Date of Award

2021

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Biochemistry & Molecular Biophysics

First Advisor

Ravinder Reddy

Abstract

Glutamate is one of the primary neurotransmitters in the human brain, and many unanswered questions in neuroscience, psychiatry and medicine revolve around this molecule: its production, transport, conversion or degradation, regulation and effects. Yet, to date, methods for actually measuring glutamate within the human body are extremely limited. Amongst the few options in the medical imaging toolbox are magnetic resonance spectroscopy (MRS) and a recently introduced specialized form of magnetic resonance imaging (MRI) known as glutamate-weighted chemical exchange saturation transfer imaging, or gluCEST. MRS, while providing good specificity at high field strengths, lacks spatial or temporal resolution. GluCEST has the potential to provide excellent spatial resolution, but has generally been limited to single-slice acquisitions with sub-optimal B1 correction, precluding its wider application to volumetric measurements of brain structures. In this thesis, we present a novel way to correct gluCEST for B1 inhomogeneity, yielding higher quality images. We then demonstrate expansion of single-slice gluCEST imaging to volumetric ‘slab’ imaging, greatly expanding our ability to capture specific structures within the brain. We apply gluCEST in both two and three dimensions to investigate healthy brain physiology as well as the response of healthy subjects to transcranial magnetic stimulation (TMS). We were able to detect elevated gluCEST in the dentate gyrus in the brains of healthy subjects, the first non invasive measurement of its kind pertaining to this small but vital structure. We also detected, for the first time, a change in glutamate concentration in the brains of subjects who have received TMS. Finally, we present work in the area of spectroscopy, presenting a technique in which –in sharp contrast to existing methodologies requiring non-standard hardware-- metabolic dynamics of glutamate can be detected using only proton-based chemical shift imaging (CSI) in conjunction with oral ingestion of deuterium labeled glucose. While itself limited in spatial resolution, this ability to detect and visualize the dynamic neural metabolism of glucose to glutamate provides a deeply complimentary source of information to gluCEST. In the future, qCSI and gluCEST could be used in tandem to provide next-generation precision diagnostics for patients suffering from neurological maladies of metabolic origin.

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