Noninvasive Modulation of the Subcallosal Cingulate and Depression With Focused Ultrasonic Waves
Thomas S. Riis, Daniel A. Feldman, Sarah S. Kwon, Lily C. Vonesh, Vincent Koppelmans, Jefferson R. Brown, Daniela Solzbacher, Jan Kubanek, Brian J. Mickey
Biological Psychiatry 2025, 97, 825-834 · 10.1016/j.biopsych.2024.09.029
Abstract
Background Severe forms of depression have been linked to excessive subcallosal cingulate cortex (SCC) activity. Stimulation of the SCC with surgically implanted electrodes can alleviate depression, but current noninvasive techniques cannot directly and selectively modulate deep targets. We developed a new noninvasive neuromodulation approach that can deliver low-intensity focused ultrasonic waves to the SCC. Methods Twenty-two individuals with treatment-resistant depression participated in a randomized, double-blind, sham-controlled study. Ultrasonic stimulation was delivered to the bilateral SCC during concurrent functional magnetic resonance imaging to quantify target engagement. Mood state was measured with the Sadness subscale of the Positive and Negative Affect Schedule before and after 40 minutes of real or sham SCC stimulation. Change in depression severity was measured with the 6-item Hamilton Depression Rating Scale at 24 hours and 7 days. Results Functional magnetic resonance imaging demonstrated a target-specific decrease in SCC activity during stimulation (p = .028, n = 16). In 7 of 16 participants, SCC neuromodulation was detectable at the individual participant level with a single 10-minute scan (p 1). Nonsignificant trends were found in the intent-to-treat sample. Conclusions This small pilot study indicates that ultrasonic stimulation modulates SCC activity and can rapidly reduce depressive symptoms. The capability to noninvasively and selectively target deep brain areas creates new possibilities for the future development of circuit-directed therapeutics and for the analysis of deep-brain circuit function in humans.
Abstract via europepmc.
Exposures
Exposure 1: Bilateral SCC ultrasonic stimulation (real stimulation arm)
Target: subgenual anterior cingulate cortex — “subcallosal cingulate cortex (SCC), bilateral”
Device: custom-built
| Waveform | pulsed | |
|---|---|---|
| Fundamental frequency (kHz) | not reported | ⚑ |
| Pulse duration (ms) | 5 | ✓✓✓⚑ |
| Pulse repetition frequency (Hz) | 100 | ✓✓✓ |
| Duty cycle (%) | not reportedpulse duration × PRF gives 50% | |
| Sonication duration (s) | 60, 180swept | ✓✓✓ |
| Free-field pressure (kPa) | not reported | |
|---|---|---|
| Free-field Isppa (W/cm²) | not reported | |
| Free-field Ispta (W/cm²) | not reported | |
| In-situ estimate | deratingsingle value | |
| In-situ pressure (kPa) | 1,000 | ✓✓✓ |
| In-situ Isppa (W/cm²) | 31.1 | ✓✓✓ |
| In-situ Ispta (W/cm²) | not reported |
During concurrent BOLD fMRI, ultrasound was delivered as a 30-ms burst duration containing pulses of 5 ms on and 5 ms off, separated by 1.4-second burst intervals, for 60 seconds, in a 10-minute block design of five 1-minute active-sonication epochs interleaved with five 1-minute rest epochs. In the subsequent 1-hour treatment session outside the scanner, three adjacent SCC targets were stimulated sequentially using the same 30-ms burst (5 ms on/5 ms off pulses) with burst intervals of 1.4 s (Blocks A and B) or 0.7 s (Block C): Block A used three to five 1-minute sonications per target, and Blocks B and C used six 3-minute sonications per target, for 39 to 41 minutes cumulative real or sham sonication across the session. The two-level burst structure (5-ms sub-pulses within a 30-ms burst, bursts repeated every 1.4 or 0.7 s) means the intended 'pulse duration'/'PRF'/'duty cycle' fields are ambiguous; both durations are given here rather than in the numeric fields.
Flags from extraction
n_subjects— 29 participants enrolled, 22 randomised, 21 actually received real stimulation and 21 received sham stimulation (crossover design); n_subjects recorded as 21 (number exposed to real ultrasound).exposures[0].fundamental_frequency_khz— The main text does not state the ultrasound fundamental/carrier frequency for this device; not reported here even though it is likely described in the cited companion methods papers, which were not used for this extraction.exposures[0].timing.pulse_duration_ms— The paper describes a two-level burst structure (5 ms on/5 ms off pulses grouped into a 30-ms burst, itself repeated at 1.4 s or 0.7 s intervals) without stating which level corresponds to 'pulse duration', PRF, or duty cycle, and never states a duty cycle percentage; left not_reported per the burst-rule guidance and both durations described in protocol_description instead.exposures[0].target.terms— Target vocabulary lists 'subgenual_anterior_cingulate_cortex' with SCC/subcallosal cingulate as a synonym; used directly since the paper's SCC matches this term.