The liver is a multi-function organ that plays important roles in nutrient metabolism, biochemical transformations and blood detoxification. The purpose of the current work was to optimize Blood Oxygen Level Dependent (BOLD) liver functional MR imaging and analysis to allow the distinction between healthy volunteers and subjects with chronic liver disorders known to lead to fibrosis and reduced liver function (in this case, Hepatitis-C). Liver BOLD signal can be modulated by breathing 100% 0 2 or through intake of a meal. Previous results using these stimuli have been inconclusive when comparing healthy and diseased livers. In addition, liver BOLD analysis has been traditionally carried out using general linear models (GLM). Since the liver has a dual blood supply (portal and arterial derived), its resultant haemodynamic response is complex. This makes it too difficult to employ GLM approaches, as they require the prediction and modeling of a response function. We chose a model-free, or data-driven approach, called principle component analysis (PCA) to analyze liver data. Initial optimization was done by determining the time of maximal hepatic portal vein (HPV) blood flow following ingestion of a controlled meal (235 mL of Ensure Plus®). Statistically significant increases in HPV flow resulted at all measurement intervals, with the maximal postprandial change (71% increase in comparison to the baseline flow) at thirty minutes after ingestion. Implementing acquisition and analysis optimizations with our dual liver challenge model (hyperoxia cycling in pre- and postprandial states), the PCA approach was able to detect all of the diseased livers (n=6), while missing four of the healthy subjects (n=ll). The GLM technique, on the other hand, did not detect two of the patients and two of the healthy subjects. Thus, if this liver challenge is to be used as a screening tool, a model-free data analysis approach is suggested as more appropriate since it minimizes the chances of reporting false-negative results (based on this preliminary cohort). Although more false positives were detected with this method, it is of less concern seeing as these inaccuracies can be screened using simple blood tests. Promising results were obtained in this project, however, further studies using data-driven approaches such as partial least squares (PLS) are needed. / Thesis / Master of Science (MSc)

Adequate placental function is essential for the growth and development of a healthy fetus. A major cause of abnormal placental function is thought to occur from inadequate maternal spiral artery remodelling, leading to maternal vascular malperfusion (MVM) of the placenta and ultimately fetal growth restriction (FGR) and stillbirth due to uteroplacental hypoxia. Current methods of investigating a pregnancy at risk of FGR rely on ultrasound estimations of fetal size and Doppler studies. A more informative measure may be to quantify placental function in-vivo. Magnetic resonance imaging (MRI) has the ability to assess placental oxygen saturation (sO2), using Blood Oxygen-Level Dependent (BOLD), and the partial pressure of oxygen (pO2) using Oxygen-Enhanced MRI (OE MRI). These MRI techniques have been shown to correlate with gestation and poor pregnancy outcomes in cross sectional studies. MRI measures of placental oxygenation are hypothesised to be a potential antenatal tool for the identification and stratification of high risk pregnancies at risk of FGR related to uteroplacental hypoxia. To address this hypothesis changes in placental oxygenation, following maternal hyperoxia, were calculated in normal and FGR pregnancies in a cross sectional study. The change in placental oxygenation was reproduced longitudinally to determine if the rate of change differed between normal and FGR pregnancies. Baseline placental MRI parameters (R1 and R2*) and measures of the change in oxygenation were incorporated into a diagnostic model to identify FGR related to uteroplacental hypoxia, which was provisionally tested in a group of high risk pregnancies to demonstrate its potential clinical utility. Placental measures of baseline R1 and R2* were significantly increased in FGR pregnancies. The change in placental pO2 following hyperoxia was found to be significantly lower in FGR pregnancies. The change in pO2 declined similarly with gestation in both cross sectional and longitudinal studies, in normal and FGR pregnancies. There were no significant correlations in the change in placental sO2 with gestation or pregnancy outcome. The use of a diagnostic model combining baseline R1 and R2* and pO2 measures identified FGR with a high specificity, and provided additional information to aid in disease stratification and decision making in a significant proportion of the high risk pregnancies tested. In conclusion, MRI parameters of placental pO2 following hyperoxia are significantly lower in FGR pregnancies, in keeping with the concept of uteroplacental hypoxia. MRI techniques show promise in the identification of FGR pregnancies related to MVM through measures of placental function, irrespective of fetal size, and may aid in the disease stratification of high risk pregnancies.

Cerebral autoregulation is an intrinsic physiological response that maintains a constant cerebral blood flow (CBF) despite dynamic changes in the systemic blood pressure. Autoregulation is achieved through changes in the resistance of the small blood vessels in the brain through reflexive vasodilatation and vasoconstriction. Cerebrovascular reactivity (CVR) is a measure of this response. CVR is defined as a change in CBF in response to a given vasodilatory stimulus. CVR therefore potentially reflects the vasodilatory reserve capacity of the cerebral vasculature to maintain a constant cerebral blood flow. A decrease in CVR (which is interpreted as a reduction in the vasodilatory reserve capacity) in the vascular territory downstream of a larger stenosed supply artery correlates strongly with the risk of a hemodynamic stroke. As a result, the use of CVR studies to evaluate the state of the cerebral autoregulatory capacity has clinical utility. Application of CVR studies in the clinical scenario depends on a thorough understanding of the normal response. The goal of this thesis therefore was to map CVR throughout the brain in normal healthy individuals using Blood Oxygen Level Dependant functional Magnetic Resonance Imaging (BOLD MRI) as an index to CBF and precisely controlled changes in end-tidal partial pressure of carbon dioxide (PETCO2) as the global flow stimulus.

Cerebral autoregulation is an intrinsic physiological response that maintains a constant cerebral blood flow (CBF) despite dynamic changes in the systemic blood pressure. Autoregulation is achieved through changes in the resistance of the small blood vessels in the brain through reflexive vasodilatation and vasoconstriction. Cerebrovascular reactivity (CVR) is a measure of this response. CVR is defined as a change in CBF in response to a given vasodilatory stimulus. CVR therefore potentially reflects the vasodilatory reserve capacity of the cerebral vasculature to maintain a constant cerebral blood flow. A decrease in CVR (which is interpreted as a reduction in the vasodilatory reserve capacity) in the vascular territory downstream of a larger stenosed supply artery correlates strongly with the risk of a hemodynamic stroke. As a result, the use of CVR studies to evaluate the state of the cerebral autoregulatory capacity has clinical utility. Application of CVR studies in the clinical scenario depends on a thorough understanding of the normal response. The goal of this thesis therefore was to map CVR throughout the brain in normal healthy individuals using Blood Oxygen Level Dependant functional Magnetic Resonance Imaging (BOLD MRI) as an index to CBF and precisely controlled changes in end-tidal partial pressure of carbon dioxide (PETCO2) as the global flow stimulus.

In der vorliegenden Arbeit wurde durch die Kombination zweier nichtinvasiver MR-Methoden in vivo untersucht, ob sich die funktionelle Sprachlateralisierung in einer strukturellen Asymmetrie der weißen Substanz widerspiegelt. Dafür wurden die Ergebnisse einer Patientengruppe mit Temporallappenepilepsie mit den Ergebnissen einer gesunden Kontrollgruppe verglichen. Es konnte gezeigt werden, dass mittels BOLD MRT eine Sprachlateralisierung in der grauen Substanz nachgewiesen werden kann, die mit einem strukturellen Korrelat in der weißen Substanz der sprachdominanten Hemisphäre einhergeht. Dieses Korrelat konnte als Asymmetrie der Mikrostruktur der weißen Substanz in DTI-Messungen belegt werden. Darüber hinaus konnte bewiesen werden, dass Patienten mit einer Temporallappenepilepsie im Vergleich zu gesunden Probanden eine atypische Lateralisierung der Sprachaktivierung im Broca-Areal aufweisen, die von einer gleichsinnig atypischen strukturelle Asymmetrie der weißen Substanz im Broca-Areal begleitet wird. Die These, dass eine funktionelle Sprachlateralisierung mit einer mikrostrukturellen Veränderung der weißen Substanz assoziiert ist, wird durch die vorliegende Arbeit sowohl für die gesunden Kontrollprobanden als auch für die Patienten mit einer fokalen Epilepsie bestätigt. Die Ergebnisse der vorliegenden Arbeit zeigen, dass DTI-Messungen eine sinnvolle Ergänzung zu BOLD MRT-Messungen in der Bestimmung der sprachrelevanten Areale darstellen können. Sprachlateralisierung könnte mit ihrer Hilfe in Zukunft exakt und nichtinvasiv bestimmt werden. Es stellte sich jedoch auch heraus, dass das in der vorliegenden Arbeit angewendete Verfahren in der Praxis sehr aufwendig ist, ohne eine entschieden höhere Aussagekraft über die Sprachlateralisierung zu erbringen. In dieser Form wird die nichtinvasive Bildgebung den Wada-Test als Goldstandard für den klinischen Alltag noch nicht ersetzen können.