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

Abstract

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.