Parametric optimization of transcranial focused ultrasound neuromodulation of the periaqueductal grey for blood pressure reduction

BACKGROUND: Hypertension affects nearly half of US adults, with 10-20% resistant to pharmacological treatment. Transcranial focused ultrasound (FUS) targeting the periaqueductal grey (PAG) offers non-invasive neuromodulation for blood pressure control, but optimal parameters remain undefined. OBJECTIVE: To systematically investigate FUS parameters for maximizing blood pressure reduction and identify the underlying biological cascade and biophysical mechanisms. METHODS: We systematically investigated 12 ultrasound exposure schemes in male and female rats, examining the biological cascade from neuronal activation (cFOS and Gad67 immunohistochemistry) through systemic biomarkers (beta-endorphin, neurotensin, angiotensin II, renin-1) to hemodynamic endpoints (systolic and diastolic blood pressure). Hydrophone measurements were used to detect cavitation emissions. RESULTS: Optimal FUS parameters produced sex-independent reductions in systolic and diastolic blood pressure (-25 mmHg) lasting 24 h. Immunohistochemistry revealed activation of GABAergic neurons (increased cFOS and Gad67), while plasma analysis demonstrated suppression of angiotensin II (-28 pg/mL) and renin-1 (-8 pg/mL) without altering beta-endorphin or neurotensin. We identified a non-monotonic relationship between ultrasound intensity and physiological responses, consistent with biphasic inhibitory neuron activation. Hydrophone measurements ruled out cavitation-mediated neuromodulation, and point towards thermal and radiation force mechanisms. CONCLUSIONS: These findings establish optimal parameters and mechanisms for PAG-targeted FUS for blood pressure control, providing a foundation for clinical translation to populations where conventional antihypertensives are ineffective or unsafe.