Physiological Basis of Functional MRI

描述(由申请人提供)：我们的总体目标是对人脑中血流和能量代谢的耦合进行量化了解，并开发用于评估这种耦合在健康和疾病中的定量方法。功能磁共振成像(FMRI)通过提供一种敏感的、非侵入性的工具来绘制大脑活动图，彻底改变了对工作人脑的研究。该方法利用磁共振信号对脱氧血红蛋白含量局部变化的敏感性，称为血氧水平依赖(BOLD)效应。BOLD效应背后的中枢生理现象是，在大脑活动增加的过程中，脑血流量(CBF)的增加超过了脑氧代谢率(CMRO2)。然而，尽管作为一种成功的作图工具，将大胆反应的大小定量解释为反映潜在生理变化的大小是有问题的，因为我们对CBF/CMRO2偶联的可变性了解很少。在之前的支持期间，我们实施并评估了一种校准的BOLD方法，除了神经激活外，还测量了局部CBF和对轻度高碳酸血症的BOLD反应，以测量CBF和CMRO2的耦合。我们的工作强调了CBF/CMRO2偶联比率对于解释跨大脑区域和疾病中的大胆反应的重要性，并证明了校准的BOLD方法为基础研究和潜在的临床环境提供了一个定量评估大脑生理学的强大工具。解释这种大胆反应的一个中心问题是，我们不知道健康人脑中CBF/CMRO2偶联的差异有多大，而这一提议的主要目标是确定这种可变性。我们以前的结果与CBF/CMRO2偶联比率随着刺激强度的增加而增加的假设是一致的，这与目前的观点一致，即CBF是由对某个区域的输入神经活动驱动的，而CMRO2响应整个诱发活动的总能量需求。我们将在健康的人脑中用实验范式来测试这一假设，这些实验范式旨在操纵所涉及的神经活动的类型，并测试CBF和CMRO2反应的分离。实验利用对比敏感度和时间频率调谐效应(目标1)、适应效应(目标2)、抑制效应和负粗体信号(目标1和3)。此外，我们将改进目前的校准-BOLD方法，为BOLD反应开发一个更完整的数学模型，其中包括血管内信号变化和动脉血容量变化的影响，并测试替代的高氧血症校准技术作为高二氧化碳的替代方案(目标4)。这些目标的实现将为BOLD-fMRI的基础科学研究和fMRI的临床应用奠定坚实的生理学基础。公共卫生相关性：校准的功能磁共振成像方法有可能通过测量血流量和氧代谢变化来提供大脑生理学的定量探针。这一工具可以作为“压力测试”来评估大脑功能，以便及早发现功能障碍，并监测疾病的进展或对药物和治疗的反应。我们的目标是通过扩展和改进方法，以及通过更好地了解流动和新陈代谢在健康大脑中是如何耦合的，为这些应用奠定基础。

DESCRIPTION (provided by applicant): Our overall goal is to develop a quantitative understanding of the coupling of blood flow and energy metabolism in the human brain, and to develop quantitative methods for assessing this coupling in health and disease. Functional magnetic resonance imaging (fMRI) has revolutionized the study of the working human brain by providing a sensitive, non-invasive tool for mapping brain activity. The method exploits the sensitivity of the MR signal to local changes in deoxy-hemoglobin content, called the Blood Oxygenation Level Dependent (BOLD) effect. The central physiological phenomenon underlying the BOLD effect is that cerebral blood flow (CBF) increases more than the cerebral metabolic rate of oxygen (CMRO2) during increased brain activity. Yet despite its success as a mapping tool, quantitative interpretation of the magnitude of the BOLD response as a reflection of the magnitude of underlying physiological changes is problematic because of our poor understanding of the variability of CBF/CMRO2 coupling. During the previous period of support we implemented and evaluated a calibrated-BOLD approach, measuring local CBF and BOLD responses to mild hypercapnia in addition to neural activation, to measure the coupling of CBF and CMRO2. Our work highlighted the importance of the CBF/CMRO2 coupling ratio for interpreting BOLD responses across brain regions and in disease, and also demonstrated that the calibrated-BOLD approach provides a powerful tool for quantitatively assessing brain physiology for both basic research and potentially in clinical settings. A central problem for the interpretation of the BOLD response is that we do not know to what degree CBF/CMRO2 coupling varies in the healthy human brain, and the primary goal of this proposal is to determine that variability. Our previous results are consistent with the hypothesis that the CBF/CMRO2 coupling ratio increases for stronger stimuli, which is consistent with current ideas that CBF is driven by the input neural activity to a region while CMRO2 responds to the total energy needs of the full evoked activity. We will test this hypothesis in the healthy human brain with experimental paradigms designed to manipulate the types of neural activity involved and test for a dissociation of the CBF and CMRO2 responses. The proposed experiments exploit contrast sensitivity and temporal frequency tuning effects (Aim 1), adaptation effects (Aim 2), and inhibitory effects and negative BOLD signals (Aims 1 and 3). In addition, we will improve the current calibrated-BOLD methodology by developing a more complete mathematical model for the BOLD response that includes effects of intravascular signal change and arterial blood volume changes, and test an alternative hyperoxia technique for calibration as an alternative to hypercapnia (Aim 4). Completion of these goals will lay a solid physiological foundation for both basic science studies with BOLD-fMRI and clinical applications of fMRI. PUBLIC HEALTH RELEVANCE: A calibrated-fMRI methodology has the potential to provide a quantitative probe of brain physiology by measuring blood flow and oxygen metabolism changes. This tool can serve as a "stress-test" to evaluate brain function for early detection of dysfunction and for monitoring the progression of disease or the response to drugs and therapy. Our goal is to lay the groundwork for these applications by extending and improving the methodology and by gaining a better understanding of how flow and metabolism are coupled in the healthy brain.