Low-Intensity Focused Ultrasound of the Amygdala in Depression and Anxiety: A First-in-Human Active-Controlled Trial
Amanda R. Arulpragasam, Mascha van ’t Wout-Frank, Yosef A. Berlow, Emily Aiken, Alison Gorbatov, Ryan Van Patten, Julia G. Gillotti, Hannah R. Swearingen, Christiana R. Faucher, Hannah Adams, Nicole C.R. McLaughlin, Israel Liberzon, Jennifer Barredo, Stephen Correia, Benjamin Greenberg, Noah S. Philip
2026 · 10.64898/2026.09.18.26363360
Abstract
Background Low-intensity focused ultrasound (FUS) offers a noninvasive method for directly modulating deep brain structures with millimeter-scale precision, potentially addressing a major limitation of existing noninvasive neuromodulation approaches. The amygdala is a key node in affective neurocircuitry and a compelling target for psychiatric intervention. We conducted a first-in-human active controlled trial ( NCT05147142 ) of amygdala-targeted FUS in patients with major depressive disorder, examining safety and target engagement. Methods Ten participants with major depressive disorder completed a single-blind randomized crossover trial with blinded symptom ratings, comparing imaging-guided FUS targeting the right amygdala versus left primary somatosensory cortex as an active control. FUS comprised two 10-minute applications within diagnostic ultrasound safety limits. Primary outcomes were safety and target engagement assessed with BOLD-fMRI during sonication, post-sonication arterial spin labeling (ASL) and resting-state functional connectivity. Secondary and exploratory outcomes included symptom change and imaging–symptom relationships. Results Nine participants completed both sessions. No serious adverse events occurred; neurological, neuropsychological, and MRI safety assessments were unremarkable. Adverse events were more frequent after amygdala than control sonication (p=0.028); one participant experienced clinical worsening following amygdala sonication and required monitoring. Amygdala sonication produced greater perfusion change in the targeted amygdala compared to the control region (p Conclusions Amygdala-targeted FUS produced anatomically specific, multimodal evidence of neuromodulation relative to active control, with a manageable safety profile. Convergent target and circuit-level signals support further development of FUS as a precision approach for modulating deep brain targets in psychiatric disorders.
Abstract via europepmc.
Exposures
Exposure 1: Right amygdala FUS
Target: amygdala — “right amygdala”
Device: BrainSonix · Brainsonix · Pulsar 1002 ✓
| Waveform | pulsed | |
|---|---|---|
| Fundamental frequency (kHz) | 650 | ✓✓✓ |
| Pulse duration (ms) | 5 | ✓✓✓ |
| Pulse repetition frequency (Hz) | 10 | ✓✓✓ |
| Duty cycle (%) | not reportedpulse duration × PRF gives 5% | ⚑ |
| Sonication duration (s) | 30 | ✓✓✓⚑ |
| Free-field pressure (kPa) | not reported | |
|---|---|---|
| Free-field Isppa (W/cm²) | 18.84 | ✓✓✓ |
| Free-field Ispta (W/cm²) | 0.938 | ✓✓✓ |
| In-situ estimate | deratingsingle value | |
| In-situ pressure (kPa) | 610 | ✓✓✓⚑ |
| In-situ Isppa (W/cm²) | 14.39 | ✓✓✓ |
| In-situ Ispta (W/cm²) | 0.72 | ✓✓✓ |
Each session included two applications of ten 30 s sonications (30 s on/off) separated by a brief break (<5 min), delivered inside the MRI bore; PRF 10 Hz, pulse width 5 ms.
Exposure 2: Left S1 FUS (active control)
Target: primary somatosensory cortex — “left primary somatosensory cortex (S1)”
Device: BrainSonix · Brainsonix · Pulsar 1002 ✓
| Waveform | pulsed | |
|---|---|---|
| Fundamental frequency (kHz) | 650 | ✓✓✓ |
| Pulse duration (ms) | 5 | ✓✓✓ |
| Pulse repetition frequency (Hz) | 10 | ✓✓✓ |
| Duty cycle (%) | not reportedpulse duration × PRF gives 5% | |
| Sonication duration (s) | 30 | ✓✓✓⚑ |
| Free-field pressure (kPa) | not reported | |
|---|---|---|
| Free-field Isppa (W/cm²) | 18.84 | ✓✓✓ |
| Free-field Ispta (W/cm²) | 0.938 | ✓✓✓ |
| In-situ estimate | deratingsingle value | |
| In-situ pressure (kPa) | 610 | ✓✓✓ |
| In-situ Isppa (W/cm²) | 14.39 | ✓✓✓ |
| In-situ Ispta (W/cm²) | 0.72 | ✓✓✓ |
Each session included two applications of ten 30 s sonications (30 s on/off) separated by a brief break (<5 min), delivered inside the MRI bore; PRF 10 Hz, pulse width 5 ms.
Flags from extraction
n_subjects— 15 consented; 10 participants completed the trial and 9 completed both sessions. Recorded 10.exposures[0].timing.duty_cycle_pct— Not stated; not computed.exposures[0].in_situ.pressure_kpa— Sentence gives 0.61 MPa and MI 0.76 after the derated intensities; assumed to belong to the derated values.exposures[0].unspecified_domain.isppa_w_cm2— Device output intensities before derating; domain (water or other) is not stated.exposures[0].in_situ.method— Derating at 0.3 dB/cm/MHz, not measurement or simulation.exposures[1].timing.sonication_duration_s— Same device parameters stated once for all FUS; applied to the S1 control exposure as well.auditory_control— No masking used; auditory cortex BOLD activation was examined post hoc.exposures[0].timing.sonication_duration_s— '30s on/off' read as 30 s sonications alternating with 30 s rest (BOLD blocks of 30 s).