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

这项拟议的项目侧重于量化皮质氧代谢和神经血管耦合的空间和时间多样性，并通过整合新的技术和概念方法向下一代生物物理模型提供血氧水平依赖(BOLD)功能磁共振成像(FMRI)测量的信息。这项应用的广泛和长期目标是(1)在空间(从毛细血管到全脑)和时间(从S到月)的多个尺度上了解大脑的活动，(2)有助于发现跨皮质组织层、功能区和微血管分支的血流动力学响应的多样性，以及(3)通过量化健康衰老清醒小鼠皮质的血流动力学响应来支持BOLD信号的建模工作。实现这些目标将有助于共同努力，通过实现大脑倡议的目标来改善人类健康，这些目标包括了解大脑在活动中的作用，发现多样性，绘制空间和时间尺度上的活动图/将活动联系起来，以及了解功能磁共振信号的生物物理基础。该项目的具体目标可以概括为：(1)建立更快、更深、纵向的脑血流量(CBF)、氧分压(PO2)和脑氧代谢率(CMRO2)的测量方法；(2)量化健康衰老小鼠不同皮质功能区、皮质层和微血管类型对功能激活的CMRO2和CBF响应的差异；(3)量化标准功能磁共振校准(如高碳酸血症、高氧和咖啡因)对静息和功能激活期间CMRO2和CBF的影响。本项目中将使用的研究设计和方法将包括(1)开发更快、更深入的绝对氧浓度的慢性成像，以评估在大脑激活过程中跨皮质区域和层的皮质PO2、CMRO2和血流变化之间的关系，以及(2)真实地测量健康衰老小鼠微血管级别的氧合、血流和代谢对功能激活的响应，以及响应BOLD功能磁共振成像中常用的校准程序。Sencan博士(麻省总医院的阿蒂努拉·马蒂诺斯生物医学成像中心和哈佛医学院放射科)的研究环境配备了执行拟议项目所需的最先进技术，并拥有丰富的神经科学、职业发展和跨学科合作方面的培训机会。她有一个由导师、合作者和顾问组成的团队，他们拥有丰富而强大的专业知识，致力于支持Sencan博士的研究和她的职业发展。所有这些因素都将促进拟议项目的成功实施，完成Sencan博士在神经成像方面的培训，以及她过渡到一个独立的终身教职跟踪教职。

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.