Focused ultrasound for memory disorders

总结/摘要 工作记忆是执行功能的核心组成部分。WM在以下情况下受损： 仅在美国就有大约2000万人，包括阿尔茨海默病（580万），帕金森病（120万）， 精神分裂症（1.5M）、注意力缺陷多动障碍（6.1M）和自闭症谱系障碍（7.3M）。 尽管如此，很少有非成瘾性的医学治疗方法能有效改善工作记忆 赤字聚焦超声（FUS）是一种新兴的非侵入性脑刺激方法， 到达大脑深处FUS已被用于直接神经调节和开放血脑 屏障（BBB）用于靶向药物递送。拟议的实验将测试FUS的效果 神经调节和药物传递对清醒行为非人灵长类动物工作记忆表现的影响 (NHP)作为开发痴呆症新疗法的一步。这些实验还将解决 使用一套MRI研究皮质-纹状体回路中FUS神经调节和BBB开放的作用机制 方法（BOLD、DTI、UTE、pcASL和qBOLD）。最后，我们将讨论FUS神经调节的安全性 以及皮层和深部脑结构中的BBB开放;这在以前没有做过， NHP的安全性是临床试验之前的关键步骤。我们已经证明，FUS可以用来改善 在NHP决策过程中的行为表现，现在建议评估FUS以改善WM。 目的1将测试单独的FUS神经调节对完整的和非完整的工作记忆容量和广度的影响。 受损的NHP，并将FUS与脑深部电刺激进行比较。目标2将测试FUS的效果- 介导的血脑屏障开放和药物递送以及对工作记忆的影响。目标3将调查 使用非侵入性MRI的FUS神经调节机制。更广泛的影响：该项目将提供 关注认知缺陷的人类神经调节研究的临床前安全性和有效性数据 与神经和精神疾病有关。

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.