Monte Carlo (MC) simulations are widely used in the field of medical biophysics, particularly for modelling light propagation in biological tissue. The iterative nature of MC simulations and their high computation time currently limit their use to solving the forward solution for a given set of source characteristics and tissue optical properties. However, applications such as photodynamic therapy treatment planning or image reconstruction in diffuse optical tomography require solving the inverse problem given a desired light dose distribution or absorber distribution, respectively. A faster means for performing MC simulations would enable the use of MC-based models for such tasks. In this thesis, a gold standard MC code called MCML was accelerated using two distinct hardware-based approaches, namely designing custom hardware on field-programmable gate arrays (FPGAs) and programming commodity graphics processing units (GPUs). Currently, the GPU-based approach is promising, offering approximately 1000-fold speedup with 4 GPUs compared to an Intel Xeon CPU.

Aortic stenosis is the most common acquired heart valve condition. Open-heart surgical aortic valve replacement is an effective treatment for patients who receive it. However, approximately one-third of patients who require this treatment do not receive it due to the risks associated with the surgery. Percutaneous aortic valve replacement (PAVR) is a minimally invasive technique that can replace the aortic valve of patients contraindicated for open-heart surgery. Although PAVR is now entering clinical practice, a closed bore hybrid x-ray/MRI (CBXMR) imaging system is under development to improve the safety and efficacy of PAVR. This system will harness the complementary strengths of x-ray imaging (surgical tool/vascular imaging) and MRI (cardiac soft tissue contrast) to deploy a bioprosthesis in the aortic annulus. An x-ray C-arm will be placed about 1 m from the entrance of the MRI scanner to facilitate smooth intermodality patient transfer during the procedure. The performance of a rotating-anode x-ray tube in the magnetic fringe field of a 1.5 T MRI scanner was investigated. A rotating-anode x-ray tube provides the fluoroscopy and angiography needed for PAVR. The magnetic fringe field can affect the ability of the x-ray tube to dissipate heat. It was shown that the fringe field perpendicular to the anode rotation axis can reduce anode rotation frequency. These effects can limit the maximum permissible power that can be safely dissipated on the anode track during a single exposure. In the fringe field strengths at the C-arm position (4-5 mT), anode rotation frequency only decreased by about 1%, which will have negligible impact on tube heat loadability. The fringe field can cause a field of view shift. The field of view shifted by approximately 3 mm, which can be corrected by active magnetic shielding and further collimation. An active magnetic shielding system was constructed that can correct focal spot deflection. These results are facilitating the construction of a prototype CBXMR system, the goal of which is to improve success rates for PAVR procedures.

This thesis describes the electrical and physiological characterization of cardiac tissue with myocardial infarction (MI) responsible for abnormal cardiac rhythms such as ventricular tachycardia (VT), using a newly-developed magnetic resonance imaging (MRI) electrophysiology system. In electrophysiology (EP), radiofrequency (RF) catheter ablation combined with cardioverter-defibrillator implantation is a first-line action to manage ventricular VT. Unfortunately, this therapy is known to have sub-optimal success rates in a large number of patients because of difficulties to accurately identifying the arrhythmic target regions. Currently, characterization of post-MI scars is performed by using catheters to measure electrical signals of the endocardial tissue (electroanatomical mapping), under x-ray fluoroscopy guidance. Prolonged radiation exposure to both the cardiologist and the patient have made the use of MRI extremely attractive; further, unlike x-ray imaging, MRI provides post-MI scars with direct visualization, characterization in three dimensions and the ability to visualize ablation lesions. Although recent research has focused on registration between pre-acquired MR images and electroanatomical maps, a potentially more useful approach is to use real-time MRI to directly locate and characterize potential arrhythmogenic regions during the EP procedure. A real-time MR-guided EP system was developed and validated to perform EP diagnostic procedures, such as mapping and pacing. In a series of animal studies, the system demonstrated the ability to use active catheter tracking and intra-procedural MR imaging to navigate to specific regions in the left ventricle and record intracardiac electrical signals. A study correlating myocardial fibrotic scar detected by multicontrast late enhancement (MCLE) MRI and electroanatomical voltage mapping demonstrated that MRI information (transmurality, tissue classification, and relaxation rate) can accurately predict areas of myocardial fibrosis identified with bipolar voltage mapping. Finally, MCLE-derived gray zone was shown to have a high correspondence to regions with a high proportion of abnormal intracardiac signals. The methods described in this thesis help advance the understanding of infarcted tissue responsible for ventricular tachycardia. Further studies are proposed to perform RF ablation lesions and correlate pre- and post-ablation tissue electrophysiological properties with MRI.

Arterial spin labeling is a completely non-invasive method for blood-flow measurement techniques. Alzheimer's disease pathology includes microvascular abnormalities in addition to practically all risk factors having a vascular component that reduces cerebral perfusion. Hemodynamic parameters of cerebral blood flow and arterial transit time were estimated via single-compartment modeling of pseudo continuous arterial spin labeling data and neurocognitive test scores (Alzheimer's disease assessment scale and mini-mental state examination) were compared between a group of healthy (N=20) and early Alzheimer's disease (N=25) subjects before and six months after the Alzheimer's subjects began treatment with cholinesterase inhibitors. The early Alzheimer's group showed improved CBF after 6 months' treatment in every Alzheimer's-prone region except the medial and lateral temporal lobes. No difference in arterial transit time was found between groups, indicating that the pathophysiological process causing hypoperfusion in Alzheimer's disease may differ from vascular dementia.

Arterial spin labeling is a completely non-invasive method for blood-flow measurement techniques. Alzheimer's disease pathology includes microvascular abnormalities in addition to practically all risk factors having a vascular component that reduces cerebral perfusion. Hemodynamic parameters of cerebral blood flow and arterial transit time were estimated via single-compartment modeling of pseudo continuous arterial spin labeling data and neurocognitive test scores (Alzheimer's disease assessment scale and mini-mental state examination) were compared between a group of healthy (N=20) and early Alzheimer's disease (N=25) subjects before and six months after the Alzheimer's subjects began treatment with cholinesterase inhibitors. The early Alzheimer's group showed improved CBF after 6 months' treatment in every Alzheimer's-prone region except the medial and lateral temporal lobes. No difference in arterial transit time was found between groups, indicating that the pathophysiological process causing hypoperfusion in Alzheimer's disease may differ from vascular dementia.

The nuclear receptor superfamily is responsible for regulating the expression of genes involved in development, reproduction and metabolism. These transcription factors control the expression of their target genes through the binding of small molecule regulators to their ligand binding domains. Classical nuclear receptors include the steroid receptors, which bind endocrine hormones and have been important targets of pharmaceutical intervention. However, approximately one half of the human nuclear receptors remain orphans and are without known cognate ligands. Focusing on the Drosophila orthologues of these orphan receptors, this project used mass spectrometry to identify the chemical diversity associated with the receptors following expression in recombinant systems. In a genome-wide screen of Drosophila nuclear receptors, this approach identified co-purifying molecules with a number of receptors. The physiological relevance of these putative ligand/receptor pairs was determined through biochemical analysis, in vivo characterization and structure determination. Ligand(s) or the ligand state was identified for the Drosophila receptors: DHR3, DHR96, E75, Ftz-f1 and USP. Of these, three were validated through the efforts of this project, and independent groups confirmed the remaining two. The most significant findings were the discoveries that the fly nuclear receptor E75 is regulated by heme, gas and redox, and that there is a similar regulatory scheme in the human orthologues, Reverbα and β. Furthermore, crystallization of the heme-bound Rev-erbβ ligand binding domain was also achieved, and this provided key insights into the mechanism of ligand regulation for the Rev-erbs. This project highlighted the role of nuclear receptors in metabolic surveillance. The ligands/signals identified in association with these receptors include: cholesterol, dehydrocholesterol, heme, NO, CO, redox and phospholipids. Unlike the classical steroid hormones, these are not dedicated signaling molecules, but instead are key substrates or products of metabolism. In the context of nuclear receptor signaling, I hypothesize that these metabolites serve as metabolic indicators/signals in the regulation of development and metabolism. Furthermore, four of these Drosophila receptors comprise the ecdysone-response pathway in the developing fly. Taken together, this suggests that both the metabolic state of the organism and steroid hormones drive nuclear receptor regulation of development.

While great strides have been made in treating many classes of human disease, the late-onset neurodegenerative diseases continue to elude modern medicine. These diseases, which include Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), the transmissible spongiform encephalopathies (TSEs), and amyotrophic lateral sclerosis (ALS), involve accumulation of insoluble aggregates of one or more causative proteins, leading to progressive loss of central nervous system neurons, progressively worsening neurological symptoms, and eventual patient death. All of these diseases are currently incurable and fatal. In the case of ALS, progressive death of upper and lower motor neurons leads to full-body paralysis, respiratory difficulty, and patient death. Of the subset of ALS cases showing familial inheritance, approximately 20% are caused by mutations in the SOD1 gene, encoding the Cu, Zn superoxide dismutase (SOD1). These mutations do not have the common property of impairing SOD1's normal function as a free radical scavenger. Instead, they are thought to increase the protein's likelihood of misfolding and aggregating via a poorly-understood aggregation cascade. It is believed that species populated along the misfolding and aggregation pathway may prove to be good targets for therapies designed to block accumulation of downstream toxic species, or to prevent aberrant protein-protein interactions responsible for neurotoxicity. In this thesis, several new techniques are developed to enable detailed elucidation of the SOD1 unfolding and misfolding pathways. Time-resolved measurements collected during SOD1 unfolding or misfolding of release of bound Cu and Zn, of changes in intrinsic fluorescence, of exposure of hydrophobic surface area, and of alterations in the chemical environment of histidine residues, are presented. A new mathematical analysis technique named the Analytical Laplace Inversion Algorithm is developed for rapid extraction of mechanistic information from these time-resolved signals. These tools are applied to the construction of the most detailed models to date of the unfolding and misfolding mechanisms of WT and ALS-causing mutant SOD1. The models presented identify several well-populated unfolding and misfolding intermediates that could serve as good targets for therapies designed to address the fundamental molecular mechanisms underlying SOD1-associated ALS, and to treat what is currently a devastating and incurable disease.

Aortic stenosis is the most common acquired heart valve condition. Open-heart surgical aortic valve replacement is an effective treatment for patients who receive it. However, approximately one-third of patients who require this treatment do not receive it due to the risks associated with the surgery. Percutaneous aortic valve replacement (PAVR) is a minimally invasive technique that can replace the aortic valve of patients contraindicated for open-heart surgery. Although PAVR is now entering clinical practice, a closed bore hybrid x-ray/MRI (CBXMR) imaging system is under development to improve the safety and efficacy of PAVR. This system will harness the complementary strengths of x-ray imaging (surgical tool/vascular imaging) and MRI (cardiac soft tissue contrast) to deploy a bioprosthesis in the aortic annulus. An x-ray C-arm will be placed about 1 m from the entrance of the MRI scanner to facilitate smooth intermodality patient transfer during the procedure. The performance of a rotating-anode x-ray tube in the magnetic fringe field of a 1.5 T MRI scanner was investigated. A rotating-anode x-ray tube provides the fluoroscopy and angiography needed for PAVR. The magnetic fringe field can affect the ability of the x-ray tube to dissipate heat. It was shown that the fringe field perpendicular to the anode rotation axis can reduce anode rotation frequency. These effects can limit the maximum permissible power that can be safely dissipated on the anode track during a single exposure. In the fringe field strengths at the C-arm position (4-5 mT), anode rotation frequency only decreased by about 1%, which will have negligible impact on tube heat loadability. The fringe field can cause a field of view shift. The field of view shifted by approximately 3 mm, which can be corrected by active magnetic shielding and further collimation. An active magnetic shielding system was constructed that can correct focal spot deflection. These results are facilitating the construction of a prototype CBXMR system, the goal of which is to improve success rates for PAVR procedures.

Monte Carlo (MC) simulations are widely used in the field of medical biophysics, particularly for modelling light propagation in biological tissue. The iterative nature of MC simulations and their high computation time currently limit their use to solving the forward solution for a given set of source characteristics and tissue optical properties. However, applications such as photodynamic therapy treatment planning or image reconstruction in diffuse optical tomography require solving the inverse problem given a desired light dose distribution or absorber distribution, respectively. A faster means for performing MC simulations would enable the use of MC-based models for such tasks. In this thesis, a gold standard MC code called MCML was accelerated using two distinct hardware-based approaches, namely designing custom hardware on field-programmable gate arrays (FPGAs) and programming commodity graphics processing units (GPUs). Currently, the GPU-based approach is promising, offering approximately 1000-fold speedup with 4 GPUs compared to an Intel Xeon CPU.

Une mutation du gène SYN1 a récemment été découverte chez plusieurs membres d'une grande famille canadienne-française ségréguant troubles du langage, épilepsie focale, et troubles du spectre autistique (TSA). Bien qu'aucune anomalie macroscopique apparente n'ait pu être identifiée dans les données d’imagerie par résonance magnétique (IRM) cérébrales, nous avons émis l'hypothèse que des modalités d'IRM quantitatives sensibles à la microstructure et à la composition des tissus permettraient l’identification d’anomalies subtiles. Nous avons fait l’acquisition de données IRM multimodale chez 13 sujets porteurs de la mutation SYN1_Q555x et 13 sujets contrôles appareillés pour l’âge et le sexe. Une analyse statistique de groupe a été effectuée sur les cartes paramétriques corticales surfaciques afin de caractériser l’effet de la mutation sur plusieurs paramètres physiques quantitatifs. En résumé, des altérations ont été observées dans le réseau langagier, de même qu’une latéralisation anormale de celui-ci sur l’hémisphère droit. Les changements les plus significatifs dans ces régions sont une diminution de la diffusivité moyenne et une augmentation de l’anisotropie fractionnelle. Un modèle biophysique est proposé pour expliquer ces résultats, qui suggèrent une augmentation de la densité ou de la fraction volumique du neuropile. Cette étude est, à notre connaissance, la première à utiliser avec succès l'imagerie de diffusion et multiparamétrique conjointement à une méthodologie de cartographie surfacique pour détecter des anomalies corticales chez un groupe de sujets avec un génotype bien défini lié aux troubles du langage, à l'épilepsie et aux TSA. Cette étude démontre également que l'IRM de diffusion, bien que traditionnellement considérée comme une modalité spécifique à la matière blanche, peut effectivement être utilisée conjointement à une cartographie de surface pour caractériser une pathologie corticale subtile non détectable autrement, même si seul un groupe relativement restreint de sujets est disponible. / A mutation of the SYN1 gene has recently been discovered in several members of a large French-Canadian family segregating language disorders, focal epilepsy, and autism spectrum disorders (ASD). Although no apparent macroscopic abnormality could be identified in brain magnetic resonance imaging (MRI) data, we hypothesized that quantitative MRI modalities sensitive to tissue microstructure and composition could allow the identification of subtle anomalies. We acquired multimodal MRI data from 13 SYN1_Q555x mutation carriers and 13 healthy controls matched for age and sex. A surface-based group statistical analysis was performed on the cortical parametric maps to characterize the effect of the mutation on several quantitative physical parameters. In summary, alterations were found in the language network, as well as abnormal lateralization of the latter over the right hemisphere. The most significant changes in these regions are a decrease in mean diffusivity and an increase in fractional anisotropy. A biophysical model is proposed to explain these results, which suggest an increase in neuropil density or volume fraction. This study is, to our knowledge, the first to successfully use diffusion imaging and multiparametric mapping in a surface-based approach to detect cortical anomalies in a group of subjects with a well-defined genotype linked to language impairments, epilepsy and ASD. Importantly, this study also shows that diffusion MRI, although traditionally seen as a white matter modality, can effectively be used in a surface-based approach to characterize subtle cortical pathology not detectable otherwise, even when only a relatively small group of subjects is available.