Low-Intensity Focused Ultrasound of the Amygdala in Depression and Anxiety: A First-in-Human Active-Controlled Trial

@misc{arulpragasam2026lowintensity,
  title = {{Low-Intensity Focused Ultrasound of the Amygdala in Depression and Anxiety: A First-in-Human Active-Controlled Trial}},
  author = {A. R. Arulpragasam and M. van 't Wout-Frank and Y. A. Berlow and E. Aiken and A. Gorbatov and R. Van Patten and J. G. Gillotti and H. R. Swearingen and C. R. Faucher and H. Adams and N. C. R. McLaughlin and I. Liberzon and J. Barredo and S. Correia and B. Greenberg and N. S. Philip},
  howpublished = {medRxiv},
  year = {2026},
  month = sep,
  doi = {10.64898/2026.09.18.26363360},
  url = {https://www.medrxiv.org/content/10.64898/2026.09.18.26363360v1},
  note = {CC BY-NC-ND},
}

TY  - UNPB
TI  - Low-Intensity Focused Ultrasound of the Amygdala in Depression and Anxiety: A First-in-Human Active-Controlled Trial
AU  - A. R. Arulpragasam
AU  - M. van 't Wout-Frank
AU  - Y. A. Berlow
AU  - E. Aiken
AU  - A. Gorbatov
AU  - R. Van Patten
AU  - J. G. Gillotti
AU  - H. R. Swearingen
AU  - C. R. Faucher
AU  - H. Adams
AU  - N. C. R. McLaughlin
AU  - I. Liberzon
AU  - J. Barredo
AU  - S. Correia
AU  - B. Greenberg
AU  - N. S. Philip
PY  - 2026
DA  - 2026/09/18
PB  - medRxiv
DO  - 10.64898/2026.09.18.26363360
UR  - https://www.medrxiv.org/content/10.64898/2026.09.18.26363360v1
AB  - BackgroundLow-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.  MethodsTen 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.  ResultsNine 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<0.001), and ipsilateral hippocampus (p<0.001). BOLD-fMRI during sonication demonstrated engagement of ventromedial prefrontal and rostral anterior cingulate regions, while post-sonication resting-state connectivity decreased between basolateral amygdala and sensorimotor regions (corrected ps<0.05). Symptom improvement did not differ between conditions, but exploratory imaging-symptom relationships were significant. Spontaneous reports of calm, clarity, or lightness occurred after amygdala but not control sonication (p<0.001).  ConclusionsAmygdala-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.
ER  -