Circuit Specific Electrical Brain Stimulation

摘要 在过去的十年中，遗传工具的革命使神经科学家能够探索良好的功能。 定义了大脑回路和这些回路内的特定细胞类型。这些研究表明可能 精神疾病的基础，以特定电路的形式存在，可以通过调节来显着改变 实验动物的情绪相关行为。挑战在于这些电路见解并不容易 转化为精神科治疗。光遗传学等实验室工具远未得到验证 人类，尤其是患有精神疾病的人生活了 40 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，已经应用于临床。 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为集中 在解剖区域，刺激场激活许多细胞类型并影响投射到许多大脑的神经元 地区。换句话说，虽然电气方法在解剖学上是特定的，但它们在功能或电路上并不重要。 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 定义的回路和这些回路内的生理特征。具体来说，局部场电位 (LFP) 振荡 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，通过这种机制 电路组织和通信。因此，控制定义的电路和频率内的相干性可能是 一种限制电刺激对特定目标/功能的影响的方法。我的实验室最近表明，通过精确地 通过控制刺激脉冲的时间，我们可以显着提高区域间的一致性。我们可以限制 影响窄频带，在某些情况下，刺激会导致持续的突触变化。我们 建议继续我们的啮齿动物研究并测试这些新方法的四个关键特性： 有效性、方向性、特异性和普遍性。我们希望表明，通过我们的控制一致性 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 将我们的效果限制在特定的解剖投影上，并且这些方法适用于多个电路和 LFP 频率。这些研究还提供了 LFP 一致性是一种机制这一假设的因果检验。 电路功能，通过显示行为是否直接跟踪连贯性。如果成功的话，我们将开发出 一套新的临床安全工具，能够控制特定的大脑回路。 PI 是一个大脑 刺激精神病学家在人体和动物实验方面拥有丰富的经验，使我们能够采取 人类飞行员的下一步。这些方法可以成为“转化桥梁”，让临床精神病学 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.