The current work investigated the stimulation induced spatial response of the cerebral microvascular network by reconstruction of the 3D microvascular morphology from in vivo two photon fluorescence microscopy (2PFM) volumes using an automated, model based tracking algorithm. In vivo 2PFM imaging of the vasculature in the forelimb representation of the primary somatosensory cortex of alpha-chloralose anesthetized rats was achieved via implantation of a closed cranial window, and intravascular injection of fluorescent dextran. The dilatory and constrictory responses of the cerebral microvascular network to functional stimulation were heterogeneous and depended on resting vascular radius and response latency. Capillaries experienced large relative dilations and constrictions, but the larger vessel absolute volume changes dominated the overall network cerebral blood volume change.

The current work investigated the stimulation induced spatial response of the cerebral microvascular network by reconstruction of the 3D microvascular morphology from in vivo two photon fluorescence microscopy (2PFM) volumes using an automated, model based tracking algorithm. In vivo 2PFM imaging of the vasculature in the forelimb representation of the primary somatosensory cortex of alpha-chloralose anesthetized rats was achieved via implantation of a closed cranial window, and intravascular injection of fluorescent dextran. The dilatory and constrictory responses of the cerebral microvascular network to functional stimulation were heterogeneous and depended on resting vascular radius and response latency. Capillaries experienced large relative dilations and constrictions, but the larger vessel absolute volume changes dominated the overall network cerebral blood volume change.

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Microvascular lesions of the brain are observed in numerous pathological conditions including Alzheimer's disease (AD). Regional patterns of microvascular abnormality can be characterized using current neuroimaging technologies. When applied to mouse models of human disease, these technologies reveal cerebral vascular patterns and help uncover genotype-to-phenotype relationships. This thesis focuses on the development and testing of techniques for measuring two perfusion-related metrics in mouse brain regions, namely, cerebral blood volume (CBV) and cerebral blood flow (CBF) using micro-computed tomography (micro-CT) and arterial spin labeling (ASL), respectively. The main developments for measurement of CBV have included: refinements to micro-CT specimen preparation; registration of micro-CT images to an MRI anatomical brain atlas; and masking of major vessels to calculate small-vessel CBV (sv-CBV). The development of this micro-CT technique provided reference values of CBV over neuroanatomical brain regions in wildtype mice. A separate study was conducted to assess regional sv-CBV in a mouse model of AD; this study was motivated by the prevalence of microvascular lesions in patients who suffer from AD. Significant regional differences in sv-CBV were found between AD-afflicted mice and controls. The main developments for measurement of CBF have included: design and implementation of accurate ASL slice positioning and optimization of inversion efficiency parameters. The development of this ASL technique provided reference values of CBF over neuroanatomical brain regions in wildtype mice. These techniques for measuring CBV and CBF over mouse brain regions could lead to improved characterization of vascularity in models of neurological diseases.

Microvascular lesions of the brain are observed in numerous pathological conditions including Alzheimer's disease (AD). Regional patterns of microvascular abnormality can be characterized using current neuroimaging technologies. When applied to mouse models of human disease, these technologies reveal cerebral vascular patterns and help uncover genotype-to-phenotype relationships. This thesis focuses on the development and testing of techniques for measuring two perfusion-related metrics in mouse brain regions, namely, cerebral blood volume (CBV) and cerebral blood flow (CBF) using micro-computed tomography (micro-CT) and arterial spin labeling (ASL), respectively. The main developments for measurement of CBV have included: refinements to micro-CT specimen preparation; registration of micro-CT images to an MRI anatomical brain atlas; and masking of major vessels to calculate small-vessel CBV (sv-CBV). The development of this micro-CT technique provided reference values of CBV over neuroanatomical brain regions in wildtype mice. A separate study was conducted to assess regional sv-CBV in a mouse model of AD; this study was motivated by the prevalence of microvascular lesions in patients who suffer from AD. Significant regional differences in sv-CBV were found between AD-afflicted mice and controls. The main developments for measurement of CBF have included: design and implementation of accurate ASL slice positioning and optimization of inversion efficiency parameters. The development of this ASL technique provided reference values of CBF over neuroanatomical brain regions in wildtype mice. These techniques for measuring CBV and CBF over mouse brain regions could lead to improved characterization of vascularity in models of neurological diseases.

Le couplage neuro-vasculaire est un domaine grandissant. Ce dernier étudie les effets de l’activité cérébrale sur le comportement du flux sanguin cérébral (cerebral blood flow, CBF) et sur le flux des vaisseaux sanguins. Avec l’aide de l’imagerie par résonance magnétique (IRM), il est possible d’obtenir des images comme les images pondérées par susceptibilité (susceptibility weighted imaging, SWI) pour voir les veines ou bien avec des images de temps de vol par angiographie (time-of-flight magnetic resonance angiography, TOF MRA) pour imager les artères. Ces images permettent d’avoir une représentation structurelle des vaisseaux dans le cerveau. Ce mémoire présente une méthode permettant la segmentation des vaisseaux sanguins à partir d’images structurelles afin d’en extraire les caractéristiques. En utilisant le masque de segmentation, il est possible de calculer le diamètre des vaisseaux ainsi que leur longueur. Avec l’aide de tels outils de segmentation automatique, nous avons conduit une étude permettant d’analyser le comportement des vaisseaux sanguins lors d’activités neuronales. Grâce à une stimulation visuelle, nous avons fait l’acquisition de deux images; la première dite au repos et la seconde avec stimulation. Nous avons pu comparer le diamètre dans chacune des images et ainsi obtenir la vasodilatation en millimètre, mais également en pourcentage, et cela pour chaque voxel. Nous avons également calculé la distance entre le site d’activation et un voxel pour observer l’amplitude de la vasodilatation en fonction de la distance. Tout ceci permet d’avoir une meilleure compréhension du système vasculaire du cerveau humain. / Abstract : The neurovascular coupling is a growing field; it studies the effects of cerebral activity on the behaviour of cerebral blood flow (CBF) and the blood vessels themselves. With the help of magnetic resonance imaging (MRI), it is possible to obtain images such as susceptibility weighted imaging (SWI) to see the veins or time-of-flight magnetic resonance angiography (TOF MRA) to visualize the arteries. These images allow having a structural representation of vessels in the brain. This thesis presents a method to segment blood vessels from structural images and extract their features. Using the segmentation mask, it is possible to calculate the diameter of the vessels as well as their length. With the help of such automatic segmentation tools, we conducted a study to analyze the behaviour of blood vessels during neuronal activities. Due to visual stimulation, we have acquired two images; one at rest and the other with stimulation. We compare the diameter in each of the images and obtain vasodilation in millimeters, but also as a percentage in each voxel. We also calculated the distance between the activation site and each voxel to see the magnitude of the vasodilation function of the distance. All this provides a better understanding of the vascular system of the human brain.

Functional magnetic resonance imaging (fMRI) based on blood oxygenation level dependent (BOLD) contrast has become a universal methodology in functional neuroimaging. However, the BOLD signal consists of a mix of physiological parameters and has relatively poor reproducibility. As fMRI becomes a prominent research tool for rehabilitation studies involving repeated measures of the human brain, more quantitative and stable fMRI contrasts are needed. This dissertation enhances quantitative measures to complement BOLD fMRI. These additional markers, cerebral blood flow (CBF) and cerebral blood volume (CBV) (and hence cerebral metabolic rate of oxygen (CMRO₂) modeling) are more specific imaging markers of neuronal activity than BOLD. The first aim of this dissertation assesses feasibility of complementing BOLD with quantitative fMRI measures in subjects with central visual impairment. Second, image acquisition and analysis are developed to enhance quantitative fMRI by quantifying CBV while simultaneously acquiring CBF and BOLD images. This aim seeks to relax assumptions related to existing methods that are not suitable for patient populations. Finally, CBF acquisition using a low-cost local labeling coil, which improves image quality, is combined with simultaneous acquisition of two types of traditional BOLD contrast. The demonstrated enhancement of CBF, CBV and CMRO₂measures can lead to better characterization of pathophysiology and treatment effects.

Zielsetzung In den Industrieländern stellt der Schlaganfall nach kardiovaskulären und Krebs – erkrankungen die dritthäufigste Krankheitsgruppe dar. Im Hinblick auf die Therapie des akuten Schlaganfalls muss die bildgebende Diagnostik schnell und einfach das Ausmaß der zerebralen Ischämie beschreiben können. Ziel dieser Studie war die Einführung und die Validierung eines CT – Protokolls, welches die Diagnostik des akuten Schlaganfalls verbessern soll. Zu diesem CT – Protokoll gehören ein Nativ – CT des Schädels, eine CT – Perfusionsuntersuchung und eine CT – Angiographie. Zusätzlich wollte diese Arbeit herausfinden, ob es physiologische Unterschiede zwischen der grauen Substanz und der weißen Substanz gibt, deren Kenntnis entscheidend für die Auswertung von computertomographischen Perfusionsuntersuchungen sind. Material und Methoden Insgesamt wurden 101 Patienten (Alter von 14 – 94 Jahre, mittleres Alter 69 Jahre) mit einem 8 – bzw. 16 – Zeilen – MSCT (Light Speed Ultra oder Light Speed pro 16, GE Healthcare), die zur Abklärung einer zerebralen Ischämie zum CT vorgestellt wurden, untersucht. Zuerst wurde eine native CT – Serie akquiriert. In der Untersuchung der zerebralen Perfusion wurde eine 2 cm breite Schicht über 60 sec mit 20 intermittierenden Aufnahmen während einer Injektion von 40 ml Kontrastmittel (Iopromid, Jodgehalt von 370 mg) aufgezeichnet. Daran an schloss sich eine CT – Angiographie Untersuchung. Zur Bestimmung des regionalen zerebralen Blutflusses, des regionalen zerebralen Blutvolumens und der mittleren Verweildauer wurden definierte Messfelder (Regions of Interests, ROIs) bestimmt und mit der kontralateralen Hemisphäre verglichen. Ergebnisse Es konnte gezeigt werden, dass der regionale zerebrale Blutfluss und das Blutvolumen im Bereich der Hirnrinde höher sind als im Hirnmark. Insgesamt wurden 66 Patienten mit einer zerebralen Ischämie wurden gefunden. Bei 22 dieser Patienten konnte ein Infarktgeschehen in der Nativ – CT diagnostiziert werden. Diese Ischämien ließen sich auch in der CT – Perfusion mit reduziertem regionalem zerebralem Blutfluss und verlängerter mittlerer Verweildauer nachweisen. Zusätzlich fanden sich 44 Patienten von 101 Untersuchten, die in der CT – Perfusion ein Perfusionsdefizit aufwiesen. Bei diesen Patienten ließ sich kein entsprechendes Korrelat in der Nativ – CT nachweisen. Für 38 dieser 44 Patienten konnte eine CTA durchgeführt werden, wovon für 35 Patienten ein Korrelat zwischen der CT – Perfusion und der CTA gefunden werden konnte. Schlussfolgerung Die Ergebnisse dieser Arbeit zeigen, dass es physiologische Unterschiede zwischen der Hirnrinde und dem Hirnmark gibt, deren Kenntnis für die Bewertung computertomographischer Perfusionsuntersuchungen eine wesentliche Interpretationshilfe darstellt. In Bezug auf die Diagnostik des akuten Schlaganfalls mit der Nativ – CT konnte diese Arbeit zeigen, dass der Nachweis von Infarktfrühzeichen eingeschränkt ist. Mit Hilfe der CT – Perfusion ist es möglich, anhand von zerebralen Perfusionswerten den Schweregrad und die Ausdehnung der zerebralen Ischämie zu bestimmen. Die CT – Angiographie zeigt eine gute Korrelation zur CT – Perfusion, es lassen sich zuverlässig Gefäßverschlüsse darstellen. Im Hinblick auf das weitere Therapievorgehen geben diese Methoden eine wichtige Hilfestellung, etwa zur Überlegung, ob man eine Lysetherapie durchführen sollte oder nicht. / Purpose Stroke is the third – leading cause of death in developed countries, following cardiovascular disease and cancer. There is a need for an easily and rapidly performed technique to detect cerebral ischemia in the first hours after its occurrence. The purpose of this study was the introduction and validation of a Stroke protocol which includes an unenhanced CT scan, a CT Perfusion and a CT Angiography. Furthermore, the purpose of this study was to determine if there is a difference between Perfusion parameters in gray and white matter, which are necessary to know while performing perfusion maps. Data and Methodology A total of 101 patients (age range 14 – 94, average age 69 years) were examined using multiple row CT (8 / 16 row multiple detector, light ultra speed or light speed 16, GE medical systems) for diagnosing cerebral ischemia. First a series of native images was acquired. During the examination of cerebral perfusion a 2 cm wide slab was recorded for 60 sec with 20 intermittent scans following injection of 40 ml of contrast medium with an iodine content of 370 mg / ml. By defining Regions of Interests (ROIs) regional cerebral blood flow (CBF), regional cerebral blood volume (CBV) and mean transit time (MTT) were calculated. Results Physiological regional cerebral blood flow and cerebral blood volume in gray matter were higher than in white matter. In total 66 patients with a cerebral ischemia were found. The unenhanced CT detected 22 patients with cerebral ischemia, which were confirmed by CT Perfusion in all cases. These ischemic areas revealed reduced regional CBF and extended MTT. Furthermore an ischemia correlative was discovered by perfusion analysis for 44 patients (out of 101 investigated) where the extent of the cerebral ischemia had not been visible by unenhanced CT. For 38 out of 44 patients with cerebral ischemia we were able to perform a CTA. For 35 out of these 38 patients, we found a sizable correlation between perfusion maps and CTA. Conclusion There are physiological differences for CT Perfusion parameters between gray and white matter, which are necessary to know for the interpretation of perfusion maps. However, this examination was able to show that unenhanced CT is not always capable of showing early CT signs. With the help of CT perfusion it is possible to detect the extent of acute cerebral ischemia. Furthermore, CT Angiography shows a sizable correlation compared to CT Perfusion. In conjunction, these methods give important Information for the early diagnosis and the therapeutic strategy of ischemic brain injury.