The cerebral tissue requires a constant supply of oxygen and nutrients. This is maintained through delivering a constant supply of blood. The delivery of sufficient blood is preserved by the cerebral vasculature and its autoregulatory function. The cerebral vasculature is composed of the Circle of Willis (CoW), a ring-like anastomoses of arteries at the base of the brain, and its peripheral arteries. However, only 50% of the population have a classical complete CoW network. This implies that the route of blood flow through the cerebral vasculature is different and dependent on where the blood is needed most in the brain. Autoregulation is a mechanism held by the peripheral arteries and arterioles downstream of the CoW. It ensures the delivery of the essential amount of cerebral blood flow despite changes in the arterial perfusion pressure, through the vasoconstriction and vasodilation of the vessels. The mechanisms that control the vessels’ vasomotion could be attributed to myogenic, metabolic, neurogenic regulation or a combination of all three. However, the variations in the CoW structure, combined with different pathological conditions such as hypertension, a stenosis or an occlusion in one or more of the supplying cerebral arteries may alter, damage or abolish autoregulation, and consequently result in a stroke. Stroke is the most common cerebrovascular disease that affects millions of people in the world every year. Therefore, it is essential to understand the cerebral hemodynamics via mathematical modelling of the cerebral vasculature and its regulation mechanisms. This thesis presents the developed model of the cerebral vasculature coupled with the different forms of autoregulation mechanisms. The model was developed over multiple stages. First, a linear model of the CoW was developed, where the peripheral vessels downstream of the CoW efferent arteries are represented as lumped parameter variable resistances. The autoregulation function in the efferent arteries was modelled using a PI controller, and a metabolic model was added to the lumped peripheral variable resistances. The model was then modified so the pressure losses encountered at the CoW bifurcations, and the vessels’ tortuosity are taken into account resulting in a non-linear system. A number of cerebral autoregulation models exist in the literature, however, no model combines a fully populated arterial tree with dynamic autoregulation. The final model presented in this thesis was built by creating an asymmetric binary arterial vascular tree to replace the lumped resistance parameters for the vasculature network downstream of each of the CoW efferent arteries. The autoregulation function was introduced to the binary arterial tree by implementing the myogenic and metabolic mechanisms which are active in the small arteries and arterioles of the binary arterial tree. The myogenic and metabolic regulation mechanisms were both tested in the model. The results indicate that because of the low pressures experienced by the arterioles downstream of the arterial tree, the myogenic mechanism, which is hypothesised by multiple researchers as the main driver of autoregulation, does not provide enough regulation of the arterioles’ diameters to support autoregulation. The metabolic model showed that it can provide sufficient changes in the arterioles’ diameters, which produces a vascular resistance that support the constancy of the autoregulation function. The work carried out for this research has the potential of being a significant clinical tool to evaluate patient-specific cases when combined with the graphical user interfaces provided. The research and modelling performed was done as part of the Brain Group of the Centre of Bioengineering at the University of Canterbury.

Altered cerebral hemodynamics contributes to mechanisms of unexplained syncope. Wecompared dynamic interaction between respiration and cerebral autoregulation in two groups ofsubjects from 28 healthy adults. Based on development of tilt-induced presyncope, subjects wereclassified as Non-Presyncopals (n=23) and Presyncopals (n=5). Airflow, CO2, Doppler cerebralblood flow velocity (CBF), ECG and blood pressure (BP) were recorded. To determine whetherinfluences of mean BP (MBP) and systolic BP (SBP) on CBF were altered in Presyncopals, thecoherencies and transfer functions between these variables and mean and peak CBF (CBFm andCBFp) were estimated. To determine influence of end-tidal CO2 (ETCO2) on CBF, relative CO2reactivity was calculated. The two primary findings were, during tilt in Presyncopals: (1) Inrespiratory frequency region, coherence between SBP and CBFp (p=0.02) and transfer functiongain between BP and CBFm was higher (MBP, p=0.01, and SBP, p=0.01) than in Non-Presyncopals. (2) In the last 3 minutes prior to presyncope, Presyncopals had a reduced relativeCO2 reactivity (p=0.005). Thus the relationship of CBF with systemic BP was more pronouncedor cerebral autoregulation was less effective preceding presyncope. This decreasedautoregulation, secondary to decreased ETCO2, may contribute in the cascade of events leadingto unexplained syncope.

La pratique régulière d’une activité physique (AP) est un important message de santé publique. L’AP améliore non seulement la santé cardiovasculaire via l’augmentation de la production de NO (nitric oxide) par l’endothélium vasculaire mais aussi la santé cérébrale via l’augmentation des taux de BDNF (brain-derived neurotrophic factor) dans le cerveau. Comme la synthèse et la sécrétion de BDNF sont proportionnelles à l’activité neuronale, il est généralement admis que l’élévation des taux cérébraux de BDNF induite par l’AP est à relier à l’hyperactivité neuronale. Nous avons testé l’hypothèse selon laquelle l’élévation du flux sanguin dans les vaisseaux de la circulation cérébrale pendant la réalisation de l’AP contribue à augmenter les taux cérébraux de BDNF. Les expériences ont été menées chez des rats soumis ou non à l’AP (tapis roulant). Nos résultats montrent : 1) que l’augmentation des taux de BDNF induite par l’AP (tapis roulant, 18m/min, 30 min/j, 7j consécutifs) est moindre lorsque l’augmentation du flux sanguin pendant la réalisation de l’AP, est prévenue par un clampage mono- ou bi- carotidien, 2) que l’effet de l’AP sur les taux de BDNF dépend de l’intensité de l’AP ( tapis horizontal versus déclive descendant), 3) que la dysfonction endothéliale (modèle de rat spontanément hypertendu) et le traitement par un inhibiteur de NO synthase diminuent les effets de l’AP sur les taux cérébraux de BDNF et 4) qu’il existe une association positive entre les taux cérébraux de BDNF et la production de NO par l’endothélium vasculaire.L’ensemble de nos résultats suggère que l’augmentation des taux cérébraux de BDNF induite par l’AP met en jeu l’augmentation du flux sanguin dans les vaisseaux de la circulation cérébrale et, plus précisément, l’augmentation de la production endothéliale de NO qui en résulte. Ils fournissent de nouvelles données pour comprendre le lien existant entre fonction endothéliale et performances cognitives, soulevant l’idée selon laquelle les modalités d’AP pour améliorer la santé cérébrale doivent être différentes en cas de pathologies associées à une dysfonction endothéliale. / The regular practice of physical activity (PA) is an important public health message. PA not only improves cardiovascular health through the increase in NO (nitric oxide) production by the vascular endothelium but also through the increase levels in brain BDNF (brain-derived neurotrophic factor) levels. As the synthesis and secretion of BDNF are proportional to neuronal activity, it is generally accepted that PA-induced brain BDNF levels elevation is linked to neuronal hyperactivity. We tested the hypothesis that the increase in blood flow in cerebrovasculature during PA contributes to increase brain BDNF levels. The experiments were carried out in sedentary and trained rats (treadmill). Our results show that: 1) brain BDNF levels elevation induced by PA (treadmill, 18m /min, 30 min /day, 7 consecutive days) is lower when the normal rise of cerebral blood flow during the PA is prevented by occluding one or both common carotid arteries, 2) the effect of PA on brain BDNF levels is dependent on PA intensity (horizontal versus downhill), 3) the presence of endothelial dysfunction (spontaneously hypertensive rat model) as well as NO synthase inhibition decrease the effects of PA on brain BDNF levels and 4) there is a positive association between brain BDNF levels and vascular endothelium NO production .Collectively, our results suggest that increase in brain BDNF levels, induced by PA, involves increase in cerebrovasculature blood flow and more precisely elevation in endothelium NO production. They provide new data for understanding the relationship between endothelial function and cognitive performance, raising the idea that PA modalities to improve brain health might be different in pathologies diseases with endothelial dysfunction.

Background: To assess acute effects of bevacizumab (anti-VEGF therapy) on cerebral microvessels and systemic cardiovascular regulation. Design and subjects: 20 consecutive patients with colorectal cancer (median age: 60.4 years, range 45.5-73.9 years) received bevacizumab intravenously (5 mg/kg) uncoupled of chemotherapy. Prior to and within the first 24 hours after bevacizumab infusion, patients were investigated for retinal endothelial function. A series of a triple 24-hour ambulatory blood pressure measurement was conducted. Retinal endothelial function was determined as flicker light-induced vasodilation. The integrity of baroreflex arc and autonomic cardiovascular control was examined by stimulatory manoeuvres. Results: Bevacizumab therapy significantly reduced the vasodilatory capacity of retinal arterioles in response to flicker light. A slight decrease in diastolic pressure and heart rate was observed after bevacizumab infusion but this was unrelated to changes in retinal function. The pressure response upon nitroglycerin was largely preserved after bevacizumab infusion. The proportion of patients with abnormal nocturnal blood pressure regulation increased under anti-angiogenic therapy. Autonomic blood pressure control was not affected by bevacizumab treatment. Conclusions: Bevacizumab acutely impairs microvascular function independent of blood pressure changes. Imaging of the retinal microcirculation seems a valuable tool for monitoring pharmacodynamic effects of bevacizumab.

Background: To assess acute effects of bevacizumab (anti-VEGF therapy) on cerebral microvessels and systemic cardiovascular regulation. Design and subjects: 20 consecutive patients with colorectal cancer (median age: 60.4 years, range 45.5-73.9 years) received bevacizumab intravenously (5 mg/kg) uncoupled of chemotherapy. Prior to and within the first 24 hours after bevacizumab infusion, patients were investigated for retinal endothelial function. A series of a triple 24-hour ambulatory blood pressure measurement was conducted. Retinal endothelial function was determined as flicker light-induced vasodilation. The integrity of baroreflex arc and autonomic cardiovascular control was examined by stimulatory manoeuvres. Results: Bevacizumab therapy significantly reduced the vasodilatory capacity of retinal arterioles in response to flicker light. A slight decrease in diastolic pressure and heart rate was observed after bevacizumab infusion but this was unrelated to changes in retinal function. The pressure response upon nitroglycerin was largely preserved after bevacizumab infusion. The proportion of patients with abnormal nocturnal blood pressure regulation increased under anti-angiogenic therapy. Autonomic blood pressure control was not affected by bevacizumab treatment. Conclusions: Bevacizumab acutely impairs microvascular function independent of blood pressure changes. Imaging of the retinal microcirculation seems a valuable tool for monitoring pharmacodynamic effects of bevacizumab.