Effects of standard fMRI calibrations on the diverse microvascular blood flow and oxygenation responses in cortical layers

本项目旨在量化皮质氧代谢和神经血管耦合的时空多样性，并通过整合新技术和概念方法，为下一代血氧水平依赖（BOLD）功能磁共振成像（fMRI）测量的生物物理模型提供信息。该应用程序的广泛和长期目标是：(1)在空间（毛细血管下到全脑）和时间（µs到数月）域的多个尺度上架起对大脑活动的理解的桥梁；(2)有助于发现皮层组织层、功能区和微血管分支之间血流动力学反应的多样性；(3)通过量化健康衰老清醒小鼠皮层的血流动力学反应来支持BOLD信号的建模工作。实现这些目标将有助于通过实现BRAIN Initiative的目标，了解大脑的活动，发现多样性，绘制/连接跨空间和时间尺度的活动，以及理解fMRI信号的生物物理基础，从而共同努力改善人类健康。建议项目的具体目标可概括为：(1)发展更快、更深入的脑血流量（CBF）、氧分压（pO2）和脑氧代谢率（cmoro2）的纵向测量；(2)量化cmoro2和CBF对健康衰老小鼠不同皮质功能区、皮质层和微血管类型的功能激活反应的多样性；(3)量化标准fMRI校准（如高碳酸血症、高氧血症、高氧血症）的影响。和咖啡因)在休息和功能激活期间对cro2和CBF的影响。本项目将采用的研究设计和方法包括：(1)开发更快、更深入的绝对氧浓度慢性成像，以评估大脑皮层区域和各层激活过程中皮质pO2、cmor2和血流量变化之间的关系；(2)对氧合、血流量、以及健康衰老小鼠微血管尺度上功能激活的代谢反应，以及对BOLD fMRI成像中常用的校准程序的反应。Sencan博士的研究环境（马萨诸塞州总医院的Athinoula . Martinos生物医学成像中心和哈佛医学院放射科）配备了执行拟议项目所需的最先进技术，并提供了丰富的神经科学培训、职业发展和跨学科合作的机会。她拥有一支由导师、合作者和顾问组成的团队，他们拥有丰富的专业知识，致力于支持Sencan博士的研究和职业发展。所有这些因素都将促进拟议项目的成功执行，Sencan博士在神经影像学方面的培训的完成，以及她向独立的终身教职的过渡。

This proposed project focuses on quantifying the spatial and temporal diversity in cortical oxygen metabolism and neurovascular coupling, and informing next generation of biophysical models of the Blood Oxygen Level Dependent (BOLD) functional Magnetic Resonance Imaging (fMRI) measurements by integrating new technological and conceptual approaches. Broad and long term objectives of this application are (1) to bridge understanding of brain in action at multiple scales in spatial (subcapillary to whole- brain) and temporal (µs to months) domains, (2) to contribute discovering diversity of hemodynamic responses across cortical tissue layers, functional areas, and microvascular branches, and (3) to support the modelling efforts of BOLD signal by to quantifying hemodynamic responses in cortex of healthy-aging awake mice. Realizing these objectives would contribute to the joined efforts towards improving human health through accomplishing BRAIN Initiative goals of understanding the brain in action, discovering diversity, mapping/linking activity across spatial and temporal scales, and understanding the biophysical basis of fMRI signal. The specific aims of the proposed project can be summarized as: (1) to develop faster, deeper, longitudinal measurements of the cerebral blood flow (CBF), partial pressure of oxygen (pO2), and cerebral metabolic rate of oxygen (CMRO2), (2) to quantify the diversity of CMRO2 and CBF responses to functional activation across different cortical functional areas, cortical layers, and microvasculature types in healthy-aging mouse, and (3) to quantify the effects of standard fMRI calibrations (e.g. hypercapnia, hyperoxia, and caffeine) on the CMRO2 and CBF at rest and during functional activation. The research design and methods that will be used in this project will include (1) developing faster and deeper chronic imaging of absolute oxygen concentration to assess relation between cortical pO2, CMRO2, and blood flow changes during brain activation across the cortical areas and layers, and (2) realistic measurements of the oxygenation, blood flow, and metabolism responses to functional activation at the microvascular scales in healthy-aging mice and in response to calibration procedures that are commonly used in BOLD fMRI imaging. The research environment of Dr. Sencan (the Athinoula A. Martinos Center for Biomedical Imaging at Massachusetts General Hospital and Radiology Department in Harvard Medical School) is equipped with state-of-the-art technologies required to execute the proposed project and is rich with opportunities for training in neuroscience, career development, and interdisciplinary collaborations. She has a team of mentors, collaborators and advisors with diverse and strong expertise, who are committed to support Dr. Sencan’s research, and her career development. All these factors will facilitate the successful execution of the proposed project, the completion of Dr. Sencan’s training in neuroimaging, and her transition to an independent tenure-track faculty position.