Experimental Evaluation of Advanced Diffusion MRI Methods Towards Improved Assessment of Myelinated Neural Tissue
Kelm, Nathaniel David
Diffusion-weighted MRI (DWI) techniques have demonstrated the ability to non-invasively assess normal and pathological neural tissue. Recently-developed advanced DWI methods have the potential to provide quantitative biomarkers with improved sensitivity and specificity to changes in tissue microstructure, yet thorough evaluation and validation of these methods have been limited. In this dissertation, two of these DWI methods that are clinically practical, diffusion kurtosis imaging (DKI) and the biophysical white matter tract integrity (WMTI) model, were experimentally evaluated through comparisons to other MRI methods, such as diffusion tensor imaging (DTI), and histological measurements in clinically-relevant animal models of abnormal brain myelination, normally- and abnormally-developing brain, and acute peripheral nerve injury and repair. First, examining hypo- and hypermyelinated adult mouse brain, it was shown that DKI offered additional sensitivity over DTI to changes in myelin content, as well as complementary information regarding diffusion in the intra- and extra-axonal spaces. WMTI exhibited increased specificity to changes in white matter microstructure, including axon fraction and myelin thickness. Next, in normal and abnormal mouse brain development, DKI was shown to better distinguish microstructural changes between different ages and mouse models compared with DTI, and WMTI again provided improved specificity to alterations in axon fraction and myelin thickness. Relationships between DWI metrics and white matter microstructure during development were consistent with those observed in adult mice, meaning these associations are applicable to a wider scope of studies examining brain white matter. Finally, in injured rat sciatic nerve, it was demonstrated that DKI and WMTI were sensitive to each stage of nerve degeneration and regeneration. Additionally, WMTI intra-axonal diffusivity displayed increased specificity to axon structure after injury and repair, making it a useful metric for future studies assessing peripheral nerve injury. Overall, this work provided significant advancement in the experimental knowledge of DKI and WMTI and their potential utility in the assessment of neurological conditions and evaluation of treatments.