Dose-Escalation Study of Amygdalar Transcranial Focused Ultrasound in Healthy Volunteers
Norman M. Spivak, Andrew A.E.D. Bishay, Jonathan Haroon, Amber R. Hopkins, Jody Tanabe, Sabrina Halavi, Bianca Hoang-Dang, Andrew J. Swenson, Samantha F. Schafer, Mark E. Schafer, Alexander Bystritsky, Susan Y. Bookheimer, Martin M. Monti
Neuromodulation: Technology at the Neural Interface 2026 · 10.1016/j.neurom.2026.03.015
Abstract
Background Transcranial focused ultrasound (tFUS) is a promising noninvasive technique for modulating deep brain structures, but the optimal and safe intensity range for neuromodulation remains unclear. Current FDA intensity limits, designed for diagnostic use rather than therapy, may limit the potential effectiveness of tFUS. Objective This study aimed to evaluate the safety and preliminary efficacy of escalating tFUS intensities targeting the right amygdala in healthy volunteers, including intensity levels exceeding current FDA diagnostic ultrasound limits. Materials and methods Ten healthy adults (mean age = 19.5 ± 1.4 years; 70% female) participated in a within-subject, repeated-measures design. Each received four randomized tFUS stimulation conditions (ISPTA.3 = 0.72-10.08 W/cm 2 ) using the BX Pulsar 1002 system. Structural magnetic resonance imaging (MRI) was performed before each stimulation to monitor for safety. Affective modulation was assessed pre- and poststimulation using the International Affective Picture System task, measuring changes in valence and arousal ratings. Acoustic modeling was conducted to estimate intracranial energy deposition. Results No adverse events or MRI-detectable structural changes (eg, edema, hemorrhage, or microstructural abnormalities) occurred under any stimulation condition. Behavioral analyses revealed no significant overall effects of intensity in response to affective stimuli. Comparisons between high and low duty cycle paradigms showed no significant differences. Conclusions tFUS of the right amygdala at intensities up to 10.08 W/cm 2 derated spatial-peak temporal-average intensity, an FDA-recognized metric used to estimate ultrasound intensity at the target, substantially exceeding the FDA diagnostic limit, was well tolerated and produced no structural or subjective adverse effects. These findings support the safety of higher-intensity tFUS and justify further investigation in larger and clinical populations to explore potential dose-response effects on emotion regulation.
Abstract via europepmc.
Exposures
Exposure 1: Parameter sets A to D to the right amygdala
Target: amygdala — “right amygdala”
Device: BrainSonix · BrainSonix Corp, Sherman Oaks, CA · BX Pulsar 1002 ✓
| Waveform | pulsed | |
|---|---|---|
| Fundamental frequency (kHz) | 650 | ✓✓✓ |
| Pulse duration (ms) | 0.7 | ✓✓✓ |
| Pulse repetition frequency (Hz) | 71, 1,000swept | ✓✓✓ |
| Duty cycle (%) | 4.97, 70swept | ✓✓✓⚑ |
| Sonication duration (s) | 30 | ✓✓✓⚑ |
| Free-field pressure (kPa) | not reported | |
|---|---|---|
| Free-field Isppa (W/cm²) | 1.33, 10.63, 18.6, 262swept | ✓✓✓ |
| Free-field Ispta (W/cm²) | 0.93, 7.44, 13.02swept | ✓✓✓ |
| In-situ estimate | deratingsingle value | |
| In-situ pressure (kPa) | 177, 477, 635, 2,260swept | ✓✓✓⚑ |
| In-situ Isppa (W/cm²) | 1.03, 8.23, 14.4, 201.6swept | ✓✓✓⚑ |
| In-situ Ispta (W/cm²) | 0.72, 5.76, 10.08swept | ✓✓✓ |
Four parameter sets (A to D) at the 650 kHz carrier, pulse length held at 0.7 ms, 10-minute sonication using a 30 s on/30 s off paradigm; one set per weekly visit in randomised, counterbalanced order.
Flags from extraction
exposures[0].in_situ.isppa_w_cm2— Paper reports FDA-style derated (0.3 dB/cm/MHz) Ispta.3, Isppa.3 and Pr.3 and also calls them free-field derated transducer output; recorded as in situ by derating. Set D has Isppa.3 201.6 W/cm2, Ispta.3 10.08 W/cm2 (same as set C).exposures[0].timing.sonication_duration_s— Sonication was 10 minutes total with a 30 s on/30 s off paradigm; 30 s taken as the single train length.exposures[0].timing.duty_cycle_pct— Set D duty cycle 4.97% (nominal 5%) to keep 0.7 ms pulses at 71 Hz PRF; parameters listed per set as lists in ascending order, not aligned across fields.exposures[0].in_situ.pressure_kpa— Pr.3 is the derated peak rarefactional pressure in MPa; converted to kPa. Table 2 BabelBrain simulations for one participant per set were not recorded.n_sessions_per_subject— Four stimulation visits plus a fifth imaging-only follow-up visit; 'four' appears as a word in the quote.