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

基本信息

批准号：
10251329
负责人：
BENJAMIN Y HAYDEN
金额：
$ 72.76万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
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/10251329
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

项目摘要

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，包括深部脑刺激 (DBS) 等侵入性方法，越来越成为一种它为治疗精神疾病提供了直接针对特定回路的可能性。不幸的是，逆转导致精神疾病的电路功能障碍的大脑的临床功效。例如，DBS 在专家学者的手中取得了非凡的成果，但仍然不可靠。尚未通过美国严格对照的临床试验，其关键障碍是研究非常困难。或优化 DBS 在精神疾病中的作用机制，动物研究将是完善的理想选择。刺激策略，但模拟精神疾病的主要物种是大鼠和小鼠。有前途的 DBS 治疗作用于缺乏真正的啮齿动物同源物的电路。研究表明，在多个大脑目标上，有效的 DBS 可以改变远端的神经活动，尤其是侧向神经活动。前额皮质（LPFC）仅存在于非人类灵长类动物（NHP），尤其是猕猴中， LFPC 与人类具有很强的同源性，因此将成为理解 DBS 如何猕猴研究在其他 DBS 应用（例如运动障碍）方面取得了重要进展。在这个项目中，我们展示了一种在非人类灵长类动物中建模 DBS 的方法，重点关注认知控制是调节自己认知的能力，例如抑制习惯性认知。倾向于更目标一致的选择的反应在抑郁症和强迫症中被破坏。（强迫症），以及新兴的 DBS 适应症（例如成瘾）最近表明 DBS 已得到充分研究。目标，腹侧内囊/腹侧纹状体（VCVS），部分通过改善认知控制来发挥作用。这种改善似乎涉及 PFC 活动的变化，但挑战在于尚不清楚原因或原因。 VCVS DBS 通过什么途径改善认知控制，因此我们缺乏优化认知控制的能力我们建议通过刺激组成的单个束和灰质核来回答这个问题。 VCVS DBS 目标，恒河猴执行标准认知控制任务（侧翼任务）。在刺激过程中，我们将记录来自多个 PFC 结构的单个单位和局部场电位，识别目标 1 描绘了 VCVS DBS 发挥促认知作用的机制。内囊中的皮质丘脑束，而目标 2 将该映射扩展到皮质纹状体束，这些研究可以通过独特的临床、工程和神经科学来实现。约翰逊中尉开发了优先“引导”电神经刺激的方法。 DBS 电极周围的目标结构，无需使用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。（联系 PI Hayden）、临床 DBS（Widge）和纹状体解剖学（co-I Heilbronner）。