Noninvasive modulation of subcallosal cingulate and depression with focused ultrasonic waves.

Background: Severe forms of depression have been linked to excessive subcallosal cingulate (SCC) activity. Stimulation of 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 subjects with treatment-resistant depression participated in a randomized, double-blind, sham-controlled study. Ultrasonic stimulation was delivered to bilateral SCC during concurrent functional MRI 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 (HDRS- 6) at 24 hours and 7 days.

Results: Functional MRI demonstrated a target-specific decrease in SCC activity during stimulation (p=0.028, n=16). In 7 of 16 participants, SCC neuromodulation was detectable at the individual-subject level with a single 10-minute scan (p<0.05, small-volume-correction). Mood and depression scores improved more with real than with sham stimulation. In the per-protocol sample (n=19), real stimulation was superior to sham for HDRS-6 at 24 hours and for Sadness (both p<0.05, d>1). Non-significant 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 future development of circuit-directed therapeutics, and for the dissection of deep-brain circuit function in humans.