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液流动和能量代谢的耦合进行定量理解，并开发定量方法来评估健康和疾病中的这种耦合。功能磁共振成像（fMRI）通过提供一种灵敏的、非侵入性的大脑活动测绘工具，彻底改变了对人脑工作的研究。该方法利用MR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效应背后的核心生理现象是，在大脑活动增加时，脑血流量（CBF）增加超过脑氧代谢率（cmor2）。然而，尽管它作为一种测绘工具取得了成功，但由于我们对CBF/ cmo2偶联的可变性了解不足，将BOLD反应的大小作为潜在生理变化的大小的定量解释是有问题的。在之前的支持期间，我们实施并评估了校准的BOLD方法，测量局部CBF和BOLD对轻度高碳酸血症的反应以及神经激活，以测量CBF和cmor2的耦合。我们的工作强调了CBF/ cmor2耦合比对于解释脑区域和疾病中的BOLD反应的重要性，并且还证明了校准的BOLD方法为基础研究和潜在的临床环境提供了定量评估脑生理学的强大工具。解释BOLD反应的一个核心问题是，我们不知道健康人脑中CBF/ cmor2偶联的变化程度，而本提案的主要目标是确定这种变异性。我们之前的研究结果与CBF/ cmoro2耦合比在更强的刺激下增加的假设一致，这与目前的观点一致，即CBF是由输入神经活动驱动到一个区域，而cmoro2响应整个激活活动的总能量需求。我们将在健康的人类大脑中测试这一假设，采用设计的实验范式来操纵所涉及的神经活动类型，并测试CBF和cmor2反应的分离。本实验利用对比敏感性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BOLD信号（目标1和目标3）。此外，我们将通过开发更完整的BOLD反应数学模型（包括血管内信号变化和动脉血容量变化的影响）来改进当前校准的BOLD方法，并测试一种替代高碳酸血症的高氧校准技术（目的4）。这些目标的完成将为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提供脑生理学的定量探测。这个工具可以作为一种“压力测试”来评估大脑功能，以早期发现功能障碍，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，并通过更好地理解流和新陈代谢如何在健康的大脑中耦合，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.