Gulf War Illness (GWI) is a medically unexplained illness that is classified by two common case criteria including the CDC chronic multisymptom illness definition and Kansas GWI criteria. It occurred among veterans who served in the Persian Gulf War from August, 1990 to February, 1991. Because of its complex chronic symptoms and multiple potential causes the neuropathological mechanisms and/or successfully clinical treatments for it remain elusive. Those in the theater of this war experienced exposures to many neurotoxicants, suggesting an association between GWI and neurologic dysfunction. In order to better understand the underlying cause of GWI, we have chosen to explore cerebral blood flow. Our hypothesis is that abnormal cerebral blood flow is associated with GWI and ultimately neurological dysfunction. By conducting a comprehensive evaluation of cerebral blood flow we will be able to determine if it has a role in Gulf War Illness. Historically, several techniques have been used to measure cerebral blood flow. Arterial spin labeling (ASL) has been widely used in research as a non-invasive and non-ionizing technique, which has the least adverse effects on the participants. An ASL subtype called pseudo-continuous arterial spin labeling (PCASL) has become a favorable technique in ASL research because it combines the advantages of continuous arterial spin labeling (CASL) and pulsed arterial spin labeling (PASL). PCASL can quantify the absolute cerebral blood flow without the exogenous contrast agents. The cost of PCASL is relatively low as most scanner can run this sequence without additional hardware. It provides higher label efficiency (to CASL) and greater signal-to-noise ratio (to PASL). We utilized the data from an ongoing study with 114 GW veterans study participants aged from 42 to 80. Their regional cerebral blood flow was scanned using a 3T Philips Achieva MRI scanner. Asltoolbox (Wang et al., 2016) was used to calculate the cerebral blood flow, and Freesurfer v6.0 was used to do the co-registration and quantification. The analysis of demographic data suggested that the presence of hypertension was the only variables that made differences between control and GWI case groups (p = 0.02). General linear models indicated that alternations of cerebral blood flow were not a component of GWI at least using CMI definition. Whether cerebral blood flow associates with GWI is still pending on further studies with utilizing a more refined case definition.

Le flux sanguin cérébral (CBF) caractérise la micro-circulation et l'irrigation des tissus. Cette information de perfusion cérébrale est utilisé en clinique pour le diagnostic et le suivi thérapeutique de nombreuses maladies. La technique de mesure de CBF la moins invasive est celle par marquage de spins artériels (ASL) où l'eau du sang fait office de traceur. L'objectif de cette thèse, menée dans le cadre d'une convention CIFRE, consistait à faciliter l'utilisation de séquences ASL continues et pseudo-continues (CASL, pCASL) ainsi qu'à améliorer leur performance en pré-clinique. En effet, la mesure quantitative de CBF par ASL est un protocole complexe qui nécessite plusieurs étapes d'ajustements, d'acquisitions et de traitement de données. Dans le but d'alléger ce protocole, un package CASL a été développé en collaboration avec Bruker. Plusieurs étapes d'ajustements et de post-processing ont été automatisées, rendant la génération de cartes CBF relatives et absolues plus aisée. Le champ magnétique élevé des scanners IRM pré-cliniques présente de nombreux avantages mais est également une source de problèmes en ASL. Nous nous sommes intéressés plus particulièrement à deux d'entre eux : l'instabilité du marquage de spins et l'échauffement induit par les séquences ASL. Pour stabiliser le marquage ASL, une stratégie d'optimisation de la séquence pCASL a été développée et testée chez le rat à 9.4 T. Ceci a permis l'obtention d'un marquage robuste, même en situations de shim dégradé. Le package pCASL a été partagé avec dix autres instituts dans le monde. L'échauffement induit lors de séquences CASL et pCASL par le dépôt d'énergie radiofréquence a été caractérisé globalement et localement, dans le cerveau et au niveau des carotides, pour deux configurations d'antenne d'émission. Pour finir, une séquence pCASL encodée en temps a été développée et appliquée à la souris, dans le cadre d'une collaboration avec des équipes néerlandaises du Leiden University Medical Center. Cet outil permet la mesure simultanée de CBF et du temps de transit artériel, un paramètre pouvant refléter des pathologies vasculaires sous-jacentes. / Cerebral blood flow (CBF) characterizes the blood supply to brain tissue. This perfusion-related parameter contributes in diagnosis and therapeutic follow-up in many diseases. The least invasive technique to measure CBF is arterial spin labeling (ASL), where arterial water is used as tracer. The aim of this PhD project, conducted within a CIFRE agreement (Convention Industrielle de Formation par la REcherche), was to increase the performance and to facilitate the use of continuous and pseudo-continuous arterial spin labeling (CASL, pCASL) tools in preclinical studies. CBF quantification by means of ASL is one of the most challenging MRI modalities in terms of the workflow, since additional adjustments, acquisitions and post-processing steps are required. First, to render the workflow smoother for the user, a CASL package has been developed in collaboration with Bruker. This workflow allows easier relative and absolute CBF measurements, thanks to the integration of automated adjustments and reconstruction steps. In a second step, problems arising at high magnetic field were addressed. A strategy to optimize the pCASL labeling sequence in order to obtain robust results was developed and its robustness towards suboptimal shim conditions was demonstrated at 9.4 T in rats. The developed pCASL-package, consisting of three sequences, was shared with ten other institutes worldwide. Another issue encountered at high magnetic fields is heating due to RF power deposition, which was assessed locally in the brain and in the carotids, as well as globally, for the CASL and pCASL sequences and for two different transmit coil configurations. In a third step, time-encoded pCASL was developed in mice in collaboration with teams of the Leiden University Medical Center. This tool enables the simultaneous mapping of CBF and arterial transit time, a parameter that can reflect underlying pathologies such as increased vessel tortuosity or occlusion.

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Die zerebrale Perfusion ist eine wichtige physiologische Größe, die den Blutfluss in grauer bzw. weißer Hirnsubstanz beschreibt. Zur Perfusionsmessung in der klinischen Anwendung hat sich pseudo-kontinuierliches Arterielles Spin-Labeling (pCASL) als nichtinvasive Methode in der Magnetresonanzbildgebung etabliert. Das Anliegen der vorliegenden Arbeit ist es, pCASL zu charakterisieren und die Ursache für dessen Empfindlichkeit gegenüber intrinsischen Magnetfeldgradienten zu untersuchen. Anhand von Simulationen mit der Bloch-Gleichung konnten optimale Messparameter abgeleitet werden, um das Verfahren in dieser Hinsicht robuster zu machen. Die damit unabhängig von intrinsischen Magnetfeldgradienten bei 3\,T vorhergesagte hohe Labeling-Effizienz von 90\,\% wurde in vivo mittels eines eigens dafür entwickelten Messverfahrens experimentell validiert. / Cerebral perfusion is an important physiological parameter that describes the blood flow in brain tissue. To measure perfusion in a clinical setting, pseudo-continuous arterial spin labeling (pCASL) has been established as noninvasive method in magnetic resonance imaging. The purpose of this work is to characterize pCASL and to investigate its susceptibility to intrinsic magnetic field gradients. By simulations based on the Bloch equation, optimal parameter settings could be derived with particular focus on robustness against their impairing influence. As a result, a high labeling efficiency of 90\% was predicted independently of magnetic field gradients at 3\,T. This finding could finally be validated in vivo by a dedicated experimental approach.