Integrated control of cerebral blood flow

Brain perfusion is controlled by an arterial network, responsive to stimuli that grades membrane potential (VM) and Ca2+ influx. Arterial VM is set by an interplay among ion channels, each uniquely expressed in smooth muscle or endothelium. Inward rectifying K+ (KIR) channels break from convention in the cerebral circulation, an observation consistent with KIR being more than resting current. Recent work has noted that KIR might be sensitive to haemodynamics forces due to their interaction with membrane lipids. In this regard, Professor Welsh and his team examined the regulation of cerebral arterial KIR channels by membrane lipids (PIP2 and cholesterol) and whether these signalling molecules enable channel mechanosensitivity. Initial experiments revealed a Ba2+-sensitive KIR current in native cerebral arterial smooth muscle and endothelial cells comprised of KIR2.1 and KIR2.2 subunits. Patch clamp observations next noted that endothelial KIR was regulated by PIP2 whereas membrane cholesterol was the main modulator of smooth muscle KIR. Further work revealed that smooth muscle KIR displays pressure-sensitivity when bound to membrane cholesterol whereas endothelial KIR shows flow-sensitivity when coupled to PIP2. Using computer models, the team integrated these observations to reveal how each cellular KIR pool controls arterial VM and tone. The researchers propose that specific membrane lipid-KIR interactions allow each cellular channel pool to sense haemodynamic stimuli, thus set the foundation of tone development and perfusion control in the cerebral circulation.

Professor Donald Welsh, University of Western Ontario, Canada

Professor Donald Welsh, University of Western Ontario, Canada

Donald G Welsh is a Scientist at the Robarts Research Institute, Professor in the Department of Physiology & Pharmacology (Schulich School of Medicine & Dentistry) at Western University and the Rorabeck Chair in Neuroscience and Vascular Biology. His research focuses on ion channels and cellular mechanisms by which these membrane proteins regulate arterial tone development. His most significant contributions include: 1) quantification of electrical communication in resistance arteries, work that has fostered a deeper understanding of excitation-contraction coupling in vascular smooth muscle; 2) characterization and function of Ttype Ca2+ channels, elusive membrane proteins which appear to play a key role in gating of large co ductance Ca2+-activated K+ channels; and 3) defining the basis of myogenic tone, work that entailed the development of new biochemical, Ca2+imaging and myography approaches. The latter is of particular importance to the blood pressure regulation and the control of blood flow delivery to the brain.

There is a very wide literature covering models of cerebral autoregulation. The early work of Ursino and colleagues has been very widely adopted and adapted, although the feedback mechanisms remain somewhat imprecisely defined and the parameter values recovered experimentally have proved difficult to interpret. This has also made it challenging to link models of cerebral autoregulation with models in other contexts. More recent models have attempted to understand both the interaction between the responses to different stimuli and to dig deeper into the physiological mechanisms that govern autoregulation. In this talk, Professor Payne will give an overview of existing models of cerebral autoregulation, starting with high level models that tend to be based on a lumped compartment approach, before turning to consider the response of individual blood vessels in more detail. He will then explore how these physiological models might be combined in the future to develop models across multiple length scales that might be applicable to experimental data and help to interrogate the response in more detail. Such models also open up the possibility of linking with models of different responses, such as reactivity and neurovascular coupling, and thus potentially providing a more coordinated approach that can be used within a clinical setting to interrogate the cerebral vasculature and its regulation of blood flow in response to multiple stimuli.

Professor Stephen Payne, University of Oxford, UK

Professor Stephen Payne, University of Oxford, UK

Professor Stephen Payne is an Associate Professor in in Biomedical Engineering at the Institute of Biomedical Engineering, part of the Department of Engineering Science (and winner of a Queen’s Anniversary Prize for Higher and Further Education in 2015) at the University of Oxford. His work lies primarily in mathematical modelling and signal processing related to cerebral blood flow and metabolism with the main focus on cerebral autoregulation. He has raised funding of over £1.2M in grants as a PI and been a Co-Investigator on three other grants (with a share of £1.3M), with funding coming from EPSRC, BBSRC, Wellcome Trust and the European Commission. His publications include three books (including Cerebral Autoregulation in 2016 and Cerebral Blood Flow and Metabolism in 2017), and 90 papers in international journals (h-index of 21 with over 1300 citations). He has supervised 23 DPhil students to successful completion. He is currently the Chair of CARNet and the Chair of the Organising Committee for both the 8th International Conference on Cerebral Autoregulation (June 2018) and the Royal Society meeting on Integrated Control of Cerebral Blood Flow (December 2018).

Classically, cerebral autoregulation has been defined as the maintenance of relatively stable cerebral blood flow across a finite range of arterial pressures, facilitated by active adjustments in cerebral vascular resistance. Initial assessment of cerebral autoregulation in humans incorporated static measurements of arterial pressure and cerebral blood flow using invasive techniques (inert gas inhalation, and indwelling venous and arterial catheters). With the development of advanced monitoring technologies that facilitate non-invasive capture of continuous arterial pressure and cerebral blood flow (or velocity), the dynamic relationship between cerebral blood flow and arterial pressure has been extensively explored. Non-invasive examination of cerebral tissue oxygenation as a primary end-point of cerebral autoregulation is also gaining popularity both in the experimental and clinical settings. These assessments have been made using recordings of spontaneous variations in arterial pressure and cerebral blood flow (and/or oxygenation), as well as forced or induced fluctuations. Common methods for inducing fluctuations in arterial pressure include the squat-to-stand test, lower body negative pressure, and thigh cuff inflation/deflation. In this presentation, the strengths and limitations of these methodological approaches for assessment of static and dynamic cerebral autoregulation will be presented and discussed, including application to the clinical setting.

Associate Professor, Caroline Rickards, University of North Texas Health Science Center, USA

Associate Professor, Caroline Rickards, University of North Texas Health Science Center, USA

Dr Caroline Rickards is an Associate Professor in the Department of Physiology & Anatomy at the University of North Texas Health Science Center in Fort Worth, Texas, USA. She is Director of the Cerebral & Cardiovascular Physiology Laboratory where her research focuses on the development of novel therapies to improve vital organ perfusion under stress (including hemorrhage, cardiac arrest, and stroke). She has received funding for this research from the US Department of Defense, the American Heart Association, private foundations, and industry contracts. Dr Rickards is also an active member within her professional societies, including service on a number of committees within the American Physiological Society, Secretary of the Cerebral Autoregulation Research Network (CARNet), and editorial board membership for the Journal of Physiology and the American Journal of Physiology – Regulatory, Integrative and Comparative Physiology.

Stroke is a leading cause of mortality and long-term adult disability, and of increasing importance with demographic population changes. Physiological perturbations, particularly with respect to systemic (eg blood pressure) and cerebral haemodynamics (eg cerebral blood flow), are common following both acute ischaemic and haemorrhagic stroke. Importantly, mechanisms that control cerebral blood flow, including cerebral autoregulation, are impaired in the acute and sub-acute period. It is vital to understand these to inform the acute management of these physiological perturbations, particularly in the context of acute stroke treatment developments, including pharmacological and mechanical reperfusion therapies. Therefore, the talk will consider: 1) the evidence for cerebral dysautoregulation in acute ischaemic and haemorrhagic stroke; 2) recent developments in pharmacological and mechanical reperfusion therapies; 3) current guidelines for blood pressure management in acute ischaemic and haemorrhagic stroke; and 4) implications for future cerebral autoregulation research.

Professor Thompson Robinson, University of Leicester, UK

Professor Thompson Robinson, University of Leicester, UK

Professor Tom Robinson undertook his medical training in Nottingham, Newcastle-Upon-Tyne and Leicester, and is currently Head of the Department of Cardiovascular Sciences and Professor of Stroke Medicine at the University of Leicester, and also an Honorary Consultant Physician in Stroke Medicine for University Hospitals of Leicester NHS Trust. He was appointed an NIHR Senior Investigator in April 2016.

His other responsibilities include: Chair of the Membership Committee of the European Stroke Organisation, President of the British Association of Stroke Physicians, and National Specialty Lead for Stroke for the NIHR Clinical Research Network.

His research interests include clinical trials in acute stroke, particularly blood pressure and thrombolysis management, and studies of cardiovascular and cerebrovascular regulatory mechanisms. His research is currently funded by the British Heart Foundation, the Stroke Association, the Engineering and Physical Sciences Research Council, and the National Institute of Health Research.

Impairments in cerebrovascular reactivity have been recognised as a comorbidity in a broad range of neurological conditions including Alzheimer’s disease, multiple sclerosis, MCI, Parkinson’s disease, stroke, and even depression. There has been a recent move to consider that CVR could be useful as a biomarker for dementia, but its near ubiquitous presence in neurological diseases means it has often been considered as lacking the required specificity to be a biomarker. Professor Bulte poses the question ‘Is impaired CVR in fact the root cause of damage that results in these conditions?’ CVR regulates the availability of oxygen to the brain on a minute by minute basis. Lack of adequate oxygen is clearly catastrophic for tissues in the brain. Instead of being a potential biomarker for diagnosing a particular condition, what if impaired CVR should be the treatment target? The Bulte group can measure regional CVR and have identified that groups with an elevated risk of a number of diseases all have impaired CVR decades before it would be expected to observe any other diagnosable symptoms. The breakthrough in treating many of these conditions may be preventing them by addressing the CVR impairments early in life rather than waiting for other symptoms to arise and getting lost in a forest of biomarkers.

Professor Daniel Bulte, University of Oxford, UK

Professor Daniel Bulte, University of Oxford, UK

Professor Daniel Bulte is an MRI physicist and an Associate Professor in Engineering Science at the University of Oxford. He is based at the Institute of Biomedical Engineering (IBME) and previously worked at the Oxford Centre for Functional Magnetic Resonance Imaging of the Brain (FMRIB) for over 10 years, and the University of Toronto before that. He obtained a PhD in Electrical Engineering and a BSc in Physics from the University of Tasmania in Australia. He is a Senior Fellow of the Higher Education Academy, and has a Postgraduate Diploma in Learning and Teaching in Higher Education from Oxford University. He is passionate about teaching and outreach and has won numerous awards for his teaching.

Cerebrovascular reactivity (CVR) is measured as the quantitative haemodynamic response to a vasodilatory challenge. This is typically done as the response to a hypercapnic challenge and measured either using trans-cranial Doppler (TCD) or magnetic resonance imaging (MRI). MRI allows local measurement both in terms of the blood oxygen level-dependent (BOLD) signal and arterial spin labelling (ASL) perfusion measures. A higher CVR is typically interpreted as a sign of greater cerebral vascular health. Professor Gauthier and her team’s work in older adults show that overall trends across the lifespan support this interpretation, but results obtained in relation to cardiorespiratory fitness indicate a more complex relationship between fitness and haemodynamics. Results suggest that in healthy older adults, CVR is in fact negatively correlated with fitness over much of grey matter. Within the regions showing this negative relationship, the group further identified a negative relationship between VO2 max and both perfusion and perfusion-based CVR measured using ASL. These results also indicate that there are caveats to using BOLD CVR as a quantitative measure of cerebrovascular health. Here these results, their impact on the group’s interpretation of different types of CVR measurements and possible interpretations and future avenues of research will be discussed.

Professor Claudine Gauthier, Concordia University/Montreal Heart Institute, Canada

Professor Claudine Gauthier, Concordia University/Montreal Heart Institute, Canada

Claudine Gauthier is an Assistant Professor in the Department of Physics at Concordia University and a researcher at the Montreal Heart Institute. Her research explores the quantification of physiological changes in the brain using MRI during aging, vascular diseases, and preventative interventions such as exercise and cognitive training. Dr Gauthier did her PhD in Neuroscience at Université de Montréal with Dr Richard Hoge on the development of calibrated fMRI methods for quantification of brain metabolism, and the study of aging-related changes in vascular and metabolic health. Her post-doctoral work at the Max Planck Institute for Human Cognitive and Brain Sciences in Leipzig with Dr Robert Turner and Dr Arno Villringer explored the use of ultra-high field MRI for enhanced metabolic quantification and quantitative multi-modal MRI of learning-induced plasticity. Dr Gauthier is the co-founder of the Imaging Cerebral Physiology network and is currently the recipient of the Heart and Stroke Foundation of Canada New Investigator Award and the Henry JM Barnett Scholarship for her work on stroke.

The brain is highly metabolic demanding 20% of the cardiac output with healthy vascular function critical for delivering metabolites and removing waste. Both acute and chronic vascular dysfunction lead to tissue injury differing only in the pace of neuronal loss with acute ischaemic stroke and vascular dementia (VaD) representing both ends of the spectrum. Importantly, recent research evidence has inferred that Alzheimer’s Dementia (AD) may be initiated by vascular dysfunction. Since greater than 90% of dementia is secondary to AD or VaD, understanding the relationship between vascular function and dementia is critical. Recent statistics show that in the last five years of life, the cost of dementia is virtually equal to that of heart disease and cancer combined. However, measurement of cerebral blood flow (CBF) has not proven effective for assessing dementia due to: 1) autoregulatory compensation with maintenance of normal CBF in the setting of vasculopathies; 2) wide variations in normal resting CBF; and 3) difficulties in measuring CBF accurately. Therefore, understanding the impact of deficiencies in the flow control system must do more than measure resting CBF alone. It must investigate the capacity and integrity of the control mechanism itself. The purpose of this presentation therefore is to explore the relationship between CBF regulation, ageing, and dementia. The method used applied utilises quantitative vasodilatory stimuli during MRI to generate maps of the speed and magnitude of blood flow responses over the entire brain. Concepts and data will be presented to support the potential efficacy of this approach.

Professor David Mikulis, University of Toronto, Canada

Professor David Mikulis, University of Toronto, Canada

David J Mikulisis is Full Professor and Director of the Functional Brain Imaging Lab in the Dept. of Medical Imaging at the University of Toronto and the University Health Network in Toronto. He is also a Senior Scientist at the Toronto Western Research Institute and Co-Chair of the Vessel Wall Imaging International Study Group of the American Society of Neuroradiology. The primary emphasis of his work has been translational research focusing on the application of novel imaging methods to the clinical environment. He established one of the first fMRI labs in Canada in 1993 and is currently involved in developing advanced neurovascular imaging methods with major program arms including: 1) quantitative measurement and clinical application of cerebrovascular reactivity (CVR) metrics via precision control of blood oxygen and carbon dioxide, 2) high resolution and functional imaging of intra and extra-cranial blood vessel walls. Work in these areas has led to improved understanding of neurovascular uncoupling that may explain the origin of chronic ischemic white matter injury a major contributor to vascular dementia, and 3) imaging the glymphatic system.