Parametric optimization of transcranial focused ultrasound neuromodulation of the periaqueductal grey for blood pressure reduction
Harriet Lea-Banks, Neha Chauhan, Onbee Kim, Thallita Rabelo, Sheng-Kai Wu, Clement Hamani, Kullervo Hynynen
Brain Stimulation 2026 · 10.1016/j.brs.2026.103146
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.
Abstract via europepmc.
Exposures
Exposure 1: PAG sonication, pressure/pulse length/duration sweep
Target: periaqueductal gray — “periaqueductal grey (PAG)”
Device: other named manufacturer · FUS Instruments · RK50 (prototype) ✓
| Waveform | pulsed | |
|---|---|---|
| Fundamental frequency (kHz) | 540, 531swept | ✓?⚑ |
| Pulse duration (ms) | 1, 10, 100swept | ✓✓✓⚑ |
| Pulse repetition frequency (Hz) | 1 | ✓✓✓ |
| Duty cycle (%) | 1, 10swept | ✓✓✓⚑ |
| Sonication duration (s) | 300, 600, 1,200swept | ✓✓✓⚑ |
| Free-field pressure (kPa) | 275, 550, 1,100, 1,650, 2,100swept | ✓✓✓⚑ |
|---|---|---|
| Free-field Isppa (W/cm²) | not reported | |
| Free-field Ispta (W/cm²) | 0.7, 4.5swept | ✓✓✓⚑ |
| In-situ estimate | not reported | |
| In-situ pressure (kPa) | not reported | |
| In-situ Isppa (W/cm²) | not reported | |
| In-situ Ispta (W/cm²) | not reported |
PRF 1 Hz throughout. Sequential sweep of peak pressure (0-2.1 MPa, 10 ms pulses, 10 min), pulse length (0, 1, 10, 100 ms at 1.65 MPa, 10 min) and sonication duration (0, 5, 10, 20 min at 1.65 MPa, 10 ms); each rat sonicated once. Cohort 4 used 531 kHz.
Exposure 2: Motor cortex (M1) active control sonication
Target: primary motor cortex — “motor cortex (M1)”
Device: other named manufacturer · FUS Instruments · RK50 (prototype) ✓
| Waveform | pulsed | |
|---|---|---|
| Fundamental frequency (kHz) | 540 | ✓✓✓ |
| Pulse duration (ms) | 10 | ✓✓✓ |
| Pulse repetition frequency (Hz) | 1 | ✓✓✓ |
| Duty cycle (%) | not reportedpulse duration × PRF gives 1% | ⚑ |
| Sonication duration (s) | 600 | ✓✓✓ |
| Free-field pressure (kPa) | 550, 2,100swept | ✓✓✓ |
|---|---|---|
| Free-field Isppa (W/cm²) | not reported | |
| Free-field Ispta (W/cm²) | not reported | |
| In-situ estimate | not reported | |
| In-situ pressure (kPa) | not reported | |
| In-situ Isppa (W/cm²) | not reported | |
| In-situ Ispta (W/cm²) | not reported |
M1 used as active control under light anaesthesia (1.5 % isoflurane); BP recorded during FUS, 0.55-2.1 MPa, 10 ms pulse length, 10 min, 1 Hz PRF.
Flags from extraction
exposures[0].free_field.pressure_kpa— Peak pressures stated as measured in water; converted from MPa. Table gives 0.275-2.1 MPa in cohort 2; 0.55-2.1 MPa range in cohort 1.exposures[0].fundamental_frequency_khz— Cohort 4 used 531 kHz, all others 540 kHz; listed as one exposure.exposures[0].timing.duty_cycle_pct— Duty cycle is only stated in the discussion for 10 ms pulses (1 %) and 100 ms pulses (10 %); 1 ms pulses not stated.exposures[0].free_field.ispta_w_cm2— Only two ISPTA values are stated in the discussion (0.7 W/cm2 at 2.1 MPa/1 % DC; 4.5 W/cm2 at 100 ms/10 % DC); other values are readable only from figures; text also gives minima 454 and 735 mW/cm2.exposures[0].timing.pulse_duration_ms— 0 ms pulse length and 0 MPa / 0 min conditions are controls and were excluded from the lists.exposures[0].timing.sonication_duration_s— Table gives minutes; converted to seconds (5, 10, 20 min).exposures[1].timing.duty_cycle_pct— Duty cycle not stated for the M1 condition.sham_type— 0 MPa condition is assumed to be device-on with no output; the paper does not describe how it was produced. M1 used as active control.n_subjects— 90 rats across four cohorts; cohort sizes in Table 1 vary and some rows overlap.direction_of_effect— Mixed neuronal findings; classified from description of BP lowering and GABAergic cFos increase.conditions— Wistar rats not described as hypertensive or normotensive in this paper.