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.

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.

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.

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.

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.

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.

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.