Imaging and Modeling Fluid Mechanics of Metabolite Transport in the Brain Interstitium

在其正常功能过程中，大脑产生有毒物质，这些物质积累并从脑细胞之间的空间运输。如果不清除这些物质，它们的积累被认为会产生阿尔茨海默病和偏头痛等严重后果。这种清除的机制还不是很清楚，因此本研究项目旨在研究和描述这一过程。实验技术和计算方法相结合，以流体流动和扩散的基本力学原理为基础，建立了一个预测间隙模型。这项实验研究是在体内进行的，这将允许大脑功能与相应的脑组织变形和相关的细胞间液体流动之间的生理相关匹配。这项研究对促进神经生理学的最新发展和未来治疗干预措施的发展具有重要意义，包括药理学和外科治疗，用于治疗包括阿尔茨海默病、脑积水和偏头痛在内的病理疾病。该项目有一个教育部分，旨在培养高级神经科学研究和生物医学工程方面的研究生和本科生。具体地说，研究人员为本科生开发和提供适合水平的实验室和计算项目，重点是神经科学中实验技术和力学的融合。这个项目的重点是提供第一个基于力学的模型，研究神经血管耦合对大脑运输的影响。正在建立一个理论和计算框架，以在一个计算框架中对多种并发传输机制进行建模，该计算框架整合了对所选刺激的脑微机械神经血管反应的在体经验观察。推动这项研究的生物医学问题是对对流和扩散机制的比较评估，以清除脑间质中的有毒代谢物。这些化合物的积聚可能具有强烈的神经毒性，并可引发神经功能不稳定，造成严重的后果-从传播除极到癫痫、阿尔茨海默病到精神疾病。虽然对大脑功能至关重要，但代谢物的运输和清除仍然知之甚少。具体的项目目标是：1)将脑组织建模为嵌入血管系统的可变形多孔介质，并应用PI开发的用于预测血管扩张驱动的运输的数值方案；2)从实验中识别相关的生理条件，并由此定义相应的代谢物运输边值问题。脉动(心脏门控血管扩张)和功能性充血(神经血管偶联驱动的血管扩张)将被考虑。在活体双光子显微镜下，可以在有颅窗的活体小鼠的大脑中推断出解剖、材料和载荷参数。基于荧光的数字图像关联将提供脑组织的微尺度变形图。将通过注入荧光染料来可视化大脑中的液体流动；3)数值解决目标2中的问题，以对流和扩散为并行机制来确定组织间的液体流动和代谢物在可变形组织中的传输。生理条件和本构参数的范围正在被测试，组织和充满液体的血管旁间隙之间的流体-结构相互作用正在被明确地模拟。血脑屏障的高选择性仍然是开发治疗脑癌、痴呆症、弥漫性去极化和癫痫的有效药物输送方法的主要挑战。通过关注代谢物在脑内的转运，这一研究项目将有助于推进许多脑部疾病的药物和外科治疗。

In the course of its normal function, the brain produces toxic substances that accumulate and are transported from the space between brain cells. If these substances are not cleared, their accumulation is thought to yield crippling results such as Alzheimer's disease and migraines. The mechanics of this clearance is poorly understood, so this research project aim to study and characterize this process. Experimental techniques and computational approaches are being combined to produce a predictive clearance model based on fundamental mechanics principles of fluid flow and diffusion. The experimental study is being conducted in vivo, which will allow for a physiologically-relevant match between brain function and the corresponding deformation of brain tissue and the associated flow of the fluid in-between cells. This study is relevant for advancing the state of the art in neurophysiology and for future development of therapeutic interventions, both pharmacological and surgical, for addressing pathologies including Alzheimer's disease, hydrocephalus, and migraine. This project has an educational component aiming at training graduate and undergraduate students in advanced neuroscience research and in biomedical engineering. Specifically, the researchers and developing and offering a level-appropriate laboratory and computational projects for undergraduates with a focus on the merging of experimental techniques and mechanics in neuroscience. This project focuses on delivering the first mechanics-based model of the effects of neurovasculature coupling on transport in the brain. A theoretical and computational framework is being created to model multiple concurrent transport mechanisms in a computational framework that integrates empirical in vivo observations of the brain micromechanical neurovascular response to chosen stimuli. The biomedical problem motivating the proposed research is the comparative assessment of convective and diffusive mechanisms for toxic metabolite clearance from the brain interstitium. Buildup of these compounds can be strongly neurotoxic and can trigger neuronal functional instabilities with severe, if not lethal, consequences---from spreading depolarization to epilepsy to Alzheimer's disease to mental illnesses. While vital for brain function, metabolite transport and clearance remains poorly understood. The specific project goals are: 1) To model brain tissue as a deformable porous medium with embedded vasculature, and to apply a numerical scheme developed by the PIs for predicting transport driven by blood vasodilation; 2) To identify sets of relevant physiological conditions from the experiments, and, from these, to define corresponding metabolite transport boundary value problems. Pulsation (heart-gated blood vessel dilation) and functional hyperemia (neurovascular coupling driven vessel dilation) will be considered. Anatomical, material, and loading parameters will be inferred using in vivo two-photon microscopy in the brains of living mice with cranial windows. Fluorescence-based digital image correlation will deliver microscale deformation maps of brain tissue. Fluid flow in the brain will be visualized by infusing fluorescent dyes; 3) To numerically solve the problems in goal 2 to determine interstitial fluid flow and metabolite transport through deformable tissue with convection and diffusion as concurrent mechanisms. Ranges of physiological conditions and constitutive parameters are being tested, and fluid-structure interaction between tissue and fluid-filled paravascular space are being explicitly modeled. The high selectivity of the blood-brain barrier remains a major challenge in developing effective drug delivery methods for brain cancer, dementia, spreading depolarization, and epilepsy. By focusing on metabolite transport in brain, this research project will contribute to advancing pharmacological and surgical therapies for many brain pathologies.