Electronic Thesis and Dissertation Repository

Thesis Format

Integrated Article

Degree

Doctor of Philosophy

Program

Medical Biophysics

Supervisor

Theberge, Jean

2nd Supervisor

Palaniyappan, Lena

Co-Supervisor

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.

Summary for Lay Audience

This thesis focuses on using magnetic resonance spectroscopy (MRS) to better understand the molecular mechanisms underlying the full range of schizophrenia symptoms. Since our understanding of why schizophrenia develops or how we can cure it still eludes us, most of our efforts are currently focused on understanding and treating the symptoms of the illness. Two brain chemicals that appear to play key roles in how schizophrenia symptoms manifest are glutamate and glutathione. This thesis works towards understanding these two metabolites using traditional MRS methods as well as a dynamic approach (functional MRS or fMRS) in schizophrenia.

The first body of work investigates the prodromal phase of psychosis. Specifically, we look at the brain’s main antioxidant, glutathione, and whether there is a difference in the amount present in individuals in the prodromal stages compared to healthy individuals.

The second body of work introduces a change from traditional neuromolecular observations (e.g., representation of all collected MRS data into a single time point) and utilizes a dynamic approach (i.e., fMRS) to investigate the difference in response between individuals with first-episode schizophrenia and healthy controls while performing a task during an MRS scan. Since human brain molecular concentrations are always fluctuating, even at rest, it is important to use dynamic tools for studying dynamic molecular systems of the brain.

The last body of work uses simulations to mimic fMRS paradigms across multiple signal-to-noise ratios (SNR) and activation schemes. The overall goal of this project was to determine the smallest detectable difference between ‘resting’ and ‘task’ periods of fMRS paradigms to ensure future fMRS studies are appropriately powered to detect changes of desired magnitudes. In other words, this work will help to answer the question of ‘are we not detecting activation in our fMRS paradigm because there truly is no activation produced or because the level of noise is masking the activation that we would otherwise see with better SNR’.

In conclusion, this thesis provides an overview of potential glutamatergic abnormalities in schizophrenia as well as the development and usage of fMRS as the appropriate tool for investigating the dynamics of the brain’s molecular mechanisms.

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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