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Dose-Escalation Study of Amygdalar Transcranial Focused Ultrasound in Healthy Volunteers
Accepted manuscript   Open access   Peer reviewed

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, …
Neuromodulation (Malden, Mass.)
Apr 2026
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url
https://www.medrxiv.org/content/medrxiv/early/2025/10/29/2025.10.21.25338018.full.pdfView
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Abstract

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. 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. 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/cm2) using the BX Pulsar 1002 system. Structural MRI was performed before each stimulation to monitor for safety. Affective modulation was assessed pre- and post-stimulation via the International Affective Picture Set (IAPS) task, measuring changes in valence and arousal ratings. Acoustic modeling was conducted to estimate intracranial energy deposition. No adverse events or MRI-detectable structural changes (e.g., 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. tFUS of the right amygdala at intensities up to 10.08 W/cm2 derated spatial-peak temporal-average intensity (ISPTA.3), 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.

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