Reaching deep emotional circuits without surgery could expand the possibilities of psychiatric neuromodulation. A first-in-human active-controlled trial now reports that focused ultrasound can produce measurable changes in the amygdala of people with major depressive disorder.
The September 2026 medRxiv preprint offers evidence of biological target engagement, rather than proof of antidepressant benefit. Its central contribution is demonstrating that a deep brain target can respond to noninvasive stimulation with effects detectable across several imaging methods.
The Challenge Of Reaching Deep Emotional Circuits
Established noninvasive approaches, including conventional transcranial magnetic stimulation, primarily stimulate cortical regions and influence deeper structures through connected networks. Deep brain stimulation can reach subcortical targets directly, but requires implanted electrodes.
The amygdala helps process threats, emotional learning, and the significance of experiences. Its involvement in depression and anxiety makes it a compelling research target, although changing its activity does not automatically translate into symptom relief.
How Focused Ultrasound For Depression Was Tested
Researchers at VA Providence and Brown University studied ten veterans with major depressive disorder. Nine completed both sessions in a randomized crossover design comparing right-amygdala stimulation with stimulation of the left primary somatosensory cortex, an active control region.
Participants were blinded to the target, and a blinded psychiatrist assessed depression symptoms. Sessions occurred at least one week apart, with each session containing two ten-minute ultrasound applications delivered inside an MRI scanner.
Using an active control allowed researchers to examine anatomical specificity while exposing participants to ultrasound in both conditions. However, the study lacked a sham condition and was designed around safety and brain engagement, rather than clinical efficacy.
Imaging Reveals Local And Network Effects
Blood-flow imaging showed greater physiological change in the targeted right amygdala than in the control region or adjacent hippocampal head. Individual responses varied in direction, underscoring that stimulation did not produce one uniform biological response.
During ultrasound delivery, functional MRI detected responses in the ventromedial prefrontal cortex, rostral anterior cingulate cortex, and insula. These regions participate in emotional regulation and the processing of internal and external signals.
After stimulation, resting-state imaging showed reduced connectivity between the basolateral amygdala and sensorimotor regions. Together, the findings suggest that a focal intervention can affect both its intended target and connected circuitry.
Biological Engagement Does Not Establish Clinical Benefit
Symptoms improved over time, but improvement did not differ significantly between stimulation conditions. The study therefore cannot establish that amygdala stimulation produced an antidepressant effect.
Exploratory analyses linked smaller amygdala blood-flow changes with greater depression improvement. Participants also spontaneously described calm, clarity, or lightness after amygdala stimulation. These observations generate hypotheses but do not establish treatment effectiveness.
No serious adverse events or MRI-detectable brain injuries occurred. Nevertheless, adverse events were more frequent after amygdala stimulation, and one participant experienced worsening depression that prompted cessation of further ultrasound and additional monitoring. Symptoms returned near baseline during follow-up.
Sound Waves Offer A Different Route To Neuromodulation
Low-intensity focused ultrasound concentrates acoustic energy within brain tissue. Unlike high-intensity ultrasound used for thermal ablation, this approach aims to alter physiology without destroying tissue.
How ultrasound produces these changes remains incompletely understood. Blood-flow and functional MRI signals provide indirect evidence of engagement; they cannot establish the precise cellular mechanism or confirm that neurons were uniformly activated or inhibited.
Earlier peer-reviewed research in 30 healthy participants found that amygdala ultrasound altered fear-related activation and connectivity compared with sham stimulation. The new trial extends this research into a depression population while combining multiple imaging measures and structured safety assessments. ScienceDirect
Precision Sets The Agenda For Future Trials
The findings support further investigation of focused ultrasound for depression, particularly studies testing different doses, repeated sessions, and longer follow-up.
Larger sham-controlled trials will need to determine whether reliable target engagement produces durable symptom improvement. For now, reaching the amygdala represents a technical and biological milestone, with therapeutic value still to be established.
Citations
- Arulpragasam, A. R., et al. (2026). Low-Intensity Focused Ultrasound Of The Amygdala In Depression And Anxiety: A First-In-Human Active-Controlled Trial. medRxiv. Preprint, not peer reviewed.
- Chou, T., et al. (2024). Transcranial Focused Ultrasound Of The Amygdala Modulates Fear Network Activation And Connectivity. Brain Stimulation, 17(2), 312–320.
Explore more at https://www.interventionalpsychiatry.org/
