Next generation MRI technologies for measuring brain oxygen metabolism

二十多年前，血液氧合水平依赖(BOLD)效应的发现开启了使用核磁共振成像大脑功能的革命，而不仅仅是它的结构。顾名思义，这种效应依赖于血液的氧合作用，因此对大脑通过燃烧葡萄糖和氧气(氧代谢)消耗能量的速度很敏感。虽然BOLD功能磁共振成像(FMRI)使我们对功能定位的了解有了很大的改善，但它仍然是大脑活动的定性指标。通过测量氧代谢，我们可以直接观察维持这种大脑活动所需的代谢工作量。氧代谢的定量测量可以使用两种技术：校准BOLD和定量BOLD。不幸的是，这两种方法都没有充分发挥其潜力。这在一定程度上是由于这些方法和要求的复杂性，以执行涉及二氧化碳的复杂呼吸挑战。在这两种情况下，都需要专业知识，将这些方法的应用限制在少数方法学研究中心。这项提议的目的是消除这些障碍，使广大用户能够利用这些方法。经过校准的BOLD能够测量由于执行任务或经历刺激而引起的氧代谢变化。然而，在目前这种方法的实施中，参与者必须呼吸含有额外二氧化碳的空气。除了这造成的不适，这样的实验很难建立，也很耗时。在这项提议中，这种所谓的“校准”将被组织内在松弛特性的简单测量所取代。一举消除了复杂设备的设置，不再需要呼吸气体。这项技术有可能成为每个功能磁共振实验的必备部分，因为它能够以简单和快速的方式获得基线生理学的变化。受试者和会议之间基线生理学的这种变化可能会混淆对fMRI实验的解释，导致不正确的推断。量化的BOLD使通过测量服务于新陈代谢的氧气提取量(氧气提取分数)来估计静止的基线氧代谢。该方法依赖于理论上的理解，即组织的内在松弛特性取决于被成像像素中存在的脱氧血红蛋白的总量。这实际上依赖于血容量和氧提取分数的乘积。因此，准确测量血容量对于消除这些影响至关重要。目前，这是通过理论预测的微小信号变化来实现的。在这项提议中，将使用氧气作为示踪剂来测量血容量。这一新技术有可能实现比目前方法更高的准确性和重复性。它还满足了医疗界尚未满足的需求：静息氧代谢的测量。实现这一点的唯一另一种公认的方法是正电子发射断层扫描(PET)。然而，这种方法需要使用三种放射性示踪剂和相关剂量的电离辐射。这种方法的费用和复杂性意味着，英国很少有网站能够进行这样的实验。相比之下，核磁共振广泛可用，大多数临床站点都可以直接接触到成像套件中的100%氧气。因此，这种方法有可能以最低的成本极大地提高英国医疗保健系统的诊断能力。

The revolution of imaging the function of the brain using MRI, rather than just its structure, was kick started by the discovery of the blood oxygenation level dependent (BOLD) effect more than twenty years ago. As its name suggests this effect is dependent on blood oxygenation and is therefore sensitive to the rate at which the brain is consuming energy by burning glucose and oxygen (oxygen metabolism). Whilst BOLD functional MRI (fMRI) has enabled great improvements in our knowledge about the localisation of function it remains a qualitative measure of brain activity. By measuring oxygen metabolism we can take a direct look at the metabolic workload required to sustain this brain activity. Quantitative measurements of oxygen metabolism are possible using two techniques: calibrated BOLD and quantitative BOLD. Unfortunately neither method has reached its full potential. This is due in part to the complexity of these methods and requirements to perform complicated breathing challenges involving carbon dioxide. In both cases specialist knowledge is required, limiting the application of these methods to a small number of methodological research centres. The aim of this proposal is to remove these barriers enabling a broad spectrum of users to take advantage of these methods. Calibrated BOLD enables changes in oxygen metabolism, which are caused by performing a task or experiencing a stimulus, to be measured. However, in the current implementation of this method the participant must breathe air with added carbon dioxide. As well as the discomfort this causes, such experiments are difficult and time consuming to set up. In this proposal this so-called 'calibration' will be replaced by a simple measurement of the intrinsic relaxation properties of tissue. At a stroke, the set up of complicated equipment is removed and gas breathing is no longer required. This technique has the potential to be a required part of every fMRI experiment as it enables changes in baseline physiology to be obtained in a simple and quick manner. Such changes in baseline physiology between subjects and sessions can confound the interpretation of fMRI experiments leading to incorrect inferences.Quantitative BOLD enables resting baseline oxygen metabolism to be estimated by measuring the amount of oxygen extracted to serve metabolism (oxygen extraction fraction). The method relies on the theoretical understanding that the intrinsic relaxation properties of tissue are dependent on the total amount of deoxygenated haemoglobin that is present in the pixel being imaged. This is effectively dependent on the product of the blood volume and the oxygen extraction fraction. Therefore an accurate measurement of blood volume is critical for disentangling these effects. Currently this is achieved using a subtle signal variation predicted by theory. In this proposal blood volume will be measured using oxygen as a tracer. This new technique has the potential to realise much higher accuracy and reproducibility than the current method. It also fulfils an unmet need of the healthcare community: a measurement of resting oxygen metabolism. The only other established method to achieve this uses Positron Emission Tomography (PET). However, this method requires the use of three radioactive tracers and the associated dose of ionising radiation. The expense and complexity of this method means that there are very few sites within the UK that are able to perform such experiments. In contrast, MRI is widely available and most clinical sites have direct access to 100% oxygen within the imaging suite. Hence this method has the potential to vastly improve the diagnostic capability of the UK healthcare system at minimal expense.