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Emphysema is a condition of the lung characterized by abnormal, permanent enlargement of the airspaces distal to the terminal bronchiole, accompanied by a destruction of their walls. The primary pathogenesis of emphysema is poorly understood. One of the major issues of COPD is that no diagnostic tests are sensitive enough to detect early disease. Standard pulmonary function tests (PFTs) do not explain the underlying pathophysiology of airflow limitation, nor do they provide information on how COPD may be affecting pulmonary blood flow. Functional imaging, specifically ventilation and perfusion (V/Q) Single Photon Emission Computed Tomography (SPECT), is a sensitive tool that can provide information on pulmonary function in different lung regions. When V/Q images are co-registered to CT, regional analysis can be coupled to structural information. The objective of this study was to examine how emphysematous change identified and localized by CT density based thresholds affects lung function as measured by V/Q SPECT in a mouse model of the disease. A dose response study was conducted where Female BALB/c mice were exposed intranasally to 0.0, 0.5, 2.5 and 5.0 units (U) of porcine pancreatic elastase (PPE). V/Q SPECT/CT scanning was performed 45 days post exposure, followed by measurement of lung compliance using the Flexivent® rodent ventilator 46 days post exposure. Whole lung slice analysis software was used to quantify airspace enlargement and alveolar capillary density from histological sections of the lung. CT pulmonary angiography (CTPA) was also performed on controls and mice exposed to 5 U PPE to examine vascular density. In this mouse model of emphysema, V/Q SPECT was useful in quantitatively examining how ventilation and perfusion is affected in mild and severe emphysema while providing evidence of low log(V/Q) ratio in otherwise normal lung densities. This could be caused by airflow obstruction as a result of widespread narrowing or loss of small conducting airways. Low log(V/Q) ratio is caused by mild emphysema indicating airflow obstruction or dysfunctional hypoxic vasoconstriction in underventilated regions of the lung. The majority of severely emphysematous regions of the lung have matched but equally reduced log(V/Q), although low log(V/Q) is also present. Pulmonary hypertension in response to chronic hypoxia may explain our finding of reduced perfusion activity and vascular density in emphysematous lung, but further research is required to investigate the presence of this pathology. V/Q SPECT was also shown to be superior in the detection of emphysema compared to CT and Flexivent measured lung compliance providing evidence towards shifting the current assessment and monitoring paradigms. Due to the widespread availability of this imaging technique, it could be used to screen asymptomatic smokers for early disease and identify and locate pathology so therapies targeting the appropriate disease pathway can be prescribed. This will inevitably improve patient care. / Thesis / Master of Science (MSc)

Yes

L'imagerie par résonance magnétique (IRM) à haut champ offre un bénéfice certain en rapport signal-sur-bruit. De ce fait, les imageurs à 3T sont souvent utilisés en pratique clinique.Cependant, à haut champ, les images d'IRM sont entachées de pertes de signal et de contraste liées à la baisse de la longueur d’onde radiofréquence (RF) en deçà des dimensions de l'objet irradié. A 3T, où la longueur d'onde est de 30 cm environ dans les tissus humains, de tels artéfacts sont fréquents en imagerie abdominale, des seins ou encore des cuisses, ce qui peut expliquer la difficulté que rencontre l'IRM à haut champ à s'imposer comme référence dans les hôpitaux. Les imageurs 3T les plus récents disposent en général d'un système de transmission parallèle à deux canaux RF. Chaque canal peut en principe émettre des formes d'impulsion RF indépendantes. En pratique, sur la plupart des systèmes IRM cliniques, la méthode dite de shim RF statique est utilisée. Les différents canaux transmettent la même forme d’onde,en ajustant amplitude et phase de sorte à entraîner des motifs d’interférences pour contrer les inhomogénéités, mesurées au préalable sur le patient: cartes de champ RF et éventuellement de champ statique. Cette méthode fonctionne d’autant mieux qu’un grand nombre de canaux est disponible, mais montre ses limites lorsqu’il s’agit d’homogénéiser l’excitation sur un grand champ de vue. La méthode des points kT, développée à NeuroSpin pour l’IRM cérébrale à ultra-haut champ (7T) utilise une alternance d’impulsions RF rectangulaires et de gradients de champ statique pour moduler à dessein l’aimantation des spins et ainsi homogénéiser l’excitation malgré un champ RF inhomogène. Les impulsions ainsi créées sont d’autant plus efficaces qu’elles peuvent exploiter la transmission parallèle (huit canaux à 7T). Dans cette thèse, les points kT sont employés à 3T avec pour objectif d’en démontrer l’intérêt et l’applicabilité en routine clinique. Dans un premier temps, nous décrivons des modifications apportées à l’algorithme de conception de points kT et à la cartographie de champ statique permettant d’adapter la technique à l’imagerie du corps – foie, seins – où la présence des poumons et de la graisse entraîne des contraintes supplémentaires par rapport au cerveau.Dans un second temps, plusieurs études cliniques sont exposées. La première concerne l’IRM du sein en pondération T₂ sur un imageur à canal d’émission unique. Elle met en évidence que le mode d’émission par défaut fonctionne correctement et n’est que peu amélioré par les points kT. Une deuxième étude se penche sur l’imagerie dynamique du foie avec injection de produit de contraste, avec deux canaux. Des analyses quantitatives et qualitatives sont menées sur un grand nombre de patients pour comparer le shim RF statique avec les points kT. Ces derniers améliorent très nettement les images obtenues chez certains patients« difficiles », permettant ainsi d’offrir une qualité d’examen et de diagnostic plus homogène sur l’ensemble de la population. Enfin,une nouvelle technique est présentée, intitulée SmartPulse, qui s’appuie sur le concept d’impulsions universelles, développé à NeuroSpin pour l’imagerie du cerveau, et dont le principe est de concevoir des impulsions de type points kT qui, pour une application donnée, soient efficaces sur toute la population et permettent de se passer de calibration. En divisant la population en catégories pour lesquelles des impulsions différentes sont conçues,et en utilisant un algorithme de classification par apprentissage automatique, SmartPulse étend la portée des impulsions universelles au corps, et en particulier à l’abdomen, où la variabilité morphologique est importante. Par ces travaux de thèse, nous espérons donner un nouveau souffle à la gestion des inhomogénéités RF en routine clinique à 3T, et apporter des éléments permettant à terme de démocratiser l’imagerie des gros organes à ultra-haut champ. / High field magnetic resonance imaging (MRI) is often used in clinical practice, for the high signal-to-noise ratio it offers.However, at high field, the radiofrequency (RF) wavelength used for imaging is shorter, which can induce loss of signal and contrast when it is close to or shorter than the dimensions of the irradiated objects. At 3T, RF wavelength is about 30 cm in human tissues,and such artefacts are frequently observed in the abdomen, as well as in the thighs or in the breasts. This is certainly one of the main reasons why high field MRI has failed to establish itself as the gold standard in hospital, where 1.5T scanners are more frequent.Recent 3T scanners usually come with a two-RF-channel parallel transmission setup: in principle, each channel can transmit completely independent waveforms. However, this technology is not exploited fully in practice, as only the static RF shimming is implemented: a single waveform is used, with adjusted amplitude and phase on each channel. This allows to create interference patterns, calculated to counteract transmission inhomogeneities measured beforehand in the patient (RF and possibly static field).This method works best when many channels are available, but shows its limits when good homogeneity is expected over a large field of view. The kT-points method, developed at CEA-NeuroSpin for brain imaging at ultra-high field (7T) relies on a succession of short rectangular RF pulses interleaved with static gradient “blips” to modulate magnetisation at will, thus producing homogeneous excitation in spite of an imperfect RF field. Those composite pulses are even more effective as they can take advantage of parallel transmission (eight channels at 7T). In this thesis, the kT-points technique is applied at 3T. The objective is to demonstrate its usefulness and its compatibility with a clinical routine workflow. First, several changes made to the kT-points pulse design algorithm and to static field mapping in order to adapt them to body imaging (liver, breasts) are described. Indeed, the presence of lungs and fat add further constraints compared to the brain. Then, several clinical studies are detailed. The first one regards T₂-weighted breast MRI on a single-channel scanner. It shows that in that case the default transmit mode is satisfactory,and only slightly improved by kT-points. A second study focuses on T₁-weighted dynamic contrast-enhanced imaging of the liver,with two transmit channels. Static RF shimming and kT-points were compared on a large cohort. For some “difficult” patients,acquisitions were quantitatively and qualitatively better with kTpoints,which therefore offer a more uniform diagnostic quality among the population. Finally, a novel method is proposed:SmartPulse. It is based on the universal pulse concept, developed in NeuroSpin for brain imaging, whose principle is to design pulses (e.g. kT-points) for a given application, that homogenise excitation in the whole population, and not only for one subject.Thus, there is no more need for cumbersome mapping and inline pulse design. SmartPulse extends the range of universal pulses to body imaging, by adequately clustering the population, designing different pulses for each cluster, and applying a machine learning classifier to assign the most appropriate pulse to any new subject.Proof of concept was undertaken in abdominal imaging, whereinter-subject variability is considerable. We hope this thesis will give a new outlook on RF inhomogeneity handling in routine 3T MRI, and in the long run will help making body imaging moreaccessible at high and ultra-high field.

The blood oxygen level dependent functional MRI (BOLD-fMRI) signal is an indirect measure of the neuronal activity that most BOLD studies are interested in. This thesis uses generative embedding algorithms to investigate some of the challenges and opportunities that this presents for BOLD imaging. It is standard practice to analyse BOLD signals using general linear models (GLMs) that assume fixed neurovascular coupling. However, this assumption may cause false positive or negative neural activations to be detected if the biological manifestations of brain diseases, disorders and pharmaceutical drugs (termed "neuromodulations") alter this coupling. Generative embedding can help overcome this problem by identifying when a neuromodulation confounds the standard GLM. When applied to anaesthetic neuromodulations found in preclinical imaging data, Fentanyl has the smallest confounding effect and Pentobarbital has the largest, causing extremely significant neural activations to go undetected. Half of the anaesthetics tested caused overestimation of the neuronal activity but the other half caused underestimation. The variability in biological action between anaesthetic modulations in identical brain regions of genetically similar animals highlights the complexity required to comprehensively account for factors confounding neurovascular coupling in GLMs generally. Generative embedding has the potential to augment established algorithms used to compensate for these variations in GLMs without complicating the standard (ANOVA) way of reporting BOLD results. Neuromodulation of neurovascular coupling can also present opportunities, such as improved diagnosis, monitoring and understanding of brain diseases accompanied by neurovascular uncoupling. Information theory is used to show that the discriminabilities of neurodegenerative-diseased and healthy generative posterior parameter spaces make generative embedding a viable tool for these commercial applications, boasting sensitivity to neurovascular coupling nonlinearities and biological interpretability. The value of hybrid neuroimaging systems over separate neuroimaging technologies is found to be greatest for early-stage neurodegenerative disease.

In this thesis, we describe several imaging techniques specifically designed and developed for the assessment of pulmonary structure, function and pathology. We then describe the application of this technology within appropriate biological systems, including the identification, tracking and assessment of lung tumors in a mouse model of lung cancer. The design and development of a Large Image Microscope Array (LIMA), an integrated whole organ serial sectioning and imaging system, is described with emphasis on whole lung tissue. This system provides a means for acquiring 3D pathology of fixed whole lung specimens with no infiltrative embedment medium using a purpose-built vibratome and imaging system. This system enables spatial correspondence between histology and non-invasive imaging modalities such as Computed Tomography (CT), Magnetic Resonance Imaging (MRI) and Positron Emission Tomography (PET), providing precise correlation of the underlying 'ground truth' pathology back to the in vivo imaging data. The LIMA system is evaluated using fixed lung specimens from sheep and mice, resulting in large, high-quality pathology datasets that are accurately registered to their respective CT and H&E histology. The implementation of an in vivo micro-CT imaging system in the context of pulmonary imaging is described. Several techniques are initially developed to reduce artifacts commonly associated with commercial micro-CT systems, including geometric gantry calibration, ring artifact reduction and beam hardening correction. A computer controlled Intermittent Iso-pressure Breath Hold (IIBH) ventilation system is then developed for reduction of respiratory motion artifacts in live, breathing mice. A study validating the repeatability of extracting valuable pulmonary metrics using this technique against standard respiratory gating techniques is then presented. The development of an ex vivo laser scanning confocal microscopy (LSCM) and an in vivo catheter based confocal microscopy (CBCM) pulmonary imaging technique is described. Direct high-resolution imaging of sub-pleural alveoli is presented and an alveolar mechanic study is undertaken. Through direct quantitative assessment of alveoli during inflation and deflation, recruitment and de-recruitment of alveoli is quantitatively measured. Based on the empirical data obtained in this study, a new theory on alveolar mechanics is proposed. Finally, a longitudinal mouse lung cancer study utilizing the imaging techniques described and developed throughout this thesis is presented. Lung tumors are identified, tracked and analyzed over a 6-month period using a combination of micro-CT, micro-PET, micro-MRI, LSCM, CBCM, LIMA and H&E histology imaging. The growth rate of individual tumors is measured using the micro-CT data and traced back to the histology using the LIMA system. A significant difference in tumor growth rates within mice is observed, including slow growing, regressive, disappearing and aggressive tumors, while no difference between the phenotype of tumors was found from the H&E histology. Micro-PET and micro-MRI imaging was conducted at the 6-month time point and revealed the limitation of these systems for detection of small lesions ( < 2mm) in this mouse model of lung cancer. The CBCM imaging provided the first high-resolution live pathology of this mouse model of lung cancer and revealed distinct differences between normal, suspicious and tumor regions. In addition, a difference was found between control A/J mice parenchyma and Urethane A/J mice ‘normal’ parenchyma, suggesting a 'field effect' as a result of the Urethane administration and/or tumor burden. In conclusion, a comprehensive murine lung cancer imaging study was undertaken, and new information regarding the progression of tumors over time has been revealed.

In ischaemic stroke a disruption of cerebral blood flow leads to impaired metabolism and the formation of an ischaemic penumbra in which tissue at risk of infarction is sought for clinical intervention. In stroke trials, therapeutic intervention has largely been based on perfusion-weighted measures, but these have not been shown to be good predictors of tissue outcome. The aim of this thesis was to develop analysis techniques for magnetic resonance imaging (MRI) of chemical exchange saturation transfer (CEST) in order to quantify metabolic signals associated with tissue fate in patients with acute ischaemic stroke. This included addressing robustness for clinical application, and developing quantitative tools that allow exploration of the in-vivo complexity. Tissue-level analyses were performed on a dataset of 12 patients who had been admitted to the John Radcliffe Hospital in Oxford with acute ischaemic stroke and recruited into a clinical imaging study. Further characterisation of signals was performed on stroke models and tissue phantoms. A comparative study of CEST analysis techniques established a model-based approach, Bloch-McConnell model analysis, as the most robust for measuring pH-weighted signals in a clinical setting. Repeatability was improved by isolating non-CEST effects which attenuate signals of interest. The Bloch-McConnell model was developed further to explore whether more biologically-precise quantification of CEST effects was both possible and necessary. The additional model complexity, whilst more reflective of tissue biology, diminished contrast that distinguishes tissue fate, implying the biology is more complex than pH alone. The same model complexity could be used reveal signal patterns associated with tissue outcome that were otherwise obscured by competing CEST processes when observed through simpler models. Improved quantification techniques were demonstrated which were sufficiently robust to be used on clinical data, but also provided insight into the different biological processes at work in ischaemic tissue in the early stages of the disease. The complex array of competing processes in pathological tissue has underscored a need for analysis tools adequate for investigating these effects in the context of human imaging. The trends herein identified at the tissue level support the use of quantitative CEST MRI analysis as a clinical metabolic imaging tool in the investigation of ischaemic stroke.