Circuit and Cognitive Mechanisms of Striatal Deep Brain Stimulation

神经刺激，包括脑深部刺激(DBS)等侵入性方法，是治疗精神疾病的一种日益重要的方法。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，由于缺乏机制理解而受到限制。我们不知道为什么/如何刺激特定的区域或途径导致症状改善。这限制了我们正确“给药”刺激的能力，或验证生物目标参与的能力。此外，人类的机制很难剖析，因为(A)我们不能轻易捕捉刺激对大脑回路的影响，以及(B)人类患者无法忍受绘制刺激参数空间所需的许多重复实验。在动物身上绘制详细的网络/机制图是可能的，但常见的精神疾病动物模型并不能很好地反映人类疾病。该项目试图通过认知功能的视角来模拟精神病DBS的机制，以克服这些障碍。认知功能是一种可以在人类和动物身上更严格地测量的行为。具体地说，我们最近发现，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。在两项人类研究中，我们表明VCVS DBS增强了认知控制--抑制习惯性/默认反应的能力，支持更符合目标的选择。此外，这种增强可以在不同物种之间转换。在类似于人类范式的认知控制任务中，我们对VCVS的大鼠同源物进行了类似DBS的刺激。我们看到了与人类结果密切相关的改进。我们现在建议使用反向转换模型来确定哪些细胞/电路元件和神经活动变量介导了这种行为改善。一种占主导地位的理论认为，精神病学中的DBS通过白质发挥作用，例如通过VCVS中的皮质-丘脑轴突逆行调制PFC。然而，我们的数据表明，局部纹状体活动的变化也很重要。我们将用群体受限的光遗传刺激取代电DBS，绘制单个皮质-丘脑回路(目标1)和纹状体亚区(目标2)的贡献。在这些操作过程中，我们将记录皮层-纹状体认知控制回路中多个部位的棘波和LFP。我们将确定哪些变量受DBS类刺激的影响最大，并与行为变化相关(目标3)。成功将确定一种有前景的神经刺激疗法的推定机制，具有近期的临床意义。已经有技术可以引导DBS电场指向特定的轴突/核，并根据生理指标滴定刺激。PI是星展银行的精神病学家，他可以在自己的临床项目中使用这些方法来针对我们确定的机制。

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.