultrasound is an emerging non-invasive neuromodulation technology with high spatial specificity and deep brain penetration. Here, we developed a tightly-focused 128-element ultrasound transducer to specifically target small mouse brains, employing dynamic focus steering. We demonstrate that transcranial focused ultrasound stimulation at pain processing brain circuits can significantly alter pain-associated behaviors in mouse models in vivo. Our findings indicate that a single-session focused ultrasound stimulation to the primary somatosensory cortex (S1) significantly attenuates heat pain sensitivity in wild-type mice and modulates heat and mechanical hyperalgesia in a humanized mouse model of chronic pain in sickle cell disease. Results further revealed a sustained behavioral change associated with heat hypersensitivity by targeting deeper cortical structures (e.g., insula) and multi-session focused ultrasound stimulation to S1 and insula. Analyses of brain electrical rhythms through electroencephalography demonstrated a significant change in noxious heat hypersensitive- and chronic hyperalgesia-associated neural signals following focused ultrasound treatment. Validation of efficacy was carried out through control experiments, tuning ultrasound parameters, adjusting inter-experiment intervals, and investigating effects on age, gender, genotype, and in a head-fixed awake model. Importantly, transcranial focused ultrasound was shown to be safe, causing no adverse effects on motor function and brain neuropathology. In conclusion, the rich experimental evidence validates the ability of novel focused ultrasound neuromodulation to suppress pain, presenting significant translational potential for next-generation chronic pain treatment without adverse effects. ### Competing Interest Statement B.H., K.Y. and X.N. are co-inventors of pending patent applications on tFUS technique. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be constructed as a potential conflict of interest. Disclosures: KG: Honoraria: Novartis and CSL Behring. Research Grants: Cyclerion, 1910 Genetics, Novartis, Grifols, Zilker, UCI Foundation and SCIRE Foundation.