Low-intensity transcranial focused ultrasound amygdala neuromodulation: a double-blind sham-controlled target engagement study and unblinded single-arm clinical trial
Bryan R. Barksdale, Lauren Enten, Annamarie DeMarco, Rachel Kline, Manoj K. Doss, Charles B. Nemeroff, Gregory A. Fonzo
Molecular Psychiatry 2025, 30, 4497-4511 · 10.1038/s41380-025-03033-w
Abstract
Mood, anxiety, and trauma-related disorders (MATRDs) are highly prevalent and comorbid. A sizable number of patients do not respond to first-line treatments. Non-invasive neuromodulation is a second-line treatment approach, but current methods rely on cortical targets to indirectly modulate subcortical structures, e.g., the amygdala, implicated in MATRDs. Low-intensity transcranial focused ultrasound (tFUS) is a non-invasive technique for direct subcortical neuromodulation, but its safety, feasibility, and promise as a potential treatment is largely unknown. In a target engagement study, magnetic resonance imaging (MRI)-guided tFUS to the left amygdala was administered during functional MRI (tFUS/fMRI) to test for acute modulation of blood oxygenation level dependent (BOLD) signal in a double-blind, within-subject, sham-controlled design in patients with MATRDs (N = 29) and healthy comparison subjects (N = 23). In an unblinded treatment trial, the same patients then underwent 3-week daily (15 sessions) MRI-guided repetitive tFUS (rtFUS) to the left amygdala to examine safety, feasibility, symptom change, and change in amygdala reactivity to emotional faces. Active vs. sham tFUS/fMRI reduced, on average, left amygdala BOLD signal and produced patient-related differences in hippocampal and insular responses. rtFUS was well-tolerated with no serious adverse events. There were significant reductions on the primary outcome (Mood and Anxiety Symptom Questionnaire General Distress subscale; p = 0.001, Cohen's d = 0.77), secondary outcomes (Cohen's d of 0.43-1.50), and amygdala activation to emotional stimuli. Findings provide initial evidence of tFUS capability to modulate amygdala function, rtFUS safety and feasibility in MATRDs, and motivate double-blind randomized controlled trials to examine efficacy.ClinicalTrials.gov registration: NCT05228964.
Abstract via europepmc.
Exposures
Exposure 1: tFUS/rtFUS to left amygdala
Target: amygdala — “left amygdala”
Device: BrainSonix · Brainsonix · Pulsar 1002 ✓
| Waveform | pulsed | |
|---|---|---|
| Fundamental frequency (kHz) | not reported | |
| Pulse duration (ms) | 5 | ✓✓✓ |
| Pulse repetition frequency (Hz) | 10 | ✓✓✓ |
| Duty cycle (%) | 5pulse duration × PRF gives 5% | ✓✓✓ |
| Sonication duration (s) | 30 | ✓✓✓ |
| Free-field pressure (kPa) | not reported | |
|---|---|---|
| Free-field Isppa (W/cm²) | not reported | |
| Free-field Ispta (W/cm²) | not reported | |
| In-situ estimate | deratingsingle value | |
| In-situ pressure (kPa) | 640 | ✓✓✓ |
| In-situ Isppa (W/cm²) | 14.4 | ✓✓✓ |
| In-situ Ispta (W/cm²) | 0.72 | ✓✓✓ |
Participants received tFUS with the following parameters: 10 Hz pulse repetition frequency (PRF), 5% duty cycle (DC), 5 ms pulse width, derated spatial peak pulse average intensity of 14.4 watts/cm2, derated spatial peak temporal average intensity of 719.91 milliwatts/cm2, and derated instantaneous peak pressure of 0.64 megapascals over 10 min in 10 sets of 30 s on/off blocks. Patients and HCs first underwent two double-blind administrations of tFUS/fMRI (active and sham order counterbalanced) separated by about a week; patients then commenced once-daily rtFUS treatment delivered 5 days a week for 3 consecutive weeks (15 sessions) using the same protocol.
Flags from extraction
n_subjects— 52 individuals (29 MATRD patients, 23 healthy controls) were enrolled and underwent tFUS/fMRI targeting; only 47 completed both active and sham sessions, so the exact number who received at least one active-condition sonication is not separately stated.n_sessions_per_subject— Session count differs by subgroup: all participants (patients and healthy controls) underwent 2 tFUS/fMRI sessions (active+sham, counterbalanced), while only MATRD patients went on to receive up to 15 additional daily rtFUS treatment sessions; recorded as a list of the two distinct session counts stated in the text rather than a single combined number.randomised— Active/sham order was 'counterbalanced' across participants; the paper does not state whether this counterbalancing was achieved via a randomisation procedure.blinding— The target-engagement tFUS/fMRI phase was double-blind and sham-controlled, but the subsequent repetitive tFUS (rtFUS) clinical trial phase was explicitly unblinded/single-arm; 'double' reflects the sham-controlled comparison only.fundamental_frequency_khz— Paper does not state the fundamental/carrier ultrasound frequency of the Brainsonix Pulsar 1002 device used.