Circuit and Cognitive Mechanisms of Striatal Deep Brain Stimulation

神经刺激，包括脑深部电刺激（DBS）等侵入性方法，是治疗精神疾病的一种越来越重要的方法。它提供了直接针对产生精神障碍的电路功能障碍的可能性。脑刺激的临床应用，特别是DBS，由于缺乏对机制的理解而受到限制。我们不知道为什么/如何刺激特定区域或通路导致症状改善。这限制了我们正确“剂量”刺激或验证生物靶点接合的能力。此外，机制难以在人类中剖析，因为（A）我们不能容易地捕获刺激对脑回路的影响，并且（B）人类患者不能忍受映射刺激参数空间所需的许多重复实验。详细的网络/机制映射在动物中是可能的，但常见的精神疾病动物模型并不能很好地反映人类疾病。这个项目试图通过认知功能的透镜来模拟精神病DBS的机制来克服这些障碍，认知功能是可以在人类和动物中更严格测量的行为。具体来说，我们最近表明，腹侧内囊/腹侧纹状体（VCVS）的DBS部分通过改善患者的执行功能发挥作用。在两项人体研究中，我们发现VCVS DBS增强了认知控制-抑制习惯/默认反应的能力，有利于更符合目标的选择。此外，这种扩增跨物种翻译。我们将DBS样刺激应用于VCVS的大鼠同源物，在类似于我们人类范式的认知控制任务期间。我们看到的改进非常接近我们的人类结果。我们现在建议使用反向翻译模型来确定哪些细胞/电路元件和神经活动变量介导这种行为改善。一种主流理论认为，精神病学中的DBS通过白色物质起作用，例如，通过VCVS中的皮质-丘脑轴突逆行调节PFC。然而，我们的数据表明，局部纹状体活动的变化也很重要。我们将用群体限制性光遗传学刺激取代电DBS，绘制个体皮质-丘脑回路（Aim 1）和纹状体子区域（Aim 2）的贡献。在这些操作过程中，我们将在皮质-纹状体认知控制回路内的多个部位记录尖峰和LFP。我们将确定哪些变量被DBS样刺激改变得最强烈，并与行为变化相关（目标3）。成功将确定一种有前途的神经刺激治疗的推定机制，具有近期临床意义。已经存在将DBS电场引导到靶向特定轴突/核的技术，以及基于生理测量滴定刺激的技术。PI是DBS精神科医生，可以在自己的临床项目中使用这些方法来定位我们确定的机制。

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 the circuit dysfunctions that produce mental disorders. The clinical use of brain stimulation, and DBS in particular, has been limited by a lack of mechanistic understanding. We do not know why/how stimulating a specific region or pathway leads to symptom improvement. This limits our ability to correctly “dose” stimulation, or to verify biological target engagement. Further, mechanisms are difficult to dissect in humans, because (A) we cannot easily capture stimulation’s effects on brain circuits and (B) human patients cannot tolerate the many repeated experiments needed to map stimulation parameter space. Detailed network/mechanism mapping is possible in animals, but common animal models of psychiatric illness are not strong mirrors of human disease. This project attempts to overcome those barriers by modeling psychiatric DBS’ mechanisms through the lens of cognitive function – behaviors that can be more rigorously measured in both humans and animals. Specifically, we recently showed that DBS of the ventral internal capsule/ventral striatum (VCVS), acts in part by improving patients’ executive function. In two human studies, we showed that VCVS DBS augments cognitive control – the ability to withhold a habitual/default response in favor of a more goal-aligned option. Further, this augmentation translates across species. We applied DBS-like stimulation to a rat homologue of VCVS, during a cognitive control task similar to our human paradigm. We saw improvements that very closely tracked our human results. We now propose to use that reverse-translational model to identify which cellular/circuit elements and neural activity variables mediate this behavioral improvement. A dominant theory argues that DBS in psychiatry works through white matter, e.g. by retrograde modulation of PFC through cortico-thalamic axons in VCVS. Our data suggest, however, that changes in local striatal activity are also important. We will replace electrical DBS with population-restricted optogenetic stimulation, mapping the contributions of individual cortico-thalamic circuits (Aim 1) and striatal sub-regions (Aim 2). During those manipulations, we will record spikes and LFP, at multiple sites within the cortico-striatal cognitive control circuitry. We will identify which variables are most strongly changed by DBS-like stimulation and correlate with behavior change (Aim 3). Success would identify putative mechanisms of a promising neurostimulation therapy, with near-term clinical implications. Technologies already exist to steer the DBS electric field to target specific axons/nuclei, and to titrate stimulation based on physiologic measures. The PI is a DBS psychiatrist, and could use those approaches in his own clinical program to target the mechanisms we identify.