| Summary: | <p>Diffusion MR methods are a powerful means to probe tissue microstructural features. Most diffusion MR methods and signal representations, however, do not explicitly acknowledge the inherent time-dependence of diffusion, although it is precisely this time-dependence which reveals the characteristics of the microstructure. More advanced diffusion MR methods have emerged to study time-dependent phenomena. Diffusion exchange spectroscopy (DEXSY) measures exchange between diffusive microenvironments, and temporal diffusion spectroscopy (TDS) measures the time-dependence of diffusion directly. These methods, while powerful, have various limitations, particularly in their high data requirement.</p>
<p>This thesis details the development and validation of rapid, information-rich methods to probe exchange and time-dependent diffusion and which improve upon DEXSY and TDS. To improve upon DEXSY, a rapid sub-sampling scheme called the `curvature' method is developed to isolate exchange from other effects such as restriction, while requiring as few as 5 total acquisitions. The speed of the method enables the study of exchange in near real-time and also permits the study of distributed exchange times, revealing new insights about the nature of exchange in tissue. To improve upon TDS, a single-shot method is developed to probe diffusion over sub-millisecond timescales while also avoiding off-resonance effects, called the static gradient, time-incremented echo train acquisition (SG-TIETA).</p>
<p>The methods are tested using a tabletop, permanent magnet system with a strong static gradient as well as pre-clinical scanners capable of imaging. Studies of simple liquids, tissue phantoms, yeast, ex vivo neonatal mouse spinal cord under various perturbations, and in vivo mice are presented to support the feasibility and utility of the developed methods. Of note, the exchange time is found to be linked to steady-state, metabolic activity in tissue, representing a potentially useful biomarker. Overall, novel diffusion MR methods sensitive to exchange and time-dependent diffusion are developed and validated in a series of pre-clinical experiments.</p>
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