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，一个用于临床应用的范例，用于评估药物的效果或跟踪疾病的进展和治疗的反应。该方法建立在前一阶段与定量功能磁共振方法相关的几项发展的基础上，以测量脑血流量(CBF)和大脑氧代谢率(CMRO2)：开发了校准的BOLD方法中不需要吸入特殊气体混合物的替代校准方法；一系列研究表明，仅靠BOLD反应对于检测大脑状态的变化相对不敏感，该变化导致对标准刺激的诱发生理反应的变化；以及咖啡因效应的特定示例研究，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，而这些变化基本上是BOLD单独检测不到的。在这项工作的基础上，我们提出了一套反映基线CBF和CMRO2及其对标准刺激(类似于‘压力测试’)的反应的四个指标，可以在~20分钟内非侵入性地获得，并且不需要特殊的混合气体。该项目的目标是通过测试这些指标跟踪个别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将测试基于在基线状态下测量松弛速率R2‘的新校准方法提供与量化CMRO2对刺激的反应的标准高碳酸血症挑战基本上相同的所需信息。目标2将在背靠背测试和相隔约1个月的研究中测试这四个指标在健康人群中的重复性。AIM 3是对这些指标检测因咖啡因而导致的大脑状态变化的能力的盲测案例。这项工作将建立这些指标的敏感性和可靠性，以跟踪个体受试者的大脑状态变化，作为未来在评估药物效果(例如，确定应答者或量化对疾病的影响)、确定疾病进展或评估治疗效果方面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.