Imaging the neuronal and metabolic basis of resting state connectivity mapping

静息态连接映射的神经元和代谢基础成像

• 批准号: 8717740
• 负责人: Elizabeth M. C. Hillman
• 金额: $ 34.22万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-15 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8717740
• 关键词: Address; Adopted; Adoption; Alzheimer' s Disease; Anesthesia procedures; Anesthetics; Animals; Area; Astrocytes; Autistic Disorder; Bilateral; Blood; Blood Pressure; Blood Pressure Monitors; Blood Vessels; Blood flow; Brain; Brain Part; Brain Pathology; Brain region; Calcium; Cell Respiration; Cephalic; Cerebrovascular Circulation; Cerebrum; Clinical; Collection; Complement; Complex; Coupling; Data; Data Analyses; Dementia; Development; Disease; Dyes; Electrophysiology (science); Flavoproteins; Fluorescence; Frequencies; Functional Magnetic Resonance Imaging; Glioma; Goals; Hemoglobin; Homeostasis; Human; Image; Imaging Techniques; Lead; Literature; Magnetic Resonance Imaging; Maps; Measures; Mediating; Mental Depression; Metabolic; Methods; Microscopy; NADH; Nature; Neurons; Noise; Optics; Property; Protocols documentation; Rattus; Research; Research Personnel; Resolution; Rest; Rodent; Scanning; Schizophrenia; Signal Transduction; Speed; Stimulus; Stroke; System; Techniques; Time; Variant; Work; absorption; awake; base; blood oxygen level dependent; data acquisition; design; hemodynamics; imaging modality; improved; in vivo; innovation; insight; novel; optical imaging; preclinical study; preference; response; tool; two-photon

DESCRIPTION (provided by applicant): This project aims to use advanced in-vivo optical imaging and microscopy techniques to study blood flow variations in the resting brain, and the meaning of synchronizations in blood flow fluctuations in different brain regions. Functional connectivity mapping (FCM) is an increasingly popular tool in functional magnetic resonance imaging (fMRI), which harnesses synchronous fluctuations in blood flow throughout the resting brain to infer connectivity between different regions. FCM is widely thought to capture a fundamental property of the brain's networks, and is rapidly being adopted for studies of complex conditions such as autism, Alzheimer's, depression and schizophrenia. However, while FCM is increasingly being applied in preference to traditional stimulation-based fMRI studies, very little is understood about the mechanisms causing the fluctuations in cerebral blood, nor the underlying meaning of hemodynamic synchrony in different brain areas. In fact, there is mounting evidence that baseline fluctuations in blood flow have a range of origins that may not all be related to the presence of neuronal activity, nor represent genuine connectivity between brain regions. In this project, we will optimize and extend the suite of advanced in-vivo exposed-cortex optical imaging and microscopy tools that we have developed to date to address the primary challenge of baseline imaging; that data must be acquired without averaging over multiple trials and therefore must have high signal to noise, and all parameters must be recorded in parallel. To this end, we will develop high-speed, high resolution parallel imaging of both hemodynamics and bulk-loaded calcium sensitive dyes over large bilateral cranial windows in rats to map the relations between baseline blood flow and neuronal activity. We will also map fluctuations in flavoprotein (FAD) autofluorescence with spontaneous hemodynamics as a measure of local oxidative metabolism, both complemented with simultaneous electrophysiology. These studies will be performed under a range of anesthesia states as well as in a small subset of awake animals (aim 1). To relate our findings directly to fMRI data in the whole brain, we will develop a system for simultaneous acquisition of exposed cortex optical imaging and fMRI data in rats, elucidating the metabolic (FAD) and neuronal (Ca2+) basis of fMRI signal fluctuations and their relation to fluctuations in the rest of the brain (aim 2). We will further use in-vivo two-photon microscopy for cellular-level metabolic imaging of FAD and NADH fluorescence, and of calcium sensitive dyes to explore the cellular correlates of spontaneous hemodynamic activity, with simultaneous wide-field reflectance imaging of hemoglobin oxygenation dynamics (aim 3). These innovative studies will allow us to determine whether spontaneous hemodynamic fluctuations have the same underlying basis as stimulus-evoked responses, and to explore the nature of the connectivity that FCM infers. Our results will be highly significant, as they will provide insight into the meaning of clinical fMRI FCM results, while also providing guidance for FCM researchers in how to avoid potential neurovascular coupling-related confounds.

描述（由申请人提供）：该项目旨在使用先进的体内光学成像和显微镜技术来研究静息大脑中的血流变化，以及在不同大脑区域的血流波动中同步的含义。功能连接映射（FCM）是功能磁共振成像（fMRI）中日益流行的工具，它可以利用整个静止大脑的血流中同步波动来推断不同区域之间的连通性。人们普遍认为FCM可以捕获大脑网络的基本特性，并迅速用于研究自闭症，阿尔茨海默氏症，抑郁症和精神分裂症等复杂疾病的研究。然而，尽管FCM越来越多地优先于传统的基于刺激的功能磁共振成像研究，但几乎没有什么理解的关于导致大脑血液波动的机制，以及不同大脑区域血液动力学同步的潜在含义。实际上，有越来越多的证据表明，血流中的基线波动具有一系列起源，这些起源可能与神经元活性的存在有关，也不代表大脑区域之间的真正连通性。 在这个项目中，我们将优化和扩展我们迄今为止开发的高级体内裸露皮层光学成像和显微镜工具的套件，以应对基线成像的主要挑战；该数据必须在不取平均值的情况下获得多个试验，因此必须具有很高的信号，并且必须并行记录所有参数。为此，我们将在大鼠的大型双侧颅窗上开发出对血液动力学和散装钙敏感染料的高速平行成像，以绘制基线血流和神经元活性之间的关系。我们还将以自发性血流动力学的自发荧光绘制黄蛋蛋白（FAD）自发荧光的波动，作为局部氧化代谢的量度，均与同时的电生理学相辅相成。这些研究将在一系列麻醉状态以及一小部分清醒动物中进行（AIM 1）。为了将我们的发现直接与整个大脑中的fMRI数据联系起来，我们将开发一个系统，用于同时获取大鼠中暴露的皮层光学成像和fMRI数据，从而阐明了FMRI信号波动的代谢（FAD）和神经元（CA2+）基础（CA2+）基础，并将其与脑之间的相互作用及其在大脑中的波动（目标）（目标2）。我们将进一步使用Vivo两光子显微镜进行FAD和NADH荧光的细胞级代谢成像，以及钙敏感染料的细胞级代谢成像，以探索自发性血液动力学活性的细胞相关性，并同时使用氧化动力学的血红蛋白反射成像（AIM 3）。这些创新的研究将使我们能够确定自发的血液动力学波动是否具有与刺激诱发的反应相同的基础，并探索FCM侵入的连通性的性质。我们的结果将非常重要，因为它们将提供对临床fMRI FCM结果含义的见解，同时还为FCM研究人员提供指导，以避免潜在的神经血管耦合相关的混杂。