Tuning the anterior cingulate from the outside in: a new way forward for treating mental health disorders and beyond

Project Summary This Pioneer Award application seeks to develop a suite of low intensity focused ultrasound strategies for a wide range and severities of brain disorders with psychiatric underpinnings. The dorsal anterior cingulate has repeatedly been implicated in such disorders ranging from depression and obsessive-compulsive disorder to substance abuse and chronic pain. Together, these conditions impact many tens of millions of Americans who do not respond to available treatment. Not surprisingly, attempts to ablate and even apply deep brain stimulation to the anterior cingulate have been attempted with some success, though adoption has been limited due to the invasive and/or irreversible nature of these strategies. Focused ultrasound delivery at low intensity presents an exciting non-invasive, neuromodulatory opportunity but there remains need for high resolution methodologies to hone and optimize the approach. My lab has piloted such methodologies recently for the proposed projects here using anterior cingulate electrophysiology both as a biomarker to guide deep brain stimulation targeting and parameterization and as an objective read-out of symptoms and treatment effect. Project 1 outlines the plan to leverage the same, standard intracranial recording strategies in humans to optimize precision and delivery strategy of externally delivered low intensity focused ultrasound. A better optimized external ultrasound strategy may provide meaningful relief to a large subpopulation of these patients but is expected to have limited utility for more severe cases in which dangerous breakthrough symptoms develop in between recurring treatments. These cases will be in need of more sustainable, continuously available treatment, demanding an implantable strategy. The implant envisioned to meet the needs of patients who have failed conservative options (including externally delivered ultrasound) is an incisionless, endovascularly implanted device capable of low intensity ultrasound delivery guided by anterior cingulate electrophysiology. Project 2 will focus on testing and developing procedural feasibility and safety of such implantation using an ovine model and will allow for developing signal processing techniques to explore an individual's specific anterior cingulate electrophysiological signals transvenously. Project 3 will leverage the ultrasound parameter testing from Project 1 and electrophysiological recordings from Project 2 to guide development of a fully implantable, closed-loop system designed with the capability to deliver low intensity ultrasound to the adjacent anterior cingulate guided by local electrophysiology detected from the central inferior sagittal sinus.