{
  "abstract": "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.\n\nMethodsTen 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.\n\nResultsNine 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).\n\nConclusionsAmygdala-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.",
  "abstract_shown": true,
  "affiliations": [
    "Center for Neurorestoration and Neurotechnology, VA Providence Healthcare System"
  ],
  "article_type": "PUBLISHAHEADOFPRINT",
  "arxiv": null,
  "author_total": 16,
  "authors": [
    {
      "name": "A. R. Arulpragasam"
    },
    {
      "name": "M. van 't Wout-Frank"
    },
    {
      "name": "Y. A. Berlow"
    },
    {
      "name": "E. Aiken"
    },
    {
      "name": "A. Gorbatov"
    },
    {
      "name": "R. Van Patten"
    },
    {
      "name": "J. G. Gillotti"
    },
    {
      "name": "H. R. Swearingen"
    },
    {
      "name": "C. R. Faucher"
    },
    {
      "name": "H. Adams"
    },
    {
      "name": "N. C. R. McLaughlin"
    },
    {
      "name": "I. Liberzon"
    },
    {
      "name": "J. Barredo"
    },
    {
      "name": "S. Correia"
    },
    {
      "name": "B. Greenberg"
    },
    {
      "affs": [
        0
      ],
      "name": "N. S. Philip"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/7w2q4grtzg3r0.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.09.18.26363360",
  "fulltext_url": "https://www.medrxiv.org/content/10.64898/2026.09.18.26363360v1.full",
  "id": "7w2q4grtzg3r0",
  "issns": [],
  "landing_url": "https://www.medrxiv.org/content/10.64898/2026.09.18.26363360v1",
  "language": null,
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "medrxiv",
      "psychiatry and clinical psychology"
    ],
    [
      "openalex",
      "2204|Ultrasound and Hyperthermia Applications"
    ]
  ],
  "openalex": "W7213788770",
  "pdf_url": "https://www.medrxiv.org/content/10.64898/2026.09.18.26363360v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-09-18",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/7w2q4grtzg3r0.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:18:56Z",
      "native_id": "10.64898/2026.09.18.26363360",
      "source": "medrxiv",
      "url": "https://www.medrxiv.org/content/10.64898/2026.09.18.26363360v1"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "medrxiv:psychiatry and clinical psychology",
      "subfield": "psychiatry"
    }
  ],
  "title": "Low-Intensity Focused Ultrasound of the Amygdala in Depression and Anxiety: A First-in-Human Active-Controlled Trial",
  "title_text": "Low-Intensity Focused Ultrasound of the Amygdala in Depression and Anxiety: A First-in-Human Active-Controlled Trial",
  "type": "preprint",
  "updated_at": "2026-10-30T12:18:56Z",
  "url": "https://research.draconitic.com/paper/7w2q4grtzg3r0",
  "venue": "medRxiv",
  "versions": []
}