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

Abstract

There is an urgent and unmet clinical need to develop nonpharmacological interventions for chronic pain management because of the critical side effects of opioids. Low-intensity transcranial focused ultrasound (tFUS) is an emerging noninvasive 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 using dynamic focus steering. We demonstrate that tFUS 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 (eg, insula) and multisession focused ultrasound stimulation to S1 and insula. Analyses of brain electrical rhythms through electroencephalography demonstrated a significant change in noxious heat hypersensitivity-related and chronic hyperalgesia-associated neural signals after focused ultrasound treatment. Validation of efficacy was carried out through control experiments, tuning ultrasound parameters, adjusting interexperiment intervals, and investigating effects on age, sex, and genotype in a head-fixed awake model. Importantly, tFUS was found to be safe, causing no adverse effects on motor function or the brain's neuropathology. In conclusion, the validated proof-of-principle experimental evidence demonstrates the translational potential of novel focused ultrasound neuromodulation for next-generation pain treatment without adverse effects.

Abstract via europepmc.

Flags from extraction

• n_subjects — Paper reports many separate per-experiment, per-sex, per-strain group sizes (e.g., n=8, n=10, n=11 mice) across dozens of sub-experiments but never gives an overall total number of animals used.
• n_sessions_per_subject — Both single-session (n_sessions=1) and 14-day multisession protocols are used in different sub-experiments; recorded as a list [1, 14].
• exposures[0].timing.duty_cycle_pct — Paper gives tone-burst duration and PRF directly (not requiring the burst rule) but never states a numeric duty cycle percentage.
• exposures[0].in_situ.isppa_w_cm2 — The 0.35 W/cm2 value is given alongside an ISPTA value in the same sentence without an explicit ISPPA label, but is inferred to be ISPPA because it is compared against the FDA ISPPA limit (190 W/cm2) in the same sentence.
• exposures[0].in_situ.ispta_w_cm2 — ISPTA values are explicitly said to be measured behind an excised mouse skull sample, so classified as in_situ (method=measurement) rather than free field or unspecified domain; list order corresponds to PRF list order [40, 1000, 3000 Hz].
• condition_other — Sickle cell disease is not itself in the closed conditions vocabulary; 'chronic_pain' is used as the closest matching modelled condition, with SCD noted in condition_other.
• provenance — A separate 'high-dose' safety value (transcranial peak-peak pressure 2059.75 kPa; ISPTA 262.30 mW/cm2 at PRF 40 Hz and ISPPA 32.79 W/cm2 at TBD 200 microseconds) is mentioned for an extended safety window but is not clearly attributable to a single exposure/target, so it is not included in any exposure's numeric fields.