New methods for assessing the control of blood flow in the brain

在英国，每年约有11万名患者中风，至少有30万人因此而患有中度至重度残疾。据估计，NHS每年的中风直接成本为28亿美元，非正式护理的额外成本约为24亿美元。中风约占死亡人数的11%，大约一半的幸存者依赖他人进行日常活动。显然需要进行进一步的研究，以减少中风的发生率和对患者生活的长期影响。大脑需要持续的血液供应，以确保始终有足够的氧气和营养物质，并迅速清除活性细胞产生的废物。一个复杂的控制系统扩张和收缩大脑中的小动脉，在健康人身上有效地实现了这一点。这个系统，仍然知之甚少，响应于血压的变化（例如在运动或站立时），呼吸模式的变化，以及大脑活动的变化（例如清醒/睡眠或对感官刺激的反应）。如果控制系统失败（例如，在创伤后或早产儿中），受试者可能会遭受血流量不足或过多，其中任何一种都可能导致暂时或永久性脑损伤，引发中风或加重其后果。重要的是要及早发现控制系统的损伤，以确保对患者进行适当的护理，例如保持血压恒定，以避免进一步的脑损伤。然而，很难测量患者的血流是否得到充分调节。目前使用的技术可能需要患者的血压发生相当大的变化，但这在脆弱的受试者中无法安全地完成。所使用的程序通常是不舒服的，结果不是很可靠。我们正在提出新的实验方法，这些方法不那么具有侵略性，因此将来可能会在更广泛的患者群体中使用。这些方法使用各种重复的血压（以及吸入的二氧化碳浓度）的小的随机变化，而不是更大的波动。扩展我们在南安普顿、莱斯特和诺维奇的团队之前开展的工作，我们将同时记录血压（使用非侵入性方法）和大脑中两条动脉的血流（使用应用于头部外侧太阳穴上方的多普勒超声），以及呼吸空气中的二氧化碳。从这些信号的长时间记录中的微小波动，我们将估计控制血流的系统的特性，特别是它是否充分运行或受损。我们将只在健康的成年志愿者身上进行实验，并通过吸入二氧化碳浓度增加的空气来引起控制系统的暂时损害，这是一个在受控实验室条件下非常安全的过程。除了开发新的实验方法，我们还将开发和应用新的数学和计算技术进行信号数据分析，我们相信这将对我们正在调查的数据更有效。将使用先进的统计方法分析结果，并将受试者之间（以及同一受试者的重复试验中）的已知随机变化与显著变化区分开来。在这个合作项目中，我们将能够比较许多不同的实验方法和数据处理技术，以确定具有最佳性能的方法。总之，该项目的目的是研究和开发新的实验方案和数据分析方法，以提供可用于评估患者脑血流控制的新技术。我们还希望这项工作有助于更好地了解控制系统如何在健康的人类受试者中工作。作为结果，我们希望推荐一种或多种新方法，供未来在医院使用。

In England, approximately 110,000 patients suffer a stroke each year, and at least 300,000 people live with moderate to severe disabilities as a result. The direct cost to the NHS of stroke is estimated to be 2.8 billion per year, with additional costs of informal care around 2.4 billion. Stroke accounts for about 11% of deaths, and around half of the survivors depend on others for everyday activities. Further research to reduce the incidence and long-term consequences of strokes on patients' lives is clearly called for. The brain requires a constant supply of blood to ensure that sufficient oxygen and nutrients are always available, and waste products produced by active cells are rapidly removed. A complex control system that dilates and constricts small arteries in the brain achieves this efficiently in healthy humans. This system, which is still poorly understood, responds to changing blood pressure (e.g. during exercise or when standing up), changes in breathing pattern, and variations in brain activity (e.g. waking / sleeping or responding to sensory stimuli). If the control system fails (e.g. following trauma or in premature babies), the subject may suffer from insufficient or excessive blood flow, either of which can lead to temporary or permanent brain damage, provoking strokes or aggravating their consequences. It is important to detect impairment of the control system early, in order to ensure appropriate care for the patient, such as keeping their blood pressure constant to avoid further brain damage. However, it is very difficult to measure whether a patient's blood flow is adequately regulated. Techniques that are currently used may require the patients' blood pressure to be changed quite considerably, but this cannot be done safely in vulnerable subjects. Procedures used are often uncomfortable and results not very reliable.We are proposing new experimental methods that are less aggressive and therefore might in the future be used in a wider group of patients. These methods use a variety of repeated small random changes in blood pressure (and also inhaled carbon dioxide concentrations), rather than larger swings. Extending previous work carried out by our teams in Southampton, Leicester and Norwich, we will simultaneously record blood pressure (using non-invasive methods) and blood flow in two arteries in the brain (using Doppler ultrasound applied on the outside of the head over the temples), together with CO2 in breathed air. From the small fluctuations in the prolonged recordings of these signals, we will estimate the characteristics of the system controlling blood flow, and in particular whether it is operating adequately, or is impaired. We will only carry out the experiments on healthy adult volunteers, and will provoke temporary impairment of the control system, by inhalation of air with increased levels of CO2, a procedure that is quite safe in the controlled laboratory conditions.In addition to developing new experimental methods, we will also develop and apply novel mathematical and computational techniques for signal-data analysis, which we believe will be more effective for the data we are investigating. Advanced statistical methods will be used to analyse results, and distinguish the known random variations between subjects (and also in repeated test in the same subject), from significant changes. In this joint project, we will be able to compare a number of different experimental methods and data processing techniques, in order to identify the ones with the best performance.In summary, the aims of the project are to investigate and develop new experimental protocols and data analysis methods, in order to provide new techniques that can be used to assess patients' brain blood flow control. We also expect this work to help understand better, how the control system works in healthy human subjects. As outcome we expect to recommend one or more new methods for future use in hospitals.