ORIGINAL RESEARCH article
Front. Psychiatry
Sec. Mood Disorders
This article is part of the Research TopicTreatment Resistant Depression (TRD): epidemiology, clinic, burden and treatment, vol IIView all 3 articles
The Effect of Non-invasive Transcranial Focused Ultrasound for Depression on the Default Mode Network: An Open-label Pilot Trial
Provisionally accepted
Jessica N Schachtner1*
Jacob F Dahill-Fuchel1Diheng Zhang1Katja E Ehrmann1
Christopher R Bawiec2
Peter J Hollender2
Sarah B Ornellas2Soren D Konecky2
Achal S Achrol2
John JB Allen1- 1The University of Arizona, Tucson, United States
- 2Openwater, San Francisco, United States
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Background: Major depressive disorder (MDD) affects one in five individuals, often recurs, and up to 50% of cases are deemed treatment resistant. Aberrant brain connectivity is associated with both depression symptoms and a thought pattern characteristic of depression, repetitive negative thought (RNT). Transcranial focused ultrasound (tFUS) is a novel neuromodulation technique that can directly target a hypothesized neural mechanism in depression, default mode network (DMN) hyperconnectivity. The present study assessed whether tFUS decreases DMN connectivity in individuals with MDD. Exploratory analyses assessed whether changes in DMN connectivity tracked changes in depressive symptoms and RNT. Methods: Twenty participants with MDD completed up to 11 sessions of tFUS treatment targeting the left anterior medial prefrontal cortex, a major hub of the DMN. Before commencing and after completing treatment, participants completed resting state functional magnetic resonance imaging, self -report assessments, and clinical interviews. Participants also completed daily self-report and adverse event assessments. Results: We previously reported a significant decrease in depression symptoms and RNT after tFUS treatment. Here we report that DMN connectivity between the left medial prefrontal cortex and left posterior cingulate cortex, major hubs of the DMN, significantly decreased after treatment. Exploratory analysis revealed no significant relationship between change in DMN connectivity and change in depressive symptoms or RNT. Conclusions: tFUS shows promise in the treatment for MDD, as hyperconnectivity within the DMN decreased, alongside decreases in depression symptoms and RNT. These findings provide evidence supporting future clinical trials. Clinical trial registration: https://clinicaltrials.gov/study/NCT06320028intr=Ultrasound&cond=depression&locStr=Arizon a&country=United%20States&state=Arizona&rank=1, identifier NCT06320028.
Keywords: Transcranial-focused ultrasound, Default Mode Network, Major Depressive Disorder, Repetitive negative thinking (RNT), Neuromodulation
Received: 10 Oct 2025; Accepted: 25 Nov 2025.
Copyright: © 2025 Schachtner, Dahill-Fuchel, Zhang, Ehrmann, Bawiec, Hollender, Ornellas, Konecky, Achrol and Allen. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Jessica N Schachtner
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