Doctor of Philosophy in Physics (PhD)
Probing Brain Tissue Microstructure with Magnetic Resonance Imaging through Bayesian Learning of Signal Dynamics
MRI of multiple sclerosis, modelling of the MRI signal, quantitative susceptibility mapping, MRI physics
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Multiple sclerosis (MS) is a complex, autoimmune disease that results in demyelination and neurodegeneration. Magnetic resonance imaging (MRI) is an essential cornerstone of MS diagnosis and clinical decision making, however, clinical MRIs lack specificity to the pathological mechanisms influencing myelin health.In this thesis, two quantitative MRI techniques were probed for their potential to study myelin health in MS. First, multi-echo spin-echo myelin water imaging (MWI) was tested for its specificity to myelin lipids, proteins and iron. We demonstrated to-date unknown sensitivity of MWI and identified MS lesion changes indicative of late-stage remyelination. Thereafter, the accuracy of MWI and its potential application at ultra-high magnetic fields were investigated. Using signal simulations, the dependence of the non-negative least-squares analysis on processing and tissue parameters was described. Myelin underestimations due to B⁺₁-inhomogeneities and noise were shown to be minimized by adjusting the T₂ range according to the echo time. To translate MWI to 7T, T₂ tissue properties in seven healthy subjects were studied in comparison to 3T. We demonstrated the feasibility of 7T-MWI and discussed current limitations in assessing short T₂ times.Secondly, susceptibility-sensitive MRI was explored, which provides greater sensitivity, albeit possibly lower specificity to myelin, than MWI. Using the phase component, we showed that the MS lesion contrast is typically not driven by iron accumulation. In simulations and with post-mortem data, it was demonstrated that iron and myelin loss in combination determine the lesions’ appearance. Thereafter, the potential of the technique to become a marker of tissue damage and repair was evaluated by studying the evolution and pathological underpinnings of acute MS lesions in eleven patients over five years. Current models and their shortcomings were discussed.Finally, two technical developments were introduced. First, a multi-dynamic, high-spatial resolution susceptibility-sensitive imaging approach was presented for visualizing the central vein sign. Using phantom and in vivo data, qualitative and quantitative agreement of the proposed approach with other imaging strategies was demonstrated. Secondly, FLAIR² was introduced, a novel contrast that improves contrast-to-noise, while shortening scan time. The potential of FLAIR² to aid automated lesion segmentation was demonstrated on real-world multi-centre clinical data.
The behavior of MR phase and frequency in demyelination and damage in central nervous tissue white matter arises not only from traditionally associated bulk susceptibility changes, but also from changes to its tissue microstructure. A recently proposed generalized Lorentzian model of microstructure-related magnetic susceptibility effects predicts an increase in MR frequency due to damage in myelin in MS lesions. The same model also predicts reduction in MR frequency due to axonal degeneration. Here, we investigate the effect of both myelin and axonal damage through transection of white matter fibers in the dorsal column of rat cervical spinal cord. This injury generates secondary damage consisting of neurodegeneration along nerve tracts bilateral to the transection site, producing cases of Wallerian and retrograde degeneration free of excessive hemorrhage and inflammation. High-resolution frequency maps of degenerating tracts were correlated with histopathology for axons, myelin, degenerated myelin, and macrophages. Damage to myelin sheaths is prominent in Wallerian degeneration, where we observe strong correlations with increasing frequency up to 8 weeks post-injury. Retrograde degeneration, which consists predominantly of axonal damage, produces decreased frequency shift over time. The MR frequency shifts are sensitive to the effects of macrophage in filtration and debris clearance, which vary with white matter fiber density and affect rates of degeneration. We demonstrate how MR frequency can successfully characterize injury in rat spinal cord white matter in a manner consistent with predictions outlined by the Generalized Lorentzian Approximation Model, and conclude that these results suggest potential applications of MR frequency to supplement or replace current clinical techniques, such as myelin water and diffusion weighted imaging, as a non-invasive and quantitative method of assessing white matter damage in CNS.