Transmissible spongiform encephalopathies (TSEs), or prion diseases, are a group of invariably fatal neurodegenerative diseases of both humans and animals, thought to be caused by the abnormally folded prion protein PrPSc. Prion disease research continues to be faced by a number of difficult challenges. First, the unequivocal diagnosis of most prion diseases currently requires the post-mortem collection of central nervous system tissue, either for histological examination or Western blot analysis; second, a viable treatment for clinical stage disease has not yet been identified; third, the exact details of disease pathogenesis have not been elucidated; and fourth, the normal function of PrPC is not definitively known. The primary objective of the studies presented here was to diagnose prion disease in live animals, using Magnetic Resonance Imaging (MRI). Increases in T2 relaxation time and apparent diffusion coefficient (ADC) were observed very early following the infection of Syrian golden hamsters with the 263K strain of scrapie. These changes were evident well before the appearance of either clinical symptoms or the typical histological changes characteristic of prion disease, suggesting that they are the result of the progressive accumulation of fluid, and that this may constitute a novel early marker of prion disease pathogenesis. Following the establishment of this model system, a secondary objective was composed: to test the viability of a potential treatment (pentosan polysulphate) using a number of different treatment regimens. It was determined that pentosan polysulphate (PPS) was ineffective as a treatment unless it was administered intra-cerebrally very early in infection, although it was shown to slow the appearance of the histological hallmarks of prion disease. In response to the results of these studies, a potential model was proposed, relating PrP, aquaporin-4 (AQP4) regulation, and oedema. Although speculative, this model may have implications for both normal PrPC function and disease pathogenesis.

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A novel approach for the analysis of spinal cord deformation based on a combined technique of non-invasive imaging and medical image processing is presented. A sopposed to traditional approaches where animal spinal cords are exposed and directly subjected to mechanical impact in order to be examined, this approach can be used to quantify deformities of the spinal cord in vivo, so that deformations — specifically those of myelopathy-related sustained compression — of the spinal cord can be computed in its original physiological environment. This, then, allows for a more accurate understanding of spinal cord deformations and injuries. Images of rat spinal cord deformations, acquired using magnetic resonance imaging (MRI), were analyzed using a combination of various image processing methods, including image segmentation, a versor-based rigid registration technique, and a B-spline-based non-rigid registration technique. To verify the validity and assess the accuracy of this approach, several validation schemes were implemented to compare the deformation fields computed by the proposed algorithm against known deformation fields. First, validation was performed on a synthetically-generated spinal cord model data warped using synthetic deformations; error levels achieved were consistently below 6% with respect to cord width, even for large degrees of deformation up to half of the dorsal-ventral width of the cord (50% deflection). Then, accuracy was established using in vivo rat spinal cord images warped using those same synthetic deformations; error levels achieved were also consistently below 6% with respect to cord width, in this case for large degrees of deformation up to the entire dorsal-ventral width of the cord (100% deflection). Finally, the accuracy was assessed using data from the Visible Human Project (VHP) warped using simulated deformations obtained from finite element (FE) analysis of the spinal cord; error levels achieved were as low as 3.9% with respect to cord width. This in vivo, non-invasive semi-automated analysis tool provides a new framework through which the causes, mechanisms, and tolerance parameters of myelopathy-related sustained spinal cord compression, as well as the measures used in neuroprotection and regeneration of spinal cord tissue, can be prospectively derived in a manner that ensures the bio-fidelity of the cord.

MRI provides a powerful tool to investigate brain structure in living humans. However a major challenge is interpreting the biological underpinnings of changes at this scale. This dissertation describes investigations into the problem of linking microscale post mortem cortical cytoarchitecture with millimeter-scale measures of cortical anatomy accessible through in vivo MRI. Chapter 1 introduces the problem and previous work done to address it. The following two chapters apply classical atlases of cortical cytoarchitecture to understanding morphological changes both in health (Chapter 2) and in disease (Chapter 3). Chapter 2 demonstrates that sensory processing hierarchies exhibit increasing gradients of cortical thickness, related to changes in cortical cytoarchitecture. In Chapter 3, cytoarchitectonically described differences in gyral and sulcal laminar structure were used to create markers of laminar change from MRI changes in schizophrenia. Classical measurements of histology have limitations; they are observer dependent, two-dimensional with limited coverage of the cortex. To address these issues, Chapters 4-6 document work carried on BigBrain, a 3D 20$\mu$m resolution histological dataset. I created a high-resolution 3D atlas of laminar cytoarchitecture, which was mapped to MRI-compatible cortical surface reconstructions. Chapter 4 records the development of an automated 1D profile-based approach to laminar analysis, revealing basic principles of cortical cytoarchitecture. In Chapter 5 this approach was extended to identify 6 cortical layers throughout the isocortex. These tools can be used to segment 1D cortical intensity profiles derived from any modality. In Chapter 6, the analysis of cortical gradients initially identified using MRI cortical thickness in Chapter 2 was replicated and extended using novel histological data. First histological cortical thicknesses were tested for the same patterns organization measured on in vivo MRI in Chapter 2. These analyses were extended to test which layers contributed most to overall thickness. High-resolution, complete maps of cortical cytoarchitecture mapped to MRI-template cortical surface reconstructions, are a powerful tool and dataset for the neuroimaging community. They offer new possibilities for linking cortical microstructure to in vivo neuroimaging.

Acetabular labral tears are associated with hip osteoarthritis. A current surgical treatment strategy for a torn labrum, labral resection, has recently shown poor patient outcomes with radiographic signs of osteoarthritis two-years post-operation. Since mechanical factors play a role in the etiology of osteoarthritis, identifying the mechanical role of the labrum may enhance current surgical treatment strategies. In this pilot study, we assessed the relationship between mean cartilage strain, maximum cartilage strain and the three-dimensional cartilage strain distribution in six human cadaver hips with various pathologic conditions of the labrum. We developed a novel technique of mapping cartilage strain using quantitative magnetic resonance imaging (qMRl). qMRl provides a non-invasive means of quantifying the cartilage strain distribution in the hip in three dimensions. Each specimen was assessed first with an intact labrum, then after surgically simulating a longitudinal peripheral labral tear, then after arthroscopically repairing the tear, and after labral resection. We validated the precision of the technique through use of an additional specimen which served as a control. To minimize motion artifact in the high-resolution MR images, we determined that 225 minutes was required for cartilage to reach a steady-state thickness under load. We also determined 16.5 hours was required for cartilage to recover to a steady-state unloaded thickness. The difference in mean and maximum cartilage strain when the labrum was repaired and resected was assessed using a paired t-test. We found that the resected group had an increased mean and maximum cartilage strain of 4% and 6%, respectively and the 3D cartilage strain distribution was elevated throughout the region of interest. When the condition of the intact labrum was compared to the torn labrum, we found no change in mean and maximum cartilage strain, and little obvious change in the 3D pattern of cartilage strain distribution. Based on our findings of increased cartilage strain after labral resection when compared to labral repair, we hypothesize that the labrum’s contribution of additional surface area assists in load distribution, which spares cartilage from excessive loads. We therefore recommend that the longitudinal peripheral torn labrum should not be resected if it is possible to be repaired, because in vivo, labral resection may create an environment with increased articular cartilage strain, which is thought to be associated with cartilage degeneration. / Applied Science, Faculty of / Mechanical Engineering, Department of / Graduate

The move towards higher static magnetic field strengths in MRI has allowed improved imaging quality from increased signal to noise ratio. However challenges have arisen from increased inhomogeneity in the radio frequency (RF) fields required to create MR signals and greater RF energy deposition – known as the specific absorption rate (SAR) – within imaging subjects. These factors have prompted the use of parallel transmission (PTx) MRI; in which multiple independent channels are used to control the RF electromagnetic fields. In this thesis the aim was to develop methods for controlling SAR using PTx and to assess the impact of RF safety in various scenarios. The electromagnetic behaviour of an 8-channel PTx RF coil was fully simulated which enabled the examination of differences between full simulations and a commonly modelled idealised situation. It was found that large discrepancies could result in the idealised model in certain situations. The full RF coil model was for producing SAR simulations of various adult male voxel models. These SAR models were used to perform RF shimming, in which a complex weighting is applied to each channel of a PTx system to yield improved RF conditions. This was done for two scenarios: to perform lower SAR cardiac MRI with greater RF field homogeneity in vivo for optimised imaging; and to explore methods for decoupling the transmit coil from a simulated prosthetic hip implant embedded within an adult male whilst still producing a uniform imaging field. In both scenarios, reduced SAR configurations could be found that enabled improved imaging with greater RF safety. A separate model of a 2-channel birdcage RF coil was developed to assess SAR deposition in neonates during MRI examinations. It was found that under normal operation at 3 T, local SAR constraints produced by the scanner are conservative by a factor of four.

Fetal growth restriction (FGR) is a serious complication of human pregnancy where the fetus fails to reach its genetically pre-determined growth potential. It is a common condition, affecting 5 -15% of all pregnancies (Gardosi 2009) and is linked to a third of all antepartum deaths (CEMACH 2008). An ongoing problem for obstetricians is the difficulty in diagnosing and predicting FGR and those at highest risk of poor outcomes. Placental insufficiency is a major cause of FGR and specific abnormalities in placental morphology and function occur in this condition; constituting an abnormal FGR placental phenotype (Sibley, Turner et al. 2005). Magnetic Resonance Imaging (MRI) is a powerful tool that allows quantitative analysis of several indices relating to tissue structure and function and, therefore, is of potential use in identifying this phenotype. We hypothesised that a range of MR indices would be feasible in the placenta at 1.5 T, that these indices would be altered in FGR and that there would be correlations with relevant parameters of placental morphology. Ultimately, we aimed to assess whether these indices could be used in the assessment of FGR in utero.Using MRI we estimated placental volume, widths, length and depths in groups of women with normal and FGR pregnancies. We also measured placental relaxation times, T1 and T2, which relate to tissue composition and assessed parameters relating to blood flow using Intra-Voxel Incoherent Motion (IVIM) and Arterial Spin Labelling (ASL). We demonstrated an FGR placental phenotype that was reduced in volume but increased in depth, by around 10mm, with a shorter T2 relaxation time and lower values of D (the diffusion coefficient) measured by IVIM. A trend for reduced perfusion measured by ASL was observed in pregnancies with birthweights less than 10th centile (Gardosi, Chang et al. 1992). T2 and D also correlated with stereological indices of placental morphology.In conclusion, the studies in this thesis illustrate these MRI indices show great potential asbiomarkers for identifying the FGR placenta

A novel approach for the analysis of spinal cord deformation based on a combined technique of non-invasive imaging and medical image processing is presented. A sopposed to traditional approaches where animal spinal cords are exposed and directly subjected to mechanical impact in order to be examined, this approach can be used to quantify deformities of the spinal cord in vivo, so that deformations — specifically those of myelopathy-related sustained compression — of the spinal cord can be computed in its original physiological environment. This, then, allows for a more accurate understanding of spinal cord deformations and injuries. Images of rat spinal cord deformations, acquired using magnetic resonance imaging (MRI), were analyzed using a combination of various image processing methods, including image segmentation, a versor-based rigid registration technique, and a B-spline-based non-rigid registration technique. To verify the validity and assess the accuracy of this approach, several validation schemes were implemented to compare the deformation fields computed by the proposed algorithm against known deformation fields. First, validation was performed on a synthetically-generated spinal cord model data warped using synthetic deformations; error levels achieved were consistently below 6% with respect to cord width, even for large degrees of deformation up to half of the dorsal-ventral width of the cord (50% deflection). Then, accuracy was established using in vivo rat spinal cord images warped using those same synthetic deformations; error levels achieved were also consistently below 6% with respect to cord width, in this case for large degrees of deformation up to the entire dorsal-ventral width of the cord (100% deflection). Finally, the accuracy was assessed using data from the Visible Human Project (VHP) warped using simulated deformations obtained from finite element (FE) analysis of the spinal cord; error levels achieved were as low as 3.9% with respect to cord width. This in vivo, non-invasive semi-automated analysis tool provides a new framework through which the causes, mechanisms, and tolerance parameters of myelopathy-related sustained spinal cord compression, as well as the measures used in neuroprotection and regeneration of spinal cord tissue, can be prospectively derived in a manner that ensures the bio-fidelity of the cord. / Applied Science, Faculty of / Electrical and Computer Engineering, Department of / Graduate

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