Investigation of Locus Coeruleus Function in Sustained Attention

项目总结 注意力失败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。对知觉、运动和认知功能的注意力控制被认为是部分 由蓝斑-去甲肾上腺素(LC-NE)系统的功能决定。LC，一个小小的脑干 核团是前脑去甲肾上腺素的主要来源，它激发了关于人类认知的假说， 包括已知注意力和认知改变的精神健康障碍(例如，注意力- 缺陷/多动障碍(ADHD)、精神分裂症)，尽管测量人类LC活动的方法 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法和功能磁共振成像。 由于瞳孔直径与LC活性相关，因此它被用作LC活性的替代指标。然而， 将LC与瞳孔扩张联系起来的解剖学途径尚未建立，而瞳孔直径也与 与其他大脑区域的活动有关。因此，仅从瞳孔测量学推断LC活动是有问题的。功能磁共振成像有 也被用来测量LC的活动，但迄今为止使用的成像方法依赖于 相对于LC的大小和形状而言，分辨率较粗。因此，之前的功能核磁共振结果并没有 足以进行事件相关分析。拟议工作的目标是开发和验证用于 使用功能磁共振成像测量LC活动，特别是与事件相关的反应，以便测试有影响力的 人类LC功能的假说。这一目标适用于R21机制，其目的是 “鼓励探索性/发展性研究，为早期阶段和概念阶段提供支持 项目开发“，并测试创新，高风险，高回报的研究。这个项目有两个明确的目标， 这两种测试都是通过持续的注意力任务进行的。第一个目标是使用高分辨率功能磁共振成像来最大化 LC内结合神经黑色素敏感成像定位BOLD的测量次数 对LC的反应。我们将衡量(A)审前活动(即，在审判间歇期间；这一时期被认为是 反映强直性LC活性)和(B)试验响应(即，相性LC活性)，通过估计每一个的β权重 审判。第二个目的是使用莫达非尼给药来调节LC活动并确定BOLD的位置 在对LC的持续注意任务中测量的反应。我们将使用莫达非尼和安慰剂 给双盲、安慰剂对照交叉研究的参与者。此外，我们亦会收集有关斜视的数据，以便 莫达非尼和安慰剂的情况下，我们将使用瞳孔测量数据来测试与 LC粗放反应幅度。这种技术的结合将证明功能磁共振成像是否可以用于 有针对性地测量LC活动。开发这些工具符合2020年的目标1(战略1.3D) NIMH的战略计划，允许直接测量注意控制中心的大脑结构。

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.