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Brain simulation techniques have demonstrated undisputable therapeutic effects on neural diseases. Invasive stimulation techniques like deep brain stimulation (DBS) and noninvasive techniques like transcranial magnetic stimulation (TMS) have been approved by FDA as treatments for many drug resist neural disorders and diseases. Developing noninvasive, deep, and targeted brain stimulation techniques is currently one of the important tasks in brain researches. Transcranial direct current stimulation (tDCS) and transcranial alternative current stimulation (tACS) techniques have the advantages of low cost and portability. However, neither of them can produce targeted stimulation due to lacking of electrical field focusing mechanism. Recently, Grossman et al. reported using the down beating signals of two tACS signals to accomplish focused stimulation. By sending two sine waves running at slightly different high frequencies (~2kHz), they demonstrated that they can modulate a “localized” neuron group at the difference frequency of the two sine waves and at the same time avoid excitation of neurons at other locations. As a result, equivalent focusing effect was accomplished by such beating mechanism. In this work, we show neither theoretically nor experimentally the beating mechanism can produce “focusing effect” and the beating signal spread globally across the full brain. The localized modulation effect likely happened right at the electrode contact sites when the electrode contact area is small and the current is concentrated. We conclude that to accomplish noninvasive and focused stimulation at current stage the only available tool is the focused TMS system we recently demonstrated.
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This content will become publicly available on April 1, 2026
Noninvasive Modulation of the Subcallosal Cingulate and Depression With Focused Ultrasonic Waves
BACKGROUND: Severe forms of depression have been linked to excessive subcallosal cingulate cortex (SCC) ac- tivity. 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-speci c 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 , .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 6-item Hamilton Depression Rating Scale scores at 24 hours and for Sadness scores (both p , .05, d . 1). Nonsigni cant 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.
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- Award ID(s):
- 2325125
- PAR ID:
- 10644307
- Publisher / Repository:
- Biological Psychiatry
- Date Published:
- Journal Name:
- Biological Psychiatry
- Volume:
- 97
- Issue:
- 8
- ISSN:
- 0006-3223
- Page Range / eLocation ID:
- 825 to 834
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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