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

摘要 神经刺激，包括像脑深部刺激(DBS)这样的侵入性方法，正日益成为一种 治疗精神疾病的重要方法。它提供了直接瞄准特定电路的可能性 导致精神障碍的反向回路功能障碍。不幸的是，脑部的临床疗效 刺激仍然是不可靠的。例如，星展银行在专家学者手中取得了非凡的成果，但 没有通过在美国进行的受控良好的临床试验。关键的障碍是研究它非常困难。 或者优化星展银行在精神疾病方面的作用机制。动物研究将是精炼的理想选择 刺激策略，但模拟精神疾病的主要物种是大鼠和小鼠。最多的 前景看好的DBS治疗作用于缺乏真正啮齿动物同源物的回路。我们和其他调查人员 已经表明，在多个大脑靶点，有效的DBS改变了远端的神经活动，特别是在外侧 前额叶皮质(LPFC)，只在灵长类动物中发现。非人灵长类动物，尤其是猕猴， 它们与人类有很强的LFPC同源性，因此将是理解DBS如何 行得通。猕猴的研究已经在DBS的其他应用中产生了重要的洞察力，例如运动障碍。 在这个项目中，我们演示了一种在非人类灵长类动物中建模DBS的方法，通过关注 认知控制。认知控制是调节自己认知的能力，例如抑制习惯 做出回应，支持更符合目标的选择。它在抑郁症、强迫症中被破坏 (强迫症)，以及星展银行的新兴迹象，如成瘾。Co-Pi Widge最近显示，星展银行在一次精心的研究 靶区，腹侧内囊/腹侧纹状体(VCVS)，部分通过改善认知控制而起作用。 这种改善似乎涉及PFC活动的改变。挑战在于，目前还不清楚原因或 VCVS DBS通过什么途径改善认知控制，因此我们缺乏优化 效果。我们建议通过刺激单独的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势，识别 VCVS DBS发挥前认知效应的机制。AIM 1将这些机制与 内囊中的皮质-丘脑束，而目标2将这种映射扩展到皮质-纹状体束和 纹状体核。通过独特的临床、工程学和神经科学，这些研究是可能的 协作。约翰逊研究出了一种方法，可以“引导”电刺激优先于 DBS电极周围的靶结构，允许电路靶向神经刺激而不使用 病毒/基因操纵。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海尔布伦纳)。

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).