Circuit Specific Electrical Brain Stimulation

摘要 在过去的十年里，基因工具的革命使神经科学家能够探索井-细胞的功能。 定义了大脑回路和这些回路中的特定细胞类型。这些研究表明，很可能 精神疾病的基础，以特定回路的形式，可以被调节以显著改变 实验动物的情绪相关行为。挑战在于，这些电路洞察力并不容易 转化为精神治疗。光遗传学等实验室手段还远未得到验证 人类，特别是一个患有精神疾病的人生活的40多年。电/磁脑 另一方面，刺激是一种已知的、安全的、长期可持续的技术，已经在临床上应用 使用。不幸的是，电刺激有其自身的挑战：尽管它可以将其干预限制在集中的 解剖区，刺激场激活多种细胞类型，影响投射到许多大脑的神经元 地区。换句话说，尽管电学方法在解剖学上是特定的，但它们在功能上或电路上不是 具体的。 我们建议通过开发电刺激方法来克服这些挑战，将其影响限制在 定义的电路和那些电路内的生理特征。具体地说，局域场势(LFP)振荡 它们在大脑区域之间的同步性(连贯性)越来越多地被认为是一种机制， 电路组织和通信。因此，控制定义的电路和频率内的相干性 一种将电刺激的影响限制在特定目标/功能的方法。我的实验室最近准确地证明了 控制刺激脉冲的时间，我们可以显著提高区域间的相干性。我们可以限制 影响到一个很窄的频段，在某些情况下，刺激会导致持续性的突触变化。我们 建议继续我们的啮齿动物调查并测试这些新方法的四个关键特性：行为 有效性、方向性、特异性和概括性。我们希望通过我们的 方法可以调节动物的行为，我们可以增强和抑制所需的行为，我们可以 将我们的影响限制在特定的解剖投影上，并且这些方法适用于多个回路和LFP 频率。这些研究还对以下假设进行了因果检验：LFP一致性是 电路功能，通过显示行为是否直接跟踪连贯性。如果成功，我们将开发出一种 临床上安全的、能够控制特定大脑回路的一套新工具。派是一个大脑 刺激精神病学家，在人类和动物实验方面有丰富的经验，定位我们然后采取 人类飞行员的下一步。这些方法可以成为临床精神病学的“翻译桥梁” 更有效地利用不断增长的科学知识库。

ABSTRACT Over the past decade, a revolution in genetic tools has allowed neuroscientists to probe the function of well- defined brain circuits and specific cell types within those circuits. Those studies have revealed likely underpinnings of mental illness, in the form of specific circuits that can be modulated to dramatically change emotion-related behaviors in laboratory animals. The challenge is that those circuit insights do not readily translate into psychiatric treatments. Laboratory tools such as optogenetics are far from being validated in humans, particularly for the 40+ years that a human lives with a mental illness. Electrical/magnetic brain stimulation, on the other hand, is a known, safe, and long-term-sustainable technology that already in clinical use. Unfortunately, electrical stimulation has its own challenge: although it can limit its intervention to a focused anatomical area, the stimulating field activates many cell types and affects neurons projecting to many brain regions. In other words, although electrical methods are anatomically specific, they are not functionally- or circuit- specific. We propose to overcome these challenges by developing electrical stimulation methods that limit their effects to defined circuits and physiologic signatures within those circuits. Specifically, local field potential (LFP) oscillations and their synchrony (coherence) between brain regions are increasingly implicated as a mechanism by which circuits organize and communicate. Controlling coherence within defined circuits and frequencies might thus be a way to limit electrical stimulation's effects to a specific target/function. My lab recently showed that by precisely controlling the timing of stimulation pulses, we can dramatically increase inter-area coherence. We can limit the effect to a narrow frequency band, and in some cases, the stimulation leads to persistent synaptic change. We propose to continue our rodent investigations and test four key properties of these new methods: behavioral efficacy, directionality, specificity, and generalizability. We expect to show that controlling coherence through our methods can modulate animals' behavior, that we can both enhance and inhibit a desired behavior, that we can limit our effects to a specific anatomic projection, and that these methods work on multiple circuits and LFP frequencies. These studies also provide a causal test of the hypothesis that LFP coherence is a mechanism of circuit function, by showing whether behavior directly tracks coherence. If successful, we will have developed a new set of tools that are clinically safe and capable of controlling specific brain circuits. The PI is a brain stimulation psychiatrist with extensive experience in human and animal experiments, positioning us to then take the next step into human pilots. These methods could become a "translational bridge" that lets clinical psychiatry more efficiently leverage the growing scientific knowledge base.