Focused ultrasound for memory disorders

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Summary/Abstract Working memory (WM) is a core component of executive function. WM is impaired in conditions that affect roughly 20M people in the US alone, including Alzheimer’s disease (5.8M), Parkinson’s disease (1.2M), schizophrenia (1.5M), attention deficit hyperactivity disorder (6.1M) and autism spectrum disorders (7.3M). Despite this, there are few non-addictive medical treatments that are effective in ameliorating working memory deficits. Focused ultrasound (FUS) is an emerging noninvasive method of brain stimulation that has the ability to reach deep brain structures. FUS has been used for direct neuromodulation and to open the blood-brain barrier (BBB) for targeted drug delivery. The proposed experiments will test the effects of FUS neuromodulation and drug delivery on working memory performance in awake, behaving nonhuman primates (NHP) as a step toward developing novel therapies for dementia. The experiments will also address the mechanism of action of FUS neuromodulation and BBB opening in cortico-striatal circuits using a suite of MRI methods (BOLD, DTI, UTE, pcASL, and qBOLD). Finally, we will address the safety of FUS neuromodulation and BBB opening in cortical and deep brain structures; this has not been done previously and establishing safety in NHP is a critical step prior to a clinical trial. We have demonstrated that FUS can be used to improve behavioral performance during decision making in NHP and now propose to evaluate FUS for improving WM. Aim 1 will test the effects of FUS neuromodulation alone on working memory capacity and span in intact and impaired NHP, and compare FUS to electrical deep brain stimulation. Aim 2 will test the effects of FUS- mediated blood-brain barrier opening and drug delivery and on working memory. Aim 3 will investigate the mechanism of FUS neuromodulation using noninvasive MRI. Broader Impact: This project will provide preclinical safety and efficacy data for human neuromodulation studies focusing on cognitive deficits associated with neurological and psychiatric disorders.