Project 4

项目4

• 批准号: 10294715
• 负责人: ANDREAS A LINNINGER
• 金额: $ 19.27万
• 依托单位: BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-16 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10294715
• 关键词: 3-Dimensional; Address; Animals; Arteries; Biological; Biophysics; Blood; Blood Vessels; Blood capillaries; Blood flow; Brain; Caliber; Cerebrovascular Circulation; Cerebrum; Coupled; Data; Endothelial Cells; Equilibrium; Exercise; Face; Foundations; Frequencies; Functional Magnetic Resonance Imaging; Gap Junctions; Goals; Human; Individual; Knowledge; Link; Liquid substance; Magnetic Resonance Imaging; Maps; Mathematics; Microcirculation; Modeling; Neurons; Oxygen; Pattern; Perfusion; Periodicity; Phase; Physics; Physiological; Property; Regulation; Resistance; Rest; Signal Transduction; Smooth Muscle; Smooth Muscle Myocytes; Specificity; Surface; Testing; Tissues; Vascular blood supply; Vasomotor; Work; arteriole; base; constriction; experimental study; hemodynamics; human subject; in vivo; mathematical model; neuroregulation; neurovascular; programs; reconstruction; response; simulation; spatiotemporal; theories; two-dimensional; vasomotion; venule

PROJECT SUMMARY/ABSTRACT – PROJECT 4 We propose to leverage our state-of-the-art expertise in theoretical biological physics and computational fluid dynamics to investigate fundamental aspects of the pial neurovascular circuit and its impact upon cortical blood supply and oxygenation. Project 4 will provide a quantitative path from in vivo responses in animal subjects (Projects 1 and 2) to the interpretation of fMRI data across human subjects (Project 3). This program will establish a link between observable neurovascular responses and the internal brain state. In particular, Project 4 will collaborate with Project 1 to integrate experimental knowledge of pial neurovascular circuit oscillations; it will collaborate with Project 2 to incorporate knowledge on the modulation of neuronal and vascular activity; finally, it will impact Project 3 by using blood oxygenation models to determine BOLD fMRI signals in response to pial neurovascular patterns. Project 4 features two specific aims: (ii) Capture the spatiotemporal neurovascular dynamics and the patterns of the pial vascular network, that is, the dilation and constriction of arterioles driven by their smooth muscle sheath; and (ii) Demonstrate the effects of the vasomotor dynamics onto the cortical blood supply and tissue pO2, thereby establishing a causal link between BOLD/CBV fMRI signals and neuronal activity patterns. For Aim 1, we shall rely on long standing experimental evidence for ultraslow, ~ 0.1 Hz oscillations of individual arteriole segments, as well as preliminary data of Project 1 on the pial neurovascular network. Their combination leads to our theoretical framework of brain arterioles forming a network of coupled oscillators that control the flow of blood throughout the entire brain. Our first goal is to develop coupled-oscillator-based mathematical models that capture the essence of the observed neurovascular and neuromodulatory dynamics across the cortical mantle and propose experimental tests. Our second goal is to demonstrate how the competition between modulatory drives and intrinsic oscillations of arterioles results in spatial parcellation and formation of the different constellations of temporally coherent regions, as observed in Projects 1 to 3. For Aim 2, we will use detailed hemodynamic simulations with an existing three dimensional reconstruction of the cortical microcirculation to gauge the regulatory effect of vasomotor actuation, modeled in the first aim and observed in experiments of Projects 1 and 2, on induced changes in cortical blood and oxygen supply. The effects of rhythmic changes in pial arteriole diameter upon the cerebral blood flow and dynamic resistance redistributions in microvessels will be specifically dissected to establish the feed forward regulation that vasomotor exercises upon cortical blood supply and tissue pO2. Vasomotor-modulated blood flow will be further used to compute spatiotemporal oxygenation maps throughout the depth of cortical layers and across the pial surface. Those maps will provide the link between the dynamics of oxygenation and the pial network, which will inform our inferences of the brain state and neuromodulatory inputs from BOLD fMRI signals.

项目摘要/摘要 – 项目 4 我们建议利用我们在理论生物物理学和计算方面最先进的专业知识 流体动力学研究软脑膜神经血管回路的基本方面及其对皮质的影响 项目 4 将提供动物体内反应的定量路径。 受试者（项目 1 和 2）对人类受试者的功能磁共振成像数据的解释（项目 3）。 将在可观察到的神经血管反应和内部大脑状态之间建立联系。 项目 4 将与项目 1 合作，整合软脑膜神经血管回路的实验知识 它将与项目 2 合作，整合有关神经和振动调制的知识。 最后，它将通过使用血氧模型来确定 BOLD fMRI 来影响项目 3 响应软脑膜神经血管模式的信号。 项目 4 有两个具体目标：(ii) 捕获时空神经血管动力学和 软脑膜血管网络的模式，即由其光滑的小动脉驱动的扩张和收缩 肌肉鞘；和 (ii) 展示血管舒缩动力学对皮质血液供应的影响和 组织 pO2，从而在 BOLD/CBV fMRI 信号和神经活动模式之间建立因果关系。 对于目标 1，我们将依靠长期存在的实验证据来证明超慢，约 0.1 Hz 的振荡 单个小动脉段，以及项目 1 关于软脑膜神经血管网络的初步数据。 组合导致我们的脑小动脉形成耦合振荡器网络的理论框架 我们的首要目标是开发基于耦合振荡器的血液流动。 捕捉所观察到的神经血管和神经调节动力学本质的数学模型 我们的第二个目标是展示如何跨越皮质地幔并提出实验测试。 调节驱动器和小动脉固有振荡之间的竞争导致空间分割和 时间相干区域的不同星座的形成，如项目 1 至 3 中所观察到的。 对于目标 2，我们将使用现有的三维重建进行详细的血流动力学模拟 皮质微循环的变化来衡量血管舒缩驱动的调节作用，以第一个目标为模型 并在项目 1 和 2 的实验中观察到皮质血液和氧气供应的诱导变化。 软脑膜小动脉直径节律性变化对脑血流量和动态阻力的影响 将专门剖析微血管中的重新分布，以建立前馈调节 血管舒缩运动取决于皮质血液供应和组织血氧饱和度。 进一步用于计算整个皮质层深度和跨度的时空氧合图 这些图将提供氧合动力学和软脑膜网络之间的联系， 这将帮助我们根据 BOLD fMRI 信号推断大脑状态和神经调节输入。