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Integrated control of cerebral blood flow

Scientific meeting

Starts:

December
032018

09:00

Ends:

December
042018

17:00

Location

Kavli Royal Society Centre, Chicheley Hall, Newport Pagnell, Buckinghamshire, MK16 9JJ

Overview

Theo Murphy international scientific meeting organised by Professor Stephen Payne, Dr Clare Howarth, Professor Daniel Bulte and Professor Shieak Tzeng

Credits: Supplied by Rushab Badiani.

The brain regulates cerebral blood flow very tightly to provide a sufficient and continuous supply of oxygen and glucose. It thus has to respond to many different challenges, which have traditionally been considered largely separately. In this meeting we aimed to move towards an integrated approach to understanding cerebral blood flow control and to explore its important clinical implications.

The schedule of talks and speaker abstracts and biographies are below. Recorded audio of the presentations will be available on this page after the meeting has taken place.

This was a residential conference, which allows for increased discussion and networking.

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Schedule of talks

03 December

Session 1 09:00-12:30

Autoregulation

10 talks Show detail Hide detail

Chairs

Professor Daniel Bulte, University of Oxford, UK

09:00-09:05 Welcome session

09:05-09:30 Flow/Pressure Sensing by Ion Channels and the Setting of Cerebral Arterial Tone Development

Professor Donald Welsh, University of Western Ontario, Canada

Abstract

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.

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09:30-09:45 Discussion

09:45-10:15 Models of cerebral autoregulation

Professor Stephen Payne, University of Oxford, UK

Abstract

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.

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10:15-10:30 Discussion

10:30-11:00 Coffee

11:00-11:30 Experimental Approaches for Assessment of Cerebral Autoregulation in Humans

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

Abstract

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.

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11:30-11:45 Discussion

11:45-12:15 Cerebral dysautoregulation in acute stroke – implications for the management of haemodynamic perturbations

Professor Thompson Robinson, University of Leicester, UK

Abstract

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.

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12:15-12:30 Discussion

12:30-13:30

Lunch

Session 2 13:30-17:00

Reactivity

9 talks Show detail Hide detail

Chairs

Professor Stephen Payne, University of Oxford, UK

13:30-14:00 Effects of Aerobic Exercise on Cerebrovascular Health in Older Adults: Insights from the Brain in Motion Study

Professor Marc Poulin, University of Calgary, Canada

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14:00-14:15 Discussion

14:15-14:45 Cerebrovascular reactivity: biomarker or target?

Professor Daniel Bulte, University of Oxford, UK

Abstract

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.

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14:45-15:00 Discussion

15:00-15:30 Tea

15:30-16:00 MRI of cerebrovascular reactivity: applications and caveats

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

Abstract

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.

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16:00-16:15 Discussion

16:15-16:45 Mapping Cerebral Blood Flow Regulation in Aging and Dementia

Professor David Mikulis, University of Toronto, Canada

Abstract

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.

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16:45-17:00 Discussion

04 December

Session 3 09:00-12:30

Neurovascular coupling

9 talks Show detail Hide detail

Chairs

Dr Clare Howarth, University of Sheffield, UK

09:00-09:30 Balancing the brain’s energy supply: neurovascular coupling in the cortex and hippocampus

Dr Kira Shaw, University of Sussex

Abstract

Neurovascular coupling has been predominantly studied in primary sensory cortices, where neuronal activation leads to increased cerebral blood flow and a large influx of oxygenated blood. However, neural activity may be less well-coupled to increased blood flow in other brain areas. For example, local field potentials are highly correlated with fMRI/BOLD signals in sensory cortex, but not in the hippocampus (Ekstrom, 2010), suggesting neurovascular coupling may differ between sensory cortex and hippocampus. To investigate this directly, Dr Hall and her team used 2-photon imaging to record fluctuations in neuronal activity and microvascular diameter in primary visual cortex (V1) and the hippocampus of awake, behaving mice, as well as combined laser doppler flowmetry and haemoglobin spectroscopy to record baseline and stimulus-induced alterations in macroscopic haemodynamics. Compared to V1, the hippocampus had lower resting blood flow and blood oxygen saturation, despite similar rates of oxygen consumption. Furthermore, individual blood vessels dilated significantly less frequently and to a smaller extent in the hippocampus compared to V1, despite equivalent-sized calcium responses. Finally, increases in regional oxygen consumption led to smaller macroscopic increases in blood flow in the hippocampus compared to V1. These data suggest that not only is the hippocampus under-supplied with oxygen compared to primary sensory cortex at rest, but it is also less able to increase local blood flow in response to increased neuronal activity. These deficits in neurovascular coupling could contribute to the vulnerability of the hippocampus to hypoxia by reducing the ability of hippocampal neurons to match energy supply with demand.

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09:30-09:45 Discussion

09:45-10:15 Building a mathematical model of brain energy metabolism

Professor Renaud Jolivet, University of Geneva and CERN, Switzerland

Abstract

The brain consumes an inordinate amount of energy with respect to its weight. Understanding brain energy metabolism is crucial as numerous studies point to a metabolic component in various neurodegenerative disorders and because energetic considerations might have played an important role during evolution, constraining behaviour and providing a powerful explanation of certain cellular features as trade-offs between performance in information processing and energy savings. Professor Jolivet will briefly discuss these points before describing how to design models of brain energy metabolism and neurovascular coupling, the importance of calibration due to the multicellular complexity of the brain and algorithmic tools to analyse the behaviour of such models. The brain consumes an inordinate amount of energy with respect to its weight. Understanding brain energy metabolism is crucial as numerous studies point to a metabolic component in various neurodegenerative disorders and because energetic considerations might have played an important role during evolution, constraining behaviour and providing a powerful explanation of certain cellular features as trade-offs between performance in information processing and energy savings. Professor Jolivet will briefly discuss these points before describing how to design models of brain energy metabolism and neurovascular coupling, the importance of calibration due to the multicellular complexity of the brain and algorithmic tools to analyse the behaviour of such models.

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10:15-10:30 Discussion

10:30-11:00 Coffee

11:00-11:30 Neuronal activity and neuroenergetics with and without CBF

Dr Anna Devor, University of California, San Diego, USA

Abstract

Neurons in the brain rely on blood vessels for supply of oxygen and glucose. An increase in neuronal activity normally leads to vasodilation increasing cerebral blood flow (CBF), so that supply meets demand. Dilation is driven by multiple mechanisms emphasising its importance for healthy brain function. Vasoactive messengers are released by different types of neurons and possibly glia. In addition, blood vessels are endowed with an array of ion channels that propagate the signal along their walls ensuring “upstream” dilation magnifying the CBF response. But what happens to the oxygen and glucose? According to standard textbooks, brain’s energy is produced mostly by the oxidation of glucose to carbon dioxide and water. This notion is based on observations that cortical neuronal activity is lost within ~15 seconds of CBF interruption. A paradox that challenges this paradigm comes from Positron Emission Tomography studies, where glucose consumption was shown to exceed the oxygen consumption predicted by the stoichiometry of complete aerobic oxidation. Most of the brain’s grey matter energy is used to restore neuronal membrane potential that involves moving ions across against their concentration gradients. Therefore, Dr Devor and her team asked whether the ability of neurons to repolarise was lost within seconds of CBF interruption. Cortical neurons in the mouse brain, when repeatedly depolarised via light-controlled ion channels, continued to restore their membrane potential for over 20 minutes after a cardiac arrest. This observation suggests that neurons can utilise oxygen-independent mechanisms such as glycolysis, possibly not only upon asphyxia but also under normal physiological conditions.

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11:30-11:45 Discussion

11:45-12:15 The neurovascular unit in health and disease: lessons from animal models

Professor Costantino Iadecola, Weill Cornell Medicine, USA

Abstract

The concept of neurovascular unit (NVU) emerged from the first Stroke Progress Review Group meeting of the National Institutes of Health in the year 2000, to highlight the close developmental, structural and functional interactions between neurons, glia and the cerebral vasculature.The NVU concept emphasised the symbiotic relationship between brain cells and cerebral blood vessels in health and disease. Over the past 18 years, the NVU construct has evolved considerably. In addition to astrocytes, neurons, smooth muscle cells, and endothelium, new cell types have emerged as critical components of the NVU, such as pericytes and perivascular macrophages, etc. The extracellular matrix, matrix proteases and basement membranes (matrisome) constitute an integral part of the NVU. The NVU has also emerged as a guardian of innate and adaptive immune homeostasis and as a key regulator of the trafficking of immune cells in and out of the brain. New trophic interactions have been discovered between vascular cells and brain cells (neurons, astrocytes and oligodendrocytes), which are essential for brain survival and repair. Furthermore, the NVU is involved in the clearance of unwanted molecules from the brain and in proteostasis through the blood–brain barrier (transvascular pathway) or the perivascular space (peri- and para-vascular pathways). These critical functions of the NVU are impaired by vascular risk factors, eg, hypertension, by ageing and by pathological changes associated with Alzheimer’s disease. Consequently the NVU has taken centerstage in a wide variety of brain diseases, but particularly in conditions associated with cognitive impairment. This presentation will provide a brief overview of the structure and function of the NVU and of its critical role in brain function and cognitive health.

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12:15-12:30 Discussion

12:30-13:30

Lunch

Session 4 13:30-17:00

Sympathetic control

8 talks Show detail Hide detail

13:30-14:00 Role of cerebral conduit arteries in cerebral blood flow adjustments

Professor Kevin Shoemaker, University of Western Ontario, Canada

Abstract

This presentation will summarise Professor Shoemaker and his team’s efforts to study the dynamic properties of basal conduit artery dilation and constriction in health and disease with additional preliminary studies on endothelial contributions to their cross-sectional area. Understanding cerebral blood flow (CBF) control has benefited dramatically from the non-invasive method of transcranial Doppler ultrasound which offers high temporal resolution, providing information regarding cerebral perfusion pulsatility to rapid postural adjustments in overall flow. However, these data are obtained from the basal conduit arteries under the major assumption that these vessels express very little reactivity to dilatory or constrictor stimuli so that their cross-sectional area remains constant. In this view, changes in flow velocity relate well to changes in total CBF. However, new applications with ultrasound imaging as well as high field magnetic resonance imaging have provided detailed information emerged regarding the vasoactive properties of these large vessels and how they may have significant impact on cerebral vascular conductance and flow. The overall conclusion is that conduit arteries do express dose-related vasoactive properties and contribute to global CBF reactivity, but in a manner that changes with age and vascular disease.

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14:00-14:15 Discussion

14:15-14:45 Autonomic interactions with central nervous system blood flow regulation

Dr Aaron Phillips, University of Calgary, Canada

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14:45-15:00 Discussion

15:00-15:30 Tea

15:30-16:00 Integrated Control of Cerebral Blood Flow in Humans

Dr Can Ozan Tan, Harvard Medical School, Spaulding Rehabilitation Hospital, and Massachusetts General Hospital, USA

Abstract

No organ in the body is as dependent as the brain on steady supply of blood flow. Thus, the ability of cerebral vasculature to maintain stable blood flow in response to fluctuations in arterial gases and systemic blood pressure is critical to neural health. However, the utility of various experimental and analytic approaches to quantify cerebrovascular responses is still in dispute. Partly as a result, the nature and physiologic underpinnings of cerebrovascular control remain equivocal. For example, there is accumulating evidence for a role for autonomic nervous system in regulating cerebral blood flow. Moreover, recent evidence that autonomic neurogenic control may be responsible for homoeostatic maintenance of cerebral blood flow, and that myogenic control may be neuroprotective against ischaemia and haemorrhage from rapid swings in pressure. However, despite these data, specific aspects of this role remain unclear under debate. This talk will provide an overview of the recent work on different experimental and analytical approaches to understand cerebrovascular function, and on the impact of carbon dioxide–blood pressure interactions in shaping cerebral blood flow, with a particular emphasis on integrated neurogenic and regional control of the cerebral vasculature.

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16:00-16:15 Discussion

16:15-17:00 Panel discussion/Overview (future directions)

Integrated control of cerebral blood flow

Theo Murphy international scientific meeting organised by Professor Stephen Payne, Dr Clare Howarth, Professor Daniel Bulte and Professor Shieak Tzeng

Kavli Royal Society Centre, Chicheley Hall Newport Pagnell Buckinghamshire MK16 9JJ
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