The Physiological Basis of Functional MRI

描述（由申请人提供）：我们的总体目标是建立一种新的方法来量化单个受试者的大脑状态变化，这是评估药物效果或跟踪疾病进展和治疗反应的临床应用范例。该方法建立在前期支持期间与用于测量脑血流量（CBF）和脑氧代谢率（CMRO2）的定量fMRI方法相关的多项进展的基础上：在校准的BOLD方法中开发了一种替代校准方法，不需要吸入特殊的气体混合物；一系列研究表明，单独的 BOLD 反应对于检测大脑状态的变化相对不敏感，而大脑状态的变化会导致对标准刺激的诱发生理反应发生变化；咖啡因效应的一个特定示例研究表明，定量 fMRI 方法能够检测 CBF 和 CMRO2 的基线和激活反应的实质性变化，而单独使用 BOLD 基本上无法检测到这些变化。基于这项工作，我们提出一组四个指标，反映基线 CBF 和 CMRO2 及其对标准刺激（类似于“压力测试”）的响应，可以在约 20 分钟内非侵入性地获取，不需要特殊的气体混合物。该项目的目标是通过测试这些指标跟踪个体受试者大脑状态变化的能力，为这种方法的临床应用奠定基础。目标 1 将测试基于测量基线状态下的弛豫率 R2' 的新校准方法是否提供与用于量化 CMRO2 对刺激的反应的标准高碳酸血症挑战基本相同的所需信息。目标 2 将在健康人群中通过背靠背测试和相隔约 1 个月的研究来测试这四个指标的重现性。目标 3 是一个盲测案例，测试这些指标检测个体因咖啡因而导致的大脑状态变化的能力。这项工作将建立这些指标的敏感性和可靠性，用于跟踪个体受试者的大脑状态变化，作为未来评估药物效果（例如，识别反应者或量化对疾病的影响）、确定疾病进展或评估治疗效果的重点临床应用的基础。

DESCRIPTION (provided by applicant): Our overall goal is to establish a new methodology for quantifying changes in brain state in single subjects, a paradigm for clinical applications in assessing the effects of a drug or for following the progression of disease and the response to therapy. The method builds on several developments during the previous period of support related to quantitative fMRI methods to measure cerebral blood flow (CBF) and the cerebral metabolic rate of oxygen (CMRO2): the development of an alternative approach to calibration in the calibrated BOLD method that does not require inhalation of special gas mixtures; a series of studies showing that the BOLD response alone is relatively insensitive for detecting a change in brain state that leads to a change in the evoked physiological response to a standard stimulus; and a particular example study of caffeine effects showing that quantitative fMRI methods are able to detect substantial changes in both baseline and activation responses of CBF and CMRO2 that were essentially undetected by BOLD alone. Based on this work we propose that a set of four metrics, reflecting baseline CBF and CMRO2 and their responses to a standard stimulus (analogous to a 'stress test'), can be acquired noninvasively and without requiring special gas mixtures in ~20 min. The goal of the project is to establish a basis for clinical applications of this approach by testing the ability of these metrics to track brain state changes in individual subjects. Aim 1 will test that the new approach to calibration based on measuring the relaxation rate R2' in the baseline state gives essentially the same required information as the standard hypercapnia challenge for quantifying the CMRO2 response to a stimulus. Aim 2 will test the reproducibility of the four metrics in a healthy population in both back to back test and in studies ~1 month apart. Aim 3 is a blinded test case of the ability of these metrics to detect changes in brain state due to caffeine on an individual basis. This work will establish the sensitivity and reliability of these metrics for following brain state changes in individual subjecs as a basis for future focused clinical applications in assessing drug effects (e.g., identifying responders, or quantifying the effect on disease), for determining the progression of disease, or for assessing the effect of therapy.