Multiscale modeling of cerebral blood flow and oxygen transport

这项建议的总体目标是定量地了解 用多尺度理论研究大脑皮层的神经激活、血流和组织氧合 微血管网络中血液流动、氧气运输和流动调节的模型。足够 由于缺氧，满足脑组织在空间和时间上不同需求的血液流动至关重要。 很快就会造成不可逆转的损害。人们对血液流动的控制机制知之甚少。 神经活动、代谢物水平、血管张力变化、网络血流、 和氧的运输是很难解开的，不能仅仅通过观察个体的行为来理解 血管。在拟议的工作中，数以千计的微血管网络的详细结构 小鼠大脑皮层的片段将使用双光子显微镜进行成像。使用以下工具观察 磷光猝灭纳米探测器将产生组织氧水平的高分辨率地图。光谱 将使用域光学相干断层扫描来测量血流。多尺度建模方法 模拟毛细血管直径和细胞尺度(~10μm，包括流动)的生物和物理过程 血管壁的力学和对血流动力学、神经和代谢刺激的主动反应) 标度(~100μm，包括管段流动阻力、氧气损失和传导响应的传播 沿着血管壁)以及在网络和组织尺度(~1000μm，包括整个网络流动，灌流， 氧提取和组织缺氧部分)。具体目标1是开发预测性多尺度模型 用于小鼠大脑皮层的血液流动和氧气运输，并使用 来自皮质微血管系统多模式成像的实验数据。建议数 研究将提供一个模型，将微观层面的现有数据与宏观层面的数据进行协调 变量，如灌流和氧气提取，将允许预测组织氧合和 出现一定范围的血液灌注量和需氧量的低氧。具体目标2是开发 小鼠脑血流自动调节和神经血管耦合的多尺度模型 并使用来自多模式成像的实验数据来测试和改进这些模型 大脑皮层微血管系统。这些模型将包括肌源性、代谢性、剪切性的影响。 并进行了反应，以及毛细管水平调节的可能作用。型号包括或 排除这些机制将测试它们代表实际监管反应的能力，因为 文献报道以及在不同生理状态下的多模式成像实验中观察到的 条件。提高对流量调节机制的理解可能会导致改进的策略 与神经血管功能有关的疾病，包括中风和神经退行性疾病，以及 解释功能性核磁共振脑成像。

The overall goal of this proposal is to gain quantitative understanding of the relationship between neural activation, blood flow and tissue oxygenation in the brain cortex, using multiscale theoretical models for blood flow, oxygen transport and flow regulation in networks of microvessels. Adequate blood flow to meet spatially and temporally varying demands of brain tissue is crucial, since lack of oxygen quickly leads to irreversible damage. The mechanisms by which blood flow is controlled are poorly understood. Multiple interactions between neural activity, metabolite levels, changes in vascular tone, network blood flow, and oxygen transport are difficult to unravel, and cannot be understood just by observing behavior of individual blood vessels. In the proposed work, the detailed structure of microvessel networks with thousands of segments in the mouse cerebral cortex will be imaged using two-photon microscopy. Observations using phosphorescence quenching nanoprobes will yield high resolution maps of tissue oxygen levels. Spectral domain optical coherence tomography will be used to measure blood flows. The multiscale modeling approach simulates biological and physical processes at the capillary diameter and cellular scale (~10 μm, including flow mechanics and active responses of vessel walls to hemodynamic, neural and metabolic stimuli), at the vessel scale (~100 μm, including segment flow resistance, oxygen loss and propagation of conducted responses along vessel walls) and at the network and tissue scale (~1000 μm, including entire network flows, perfusion, oxygen extraction and tissue hypoxic fraction). Specific Aim 1 is to develop predictive multiscale models for blood flow and oxygen transport in the mouse cerebral cortex, and validate these models using experimental data derived from multimodal imaging of the cortex microvasculature. The proposed studies will provide a model that will reconcile available data at the microscopic level with macroscopic level variables such as perfusion and oxygen extraction and will allow prediction of tissue oxygenation and occurrence of hypoxia for a range of blood perfusion and oxygen demand. Specific Aim 2 is to develop multiscale models for blood flow autoregulation and neurovascular coupling in the mouse cerebral cortex, and to test and refine these models using experimental data derived from multimodal imaging of the cortical microvasculature. The models will include effects of myogenic, metabolic, shear-dependent and conducted responses, as well as the possible role of capillary-level regulation. Models including or excluding these mechanisms will be tested for their ability to represent actual regulatory responses, as reported in the literature and as observed in multimodal imaging experiments under varying physiological conditions. Improved understanding of the mechanisms of flow regulation could lead to improved strategies for disorders related to neurovascular function, including stroke and neurodegenerative diseases, and for interpreting fMRI brain imaging.