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

脑间质代谢物运输的成像和流体力学建模

• 批准号: 1705854
• 负责人: Francesco Costanzo
• 金额: $ 40万
• 依托单位: Pennsylvania State Univ University Park
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1705854&HistoricalAwards=false
• 关键词: Imaging; Modeling; Fluid; Mechanics; Metabolite

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.

在其正常功能的过程中，大脑会产生有毒物质，这些有毒物质会从脑细胞之间的空间积聚和运输。如果这些物质没有被清除，它们的积累被认为会产生严重的后果，如阿尔茨海默病和偏头痛。这种清除的机制知之甚少，所以本研究项目的目的是研究和表征这一过程。 实验技术和计算方法相结合，以产生一个预测的间隙模型的基础上的基本力学原理的流体流动和扩散。该实验研究正在体内进行，这将允许脑功能与脑组织的相应变形以及细胞之间流体的相关流动之间的生理相关匹配。这项研究与推进神经生理学的最新技术水平和未来开发治疗干预措施有关，包括药理学和外科手术，用于解决包括阿尔茨海默病，脑积水和偏头痛在内的病理学。该项目有一个教育部分，旨在培训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。 具体来说，研究人员开发和提供一个适合本科生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。该项目的重点是提供第一个基于力学的模型，神经血管耦合对大脑中的运输的影响。一个理论和计算框架正在创建一个计算框架，集成经验的大脑微机械神经血管反应的体内观察选择的刺激，以模拟多个并发传输机制。生物医学的问题，激励拟议的研究是比较评估的对流和扩散机制的有毒代谢物清除从脑垂体。这些化合物的积累可能具有强烈的神经毒性，并可能引发神经元功能不稳定，造成严重的（如果不是致命的）后果-从扩散去极化到癫痫到阿尔茨海默病到精神疾病。虽然对脑功能至关重要，但代谢物的转运和清除仍然知之甚少。 具体的项目目标是：1）将脑组织建模为具有嵌入式脉管系统的可变形多孔介质，并应用PI开发的数值方案来预测由血管舒张驱动的运输; 2）从实验中识别相关生理条件集，并从这些生理条件中定义相应的代谢物运输边界值问题。将考虑搏动（心脏门控血管扩张）和功能性充血（神经血管耦合驱动的血管扩张）。解剖，材料和负载参数将推断使用在体内双光子显微镜在活小鼠的大脑与颅窗。基于双折射的数字图像相关将提供脑组织的微尺度变形图。通过注入荧光染料使脑中的流体流动可视化; 3）数值解决目标2中的问题，以确定通过可变形组织的间质流体流动和代谢物运输，其中对流和扩散作为并发机制。生理条件和本构参数的范围正在进行测试，组织和充满液体的血管旁空间之间的流体-结构相互作用正在明确建模。血脑屏障的高选择性仍然是开发用于脑癌、痴呆、扩散性去极化和癫痫的有效药物递送方法的主要挑战。通过专注于脑中代谢物的转运，该研究项目将有助于推进许多脑病理的药理学和外科治疗。

项目成果

Anatomical basis and physiological role of cerebrospinal fluid transport through the murine cribriform plate

• DOI: 10.7554/elife.44278
• 发表时间: 2019-05-07
• 期刊: ELIFE
• 影响因子: 7.7
• 作者: Norwood, Jordan N.;Zhang, Qingguang;Drew, Patrick J.
• 通讯作者: Drew, Patrick J.

Functional hyperemia drives fluid exchange in the paravascular space

• DOI: 10.1186/s12987-020-00214-3
• 发表时间: 2020-08-20
• 期刊: FLUIDS AND BARRIERS OF THE CNS
• 影响因子: 7.3
• 作者: Kedarasetti, Ravi Teja;Turner, Kevin L.;Costanzo, Francesco
• 通讯作者: Costanzo, Francesco

Arterial pulsations drive oscillatory flow of CSF but not directional pumping

• DOI: 10.1038/s41598-020-66887-w
• 发表时间: 2020-06-22
• 期刊: SCIENTIFIC REPORTS
• 影响因子: 4.6
• 作者: Kedarasetti, Ravi Teja;Drew, Patrick J.;Costanzo, Francesco
• 通讯作者: Costanzo, Francesco