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Thesis Format

Integrated Article

Degree

Doctor of Philosophy

Program

Neuroscience

Collaborative Specialization

Machine Learning in Health and Biomedical Sciences

Supervisor

Khan, Ali R.

Abstract

The hippocampus is a widely studied yet enigmatic region of the central nervous system which plays a major role in encoding perception in both spatial and temporal domains. The glial cells, neurites, and fiber pathways that make up the micron-scale structures (i.e. microstructure) of the hippocampus are essential in producing these functions. Thus there has been great interest in probing its microstructure non-invasively to characterize its function, or potential dysfunction in a variety of diseased states. Diffusion magnetic resonance imaging has emerged as a popular technique to probe microstructure, as it is sensitive to the diffusion of water which is on the scale of micrometres. Inspired by advances in both diffusion MRI and in the ability to faithfully capture the topology of the hippocampus, the current thesis aimed to test the capabilities of diffusion MRI and improve our understanding of the microstructure of the hippocampus in both healthy and diseased states. Leveraging a popular diffusion acquisition and model in healthy adults, in Chapter 2 I show spatially distinct microstructural distributions of parameters related to stick-like process (i.e. potential glia, axon, dendrite) density and dispersion as well as in commonly used diffusion derivatives including fractional anisotropy and mean diffusivity. We further show that these microstructural measures were separable across the hippocampal subfields which are defined via cyto- and myeloarchitectonics, suggesting that they may be faithfully capturing the underlying structure of the hippocampus. In Chapter 2 I also developed a method to quantify diffusion orientations relative to the three canonical hippocampal axes. In Chapter 3 I applied such developments to examine hippocampal microstructure in Alzheimer’s disease, mild cognitive impairment, and healthy elderly controls. Specifically, I show that there are distinct changes in diffusion orientations within the hippocampus of individuals with Alzheimer’s disease and mild cognitive impairment. Such changes may reflect the known degeneration of the perforant path. The AD-related changes in diffusion orientations were found to not have significant spatial overlap with AD-related changes in mean diffusivity, suggesting that they may be capturing varying spatially-localized disease processes. Finally, in Chapter 4 using an extended diffusion acquisition, I applied a novel diffusion model which aims to capture cell bodies to probe the development of hippocampal microstructure in childhood and adolescence. I found significant changes in microstructure measures ostensibly related to neurites and soma between 8-19 years of age. Furthermore, I show how these age-related changes in microstructure may be related to synaptic density, myelin content, and hippocampal interneurons. ii Overall, the work presented in this thesis provides new knowledge of the structural organization of the hippocampus in vivo, and provides impetus for future work studying the relation between hippocampal microstructure, cognition and its deterioration in diseased states.

Summary for Lay Audience

The brain is a complex organ made up of many tiny cells, which we refer to as microstructure. A particular technique called diffusion magnetic resonance imaging (dMRI) provides the unique ability to study such microstructure non-invasively. One brain region that is often targeted both in research and in the clinic is called the hippocampus. The hippocampus is thought to play an important role in producing functions such as memory and navigation. It is well known that the microstructure of the hippocampus is affected in a variety of disorders and diseases, including Alzheimer’s disease, schizophrenia, epilepsy, and more. The current thesis aimed to explore the application of dMRI within the hippocampus to improve our understanding of its microstructure in health, disease, and development. In chapter 2 we show a variety of measures from dMRI across the whole hippocampus of healthy adults, providing background for the kinds of microstructural properties we may be able to capture and as a baseline for further work. In chapter 3 we apply the knowledge from chapter 2 to examine the hippocampus in Alzheimer’s disease. We found large changes within the hippocampus between healthy elderly individuals, individuals with mild cognitive impairment, and individuals with Alzheimer’s disease, suggesting that the hippocampal microstructure is greatly affected in such a disease state. In chapter 4 we used data from a very strong MRI scanner to look at new dMRI measures in the hippocampus across childhood and adolescence, a formative development period. We found notable changes relating to specific aspects of the hippocampal microstructure. Altogether, this thesis shows how dMRI can be used in conjunction with new ways to model the hippocampus to study its microstructure in a variety of populations.

Creative Commons License

Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.

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