The Circle of Willis (CoW) is a ring-like arterial structure forming the major anastomotic connection between arterial supply systems in the brain, and is responsible for the distribution of oxygenated blood throughout the cerebral mass. Among the general population, only approximately 50% have a complete CoW, where absent or hypoplastic vessels are common among a multitude of possible anatomical variations, reducing the degree to which blood may be rerouted. While an individual with one of these variations may under normal circumstances suffer no ill effects, there are certain pathological conditions which can present a risk to the person's health and increase the possibility of suffering an ischaemic stroke when compounded with an anatomical variation. This body of work presents techniques for generating 3D models of the cerebral vasculature using magnetic resonance imaging (MRI) and performing computational fluid dynamics (CFD) simulations in order to simulate the flow patterns throughout a circle of Willis. Incorporated with the simulations is a mathematical model of the cerebral autoregulation mechanism, simulating the ability of the smaller arteries and arterioles in the brain to either constrict or dilate in response to alterations in cerebral blood flow, thereby altering the cerebrovascular resistance of each major brain territory and regulating the amount of blood flow within a physiological range of cerebral perfusion pressure. The CFD simulations have the ability to predict the amount of collateral flow rerouted via the communicating arteries in response to a stenosis or occlusion, and the major objective of this study has been the investigation of how anatomical variations of the circle of Willis affect the capacity to provide this collateral flow. Initial work began with the development of three idealized models of common anatomical variations, created using computer aided design software (CAD) and based on the results of MRI scans. The research then shifted to developing a technique whereby patient specific models of the circle of Willis could be directly segmented from the MRI data. As a result of this shift, an interactive GUI-based tool was developed for the processing of the MRI datasets, allowing for rapid data enhancement and creation of a surface topology representing the arterial wall of the circle of Willis, suitable for a CFD simulation. The results of both sets of simulations illustrate that there exist a number of variables associated with a patients circle of Willis geometry, such as cerebral blood flow and combinations and degrees of stenosis, implying that the initial goal of drawing generalized conclusions was perhaps flawed. Instead, a crucial outcome of this body of work is that the future research should be directed toward extending the physiological complexity of both the geometry and the autoregulation model, with the intention of a patient specific application rather than producing large datasets with which to make broad generalizations.

Cardiovascular disease (CVD) is a progressive disease that presents signs, such as abnormal thickening or stiffening of arteries, early in its preclinical stage, and screening tools such as carotid intima media thickness (CIMT) measurement and pulse wave velocity (PWV) assessment have the potential to identify individuals prior to the clinical manifestation of CVD. The purpose of this study was to determine the prevalence of preclinical atherosclerosis, as indicated by high CIMT and PWV values, in an adult population aged 40-70 years and free of diagnosed CVD using these screening tools. Secondarily, this study aimed to compare established CVD risk factors and other health parameters between those with elevated or normal arterial health values. Sixty subjects made 2 visits to the Ball State University Human Performance Laboratory. The first visit included basic anthropometric measurements as well as assessment of CIMT and PWV. After a one week objective physical activity assessment, subjects returned to the HPL for assessment of blood lipids and body composition via dual energy x-ray absorptiometry scan. Prevalence of preclinical atherosclerosis was calculated from the total sample as well as within both genders, and an independent samples t-test was conducted in order to identify significant differences in health characteristics between those in the normal and high groups. Abnormal CIMT or PWV values were present in 43% of study subjects; 30% and 18% of the test sample met the criteria for elevated CIMT and PWV, respectively. Significant differences existed between normal and high CIMT and PWV study groups for physical activity, body composition, and blood lipid profile variables. Comparisons within each gender revealed differences in health profile elements. Both the CIMT and PWV measurement techniques may be valuable additions for community CVD screenings, as certain health profile abnormalities may impact each marker of arterial health differently. Additional research is needed in order to determine the cost-effectiveness of these screening tools as a preventive health method. / School of Physical Education, Sport, and Exercise Science

Contrast enhanced ultrasound offers a unique method to measure the blood flow, perfusion, vascular volume and morphology of microvascular networks. This is achieved by exploiting the ability of microbubble contrast agents to be disrupted and preferentially detected with contrast specific imaging techniques – using a method known as disruption-replenishment. In its current form, disruption-replenishment suffers from poor reproducibility and accuracy, largely due to the inappropriate application of a mono-exponential model of microbubble replenishment, and an incomplete understanding of the dependencies of the measurement. In this thesis, we hypothesize that disruption-replenishment measurements can be improved by applying a perfusion model that considers the physical elements of the measurement, including the haemodynamics and morphology of the vascular system, the ultrasound field distribution and microbubble properties. We present a flexible, theoretical framework to model microbubble replenishment within the microvasculature. The replenishment model is further developed by in vitro and in vivo validation, and clinical translation in a trial of anti-angiogenic therapy in patients, resulting in a proposed clinical protocol. The presented formalism was shown to be more robust and demonstrated better agreement of both fitting quality and estimates of flow velocity when compared to the established model (accuracy to within 3-9%). The reproducibility of repeated in vivo disruption-replenishment flow measurements was 11.9% using the proposed perfusion model compared to 24% using the established model. Variability of clinical perfusion measurements was also reduced with a method that discards the contribution of flow from larger arteries. Excluding the large vessel component in clinical measurements of tumour blood volume decreased the inter-plane variability by up to 20%. The proposed perfusion model can be used to generate parametric maps of vascularity through which additional quantitative parameters become available. These improvements will help translate the method of disruption-replenishment into routine clinical practice and clinical trials.

Contrast enhanced ultrasound offers a unique method to measure the blood flow, perfusion, vascular volume and morphology of microvascular networks. This is achieved by exploiting the ability of microbubble contrast agents to be disrupted and preferentially detected with contrast specific imaging techniques – using a method known as disruption-replenishment. In its current form, disruption-replenishment suffers from poor reproducibility and accuracy, largely due to the inappropriate application of a mono-exponential model of microbubble replenishment, and an incomplete understanding of the dependencies of the measurement. In this thesis, we hypothesize that disruption-replenishment measurements can be improved by applying a perfusion model that considers the physical elements of the measurement, including the haemodynamics and morphology of the vascular system, the ultrasound field distribution and microbubble properties. We present a flexible, theoretical framework to model microbubble replenishment within the microvasculature. The replenishment model is further developed by in vitro and in vivo validation, and clinical translation in a trial of anti-angiogenic therapy in patients, resulting in a proposed clinical protocol. The presented formalism was shown to be more robust and demonstrated better agreement of both fitting quality and estimates of flow velocity when compared to the established model (accuracy to within 3-9%). The reproducibility of repeated in vivo disruption-replenishment flow measurements was 11.9% using the proposed perfusion model compared to 24% using the established model. Variability of clinical perfusion measurements was also reduced with a method that discards the contribution of flow from larger arteries. Excluding the large vessel component in clinical measurements of tumour blood volume decreased the inter-plane variability by up to 20%. The proposed perfusion model can be used to generate parametric maps of vascularity through which additional quantitative parameters become available. These improvements will help translate the method of disruption-replenishment into routine clinical practice and clinical trials.

Purpose To investigate the impact of cigarrete smoking in a group of otherwise healthy young individuals on: 1) Retinal blood flow using Doppler based SD-OCT, 2) Retinal vascular reactivity using a gas sequencer to provoke hypercapnia via constant changes in PETCO2 (end-tidal partial pressure of CO2) and in PETO2 (end-tidal partial pressure of O2). Methods An automated gas flow controller was used to achieve normoxic hypercapnia in ten non-smokers (mean age 28.9 yrs, SD 4.58) and nine smokers (mean age 27.55 yrs, SD 4.77). Retinal blood flow measurements were obtained using Doppler OCT and cannon laser blood flowmeter (CLBF) during baseline, normoxic hypercapnia (15% increase in PETCO2 relative to homeostatic baseline) and post-hypercapnia in both the groups. Exhaled carbon monoxide level was measured in all subjects. Results In non-smokers, retinal arteriolar diameter, blood velocity and flow increased by +4.1% (SD 2.8, p<0.0001), +16.7% (SD 14.6, p=0.0004) and +29.6% (SD 12.5, p<0.0001) respectively, during normoxic hypercapnia; Similarly, the venous area, venous velocity and total retinal blood flow increased by 7% (SD 8.6, p=0.0418), 18.1% (SD 20.8, p=0.0068) and 26% (SD 22.9, p<0.0001) respectively. In smokers, normoxic hypercapnia resulted in a significant increase in velocity by 12.0% (SD 6.2, p=0.0019) and flow by 14.6% (SD 9.5, p=0.0029); though arteriolar diameter increased by 1.7% (SD 1.7, p=0.2616), the result was not statistically significant. Total retinal blood flow increased significantly by 19.3% (SD 18.4, p=0.002) in response to normoxic hypercapnia. However, there was no significant difference in venous area (p=0.3322) and venous velocity measurements (p=0.1185) during hypercapnia compared to baseline and recovery. Comparing smokers and non-smokers, only the percentage change in arteriolar diameter (p=0.0379) and flow (p=0.0101) was significantly different among the groups. Group mean PETCO2 was increased by 15.9% in the non-smoking group and by 15.7% in the smoking group, with a concomitant increase in PETO2 by approximately 1.5 to 2% in both groups. There was no significant difference in baseline PETCO2 level between smokers and non-smokers. Conclusions Retinal vascular reactivity in response to normoxic hypercapnia is significantly reduced in young healthy individuals who smoke compared to non-smokers. Further studies are needed to elucidate the exact reason behind the impaired retinal autoregulation to provocative stimuli in smokers.

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Bibliography: leaves 249-279. / xv, 279 leaves : ill. ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (Ph.D.)--The University of Adelaide, Dept. of Applied Mathematics, 1999

Diss. (sammanfattning) Göteborg : Göteborgs universitet, 2007. / Härtill 4 uppsatser.

Thesis (Ph.D.)--University of Melbourne, Dept. of Medicine, 2002. / Typescript (photocopy). Includes bibliographical references (leaves 308-353).

Thesis (M.S.)--Oregon State University, 2009. / Printout. Includes bibliographical references (leaves 157-161). Also available on the World Wide Web.