Diversity in blood flow control to the brain: moving from individualized modelling towards personalized treatment of the injured brain

大脑比身体任何其他器官都更需要持续的血液供应来维持其功能。当血压下降时，小动脉扩张以恢复血流水平，当血压上升时，它们收缩以保护最脆弱的血管，避免大脑出血。然而，这种控制系统可能会受损，例如在中风、头部创伤、痴呆或早产后，这与患者的预后更差有关。控制系统的故障对患者血压的管理也有重要的影响：没有这种“自动调节”系统的保护，血压的变化可能是危险的。该项目旨在改进测量大脑自动调节的方法，并深入了解健康个体和中风患者血压和血流之间的复杂关系。虽然在这个领域已经做了很多工作，但迄今为止，在评估控制功能方面的实验和技术挑战只给患者带来了有限的好处。控制系统是高度复杂的，典型的这种生物系统，有多个互补的生理机制并行工作。有迹象表明，即使在健康的个体中，他们控制血流量的方式和程度也存在差异。在不同的个体中，损伤也可能对不同的机制产生不同程度的影响。这对于评估个人的自动调节能力具有重要意义，因为传统的方法，基于单个数字来量化自动调节的强度，可能是不充分的。该项目为该领域开辟了一个新的方向，通过关注不同个体的脑血流运作方式的多样性，而不是研究到目前为止占主导地位的平均群体行为。它还在方法上开辟了新的领域，将血流控制研究与血压控制研究结合起来，基于两者在确保大脑获得足够血液方面的互补作用。因此，我们将详细调查健康志愿者的样本。我们将反复记录血压和血流、心率和二氧化碳水平在休息时的自发波动，以及在一系列方案的挑战中（定期下蹲、抬高志愿者的上半身、对大腿周围的袖带施加随机压力变化、呼吸含有5%二氧化碳的空气）。使用先进的数据分析方法（信号处理和数学建模），其中一些将作为该项目的一部分开发和优化，我们将量化血压和血流的同时控制，并旨在确定个体和子群体之间的特征差异。基于在健康受试者中观察到的差异，我们还将研究一组中风后最初几天和几周的患者。我们的目标是量化血流和血压控制的损害，以提高对这种情况演变的理解，以及这可能如何影响急性和慢性期血压的管理。这些控制系统的正确运作被认为是做出有效临床决策的关键，但由于缺乏对每个患者的损伤及其测量方法的了解，目前没有明确的指导方针。因此，这个多中心多学科项目的总体目标是为中风后管理血压控制的个性化方法奠定基础，基于个体血压和血流控制的特征，从而保护患者的大脑免受进一步损害。

The brain, more than any other organ in the body, requires a constant supply of blood in order to maintain its function. When blood pressure drops, small arteries dilate to restore flow levels, and when pressure rises, they constrict to protect the most delicate blood vessels and avoid bleeding in the brain. This control system can however become impaired for example following stroke, head trauma, in dementia or following premature birth and this has been associated with worse outcomes for the patient. Failure of the control system also has important implications for the management of patient's blood pressure: changes in blood pressure could be dangerous without the protection of this 'autoregulatory' system.This project aims to improve methods for measuring cerebral autoregulation and to gain a deeper understanding of the complex relationship between blood pressure and blood flow in healthy individuals and patients following stroke. While much work has been done in this field, experimental and technical challenges in assessing the control function has so far led to only limited benefit to patients. The control system is highly complex and, typical of such biological systems, there are multiple complementary physiological mechanisms working in parallel. There are indications that even in healthy individuals there are differences in the manner and the extent to which they control the flow. Impairment may also affect different mechanisms to a varying extent in different individuals. This has important implications for grading an individual's autoregulation, as the conventional approach, based on a single number to quantifying the strength of autoregulation, is likely to be inadequate. This project sets out in a new direction for the field, by focussing on the diversity of ways in which brain blood flow may operate in different individuals, rather than studying average group behaviour, which has so far been the predominant approach. It also breaks new ground methodologically by integrating the study of blood flow control with that of blood pressure control, based on the complementary roles these have in ensuring that the brain receives sufficient blood.We will thus investigate a sample of healthy volunteers in detail. We will repeatedly record blood pressure and flow, heart-rate and carbon dioxide levels during spontaneous fluctuations at rest, and during challenges in a range of protocols (periodic squatting, raising the upper body of volunteers, applying random pressure changes to a cuff around the thighs, breathing air with 5% CO2). Using advanced data analysis methods (signal processing and mathematical modelling), some of which will be developed and optimized as part of this project, we will quantify the simultaneous control of blood pressure and flow and aim to identify characteristic differences between individuals and sub-groups. Building on the differences observed in the healthy subjects, we will also study a group of patients during the first days and weeks after they have suffered a stroke. We aim to quantify the impairments in blood flow and blood pressure control, with a view to improving understanding of the evolution of this condition, and how this might impact the management of their blood pressure in the acute and chronic phase. Correct functioning of these control systems is thought to be key in making effective clinical decisions, but currently there are no clear guidelines due to a lack of understanding of the impairments in each individual patient and also the methods for their measurement.The overarching aim of this multicentre and multidisciplinary project is thus to lay the foundations for a personalized approach to managing blood pressure control after stroke, based on characterising individuals' blood pressure and flow control, and thus to protect patients' brains from further damage.