Durable effects of deep brain ultrasonic neuromodulation on major depression: a case report.

BACKGROUND: Severe forms of depression have been linked to hyperactivity of the subcallosal cingulate cortex. The ability to stimulate the subcallosal cingulate cortex or associated circuits noninvasively and directly would maximize the number of patients who could receive treatment. To this end, we have developed an ultrasound-based device for effective noninvasive modulation of deep brain circuits. Here we describe an application of this tool to an individual with treatment-resistant depression. CASE PRESENTATION: A 30-year-old Caucasian woman with severe treatment-resistant non-psychotic depression was recruited into a clinical study approved by the Institutional Review Board of the University of Utah. The patient had a history of electroconvulsive therapy with full remission but without sustained benefit. Magnetic resonance imaging was used to coregister the ultrasound device to the subject's brain anatomy and to evaluate neural responses to stimulation. Brief, 30-millisecond pulses of low-intensity ultrasound delivered into the subcallosal cingulate cortex target every 4 seconds caused a robust decrease in functional magnetic resonance imaging blood-oxygen-level-dependent activity within the target. Following repeated stimulation of three anterior cingulate targets, the patient's depressive symptoms resolved within 24 hours of the stimulation. The patient remained in remission for at least 44 days afterwards. CONCLUSIONS: This case illustrates the potential for ultrasonic neuromodulation to precisely engage deep neural circuits and to trigger a durable therapeutic reset of those circuits. Trial registration ClinicalTrials.gov, NCT05301036. Registered 29 March 2022, https://clinicaltrials.gov/ct2/show/NCT05301036.

Propofol for treatment resistant depression: A randomized controlled trial.

Background: Anesthetic agents including ketamine and nitrous oxide have shown antidepressant properties when appropriately dosed. Our recent open-label trial of propofol, an intravenous anesthetic known to elicit transient positive mood effects, suggested that it may also produce robust and durable antidepressant effects when administered at a high dose that elicits an electroencephalographic (EEG) burst-suppression state. Here we report findings from a randomized controlled trial ( NCT03684447 ) that compared two doses of propofol. We hypothesized greater improvement with a high dose that evoked burst suppression versus a low dose that did not. Methods: Participants with moderate-to-severe, treatment-resistant depression were randomized to a series of 6 treatments at low versus high dose (n=12 per group). Propofol infusions were guided by real-time processed frontal EEG to achieve predetermined pharmacodynamic criteria. The primary and secondary depression outcome measures were the 24-item Hamilton Depression Rating Scale (HDRS-24) and the Patient Health Questionnaire (PHQ-9), respectively. Secondary scales measured suicidal ideation, anxiety, functional impairment, and quality of life. Results: Treatments were well tolerated and blinding procedures were effective. The mean [95%-CI] change in HDRS-24 score was -5.3 [-10.3, -0.2] for the low-dose group and -9.3 [-12.9, -5.6] for the high-dose group (17% versus 33% reduction). The between-group effect size (standardized mean difference) was -0.56 [-1.39, 0.28]. The group difference was not statistically significant (p=0.24, linear model). The mean change in PHQ-9 score was -2.0 [-3.9, -0.1] for the low dose and -4.8 [-7.7, -2.0] for the high dose. The between-group effect size was -0.73 [-1.59, 0.14] (p=0.09). Secondary outcomes favored the high dose (effect sizes magnitudes 0.1 - 0.9) but did not generally reach statistical significance (p>0.05). Conclusions: The medium-sized effects observed between doses in this small, controlled, clinical trial suggest that propofol may have dose-dependent antidepressant effects. The findings also provide guidance for subsequent trials. A larger sample size and additional treatments in series are likely to enhance the ability to detect dose-dependent effects. Future work is warranted to investigate potential antidepressant mechanisms and dose optimization.