MAPPING FUNCTIONAL CONNECTIVITY WITH FLUORESCENCE MOLECULAR TOMOGRAPHY

使用荧光分子断层扫描绘制功能连接图

• 批准号: 10160971
• 负责人: JOSEPH P CULVER
• 金额: $ 56.7万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10160971
• 关键词: ARHGEF5 gene; Aging; Alzheimer' s Disease; Anatomy; Astrocytes; Biological Assay; Blood; Blood Vessels; Brain; Brain region; Calcium; Calcium Signaling; Cells; Computer software; Coupled; Coupling; Data; Development; Disease; Evolution; Formulation; Functional Magnetic Resonance Imaging; Gene Expression; Genetic Engineering; Genetically Engineered Mouse; Glial Fibrillary Acidic Protein; Grant; Head; Hemoglobin; Histology; Human; Image; Ischemic Stroke; Light; Lighting; Maps; Measures; Methods; Modeling; Molecular; Monte Carlo Method; Mus; Nature; Neurons; Noise; Optical Tomography; Optics; Pattern; Performance; Physiological; Physiology; Reproducibility; Rest; Sampling; Signal Transduction; Specificity; Speed; Stroke; Structure; System; Techniques; Technology; Uncertainty; Validation; base; calcium indicator; cell type; cerebral hemodynamics; contrast imaging; data analysis pipeline; data modeling; design; detector; diffuse optical tomography; flexibility; fluorescence molecular tomography; hemodynamics; imaging system; improved; in vivo evaluation; instrumentation; mouse model; nervous system disorder; neuroimaging; neurovascular coupling; non-invasive imaging; optical imaging; postnatal; relating to nervous system; stroke model; stroke recovery; tomography

Project Summary: Functional mapping of spontaneous brain activity with resting-state functional connectivity (FC) analysis of fMRI data has recently become a dominant approach to mapping human brain function and continues to gain momentum. However fMRI is based on cerebral hemodynamics that is relatively indirectly coupled to neuronal activity and much slower (~0.3 Hz). Further the physiological underpinnings of FC are relatively un-resolved, such that the mechanisms and implications altered FC are often unclear. For example in ischemic stroke, it is well known that the penumbra surrounding the ischemic core has altered neurovascular coupling (NVC), complicating the interpretation of the FC deficits. As FC measures are extended further into studies of brain development, aging and disease, the importance of understanding the fundamental basis for FC will grow. We recently developed hemodynamic mapping of functional connectivity in mice using optical intrinsic signal imaging (fcOIS), and found fcOIS sensitive to several neurological diseases, including mouse models of stroke and Alzheimer's disease. However, with the advent of genetic engineering techniques for mice, there are new opportunities for extending optical wide-field imaging to calcium activity, which is >10x faster and more directly coupled to neural activity than hemoglobin. By combining calcium and hemodynamic imaging, there is the potential to quantify the relationship between cell-specific calcium dynamics and hemodynamics throughout brain regions. Further concurrent calcium and hemoglobin imaging could help resolve questions about the impact of altered NVC in diseases such as stroke, and in early brain development. However, as yet, no imaging system has been developed to examine these rich relationships throughout the mouse cortex. In this project, we will develop optical imaging hardware and software for characterizing calcium dynamics in mice engineered for genetically encoded calcium indicators (GECI's). For exemplar applications where the functional networks are changing quickly, we will quantify FC during stroke recovery and brain development, tracking the progression of both functional connectivity and neurovascular coupling (NVC). Aim 1 will develop fluorescence molecular tomography (FMT) and diffuse optical tomography (DOT) instrumentation for concurrent mapping of calcium and hemoglobin in mice. Aim 2 will optimize system performance for high speed FMT/DOT of mouse brain function. Aim 3 will establish FMT/DOT for mapping the functional networks of cell-specific calcium signals in mice with GECIs. Concurrent imaging with hemoglobin will enable mapping of neurovascular coupling. In aim 4, with establish feasibility of FMT/DOT in both stroke recovery and brain developmental. In both applications we will quantify calcium- FC and the influence of altered NVC on hemoglobin-FC.

项目总结： 静息状态功能连接性(FC)分析脑自发活动的功能图 最近已经成为绘制人脑功能图的主要方法，而且还在继续 以获得动力。然而，功能磁共振成像是基于相对间接的脑血流动力学。 再加上神经元活动，速度要慢得多(~0.3赫兹)。进一步探讨FC的生理基础 都是相对未解决的，因此改变FC的机制和影响往往不清楚。为 例如在缺血性中风中，众所周知，缺血核心周围的半影区已经改变。 神经血管偶联(NVC)，使FC缺陷的解释复杂化。由于FC措施是 进一步扩展到对大脑发育、衰老和疾病的研究，了解 FC的基本基础将会增长。我们最近开发了功能性的血流动力学标测 在小鼠中使用光学固有信号成像(FcOIS)进行连接，并发现fcOIS对几种 神经系统疾病，包括中风和阿尔茨海默病的小鼠模型。然而，随着 小鼠基因工程技术的出现，为扩展光学技术提供了新的机会 钙活动的广域成像，速度快10倍，更直接地与神经活动联系在一起 而不是血红蛋白。通过结合钙和血流动力学成像，有可能量化 细胞特异性钙动力学与整个脑区血流动力学的关系。 进一步同时进行钙和血红蛋白成像可能有助于解决有关 在中风等疾病和早期大脑发育中，NVC发生了变化。然而，到目前为止，还没有成像 已经开发了一种系统来检查整个小鼠皮质的这些丰富的关系。在这 项目，我们将开发用于表征钙动力学的光学成像硬件和软件 为基因编码的钙指示器(Geci‘s)设计的小鼠。对于示例应用程序，其中 功能网络正在快速变化，我们将量化中风恢复和脑内的功能障碍 发展，跟踪功能连接和神经血管偶联(NVC)的进展。 AIM 1将开发荧光分子断层扫描(FMT)和漫反射光学断层扫描(DOT) 同时绘制小鼠体内钙和血红蛋白图谱的仪器。目标2将优化系统 表现为小鼠脑功能的高速FMT/DOT。目标3将为以下目标建立FMT/DOT 定位GECI小鼠细胞特异性钙信号的功能网络。并发成像 与血红蛋白的结合将使神经血管偶联的映射成为可能。在目标4中，确定了 FMT/DOT在卒中康复和脑发育中的作用在这两个应用中，我们将量化钙- Fc及改变NVC对Hb-Fc的影响。

项目成果

Effective Connectivity Measured Using Optogenetically Evoked Hemodynamic Signals Exhibits Topography Distinct from Resting State Functional Connectivity in the Mouse.

• DOI: 10.1093/cercor/bhx298
• 发表时间: 2018-01-01
• 期刊: Cerebral cortex (New York, N.Y. : 1991)
• 作者: Bauer AQ;Kraft AW;Baxter GA;Wright PW;Reisman MD;Bice AR;Park JJ;Bruchas MR;Snyder AZ;Lee JM;Culver JP
• 通讯作者: Culver JP

Separability of calcium slow waves and functional connectivity during wake, sleep, and anesthesia.

• DOI: 10.1117/1.nph.6.3.035002
• 发表时间: 2019-07-01
• 期刊: Neurophotonics
• 影响因子: 5.3
• 作者: Brier, Lindsey M;Landsness, Eric C;Culver, Joseph P
• 通讯作者: Culver, Joseph P

Normalization of optical fluence distribution for three-dimensional functional optoacoustic tomography of the breast.

• DOI: 10.1117/1.jbo.27.3.036001
• 发表时间: 2022-03
• 期刊: Journal of biomedical optics
• 影响因子: 3.5
• 作者: Park S;Brooks FJ;Villa U;Su R;Anastasio MA;Oraevsky AA
• 通讯作者: Oraevsky AA