Low-intensity transcranial focused ultrasound amygdala neuromodulation: a double-blind sham-controlled target engagement study and unblinded single-arm clinical trial

• Published in: Molecular psychiatry Vol. 30; no. 10; pp. 4497 - 4511
• Main Authors: Barksdale, Bryan R., Enten, Lauren, DeMarco, Annamarie, Kline, Rachel, Doss, Manoj K., Nemeroff, Charles B., Fonzo, Gregory A.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.10.2025; Nature Publishing Group
• Subjects: 59/36; 59/57; 631/378; 692/699/476/1414; Adult; Amygdala; Amygdala - diagnostic imaging; Anxiety; Anxiety - therapy; Behavioral Sciences; Biological Psychology; Bipolar disorder; Blindness; Blood levels; Brain research; Cerebrospinal fluid; Clinical trials; Double-Blind Method; Emotions; Female; Functional magnetic resonance imaging; Generalized anxiety disorder; Health care; Hippocampus; Humans; Hyperactivity; Informed consent; Magnetic Resonance Imaging - methods; Male; Medicine; Medicine & Public Health; Mental disorders; Mental health; Middle Aged; Mood; Mood Disorders - therapy; Neuromodulation; Neurosciences; Patients; Pharmacotherapy; Post traumatic stress disorder; Psychiatry; Scanners; Stress Disorders, Post-Traumatic - therapy; Treatment Outcome; Ultrasonic imaging; Ultrasonic Therapy - methods; Ultrasound; Young Adult
• ISSN: 1359-4184; 1476-5578; 1476-5578
• DOI: 10.1038/s41380-025-03033-w

Mood, anxiety, and trauma-related disorders (MATRDs) are highly prevalent and comorbid. A sizable number of patients do not respond to first-line treatments. Non-invasive neuromodulation is a second-line treatment approach, but current methods rely on cortical targets to indirectly modulate subcortical structures, e.g., the amygdala, implicated in MATRDs. Low-intensity transcranial focused ultrasound (tFUS) is a non-invasive technique for direct subcortical neuromodulation, but its safety, feasibility, and promise as a potential treatment is largely unknown. In a target engagement study, magnetic resonance imaging (MRI)-guided tFUS to the left amygdala was administered during functional MRI (tFUS/fMRI) to test for acute modulation of blood oxygenation level dependent (BOLD) signal in a double-blind, within-subject, sham-controlled design in patients with MATRDs (N = 29) and healthy comparison subjects (N = 23). In an unblinded treatment trial, the same patients then underwent 3-week daily (15 sessions) MRI-guided repetitive tFUS (rtFUS) to the left amygdala to examine safety, feasibility, symptom change, and change in amygdala reactivity to emotional faces. Active vs. sham tFUS/fMRI reduced, on average, left amygdala BOLD signal and produced patient-related differences in hippocampal and insular responses. rtFUS was well-tolerated with no serious adverse events. There were significant reductions on the primary outcome (Mood and Anxiety Symptom Questionnaire General Distress subscale; p  = 0.001, Cohen’s d  = 0.77), secondary outcomes (Cohen’s d of 0.43–1.50), and amygdala activation to emotional stimuli. Findings provide initial evidence of tFUS capability to modulate amygdala function, rtFUS safety and feasibility in MATRDs, and motivate double-blind randomized controlled trials to examine efficacy. ClinicalTrials.gov registration: NCT05228964