Quantitative functional MRI: developing non-invasive neuroimaging to map the human brain's consumption of oxygen

脑部疾病，包括癫痫、多发性硬化症和痴呆症等神经疾病，以及抑郁症和精神分裂症等常见精神疾病，对患者及其照顾者都有相当大的个人、社会和经济代价。改进我们掌握的量化大脑功能的工具将有助于诊断，为患者选择正确的治疗方法，并开发新的、更有效的治疗方法。这项提议旨在开发一种使用磁共振成像(MRI)的可靠非侵入性脑成像方法，该方法以几毫米的空间分辨率在整个人类大脑中绘制大脑消耗的氧气量。耗氧率，即CMRO2，反映了神经活动，并可以通过疾病过程发生变化。它提供了与疾病和治疗相关的大脑活动变化的标志。我们提出的方法还将绘制脑血管的功能特征图，这些血管的健康对大脑的氧气和营养供应至关重要。直到最近，还只能通过依赖于放射性示踪剂的正电子发射断层扫描(PET)来定量绘制人类大脑的代谢能量使用图。这种测量的应用是有限的，因为为了最大限度地减少辐射剂量，它不能在同一患者或健康志愿者身上多次应用。这阻碍了对疾病或治疗进展的重复研究，以及对正常大脑发育和衰老的研究。我们建议的方法将避免使用电离辐射，将比PET更便宜，更广泛地使用，并将量化CMRO2地图的应用扩展到更多的中心，导致更好的治疗靶向和潜在的医疗成本节约。我们已经进行了一些初步测试，表明我们的建议方法是可行的。它依赖于同时绘制流向大脑每个部分的血液和离开大脑每个部分的血液的氧气。测量需要调节大脑血流量和氧气水平，通过让志愿者呼吸富含二氧化碳和氧气的空气来实现。这些程序要求志愿者戴上口罩，但很安全，耐受性很好。与其他最近提出的方法相比，我们提出的方法应该能产生描述脑血管特性的额外信息。这意味着它需要更少的假设，这些假设在患病的大脑中可能不是无效的，从而使我们的方法有更广泛的应用范围，并提供可能更丰富的临床信息。这一建议优化了我们的方法，以确保它对于广泛的研究和最终的临床应用是有效和可靠的。我们建议开发神经成像方法的物理学家和临床学术研究人员密切合作，他们将帮助我们在两种常见的神经疾病--癫痫和多发性硬化症(MS)--中展示其临床可行性。大约70%的项目将是方法开发，以优化我们的图像采集和数据分析策略，以在大约10分钟的扫描时间内产生准确和可重复的测量结果。该项目的其余30%将在自愿帮助我们进行研究的癫痫和多发性硬化症患者群体中验证该方法。验证将通过与目前的“黄金标准”PET进行比较。该项目将与英国和国际上的学术和工业研究人员建立合作伙伴关系并从中受益。特别是，这项工作在药物开发行业具有很好的应用潜力，该行业是英国一个强大的工业部门，用于开发治疗精神和神经疾病的新的有效化合物。该项目将有助于保持英国在神经成像研究方面的国际领先地位，英国长期以来一直保持这一地位，并从中受益。

Diseases of the brain including neurological conditions, such as epilepsy, multiple sclerosis and dementia, and common psychiatric conditions such as depression and schizophrenia, have considerable personal, social and economic costs for the sufferers and their carers. Improving the tools at our disposal for quantifying brain function would help with diagnosis, choosing the right treatment for the patient and developing new, more effective, treatments. This proposal aims to develop a reliable non-invasive brain imaging method using magnetic resonance imaging (MRI) that maps, across the whole human brain with a spatial resolution of a few millimetres, the amount of oxygen that the brain is consuming. The rate of oxygen consumption, known as CMRO2, reflects neural activity and can change through disease processes. It provides a marker of disease and treatment related alterations in brain activity. Our proposed method would also map the functional characteristics of brain blood vessels whose health is crucial for the supply of oxygen and nutrients to the brain.Until recently, it has only been possible to quantitatively map the human brain's metabolic energy use through positron emission tomography (PET), which relies on radioactive tracers. The application of such measurements is limited, as in order to minimise radiation doses, it cannot be applied many times in the same patients or healthy volunteers. This hampers the repeated study of disease or treatment progression and the study of normal brain development and aging. Our proposed method would avoid the use of ionizing radiation, would be cheaper than PET and more widely available, and would expand the applications of quantified CMRO2 mapping to more centres, leading to improved treatment targeting and potential healthcare cost savings.We have performed some initial tests that show our proposed method to be feasible. It relies on mapping simultaneously the flow of blood to each part of the brain and the oxygenation of the blood leaving each part of the brain. Necessary for the measurement is the modulation of brain blood flow and oxygen levels, achieved by asking volunteers to breathe air enriched with carbon dioxide and oxygen. These procedures involve the volunteer wearing a face-mask but are safe and well tolerated. Our proposed method should yield additional information describing cerebrovascular properties compared to other recently-proposed methods. This means that it would require fewer assumptions which may be not be invalid in the diseased brain, giving our approach a wider scope of application and offering potentially richer clinical information.This proposal optimises our method to ensure it is efficient and reliable for widespread research and eventually clinical use. We propose a close collaboration between physicists developing the neuroimaging methodology and clinical academic researchers who will help us to demonstrate its clinical feasibility in two common neurological diseases, epilepsy and multiple sclerosis (MS). About 70% of the project will be methodological development to optimise our image acquisition and data analysis strategy to yield accurate and repeatable measurements within about 10 minutes of scanning. The remaining 30% of the project will validate the method in groups of epilepsy and MS patients who volunteer to help us with our research. Validation will be performed by comparison with PET, the current 'gold standard.'The project will develop and benefit from partnerships with academic and industrial researchers in the UK and internationally. In particular, the work has good potential for application in the drug development industry, a strong industrial sector in the UK, for the development of new and effective compounds to treat psychiatric and neurological disorders. This project would help maintain the UK at the forefront internationally of neuroimaging research, a position it has long held and from which it has benefitted.