Modeling circuit-specific psychiatric deep brain stimulation and its cognitive effects in macaques

模拟回路特异性精神深部脑刺激及其对猕猴的认知影响

• 批准号: 10462804
• 负责人: BENJAMIN Y HAYDEN
• 金额: $ 68.24万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10462804
• 关键词: Anatomy; Animal Model; Animals; Axon; Behavioral; Biological Models; Brain; Cell Nucleus; Clinical; Clinical Engineering; Clinical Trials; Cognition; Cognitive; Collaborations; Complex; Corpus striatum structure; Deep Brain Stimulation; Disease; Distal; Electrodes; Electrophysiology (science); Elements; Fiber; Functional disorder; Goals; Homologous Gene; Human; Impairment; Implant; Individual; Institution; Internal Capsule; Lateral; Lead; Macaca; Macaca mulatta; Maps; Mental Depression; Mental disorders; Methods; Modeling; Movement Disorders; Mus; Obsessive-Compulsive Disorder; Pathway interactions; Patients; Pattern; Performance; Post-Traumatic Stress Disorders; Prefrontal Cortex; Primates; Process; Psychiatry; Rattus; Research; Research Domain Criteria; Research Personnel; Resolution; Rodent; Role; Running; Site; Structure; Techniques; Testing; Thalamic structure; Ventral Striatum; Work; addiction; base; clinical efficacy; clinical practice; cognitive ability; cognitive control; cognitive neuroscience; exhaustion; genetic manipulation; gray matter; improved; insight; neural correlate; nonhuman primate; relating to nervous system; response; success; tool; virus genetics; white matter

Abstract Neurostimulation, including invasive methods like deep brain stimulation (DBS), is an increasingly important approach to treating mental illness. It offers the possibility of directly targeting specific circuits to reverse circuit dysfunctions that underpin mental disorders. Unfortunately, the clinical efficacy of brain stimulation is still unreliable. DBS, for instance, has extraordinary results in the hands of expert academics, but has not passed a well-controlled US-based clinical trial. The critical barrier is that it is very difficult to study or optimize DBS’ mechanisms of action in psychiatric illness. Animal studies would be ideal for refining stimulation strategies, but the primary species for modeling mental illness are rats and mice. The most promising DBS treatments act on circuits that lack true rodent homologues. We and other investigators have shown that, at multiple brain targets, effective DBS alters neural activity distally, especially in lateral prefrontal cortex (LPFC), which is only found in primates. Non-human primates (NHPs), especially macaques, which have strong LFPC homology to humans, would thus be an excellent model for understanding how DBS works. Macaque studies have yielded major insight in other DBS applications such as movement disorders. In this project, we demonstrate an approach to modeling DBS in non-human primates by focusing on cognitive control. Cognitive control is the ability to regulate one’s own cognition, such as withholding a habitual response in favor of a more goal-aligned option. It is disrupted in depression, obsessive compulsive disorder (OCD), and emerging DBS indications like addiction. Co-PI Widge recently showed that DBS at a well-studied target, the ventral internal capsule/ ventral striatum (VCVS), acts in part by improving cognitive control. That improvement appears to involve PFC activity changes. The challenge is that it is not clear why or through what pathways VCVS DBS improves cognitive control, and thus we lack the ability to optimize the effect. We propose to answer that question by stimulating individual tracts and gray matter nuclei that comprise the VCVS DBS target, in rhesus macaques performing a standard cognitive control task (the Flanker task). During stimulation, we will record single units and local field potentials from multiple PFC structures, identifying mechanisms by which VCVS DBS exerts pro-cognitive effects. Aim 1 maps these mechanisms relative to cortico-thalamic tracts in the internal capsule, while Aim 2 extends that mapping to cortico-striatal tracts and striatal nuclei. These studies are possible through a unique clinical, engineering, and neuroscientific collaboration. Co-I Johnson has developed methods for “steering” electrical neurostimulation to preferentially target structures surrounding a DBS electrode, allowing circuit-targeted neurostimulation without the use of viral/genetic manipulations. His expertise supports our team’s capabilities in macaque cognitive neuroscience (contact PI Hayden), clinical DBS (Widge), and striatal anatomy (co-I Heilbronner).

抽象的 神经刺激，包括诸如深脑刺激（DBS）之类的侵入性方法，越来越多 治疗精神疾病的重要方法。它提供了直接针对特定电路的可能性 基于精神障碍的反向电路功能障碍。不幸的是，大脑的临床效率 刺激仍然不可靠。例如，DBS在专家学者手中取得了非凡的成果，但 尚未通过基于美国的临床试验。关键的障碍是很难学习 或优化DBS在精神病中的作用机制。动物研究是精炼的理想选择 刺激策略，但是建模精神疾病的主要物种是大鼠和小鼠。最多 有前途的DBS治疗法对缺乏真正的啮齿动物同源物的电路。我们和其他调查员 已经表明，在多个大脑目标下，有效的DB分别改变了神经活动，尤其是在以后 前额叶皮层（LPFC），仅在私人中找到。非人类素数（NHP），尤其是猕猴， 因此，与人类具有强大的LFPC同源性，将是理解DB的绝佳模型 作品。猕猴的研究对其他DBS应用（例如运动障碍）产生了重大见解。 在这个项目中，我们通过专注于非人类隐私来建模DB的方法 认知控制。认知控制是能够调节自己的认知的能力，例如保留习惯性 响应更有利于目标一致的选项。它在抑郁症，强迫症中被残疾 （OCD）和成瘾等新兴DBS指示。 Co-Pi Widge最近显示了DBS的DB 靶标，腹侧胶囊/腹侧纹状体（VCV），部分通过改善认知控制。 这种改进似乎涉及PFC活动的变化。挑战是尚不清楚为什么或 通过途径VCVS DBS可以改善认知控制，因此我们缺乏优化的能力 影响。我们建议通过刺激完成的单个道和灰质核来回答这个问题 VCVS DBS目标，在执行标准认知控制任务（侧面任务）的恒河猕猴中。 在刺激期间，我们将记录来自多个PFC结构的单个单元和本地场电位，以识别 VCVS DBS执行促进认知效应的机制。 AIM 1地图这些机制相对于 内部胶囊中的皮质 - 丘脑区域，而AIM 2则将其映射到皮质 - 纹状体区域，并将其映射到 纹状体核。这些研究是通过独特的临床，工程和神经科学方法进行的 合作。约翰逊（Co-I Johnson）开发了“转向”电神经刺激的方法 DBS电极周围的目标结构，允许靶向电路的神经刺激，而无需使用 病毒/遗传操作。他的专业知识支持我们团队在猕猴认知神经科学方面的能力 （与Pi Hayden联系），临床DBS（Widge）和纹状体解剖结构（Co-I Heilbronner）。