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

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.

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.

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<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).

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.