A New Approach for Quantitative fMRI

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，该范式可以用绝对脑血流量(CBF)的定量单位来确定复杂任务执行期间、休息时或对药物反应时脑活动的波动模式。传统的功能磁共振成像(FMRI)是基于检测血氧水平依赖(BOLD)信号调制的。BOLD信号是潜在生理变化的敏感指标，但BOLD-fMRI的应用目前受到限制，因为BOLD信号的大小不能提供有生理意义的量的可靠定量测量。动脉自旋标记(ASL)方法提供了CBF的定量测量，这是一个明确定义的生理变量。然而，由于ASL测量的低信噪比，对CBF动力学的敏感测量仍然具有挑战性。这一建议的关键思想是一种新的方法，可以同时测量ASL和BOLD时间序列，并使用适当的BOLD响应模型，将这些信号视为两者都来自相同的CBF波动潜在时间序列。合并后的数据被用来估计CBF波动，而不知道这些波动的根本驱动因素。所提出的新方法基于两个假设：1)局部区域的CBF/CMRO2耦合比在测量期间保持不变；2)BOLD信号不存在与CBF波动无关的系统性波动。这两种假设都不是严格意义上的，因此这一提议的“高风险”是一个悬而未决的问题，即这些影响是否足够小，或者是否可以得到足够的修正，以使方法变得稳健。我们建议通过以下方法来测试该方法的可行性：使用旨在挑战方法学基本假设的实验范式来测量健康受试者对视觉刺激的同时ASL和BOLD反应(目标1)；以及开发两种新的分析技术来提高方法的准确性，一种是采用最近的独立分量分析(ICA)方法，使用我们的多回声采集来识别和去除测量的BOLD信号中的伪像分量，第二种是改进模型参数的估计，并使用贝叶斯方法处理随时间变化的CBF/CMRO2耦合比率。对系统误差的评估，以及为最大限度地减少其影响而开发的稳健分析工具，将为新方法的广泛应用奠定基础。这将大大拓宽功能磁共振成像的可能应用范围，包括测量复杂行为期间的大脑活动，以及定量评估发育、疾病或药物给药对基线生理状态和刺激诱发反应的影响。 公共卫生相关性：使用血氧水平依赖(BOLD)方法对大脑进行功能磁共振成像(FMRI)研究目前受到以有意义的生理学方式解释这些信号的困难的限制。这项提案的目标是 是开发一种新的方法来定量测量脑血流的波动。这种方法论将为疾病研究和药物效果评估开辟新的方向，以及探索复杂行为过程中的大脑动力学。

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 the determination of fluctuating brain activity patterns during performance of complex tasks, at rest, or in response to a drug, in quantitative units of absolute cerebral blood flow (CBF). Conventional functional magnetic resonance imaging (fMRI) is based on detection of blood oxygenation level dependent (BOLD) signal modulations. The BOLD signal is a sensitive indicator of underlying physiological changes, but BOLD-fMRI applications are currently limited because the magnitude of the BOLD signal does not provide a reliable quantitative measure of a physiologically meaningful quantity. Arterial spin labeling (ASL) methods provide quantitative measurements of CBF, a well-defined physiological variable. However, sensitive measurement of CBF dynamics remains challenging because of the low signal to noise ratio of the ASL measurement. The key idea of this proposal is a new method to take simultaneous measurements of ASL and BOLD time series, and with an appropriate model of the BOLD response, treat these signals as both being generated from the same underlying time series of CBF fluctuations. The combined data are used to estimate the CBF fluctuations without knowing anything about the underlying drivers of those fluctuations. The proposed new methodology rests on two assumptions: 1) the CBF/CMRO2 coupling ratio for a local region remains constant during the measurement period; and 2) there are no systematic fluctuations of the BOLD signal that are unrelated to CBF fluctuations. Neither assumption is strictly true, so the "high risk" hal of this proposal is the open question of whether these effects are sufficiently small or can be adequately corrected for the methodology to be robust. We propose to test the feasibility of this method by: Measuring simultaneous ASL and BOLD responses to visual stimuli in healthy human subjects with an experimental paradigm designed to challenge the basic assumptions of the methodology, including variable CBF/CMRO2 coupling, dynamic transitions and BOLD transients (Aim 1); and developing two new analysis techniques to improve the accuracy of the method, one to adapt a recent independent components analysis (ICA) method to use our multi-echo acquisition to identify and remove artifact components in the measured BOLD signals, and the second to improve estimation of the model parameters and deal with a time varying CBF/CMRO2 coupling ratio with a Bayesian approach. The assessment of systematic errors, and the development of robust analysis tools for minimizing their effect, will establish a basis fo widespread application of the new method. This will substantially broaden the possible applications of fMRI, including measurement of brain activity during complex behavior, and quantitative assessments of the effects of development, disease, or drug administration on both the baseline physiological state and stimulus-evoked responses. PUBLIC HEALTH RELEVANCE: Functional magnetic resonance imaging (fMRI) studies of the brain using blood oxygenation level dependent (BOLD) methods are currently limited by the difficulty of interpreting these signals in a meaningful physiologic way. The goal of this proposal is to develop a new methodology for measuring fluctuations in cerebral blood flow in a quantitative way. This methodology will open new directions for research in disease and evaluating the effects of drugs, as well as explorations of brain dynamics during complex behavior.