Electronic Thesis and Dissertation Repository

Thesis Format

Integrated Article

Degree

Doctor of Philosophy

Program

Neuroscience

Supervisor

Palaniyappan, Lena

Affiliation

McGill University

2nd Supervisor

Khan, Ali R.

Co-Supervisor

Abstract

White matter alterations observed using diffusion weighted imaging are characteristic of chronic schizophrenia, but it is unclear when these changes arise over the course of the disease. Schizophrenia has long been considered both a neurodevelopmental disorder, given its genetic and prenatal risk factors, its long childhood prodromal period, and its onset in late adolescence, as well as a neurodegenerative disorder with a chronic, often declining trajectory. Both of these frameworks have been used to describe white matter pathology in the disease, either as insufficient maturation by disease onset, or as premature deterioration over disease chronicity. However, these hypotheses are based primarily on cross-sectional data from chronic patients. Such data do not adequately address the early stages of the disease and cannot refute an alternative hypothesis---that pre-existing white matter damage predisposes patients to more chronic forms of schizophrenia.

This thesis tests neurodevelopmental and neurodegenerative hypotheses using data from three controlled cohorts of early schizophrenia patients. In the first study, diffusion tensor imaging was used to compare first episode and early schizophrenia patients to chronic patients and healthy controls. While chronic patients had evidence of white matter degradation, no differences were observed between controls and first episode patients in two separate datasets. In the second study, a microstructure-informed model of diffusion called NODDI was used to compare the grey and white matter of early schizophrenia patients with controls. No differences were found in the white matter, but a greater proportion of free water was found throughout the grey matter along with reduced cortical thickness. In the third study, two years of annual follow-up data from early schizophrenia patients were compared with healthy controls in two separate datasets. No longitudinal differences were observed in any diffusion tensor imaging parameters between patients and controls in either dataset. However, complementary associations between white matter alterations and negative symptoms were observed in both datasets.

These data suggest white matter pathology is not a causative factor in psychosis, but may mediate disease severity and outcomes, especially respecting negative symptoms.

Summary for Lay Audience

The symptoms of schizophrenia, ranging from hallucinations, delusions, and disorganized thought and language patterns, to a complete lack of communicative effort or a lack of interest in any activities, seem to stem from one common problem: a breakdown of connectivity in the brain. In long-term schizophrenia, the wiring of the brain also appears to be degraded, potentially causing inefficient information processing.

Many researchers believe this degraded wiring occurs over the course of development. Many also believe the wiring further degrades as the disease progresses. However, both of these ideas are based primarily on data from patients observed one single time in the later stages of disease. Thus, we do not yet know if white matter changes are always present early on the disease course. Furthermore, without watching individual patients over time to see if their white matter is changing, we cannot tell whether schizophrenia actually causes degradation of white matter, or if patients with worse pre-existing white matter are more likely to develop chronic versions of the disease.

This thesis tackles both of these problems. It uses diffusion weighted imaging, a type of MRI used to probe the structural properties of the white matter. We first investigated the white matter of patients who recently received a diagnosis of schizophrenia. Unlike chronic patients, who had all the usual signs of degradation, the early schizophrenia patients were almost completely indistinguishable from controls. We then used a more advanced form of diffusion weighted imaging to see if we could detect subtler changes. Once again, no differences were found between early schizophrenia patients and controls, although we did find some changes in the non-wiring regions of the brain (grey matter). Finally, we looked at at a group of patients followed over two years to see if white matter got worse over time. We failed to find any differences with controls, although patients with worse symptoms appeared to have more degraded white matter.

From these data, we argue that white matter pathology may contribute to worse outcomes in schizophrenia, but does not directly cause the psychotic aspects of the disease.

Creative Commons License

Creative Commons Attribution-Noncommercial 4.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial 4.0 License

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