Electronic Thesis and Dissertation Repository

Degree

Doctor of Philosophy

Program

Medical Biophysics

Supervisor

Dr. Jean Théberge, Dr. Peter Williamson

Abstract

Schizophrenia is a debilitating disease that affects about 1% of the population. Current therapeutic interventions mostly target dopaminergic neurotransmission but are not effective in treating all symptoms. There is growing evidence to support involvement of glutamatergic neurotransmission, which may better account for the symptomatology of schizophrenia.

Glutamate concentrations can be measured in vivo using magnetic resonance spectroscopy (MRS). Stronger MRIs provide benefits for MRS, but they also present challenges. Simulations were designed to examine how MRI field strength influences metabolite quantification. Glutamate and its metabolic precursor, glutamine, were more reliably and independently quantified with higher MRI field strengths, showing a clear benefit for MRS.

Using a 7T MRI, voxels were placed within the dorsal anterior cingulate cortex (dACC) and thalamus of volunteers with schizophrenia, a psychiatric control group of volunteers with major depressive disorder (MDD), and healthy controls. Glutamine and glycine, both involved in glutamate neurotransmission, were lower in the thalamus in schizophrenia relative to healthy controls, whereas dACC glutamate concentrations were higher, demonstrating glutamatergic abnormalities in schizophrenia at rest.

Prior MRS studies of schizophrenia have been in resting conditions. In a proof of concept study with healthy controls, it was shown that the Stroop Task was able elicit a significant glutamate increase in the dACC when in a functional state (glutamate fMRS) relative to resting conditions using the 7T MRI. This was then explored in the same schizophrenic and MDD subjects as the resting MRS study. Healthy controls significantly increased glutamate concentrations, but the schizophrenic and MDD groups did not significantly. The schizophrenic group had a slower glutamatergic response followed by a slower recovery, and, was the only group to demonstrate significant glutamine increases when activated, indicating potential abnormalities in glutamate dynamics.

Using a 7T MRI, glutamate was explored in resting and activated conditions in schizophrenia. Glycine was demonstrated to be lower in schizophrenia using MRS for the first time, and the first functional MRS study was performed in a psychiatric population. The studies were made stronger by inclusion of a psychiatric control group. Future studies of schizophrenia with glutamate fMRS should focus on the delayed glutamatergic response to functional activation and abnormal recovery.


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