Dynamics of oxygen metabolism in the human brain

描述(申请人提供)：我们的总体目标是为功能磁共振成像(FMRI)的新实验范式奠定基础，使非侵入性地定量测量人脑中大脑氧代谢代谢率(CMRO2)的动力学成为可能。基于血氧水平依赖(BOLD)信号变化的功能MRI方法显然有可能提供CMRO2动力学的窗口，使用螺旋双回波动脉自旋标记(ASL)技术同时测量BOLD对激活的反应和脑血流(CBF)反应。我们和其他人在经过校准的大胆研究中结合了这些工具，以量化CMRO2的变化，但这些研究侧重于近似稳定状态下的持续变化。将这些方法扩展到完全测量CMRO2动力学的主要障碍是一个生理学问题：静脉脑血容量(CBVV)的动力学与CBF的动力学有很大不同吗？估计CMRO2动力学所需的关键变量是静脉血红蛋白饱和度的动力学，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力学。只有当CBVV跟随CBF时，CBF和BOLD信号的动态测量才能提供足够的信息来估计CMRO2的动力学。BOLD信号的这种根本模糊性的一个主要例子是功能磁共振成像中的一个长期问题：BOLD信号的刺激后未达标是神经、血管还是代谢影响？尽管许多小组做出了相当大的努力，但仍然没有明确的答案，而且由于动态时间常数的不同，静脉血容量变化与CBF变化分离的可能性目前阻碍了开发可靠的工具来测量CMRO2动力学。这一高风险/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，方法是对CBVV特别敏感。此外，目前用于大胆反应和分析ASL实验的模型基本上都是稳态模型，需要扩展到包括完整的动态模型。我们将通过两个目标来解决测量CMRO2动力学的这两个基本限制。目标1：扩展我们当前的建模框架，以包括动力学以及潜在的混杂的生理变量，并利用这一点来开发用于估计CMRO2动力学的贝叶斯框架。目的：以刺激后欠冲为测试对象，采用高氧法测定人初级视皮层CBVV对不同持续时间和不同强度视觉刺激的反应。终点将是对CBVV动态的新评估，它将建立测量CMRO2动态的可行性，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.