Investigation of Locus Coeruleus Function in Sustained Attention

持续注意力中蓝斑功能的研究

• 批准号: 10693968
• 负责人: SAMUEL M MCCLURE
• 金额: $ 19.94万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10693968
• 关键词: 3-Dimensional; Affect; Anatomy; Area; Attention; Attention deficit hyperactivity disorder; Brain; Brain Stem; Cardiac; Cell Nucleus; Cognition; Cross-Over Studies; Data; Development; Diameter; Double-Blind Method; Environment; Event; Exploratory/Developmental Grant; Failure; Functional Imaging; Functional Magnetic Resonance Imaging; Functional disorder; Goals; Grant; Human; Image; Imaging Techniques; Influentials; Investigation; Knowledge; Link; Location; Magnetic Resonance Imaging; Measurement; Measures; Mediating; Mental Health; Mental disorders; Methods; Modafinil; Motor; Mydriasis; National Institute of Mental Health; Norepinephrine; Participant; Pathway interactions; Performance; Persons; Pharmacology; Phase; Placebo Control; Placebos; Pontine structure; Prosencephalon; Proxy; Pupil; Reaction Time; Research; Resolution; Schizophrenia; Shapes; Source; Strategic Planning; Structure; Task Performances; Techniques; Testing; Validation; Variant; Weight; Work; anatomic imaging; attentional control; biological sex; blood oxygenation level dependent response; cognitive ability; cognitive function; high resolution imaging; high reward; high risk; human imaging; imaging modality; individual variation; innovation; interest; locus ceruleus structure; neuroimaging; neuromelanin; nonhuman primate; norepinephrine system; pharmacologic; response; structural imaging; sustained attention; tool

PROJECT SUMMARY Attention failures negatively impact goal pursuit and have significant consequences on performance in many environments. Attentional control of perceptual, motor and cognitive functions are believed to be partly determined by functioning of the locus coeruleus-norepinephrine (LC-NE) system. The LC, a small brainstem nucleus that is the primary source for NE in the forebrain, has motivated hypotheses about human cognition, including mental health disorders with known alterations in attention and cognition (e.g., attention- deficit/hyperactivity disorder (ADHD), schizophrenia) even though methods for measuring human LC activity have significant limitations. Existing methods to study LC function in humans rely on pupillometry and fMRI. Because pupil diameter correlates with LC activity, it has been used as a proxy for LC activity. However, the anatomical pathway linking the LC to pupil dilation has not been established and pupil diameter also correlates with activity in other brain areas. Thus, inferring LC activity from pupillometry alone is problematic. fMRI has also been used to measure activity from the LC, but the imaging methods used to date have relied on resolutions that are coarse relative to the size and shape of LC. Prior fMRI results have therefore not been adequate for event-related analyses. The goal of the proposed work is to develop and validate methods for using fMRI to measure LC activity, specifically event-related responses that will allow for testing of influential hypotheses of LC function in humans. This goal is appropriate for the R21 mechanism, which is meant to “encourage exploratory/developmental research by providing support for the early and conceptual stages of project development” and to test innovative, high-risk, high reward research. This project has two specific aims, which are both tested with sustained attention tasks. The first aim uses high-resolution fMRI to maximize the number of measurements within LC combined with neuromelanin-sensitive imaging to localize BOLD responses to LC. We will measure (a) pre-trial activity (i.e., during inter-trial intervals; this period is thought to reflect tonic LC activity) and (b) trial response (i.e., phasic LC activity) by estimating the beta weights for each trial. The second aim uses modafinil administration to modulate LC activity and confirm the location of BOLD responses measured during the sustained attention tasks to the LC. We will administer modafinil and placebo to participants in a double-blind, placebo-controlled crossover study. Pupillometry data will also be collected for both the modafinil and placebo conditions, and we will use the pupillometry data to test for a correlation with LC BOLD response amplitude. This combination of techniques will demonstrate whether fMRI can be used to measure LC activity in a targeted fashion. Developing these tools meets Goal 1 (Strategy 1.3D) of the 2020 Strategic Plan of the NIMH by permitting direct measurement of a brain structure central in attentional control.

项目摘要 注意力缺失会对目标追求产生负面影响，并对许多人的表现产生重大影响。 环境.知觉，运动和认知功能的注意控制被认为是部分 由蓝斑-去甲肾上腺素（LC-NE）系统的功能决定。LC，一个小脑干 作为前脑NE的主要来源的核，激发了关于人类认知的假设， 包括具有已知的注意力和认知改变的精神健康障碍（例如，注意- 缺陷/多动障碍（ADHD）、精神分裂症），尽管测量人LC活性的方法 有很大的局限性。现有的研究人类LC功能的方法依赖于瞳孔测量和功能磁共振成像。 由于瞳孔直径与LC活性相关，因此它已被用作LC活性的代表。但 尚未建立LC与瞳孔扩张之间的解剖学通路，瞳孔直径也与LC相关 大脑其他区域的活动。因此，仅从瞳孔测量推断LC活性是有问题的。fMRI具有 也被用于测量LC的活性，但迄今为止使用的成像方法依赖于 相对于LC的尺寸和形状而言，分辨率较粗糙。因此，之前的fMRI结果并没有被 足以进行事件相关分析。拟议工作的目标是开发和验证方法， 使用fMRI测量LC活动，特别是与事件相关的反应，这将允许测试有影响力的 人类LC功能的假设。这一目标适用于R21机制，其目的是 “鼓励探索性/发展性研究，为以下方面的早期和概念阶段提供支持： 项目开发”和测试创新，高风险，高回报的研究。该项目有两个具体目标， 这两种测试都是通过持续注意力任务进行的。第一个目标是使用高分辨率的fMRI来最大化 LC内的测量次数与神经黑色素敏感成像结合以定位BOLD 回答LC。我们将测量（a）试验前活动（即，在审判间隔期间;这段时间被认为是 反映紧张性LC活性）和（B）试验反应（即，阶段性LC活性），通过估计每个阶段的β权重来确定 审判第二个目的是使用莫达非尼给药来调节LC活性并确定BOLD的位置 在对LC的持续注意任务期间测量的反应。我们会给你莫达非尼和安慰剂 一项双盲安慰剂对照交叉研究的参与者。还将收集瞳孔测量数据， 莫达非尼和安慰剂条件下，我们将使用瞳孔测量数据来测试与 LC BOLD响应振幅。这种技术的结合将证明功能磁共振成像是否可以用于 以有针对性的方式测量LC活性。开发这些工具符合2020年目标1（战略1.3D） NIMH的战略计划，允许直接测量大脑结构的注意力控制中心。