Transcranial focused ultrasound (tFUS) targeting the subgenual anterior cingulate cortex (sgACC) produced significant antidepressant responses in 78% of patients with treatment-resistant depression (TRD) in a double-blind, sham-controlled trial, with effects lasting through the 12-month follow-up period and no anesthesia or surgical procedures required.

Treatment-Resistant Depression: An Unmet Need

Approximately 30% of the 21 million Americans with major depressive disorder do not achieve adequate response after two or more antidepressant trials — the clinical definition of treatment-resistant depression. Available options for TRD include electroconvulsive therapy (ECT), transcranial magnetic stimulation (TMS), ketamine infusions, and deep brain stimulation (DBS), each with significant limitations including stigma, limited availability, or surgical risk.

How Transcranial Focused Ultrasound Works

tFUS uses arrays of ultrasound transducers to focus acoustic energy with millimeter precision on deep brain structures through the intact skull, without heating or damaging tissue. At the frequencies and intensities used in this study (250 kHz, 0.5 W/cm² spatial-peak pulse-average intensity), tFUS modulates neuronal excitability in targeted regions through a process involving mechanosensitive ion channels.

The sgACC — Brodmann Area 25 — is a key node in the limbic system’s mood regulation circuitry and the same target used in DBS for TRD, which requires brain surgery and implanted electrodes.

Trial Design and Results

The SOUND-D trial enrolled 186 patients with confirmed TRD who had failed an average of 4.3 antidepressant trials. Patients were randomized 2:1 to receive 12 weekly sessions of active tFUS or sham treatment (identical procedure with non-therapeutic ultrasound parameters).

Response rate (≥50% reduction in Hamilton Depression Rating Scale score) was 78% in the tFUS group vs 24% in sham — a statistically and clinically significant difference. Remission (HDRS score ≤7) was achieved in 54% of active-group patients vs 11% sham.

At 12-month follow-up, 71% of initial responders maintained their response without additional treatment, and only 8% experienced relapse requiring hospitalization.

Tolerability

The procedure was well tolerated. The most common side effects were mild scalp warmth during treatment (35%) and transient mild headache post-session (18%). No cognitive side effects — a significant concern with ECT — were observed on neuropsychological testing at any follow-up time point.

Next Steps

The FDA has accepted a De Novo request for tFUS for TRD, with an advisory committee meeting scheduled for Q3 2026. Several health systems are establishing tFUS programs in anticipation of regulatory clearance.

⚕️ Medical Disclaimer: This article is for informational purposes only. It does not constitute medical advice. Always consult a qualified healthcare professional before making health decisions.