Dynamics of oxygen metabolism in the human brain

描述（由申请人提供）：我们的总体目标是为功能性磁共振成像（fMRI）的新实验范例建立基础，该新实验范例使得能够非侵入性地定量测量人脑中氧代谢的脑代谢率（CMRO 2）的动态。基于血氧水平依赖性（BOLD）信号变化的功能性MRI方法显然有可能提供一个窗口CMRO 2动态，同时测量BOLD对激活的反应和脑血流量（CBF）反应与螺旋双回波动脉自旋标记（ASL）技术。我们和其他人在校准BOLD研究中结合了这些工具来量化CMRO 2的变化，但这些研究都集中在近似稳态的持续变化上。将这些方法扩展到测量完整CMRO 2动力学的主要障碍是一个生理问题：静脉脑血容量（CBVV）的动力学与CBF的动力学是否有很大不同？估计CMRO 2动态所需的关键变量是静脉血红蛋白饱和度的动态，基本问题是BOLD效应主要取决于总脱氧血红蛋白的变化，因此也取决于静脉血容量的动态。CBF和BOLD信号的动态测量仅在CBVV遵循CBF时才提供足够的信息来估计CMRO 2动态。BOLD信号的这种基本模糊性的一个主要例子是fMRI中的一个长期存在的问题：BOLD信号的刺激后下冲是神经，血管还是代谢效应？尽管许多研究小组付出了相当大的努力，但仍然没有明确的答案，并且由于不同的动态时间常数，静脉血容量变化与CBF变化分离的可能性目前阻碍了开发用于测量CMRO 2动态的可靠工具。这种高风险/高收益建议的动机是，我们最近对高氧对BOLD信号的影响的研究提出了一种新的方法来解决这个主要的生理问题，该方法对CBVV特别敏感。此外，目前的模型BOLD响应和分析ASL实验基本上是稳态模型，这些需要扩展到包括完整的动态。我们将解决这两个基本的限制，测量CMRO 2动态与两个目标。目标1：扩展我们目前的建模框架，包括动态以及潜在的混淆生理变量，并使用此来开发一个贝叶斯框架，估计CMRO 2动态。目标二：使用刺激后下冲作为测试用例，使用高氧方法来测量人类初级视皮层中响应于具有不同持续时间和强度的视觉刺激的CBVV的动态。该终点将是对CBVV动力学的新评估，这将建立测量CMRO 2动力学的可行性，以用于未来在健康和疾病中的应用。

DESCRIPTION (provided by applicant): Our overall goal is to establish the basis for a new experimental paradigm for functional magnetic resonance imaging (fMRI) that makes possible quantitative measurement of the dynamics of the cerebral metabolic rate of oxygen metabolism (CMRO2) noninvasively in the human brain. Functional MRI methods based on blood oxygenation level dependent (BOLD) signal changes clearly have the potential to provide a window on CMRO2 dynamics, using simultaneous measurement of both the BOLD response to activation and the cerebral blood flow (CBF) response with a spiral dual-echo arterial spin labeling (ASL) technique. We and others have combined these tools in calibrated-BOLD studies to quantify changes in CMRO2, but these studies have focused on sustained changes in an approximate steady-state. The primary obstacle to extending these methods to measuring full CMRO2 dynamics is a physiological question: Do the dynamics of venous cerebral blood volume (CBVV) strongly differ from the dynamics of CBF? The key variable needed to estimate the dynamics of CMRO2 is the dynamics of the venous hemoglobin saturation, and the basic problem is that the BOLD effect depends primarily on changes in total deoxyhemoglobin, and thus also on the dynamics of venous blood volume. Dynamic measurements of CBF and BOLD signals provide sufficient information to estimate CMRO2 dynamics only if CBVV follows CBF. A primary example of this fundamental ambiguity of the BOLD signal is a long-standing issue in fMRI: is the post-stimulus undershoot of the BOLD signal a neural, vascular or metabolic effect? Despite considerable effort by many groups, there is still no clear answer, and the possibility of a dissociation of venous blood volume changes from CBF changes due to different dynamic time constants currently stands in the way of developing reliable tools for measuring CMRO2 dynamics. The motivation for this high risk/high gain proposal is that our recent studies of the effect of hyperoxia on the BOLD signal suggest a novel approach for addressing this primary physiological question, with a method that is specifically sensitive to CBVV. In addition, current models for the BOLD response and for analyzing the ASL experiment are essentially steady-state models, and these need to be expanded to include full dynamics. We will address these two basic limitations to measuring CMRO2 dynamics with two Aims. Aim 1: Extend our current modeling framework to include dynamics as well as potentially confounding physiologically variables, and use this to develop a Bayesian framework for estimating CMRO2 dynamics. Aim 2: Using the post- stimulus undershoot as a test case, use the hyperoxia approach to measure the dynamics of CBVV in human primary visual cortex in response to visual stimuli with varying duration and intensity. The endpoint will be a novel assessment of the dynamics of CBVV that will establish the feasibility of measuring the dynamics of CMRO2 for future applications in health and disease.