Cortical Structure in Early Schizophrenia
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.