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

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.

In the UK, an estimated 150 000 people suffer a stroke each year, with about 1/4 of cases in patients of working age and an estimated cost of £8.2 billion*. Following a stroke, 50 - 70% of survivors regain independence, 15 - 30% are permanently disabled and 20% still require institutional care after three months. In the over 65 age group, 30% were found unable to walk after 6 months, and 26% were institutionalized in a nursing home [1]. The personal, social and economic (cost of care/loss of income) impact of stroke is clearly severe. One of the main risk factors for stroke is hypertension (high blood pressure) associated with an approximately 50% increase in stroke occurrence. The quality of care immediately following a stroke can greatly improve recovery, by saving neurons in the area around the primary insult, but how and when to control blood pressure during this period remains unclear [2].
This proposal seeks to lay the foundations for a new approach in evidence-based personalized care following stroke, based around the interaction between the management of blood pressure and cerebral blood flow. The goal is to reduce mortality and improve patients' and carers' quality of life and independent living, reduce the cost of care, and to develop new methods and associated healthcare technologies for this purpose. Promising results at this stage will be followed up by larger clinical studies to impact over the next 5 - 10 years on the development of clinical guidelines (recommended by medical societies and NICE) for the management of blood pressure after stroke. In addition, this work will also impact on patients following premature birth, traumatic head injury and with some forms of dementia or a number of other conditions, where autoregulation is key. There is also a very real opportunity to exploit the proposed personalized approach to the control of hypertension in the wider population and address an even larger societal challenge in the prevention of stroke and heart-attacks. The new diagnostic approach aims to allow drug (and other) therapies to be targeted to the specific needs of the individual, improving patients' long term outcomes and making treatments more effective and cheaper.
The tools for estimating autoregulation that will be developed here will be non-invasive and portable, able to be applied cheaply at the bedside. Such new diagnostic systems (including the necessary hardware and software) would provide new commercial opportunities for healthcare industries, most likely in the SME sector, and a significant income stream to the UK when exploited worldwide.
Our integrated team with engineers, a physician and a neurosurgeon, and our leadership in the Cerebral Autoregulation Research Network (www.car-net.org) will allow this work to be disseminated for wide impact on clinical practice, relevant industries, and related research. The multidisciplinary and multicentre research environment will provide excellent training for research fellows (and PhD students) developing their career at the interface of engineering, medicine and physiology. This team will also engage in outreach to disseminate to the broader public (especially those approaching the end of school) an insight into the process of scientific research and the excitement of applying technology for the benefit of patients.


1 Roger VL et. al.: Heart Disease and Stroke Statistics-2012 Update: A Report From the American Heart Association. Circulation 2012;125:E2-E220.
2 Jordan JD, Powers WJ: Cerebral Autoregulation and Acute Ischemic Stroke. American Journal of Hypertension 2012;25:946-950.

* http://www.stroke.org.uk/news/stroke-facts-and-statistics-your-area, accessed 14/8/2012