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

摘要 神经刺激，包括侵入性方法，如脑深部电刺激（DBS），是一种越来越多的 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， 逆转导致精神障碍的回路功能障碍不幸的是，大脑的临床疗效 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 还没有通过美国的临床试验关键的障碍是， 或优化DBS在精神疾病中的作用机制。动物研究是提炼 刺激策略，但主要用于模拟精神疾病的物种是大鼠和小鼠。最 有希望的DBS治疗作用于缺乏真正的啮齿动物同源物的电路。我们和其他调查人员 已经表明，在多个脑靶点，有效的DBS改变了远端的神经活动，特别是在外侧 前额皮质（LPFC），这是只在灵长类动物中发现的。非人类灵长类动物（NHP），尤其是猕猴， 与人类有很强的LFPC同源性，因此将是了解DBS如何 工程.猕猴研究在其他DBS应用（如运动障碍）中产生了重要见解。 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， 认知控制认知控制是一种调节自己认知的能力，如抑制习惯性的 更倾向于目标一致的选择。在抑郁症，强迫症， (OCD)，以及新兴的DBS适应症，如成瘾。Co-PI Widge最近表明，DBS在一个经过充分研究的 腹侧内囊/腹侧纹状体（Ventral internal capsule/ ventral striatum，VCVS）的作用部分是通过改善认知控制。 这种改进似乎涉及全氟化学品活动的变化。挑战在于，不清楚为什么或 通过什么途径VCVS DBS改善认知控制，因此我们缺乏优化 效果我们建议通过刺激单个神经束和灰质核来回答这个问题， VCVS DBS目标，在恒河猴中执行标准认知控制任务（侧卫任务）。 在刺激过程中，我们将记录来自多个PFC结构的单个单元和局部场电位， VCVS DBS发挥促认知作用的机制。目的1映射这些机制相对于 内囊中的皮质丘脑束，而Aim 2将映射扩展到皮质纹状体束， 纹状体核这些研究是可能的，通过一个独特的临床，工程和神经科学 协作Co-I约翰逊已经开发了“引导”电神经刺激的方法， DBS电极周围的目标结构，允许电路靶向神经刺激，而无需使用 病毒/基因操作。他的专业知识支持了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（co-I Heilbronner）。

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).