Project 2_Dougherty: Invasive Recording and Neurostimulation Studies of Approach/Avoidance Behaviors in Humans

项目总结(项目2，项目负责人：马萨诸塞州总医院多尔蒂) 项目2的目标是因果性地探索皮质-纹状体回路在接近-避免冲突使用中的作用 行为正常的清醒人类的侵入性记录和神经刺激。对人类的侵入性研究是一种 在其他项目中，互为补充的侵入性动物研究和非侵入性人类研究之间的桥梁。 无创人体功能成像研究提供了对特定疾病潜在电路的有价值的见解 大脑的功能，但从根本上讲，本质上是相互关联的。任务期间人体的侵入性测量 提供明显更好的空间分辨率(低至单个神经元)和时间分辨率(低至5-10 毫秒)。更关键的是，使用相同电极进行刺激的能力允许独特的“反向” 神经影像学“。人们不需要执行任务并观察哪些大脑网络参与，而是可以刺激 不同脑区在不同幅度、不同频率和不同任务时期下观察对任务的影响 在同时录制的同时进行表演。在本项目中，我们建议研究方法--避免冲突 在两种人体模型中：(1)腹侧被膜/腹侧纹状体(VC/VS)的脑深部刺激(DBS)和(2) 外科癫痫监测。在五年内，我们将招募20名慢性DBS电极的DBS患者 VC/VS治疗神经精神障碍及急性深部电极治疗癫痫20例 癫痫监测。我们将调查DBS对接近-回避行为的行为和神经影响 在Vc/VS植入DBS电极的重度抑郁障碍(MDD)患者。利用 我们之前的研究和大量的初步数据，我们将使用接近/回避决策任务 评估与刺激腹侧纹状体相关的行为和神经变化(与NO相反 植入DBS深度电极的神经精神疾病患者的刺激)。我们还将调查大型- 植入深度电极的癫痫患者接近回避行为的尺度神经网络，以及 测试以关键皮质-纹状体结节为靶点的闭环刺激将双向调节的假设 抑郁症患者的回避行为。基于我们在这一领域的丰富经验，我们将 记录入院患者多个前额叶结构的同时活动，在某些情况下，还记录纹状体 对MGH癫痫监测单元植入深度电极。在以下方面最大限度地提高协同效应 项目，任务将与项目1中使用的任务相同(对于患有MDD或焦虑症的未服用药物的人 疾病)，功能类似于项目3中的(非人灵长类)。对以下项目的贡献 总体中心目标和与其他中心组件的交互。通过测试直接刺激 与接近相关的区域(例如，纹状体)和与回避相关的区域(例如，前膝前扣带回皮质) 影响人类的接近回避行为，项目2将直接将无创功能磁共振研究与 患有未经药物治疗的MDD的个人(项目1)与非人灵长类动物(项目3)和啮齿动物(项目4) 将机械地剖析支配接近/回避行为的神经生物学机制的研究。

PROJECT SUMMARY (PROJECT 2, Project Leader: Dougherty, Massachusetts General Hospital) The goal of Project 2 is to causally probe the role of cortico-striatal circuits in approach-avoidance conflict using invasive recording and neurostimulation in awake, behaving humans. Invasive studies in humans serve as a bridge between the complementary invasive animal and non-invasive human studies in other Projects. Noninvasive human functional imaging studies provide valuable insights into the circuitry underlying specific brain functions but – fundamentally – are correlative in nature. Invasive measurements in humans during tasks provide markedly better spatial resolution (down to the single neuron) and temporal resolution (down to 5-10 milliseconds). More critically, the ability to stimulate using the same electrodes allows for unique “backwards neuroimaging”. Instead of performing a task and observing which brain networks are involved, one can stimulate different brain regions at different amplitudes, frequencies and task epochs to observe effects on task performance all while simultaneously recording. In this project we propose to study approach-avoidance conflict in two human models: (1) deep brain stimulation (DBS) of the ventral capsule/ventral striatum (VC/VS) and (2) surgical epilepsy monitoring. Over five years, we will recruit 20 DBS patients with chronic DBS electrodes in the VC/VS for treatment of neuropsychiatric disorders and 20 patients with epilepsy with acute depth electrodes for seizure monitoring. We will investigate the behavioral and neural effects of DBS on approach-avoidance behavior in patients with major depressive disorder (MDD) with implanted DBS electrodes in the VC/VS. Capitalizing on our prior studies and extensive set of preliminary data we will use an approach/avoidance decision making task to assess behavioral and neural changes associated with stimulation of the ventral striatum (as opposed to no stimulation) in neuropsychiatric patients with implanted DBS depth electrodes. We will also investigate the large- scale neural network of approach-avoidance behavior in epilepsy patients implanted with depth electrodes, and test the hypothesis that closed-loop stimulation targeting key cortico-striatal nodes will bidirectionally modulate approach-avoidance behaviors in depressed patients. Building on our extensive experience in this area we will record simultaneous activity of multiple prefrontal structures and, in some cases, striatum, in patients admitted to the MGH Epilepsy Monitoring Units following implantation of depth electrodes. To maximize synergies across Projects, the task will be identical to the one used in Project 1 (with unmedicated individuals with MDD or anxiety disorders) and functionally analogous to the one in Project 3 (with non-human primates). Contribution to Overall Center Goals & Interactions with Other Center Components. By testing that direct stimulation of both approach-related (e.g., striatum) and avoidance-related (e.g., pregenual anterior cingulate cortex) areas affects approach-avoidance behavior in humans, Project 2 will directly link the non-invasive fMRI studies in individuals with unmedicated MDD (Project 1) with the non-human primate (Project 3) and rodent (Project 4) studies that will mechanistically dissect neurobiological mechanisms governing approach/avoidance behaviors.