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

摘要 神经刺激，包括深部脑刺激 (DBS) 等侵入性方法，正日益成为一种 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，大脑的临床功效 刺激仍然不可靠。例如，星展银行在专家学者的手中取得了非凡的成果，但是 尚未通过美国严格控制的临床试验。关键的障碍是学习非常困难 或优化星展银行在精神疾病方面的作用机制。动物研究对于精炼来说是理想的选择 刺激策略，但模拟精神疾病的主要物种是大鼠和小鼠。最 有前途的 DBS 疗法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 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），仅存在于灵长类动物中。非人类灵长类动物（NHP），尤其是猕猴， LFPC 与人类具有很强的同源性，因此将成为理解 DBS 如何 作品。猕猴研究对其他 DBS 应用（例如运动障碍）产生了重要的见解。 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，重点关注 认知控制。认知控制是调节自己认知的能力，例如抑制习惯性认知 响应有利于更加目标一致的选择。它在抑郁症、强迫症中被破坏 （强迫症），以及新兴的 DBS 适应症，如成瘾。 Co-PI Widge 最近表明，星展银行 (DBS) 在经过充分研究后 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。挑战在于尚不清楚原因或 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 效果。我们建议通过刺激组成的单个纤维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 VCVS DBS 发挥促认知作用的机制。目标 1 将这些机制映射到 内囊中的皮质丘脑束，而目标 2 将映射扩展到皮质纹状体束， 纹状体核。这些研究可以通过独特的临床、工程和神经科学来实现 合作。约翰逊中尉开发了“引导”电神经刺激优先进行的方法 DBS 电极周围的目标结构，无需使用 病毒/基因操作。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 （联系 PI Hayden）、临床 DBS（Widge）和纹状体解剖学（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).