Focused ultrasound for memory disorders

摘要/摘要 工作记忆是执行功能的核心组成部分。WM在影响健康的条件下受损 仅在美国就有大约2000万人，包括阿尔茨海默氏症(580万)，帕金森氏症(120万)， 精神分裂症(150万人)、注意力缺陷多动障碍(610万人)和自闭症谱系障碍(730万人)。 尽管如此，几乎没有非上瘾的药物可以有效地改善工作记忆 赤字。聚焦超声(FUS)是一种新兴的无创脑刺激方法，具有 才能到达大脑深处的结构。FUS已被用于直接神经调节和开放血脑 靶向给药的屏障(BBB)。拟议中的实验将测试FUS的效果 神经调节和药物释放对清醒的非人灵长类动物工作记忆的影响 (NHP)作为开发痴呆症新疗法的一步。这些实验还将解决 用一套MRI研究FUS神经调节和皮质纹状体回路血脑屏障开放的作用机制 方法(BOLD、DTI、UTE、pcASL和qBOLD)。最后，我们将讨论FUS神经调节的安全性。 以及大脑皮质和深层结构中的血脑屏障开放；这是以前没有做过的，并建立了 NHP的安全性是临床试验前的关键一步。我们已经证明了FUS可以用来改进 NHP决策过程中的行为表现，现在建议评估FUS以改进WM。 目标1将测试单独的FUS神经调节对正常和正常大鼠工作记忆容量和广度的影响 NHP受损，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输送以及对工作记忆的影响。目标3将调查 无创性磁共振成像对FUS神经调节机制的研究。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 与神经和精神障碍有关。

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.