{"doi":"10.1038/s41380-025-03033-w","title":"Low-intensity transcranial focused ultrasound amygdala neuromodulation: a double-blind sham-controlled target engagement study and unblinded single-arm clinical trial","abstract":"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.","journal":"Molecular Psychiatry","year":2025,"id":508997,"datarank":1.1713850586501882,"base_score":4.02535169073515,"endowment":4.02535169073515,"self_citation_contribution":0.6038027536102726,"citation_network_contribution":0.5675823050399155,"self_endowment_contribution":0.6038027536102726,"citer_contribution":0.5675823050399155,"corpus_percentile":null,"corpus_rank":null,"citation_count":55,"citer_count":53,"citers_with_citation_signal":27,"citers_with_endowment":27,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9621,"is_data_producer":true,"deposit_databanks":{"ClinicalTrials.gov":["NCT05228964"]},"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1362715,"name":"Lauren Enten","orcid":null,"position":1,"is_corresponding":false},{"id":1361614,"name":"Annamarie DeMarco","orcid":"0000-0002-4359-5927","position":2,"is_corresponding":false},{"id":382910,"name":"Rachel Kline","orcid":"0000-0002-1692-2208","position":3,"is_corresponding":false},{"id":230895,"name":"Manoj K. Doss","orcid":"0000-0003-2939-2522","position":4,"is_corresponding":false},{"id":21454,"name":"Charles B. Nemeroff","orcid":"0000-0001-7867-1160","position":5,"is_corresponding":false},{"id":258805,"name":"Gregory A. Fonzo","orcid":"0000-0002-0213-1034","position":6,"is_corresponding":false},{"id":887703,"name":"Bryan Barksdale","orcid":null,"position":0,"is_corresponding":true}],"reference_count":113,"raw_metadata":null,"created_at":"2026-07-19T02:47:00.188082Z","pmid":"40275098","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}