Magnetic Resonance Imaging (MRI) is an imaging modality that acquires an image with little to no damage to the tissue. MRI does not introduce foreign particles or high energy radiation into the body, making it one of the least invasive medical imaging modalities. MRI can achieve excellent soft tissue contrast and is therefore useful for diagnosis of a wide variety of diseases. While there are a wide variety of available techniques for generating contrast in MRI, there are still many open areas for research. For example, many tissues in the human body exhibit such rapid signal decay that they are difficult to image with MRI: they are "MRI invisible". Furthermore, some of the newer MRI imaging techniques have not been fully validated to ensure that they are truly revealing accurate information about the underlying anatomical microstructure that they purport to image. This dissertation focuses on the development of new techniques in two distinct areas. First, a novel method for accurately assessing the MRI signal decay properties of tissues that are normally MRI invisible, such as tendons, ligaments, and certain pathological chemical deposits in the brain, is presented. This is termed "ultrashort MRI relaxometry". Second, two new image processing algorithms that operate on high resolution images of stained histological slices of the ex vivo brain are presented. The first of these image processing algorithms allows the semi-automated extraction of nerve fiber directionality from the histological slice images, a process that is normally done manually, is incredibly time consuming, and is prone to human error. This new technique represents one significant step in the complicated problem of attempting to validate a popular MRI technique, Diffusion Tensor Imaging (DTI), by ensuring that DTI results correlate with the true underlying physiology revealed by histological slicing and staining. The second of these image processing algorithms attempts to extract and segment regions of different "cytoarchitectonic characteristics" from stained histological slices of ex vivo brain. Again, traditional cytoarchitectonic segmentation relies on manual segmentation by an expert neuroanatomist, which is slow and sometimes inconsistent. The new technique is a first step towards automated this process, potentially providing greater accuracy and repeatability of the segmentations in a much shorter time. Together, these contributions represent a significant contribution to the body of MR imaging techniques, and associated image processing techniques for validation of newer MR neuroimaging techniques against the gold standard of stained histological slices of ex vivo brain.

Healthy white matter in the brain and spinal cord is composed primarily of myelinated axons and glial cells. Myelinated axons transfer information between the peripheral nervous system and the central nervous system (CNS) as well as between centres within the CNS. Demyelination, a hallmark of neurodegenerative autoimmune diseases such as multiple sclerosis (MS), can cause nerve damage and degrade signal propagation. Magnetic resonance imaging (MRI) methods thought to assess myelin integrity and the structural integrity of axons are improving both the diagnosis and understanding of white matter diseases such as MS. Current methods, however, are sensitive to many different pathologies, making the interpretation of individual MRI results difficult. For this dissertation, several quantitative MRI methods were developed and compared, including single component T1 and T2 relaxometry, multicomponent T2 relaxometry, diffusion tensor imaging (DTI), and quantitative magnetization transfer imaging (qMTI). These methods were tested on agarose gels, fixed rat spinal cords, healthy control mice, and the cuprizone mouse model of demyelination. Quantitative MRI measurements were correlated to ultrastructural measurements of white matter to determine the influence myelin content and axonal structure have on different MRI methods. Cellular distributions measured in electron micrographs of the corpus callosum correlated strongly to several different quantitative MRI metrics. The largest Spearman correlation coefficient varied depending on cellular type: longitudinal relaxation rates (RA/T1) vs. the myelinated axon fraction ( r = 0.90/-0.90), the qMTI-derived bound pool fraction (f) vs. the myelin sheath fraction ( r = 0.93), and the DTI-derived axial diffusivity vs. the non-myelinated cell fraction (r = 0.92). Using Pearson’s correlation coefficient, f was strongly correlated to the myelin sheath fraction (r = 0.98) with a linear equation predicting myelin content (5.37f −0.25). Of the calculated MRI metrics, f was the strongest indicator of myelin content while longitudinal relaxation rates and diffusivity measurements were the strongest indicators of changes in tissue structure. Multiparametric MRI measurements of relaxation, diffusion, and magnetization transfer give a more complete picture of white matter integrity.

Magnetic Resonance Imaging (MRI) is an important diagnostic tool for imaging soft tissue without the use of ionizing radiation. Moreover, through advanced signal processing, MRI can provide more than just anatomical information, such as estimates of tissue-specific physical properties. Signal processing lies at the very core of the MRI process, which involves input design, information encoding, image reconstruction, and advanced filtering. Based on signal modeling and estimation, it is possible to further improve the images, reduce artifacts, mitigate noise, and obtain quantitative tissue information. In quantitative MRI, different physical quantities are estimated from a set of collected images. The optimization problems solved are typically nonlinear, and require intelligent and application-specific algorithms to avoid suboptimal local minima. This thesis presents several methods for efficiently solving different parameter estimation problems in MRI, such as multi-component T2 relaxometry, temporal phase correction of complex-valued data, and minimizing banding artifacts due to field inhomogeneity. The performance of the proposed algorithms is evaluated using both simulation and in-vivo data. The results show improvements over previous approaches, while maintaining a relatively low computational complexity. Using new and improved estimation methods enables better tissue characterization and diagnosis. Furthermore, a sequence design problem is treated, where the radio-frequency excitation is optimized to minimize image artifacts when using amplifiers of limited quality. In turn, obtaining higher fidelity images enables improved diagnosis, and can increase the estimation accuracy in quantitative MRI.

Healthy white matter in the brain and spinal cord is composed primarily of myelinated axons and glial cells. Myelinated axons transfer information between the peripheral nervous system and the central nervous system (CNS) as well as between centres within the CNS. Demyelination, a hallmark of neurodegenerative autoimmune diseases such as multiple sclerosis (MS), can cause nerve damage and degrade signal propagation. Magnetic resonance imaging (MRI) methods thought to assess myelin integrity and the structural integrity of axons are improving both the diagnosis and understanding of white matter diseases such as MS. Current methods, however, are sensitive to many different pathologies, making the interpretation of individual MRI results difficult. For this dissertation, several quantitative MRI methods were developed and compared, including single component T1 and T2 relaxometry, multicomponent T2 relaxometry, diffusion tensor imaging (DTI), and quantitative magnetization transfer imaging (qMTI). These methods were tested on agarose gels, fixed rat spinal cords, healthy control mice, and the cuprizone mouse model of demyelination. Quantitative MRI measurements were correlated to ultrastructural measurements of white matter to determine the influence myelin content and axonal structure have on different MRI methods. Cellular distributions measured in electron micrographs of the corpus callosum correlated strongly to several different quantitative MRI metrics. The largest Spearman correlation coefficient varied depending on cellular type: longitudinal relaxation rates (RA/T1) vs. the myelinated axon fraction ( r = 0.90/-0.90), the qMTI-derived bound pool fraction (f) vs. the myelin sheath fraction ( r = 0.93), and the DTI-derived axial diffusivity vs. the non-myelinated cell fraction (r = 0.92). Using Pearson’s correlation coefficient, f was strongly correlated to the myelin sheath fraction (r = 0.98) with a linear equation predicting myelin content (5.37f −0.25). Of the calculated MRI metrics, f was the strongest indicator of myelin content while longitudinal relaxation rates and diffusivity measurements were the strongest indicators of changes in tissue structure. Multiparametric MRI measurements of relaxation, diffusion, and magnetization transfer give a more complete picture of white matter integrity.

La fibrose systémique néphrogénique (FSN) est une maladie rare et relativement récente, observée uniquement chez des patients souffrant d’insuffisance rénale sévère ou terminale. Elle est liée à l’administration d’une certaine catégorie de complexes de gadolinium (CG), les CGs thermodynamiquement moins stables, utilisés comme produits de contraste pour l’imagerie par résonance magnétique. L’hypothèse mécanistique la plus couramment citée concerne les effets profibrosants du Gd3+ « libre » après dissociation in vivo des CGs les moins stables mais il n’en existe pas de démonstration formelle. La physiopathologie de cette maladie reste mal connue, notamment par manque de modèles précliniques pertinents. Les travaux de cette thèse répondent donc à la nécessité d’approfondir nos connaissances concernant les relations entre les propriétés physicochimiques des CGs (structure, stabilité) et le risque de toxicité chronique, afin de mieux comprendre leur rôle dans le mécanisme de la FSN. Nous avons mis aux points plusieurs modèles de FSN chez le Rat. Nous avons aussi comparé les effets de toutes les catégories structurales des CGs sur ces modèles. Une toxicité systémique importante et la survenue de lésions cutanées macroscopiques et d’une fibrose du derme sont notées après administration de gadodiamide (un CG linéaire et ionique de faible stabilité), ce qui est cohérent avec le fait que la grande majorité des cas de FSN sont associés à cet agent. Nous avons aussi montré que cette toxicité dépend du degré d’insuffisance rénale et que l’hyperphosphatémie sensibilise les animaux aux effets profibrosants du gadodiamide. Nos données suggèrent donc que ces facteurs associés sont des facteurs de risque de la FSN. Nous avons observé la dissociation progressive in vivo de deux CGs linéaires présentant une faible stabilité, le gadodiamide et l’acide gadopentétique, après administration chez le Rat insuffisant rénal, avec libération de Gd3+ sous forme libre et soluble. Les CGs macrocycliques sont restés stables. Nous avons confirmé cette stabilité sur du sérum de Rat et du sérum humain alors que le gadodiamide se dissocie in vitro. Nos données suggèrent aussi une interaction entre l’ion Gd3+ dissocié à partir du gadodiamide et les protéines sériques. Cette libération de Gd3+ est accélérée en présence d’une forte concentration de phosphate. Globalement, nos résultats suggèrent ainsi un rôle causal du Gd3+ libre dans les lésions cutanées observées chez les animaux insuffisants rénaux. Enfin, nous avons observé l’implication de la voie de signalisation canonique de TGFβ, le marqueur clé de la fibrose, uniquement chez des rats ayant reçu le gadodiamide et dont l’insuffisance rénale est modérée. Nos travaux sont donc en faveur de l’hypothèse mécanistique d’une dissociation des CGs peu stables. / Nephrogenic systemic fibrosis (NSF) is a rare systemic fibrosing disorder which has been described in patients with severe or end stage renal failure. NSF is associated with prior administration of certain gadolinium complexes (GCs), used as magnetic resonance imaging contrast agents, particularly those which have the lowest thermodynamic stability. The most widely accepted hypothesis regarding the mechanism is based on profibrotic effects of free Gd3+ following in vivo dissociation of the less stable GCs. Nevertheless, there is no conclusive evidence so far. The pathophysiology is not completely understood, especially due to the lack of relevant non-clinical models. The purpose of our thesis was to investigate the relationship between physicochemical properties of GCs (molecular structure, thermodynamic stability) and the risk of chronic toxicity (especially fibrosis), in order to enhance our understanding of their role in the mechanism of NSF. We have set-up various non-clinical models of NSF in renally-impaired rats. We also compared the effects of all categories of GCs on these models. A high systemic toxicity, associated with macroscopic skin lesions and dermal fibrosis, was observed after the administration of gadodiamide (a linear and nonionic GC with a low thermodynamic stability). Whereas more stable, macrocyclic GCs were well tolerated. These findings seem clinically-relevant because the vast majority of NSF cases are associated with gadodiamide. We also showed that systemic and skin toxicities depend on the baseline renal function, and that hyperphosphataemia sensitizes renally-impaired rats to the fibrotic effects of gadodiamide. Our data suggest that these factors are, actually, risk factors for NSF. We observed in vivo dissociation of two linear GCs, gadodiamide and gadopentetic acid, with gradual release of soluble Gd3+, in renally-impaired rats. Macrocyclic agents remained stable. This observation was also confirmed both in rat and human serum by the relaxometry technique. Our results are also consistent with an interaction between dissociated Gd3+ and serum proteins. We also demonstrated that elevated serum phosphate levels accelerates the release of Gd3+. Taken all together, our results suggest a causal role of dissociated Gd3+ in gadodiamide-induced skin lesions in renally-impaired rats. Finally, we identified the involvement of the canonical signaling pathway of TGFβ, the central mediator of the fibrotic response, in gadodiamide-treated rats with a moderate renal failure. Our work is consistent with a causal role of dissociated Gd in the mechanism of NSF.

Ce manuscrit de thèse présente la synthèse de nanoparticules d’oxyde de fer superparamagnétiques couramment appelées SPIONs servant d’agents de contraste pour l’imagerie par résonance magnétique (IRM) et la génération de chaleur pour la thérapie cellulaire par hyperthermie induite par champ magnétique radiofréquence (HMRF). Le contrôle des tailles et de la distribution en tailles des SPIONs et donc de leurs propriétés magnétiques a été obtenu en utilisant un copolymère arborescent G1 (substrat de polystyrène branché en peigne noté G0, greffé avec des groupements pendants poly(2-vinyle pyridine) ) comme milieu « gabarit », tandis que la stabilité colloïdale et la biocompatibilité des SPIONs ont été apportées par un procédé de poly-complexation ionique grâce à un copolymère double-hydrophile acide polyacrylique-bloc-poly(acrylate de 2-hydroxyéthyle) PAA-b-PHEA. / This Ph.D. dissertation describes the synthesis of superparamagnetic iron oxide nanoparticles (SPIONs) designed to serve as magnetic resonance imaging (MRI) contrast agents and for heat generation in cellular radiofrequency magnetic field hyperthermia (MFH) treatment. Control over the size and size distribution of the iron oxide nanoparticles (NPs), and thus over their magnetic properties, was achieved using a G1 arborescent copolymer (comb-branched (G0) polystyrene substrate grafted with poly(2-vinylpyridine) side chains, or G0PS-g-P2VP) as a template. Good colloidal stability and biocompatibility of the SPIONs were achieved via the formation of polyion complex (PIC) micelles with a poly(acrylic acid)-block-poly(2-hydroxyethyl acrylate) (PAA-b-PHEA) double-hydrophilic block copolymer.

L’IRM quantitative recouvre l’ensemble des méthodes permettant de mesurer des paramètres physiques accessibles en Résonance Magnétique Nucléaire. Elle offre un bénéfice par rapport à l’imagerie en pondération classiquement utilisée, notamment pour la détection, la caractérisation physiopathologique mais aussi pour le suivi thérapeutique des pathologies. Malgré ce potentiel avéré connu de longue date, ces méthodes restent peu utilisées dans la routine clinique. La raison principale est la longueur des acquisitions par rapport à l’approche classique. Les paramètres physiques que nous souhaitons étudier plus particulièrement sont le temps de relaxation longitudinal (T₁), transversal (T₂), le coefficient de diffusion apparent (ADC), et la densité de protons (DP). Malgré la possibilité d’atteindre une meilleure qualité d’images, ces cartographies in vivo sont quasiment inexistantes dans la littérature au-delà de 3T car leur implémentation nécessite de surmonter un certain nombre de limites spécifiques aux IRM ultra-haut champs (UHF). Au travers de ce projet de thèse, une méthode d’imagerie quantitative basée sur les états de configurations (QuICS) a été implémentée, pour déterminer ces paramètres quantitatifs de façon simultanée sous fortes contraintes propres aux UHF. L’approche a été optimisée dans le but d’obtenir des cartographies fiables et rapides. Le potentiel de la méthode a été démontré dans un premier temps in vitro sur un noyau tel que le sodium démontrant des propriétés complexes à cartographier. Puis dans un second temps, des acquisitions ont été réalisées sur proton, in vivo, en un temps d’acquisition compatible avec une utilisation en routine clinique à 7T. L’application d’une telle méthode d’IRM quantitative à UHF sur des populations permettra d’ouvrir de nouvelles voies d’études pour le futur. / Quantitative MRI refers to methods able to measure different physical parameters accessible in Nuclear Magnetic Resonance. It offers benefits compared to weighting imaging commonly used, for the detection, the pathophysiological characterization but also for the therapeutic follow-up of pathologies for example. Despite this long-established potential, these methods remain little used in clinical routine. The main reason is the long acquisition time compared to the classical approach. The physical parameters that we will study more particularly are the longitudinal (T₁), transverse (T₂) relaxation time, the apparent diffusion coefficient (ADC), and the proton density (DP). Despite the possibility to achieve a better image quality, these in vivo mappings are virtually non-existent in the literature beyond 3T because their implementation requires overcom-ing a number of specific ultra-high-field (UHF) MRI limits. Through this thesis project, a Quantitative Imaging method using Configuration States (QuICS) was implemented under strong UHF constraints, to determine these parameters simultaneously. The technique has been optimized to obtain fast and reliable maps. The potential of the method was first demon-strated in vitro on a nucleus such as sodium, exhibiting complex properties. As a second step, acquisitions were performed in proton, in vivo, in an clinically-relevant acquisition time, compatible with a routine use at 7T for population imaging. The application of such a method of quantitative MRI to UHF will open new research possibilities for the future.

Magnetic nanoparticles have received extensive attention in the biomedical research, e.g. as prospective contrast agents for T2-weighted magnetic resonance imaging. The ability of a contrast agent to enhance the relaxation rate of 1 H in its vicinity is quantified by relaxivity. The main aim of this thesis is to evaluate the transversal re- laxivity of ε-Fe2−x Alx O3 nanoparticles coated with amorphous silica or citrate - its dependence on external magnetic field, temperature and thickness of silica coating - by means of nuclear magnetic resonance. The aluminium content x = 0.23(1) was determined from XRF, the material was further characterised by XRPD, Möss- bauer spectroscopy, DLS, TEM and magnetic measurements. The size of magnetic cores was ∼ 21 nm, the thickness of silica coating ∼ 6,10,17 and 21 nm. Magne- tization of the ε-Fe2−x Alx O3 nanoparticles increased by ∼ 30 % when compared to ε-Fe2O3. The saturating dependence of relaxivity on external magnetic field and on the linear decrease with increase of thickness of silica coating contravene the theo- retical model of motional averaging regime (MAR); nevertheless, the temperature dependence acquired in 0.47 T and 11.75 T may be explained by MAR. In compari- son to ε-Fe2O3 nanoparticles, the relaxivity of examined samples was higher for par-...

Clinical course of multiple sclerosis (MS) is heterogenous and white matter lesion count and volume on brain magnetic resonance imaging (MRI) correlate with clinical course only partially. Therefore, there is an urgent need for more reliable prognostic biomarkers. This work explored three imaging markers - spinal cord (SC) imaging (specifically SC volume measurement and assessment of focal and diffuse SC changes), atlas-based model of "disconnectome" (i.e. disruption of brain connectivity due to white matter lesions) and periventricular white matter gradient assessed with T1 relaxometry. For the SC projects, we assessed MRI from 2044 MS patients with a semi-automatic method for SC volume measurement. We confirmed (i) a relationship between diffuse SC changes, SC volume and disability; (ii) a novel finding was that in patients with EDSS ≤ 4.0, diffuse changes contributed to higher disability more than SC volume; (iii) SC volume explains the paradox in patients with dissociation between brain white matter lesion load and disability; (iv) SC focal and/or diffuse changes are present in 75% patients with early MS, of which 43% have diffuse changes that are related to brainstem lesions. In the disconnectome project, we evaluated the disruption of connectivity caused by white mater lesions in 745 patients...

Computed Tomography (CT) is often used for building 3D biomechanical models of human anatomy. This method exposes the subject to a significant x-ray dose and provides limited soft-tissue contrast. Magnetic Resonance Imaging (MRI) is a potential alternative to CT for this application, as MRI offers significantly better soft-tissue contrast and does not expose the subject to ionizing radiation. However, MRI requires long scan times to achieve 3D images at sufficient resolution, signal-to-noise ratio (SNR), and contrast-to-noise ratio (CNR). These long scan times can make subject motion a problem. This thesis describes my work to reduce scan time while achieving sufficient resolution, SNR, and CNR for 3D biomechanical modeling of (1) the human larynx, and (2) the human hip. I focused on two important strategies for reducing scan time and improving SNR and CNR: the design of RF coils optimized to detect MRI signals from the anatomy of interest, and the determination of MRI relaxation properties of the tissues being imaged (allowing optimization of imaging parameters to improve CNR between tissues). Work on the larynx was done in collaboration with the Thomson group in Mechanical Engineering at BYU. To produce a high-resolution 3D image of the larynx, a 2-channel phased array was constructed. Eight different coil element designs were analyzed for use in the array, and one chosen that provided the highest Q-ratio while still meeting the mechanical constraints of the problem. The phased array was tested by imaging a pig larynx, a good substitute for the human larynx. Excellent image quality was achieved and MR relaxometry was then performed on tissues in the larynx. The work on the hip was done in collaboration with the Anderson group in orthopedics at the University of Utah, who are building models of femoral acetabular impingement (FAI). Accurate imaging of hip cartilage requires injection of fluid into the hip joint capsule while in traction. To optimize contrast, MR relaxometry measurements were performed on saline, isovue, and lidocaine solutions (all typically injected into the hip). Our analysis showed that these substances actually should not be used for MR imaging of the hip, and alternate strategies should be explored as a result.