Intraoperative studies of flexible decision-making

术中灵活决策研究

• 批准号: 9421087
• 负责人: GORDON H BALTUCH
• 金额: $ 41.53万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-25 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9421087
• 关键词: Adverse effects; Affect; Basal Ganglia; Behavior; Behavioral; Brain; Clinical; Cognitive; Computer Simulation; Contralateral; Data; Data Set; Databases; Decision Making; Deep Brain Stimulation; Disease; Electric Stimulation; Electrodes; Eye Movements; Foundations; Goals; Human; Image; Imaging Techniques; Impairment; Implant; Income; Individual; Instruction; Ipsilateral; Knowledge; Measures; Modeling; Monkeys; Motion; Neurons; Operative Surgical Procedures; Outcome; Output; Parkinson Disease; Pathologic; Patients; Physiological; Play; Process; Property; Psychophysics; Reaction Time; Reporting; Reproducibility; Research; Research Infrastructure; Research Personnel; Role; Saccades; Sensory; Site; Solid; Speed; Substantia nigra structure; Surgeon; Testing; Time; Visual; Visual Motion; Work; awake; base; behavioral study; cognitive ability; computer studies; disabling symptom; electrical microstimulation; expectation; flexibility; human data; human imaging; innovation; insight; microstimulation; nonhuman primate; novel; oculomotor; preference; programs; relating to nervous system; response; temporal measurement

Project Summary/Abstract Deep Brain Stimulation (DBS) is a surgical procedure that is used to treat the debilitating symptoms of Parkinson's Disease (PD). In the process of surgically implanting the stimulating electrodes, surgeons and researchers have a unique opportunity to measure and manipulate the activity of individual neurons while the awake PD patient performs a perceptual, cognitive, or other kind of relatively simple task. These studies are important because they far surpass the spatial and temporal resolution of state-of-the-art human imaging techniques and can yield insights into the basic building blocks of higher brain function, and how those building blocks may be disrupted in PD. Our proposed studies take advantage of this opportunity to establish a novel and sustainable research program to identify mechanisms of decision-making at the single-neuron level. We target the Substantia Nigra, Pars Reticulata (SNr), an output nucleus of the basal ganglia (BG) that acts as a gating mechanism that suppresses unwanted eye movements but allows wanted ones. Because goal-directed eye movements are used to select and attend to features of the visual scene for further processing, their underlying mechanisms must incorporate rapid and sophisticated decision-making. Ours will be the first research program to systematically test the SNr's role in these decision processes. These studies will have a major impact because of our use of: 1) our established and high-volume infrastructure and clinical program to obtain reliable SNr recordings and apply microstimulation in awake, behaving patients undergoing DBS surgery; 2) a visual motion-saccadic decision (“dots”) task that has been used with PD patients and is amenable to the kinds of quantitative modeling approaches that we use regularly; 3) task manipulations that are differentially sensitive to PD-related deficits, allowing us to gain insights into normal and abnormal BG function; 4) complementary studies in non-human primates that act as critical, healthy controls; and 5) electrical microstimulation to test if and how the SNr can play a causal role in the decision process, even with the BG in a pathological state. The proposed project has three Specific Aims. Aim 1 is to identify single-unit correlates of evidence accumulation and commitment in SNr of PD patients and monkeys. Aim 2 is to identify single-unit correlates of speed-accuracy and choice-bias instructions in SNr of PD patients. Aim 3 is to use electrical microstimulation to test for a causal role of the SNr in oculomotor decisions. Together, these Aims will form a solid foundation for a long-term program to understand how the dynamic response properties of individual neurons in the SNr and BG contribute to flexible decision-making. The use of complementary monkey studies is particularly noteworthy, allowing us to firmly establish the quantitative rigor and reproducibility of the human work. We will then build on this solid foundation to better understand the neuronal basis of normal decision-making, decision-making deficits associated with BG malfunction, and potential causes of and remedies to the cognitive side effects associated with DBS.

项目概要/摘要 深部脑刺激（DBS）是一种外科手术，用于治疗以下疾病的衰弱症状： 帕金森病（PD）。在通过手术植入刺激电极的过程中，外科医生和 研究人员有一个独特的机会来测量和操纵单个神经元的活动，同时 清醒的帕金森病患者执行感知、认知或其他相对简单的任务。这些研究是 重要的是因为它们远远超过了最先进的人类成像的空间和时间分辨率 技术，可以深入了解高级大脑功能的基本构建模块，以及这些构建模块如何构建 PD 中的块可能会被破坏。我们提出的研究利用这个机会建立了一种新颖的 和可持续的研究计划，以确定单神经元水平的决策机制。我们 目标是黑质、网状部 (SNr)，这是基底神经节 (BG) 的输出核，充当 门控机制可以抑制不需要的眼球运动，但允许需要的眼球运动。因为目标导向 眼球运动用于选择和关注视觉场景的特征以进行进一步处理，它们的 基本机制必须纳入快速和复杂的决策。我们的将是第一个 研究计划系统地测试 SNr 在这些决策过程中的作用。这些研究将有一个 重大影响是因为我们使用了：1）我们已建立的大容量基础设施和临床计划 获得可靠的 SNr 记录并对接受 DBS 的清醒、行为良好的患者应用微刺激 外科手术; 2) 视觉运动扫视决策（“点”）任务，已用于 PD 患者，并且是 适合我们经常使用的定量建模方法； 3）任务操作 对 PD 相关缺陷的敏感性不同，使我们能够深入了解正常和异常的 BG 功能; 4) 对非人类灵长类动物进行补充研究，作为关键的健康对照；和 5) 电微刺激来测试 SNr 是否以及如何在决策过程中发挥因果作用，即使 BG处于病理状态。拟议项目有三个具体目标。目标 1 是识别单个单元 PD 患者和猴子的 SNr 证据积累和承诺的相关性。目标 2 是确定 PD 患者 SNr 中速度准确度和选择偏差指令的单单元相关性。目标 3 是使用 电微刺激测试 SNr 在动眼神经决策中的因果作用。这些目标共同将 为长期计划奠定坚实的基础，以了解动态响应特性如何 SNr 和 BG 中的单个神经元有助于灵活的决策。互补的使用 猴子研究尤其值得注意，它使我们能够牢固地建立定量的严谨性和 人类工作的可重复性。然后我们将在此坚实的基础上更好地理解神经元 正常决策的基础、与 BG 故障相关的决策缺陷以及潜在的 与 DBS 相关的认知副作用的原因和治疗方法。