Investigating Oxidative Stress in Early Stages of Schizophrenia Using 7-Tesla Glutathione and Glutamate Functional Magnetic Resonance Spectroscopy
Abstract
Schizophrenia is a neurodevelopmental illness characterized by a complex combination of positive, negative, and cognitive symptoms. Best practices for treating schizophrenia are to manage the symptoms using antipsychotic medication. However, around a third of patients will not experience full alleviation of symptoms. In this subset of patients, there is growing evidence of abnormal pathophysiology in the brain circuitry that relate to glutamate and glutathione. The purpose of this thesis was to examine potential differences in resting levels of glutamate and glutathione and task-induced level dynamics in early-stage schizophrenia as well as to further develop effective practices in experimental designs of human brain functional magnetic resonance spectroscopy (fMRS) of glutamate and glutathione.
This thesis consists of five chapters. Chapter 1 introduces core concepts of schizophrenia and magnetic resonance imaging physics that provide a deeper understanding of the motivations behind the studies included in this thesis.
Chapter 2 was a cross-sectional study aimed at uncovering group-level differences in glutathione levels in individuals with clinical high-risk (CHR) mental states. Thirteen CHR and 30 healthy control volunteers underwent a 7-Tesla MRS scan, focusing on the dorsal anterior cingulate cortex (ACC). Positive associations between glutathione levels and social and occupational functioning were found in the CHR group, with higher glutathione levels observed in this group after accounting for variations in functional scores. Median splitting of glutathione concentrations in CHR cohorts revealed significant differences in functional outcomes, indicating glutathione as a potential marker for prognosis in emerging adults with risk features for severe mental illnesses.
In Chapter 3, functional MRS (fMRS) was applied to medication-naïve first-episode schizophrenia (FES) cohorts to investigate glutamatergic abnormalities and their role in schizophrenia symptoms. The study compared neurometabolite dynamics in response to short-term cognitive stress between 33 FES individuals and 23 healthy controls. Using a four-block fMRS paradigm, significant differences were observed in glutathione dynamics, with healthy controls showing activation and prolonged elevation of glutathione in response to cognitive stimuli, unlike FES cohorts. Lower glutamate concentrations were also observed during late recovery period in both groups, with positive correlations between normalized glutamate levels and symptom severity scores, highlighting potential antioxidant response deficiencies in early schizophrenia stages.
Chapter 4 explored spectral simulations to determine the percentage smallest detectable difference (%SDD) between active and non-active blocks in fMRS paradigms. A template spectrum from the dorsal ACC of a healthy individual was used, and spectral simulations were generated for various NAA-peak-height signal-to-noise ratios (SNRNAA) and metabolite activation schemes. The study produced a table of %SDD for glutamate and glutathione under different SNRNAA and activation conditions, providing a reference for interpreting non-significant activation findings in future fMRS studies. This work is crucial in appropriately powering the experimental design of block-based fMRS paradigms to avoid type 2 statistical errors (false negative).
Chapter 5 summarizes the work presented in this thesis and explores future directions for both schizophrenia and imaging research. Overall, these chapters highlight abnormalities in glutathione levels and dynamics in various stages of schizophrenia and provide valuable insights and methodologies for future research in this area.