Noninvasive modulation of deep brain circuits for treatment-resistant depression

Current interventions for depression lack the capability to directly, precisely, and noninvasively engage the deep brain circuits at the core of the illness. We have developed a non-significant-risk, MRI-compatible, individually-targeted, ultrasonic neuromodulation device that can stimulate deep circuits in humans noninvasively with a precision previously achievable only with surgically implanted electrodes. This R61/R33 project will evaluate the potential for this novel device to engage deep brain targets and modulate mood symptoms in individuals with treatment-resistant depression. The R61 phase will demonstrate target engagement by delivering low-intensity ultrasound to the subcallosal cingulate during functional magnetic resonance imaging. This phase aims to evaluate the intensity dependence, target specificity, and tolerability of this neuromodulation intervention. If predefined go/no-go criteria are met, the R33 phase will then evaluate the short-term effects of subcallosal cingulate neuromodulation using a randomized sham-controlled study design. The aims of this phase are to examine the associations between target engagement, short-term mood changes, and immediate changes in brain functional connectivity. The R33 also aims to evaluate tolerability and feasibility of a subsequent efficacy trial. This project will address an unmet need by providing new, noninvasive, circuit-directed treatment options for patients with treatment-resistant depression. Because this ultrasonic neuromodulation device offers access to deep brain structures with a unique combination of flexibility, precision, and noninvasiveness, the proposed work is expected to have broader positive impacts for understanding and treating other disorders of deep brain circuits.