White matter organisation in the human brain: diffusion MRI investigation of microstructural alterations in chronic schizophrenia and post-mortem validation

Abstract

Schizophrenia is a chronic and disabling mental disorder affecting 0.7% of the worldwide population, characterised by psychotic symptoms such as delusions, hallucinations, disorganised speech and behaviour, and by social or occupational dysfunction as outlined by the DSM-V. The aetiology of schizophrenia is not yet known and requires multi-disciplinary research methods in order to understand the pathology of the disorder. To date neuroimaging is not used to determine a diagnosis of schizophrenia, however, neuroimaging research contributes to the development of in vivo biomarkers, which can be used to establish reliable treatment methods, and improve patient quality of life. This thesis investigates white matter organisation in chronic schizophrenia using novel neuroimaging acquisition and analysis approaches. The methods used to assess white matter organisation in this clinical neuroimaging analysis were then validated with neuroimaging and histology measurements of the human post-mortem brain. Chapter two of this thesis details the use of diffusion MRI, a relatively new neuroimaging technique, to investigate white matter microstructural alterations in a cohort of participants with severe chronic schizophrenia. This study used both traditional and novel approaches to analyse in vivo diffusion MRI data, and have not previously been carried out in a similar cohort of participants. The use of more advanced image analysis methods may provide additional information of the neuropathology of schizophrenia which would not be detected using conventional approaches. The accuracy of multi-fibre orientation estimation methods used to model diffusion MRI data in vivo requires investigation to ensure novel approaches reflect the underlying neuroanatomy. Chapters three and four outline the validation study carried out using post-mortem human brains, which provides information to bridge the gap between diffusion MRI data and the underlying white matter organisation. The direct comparison of fibre orientation measurements from imaging and histology of human neuroanatomy provides evidence to support the assumptions of white matter organisation made from diffusion MRI in vivo. This validation of in vivo fibre orientation reconstructions can only be carried out using the post-mortem human brain. The work presented here, provides evidence of white matter alterations in schizophrenia, detected using traditional and novel approaches to analyse diffusion MRI data. We have also presented validation of the novel approaches applied in vivo using histology of the human post-mortem brain. The histology method used has not previously been carried out to directly compare white matter organisation reconstructed from neuroimaging and histology data. This post-mortem analysis validates the use of advanced methods for diffusion MRI analysis in vivo, which supports its use for future studies to accurately investigate white matter organisation in schizophrenia.