New Approaches to the Use of Magnetic Resonance Spectroscopy for Investigating the Pathophysiology of Auditory-Verbal Hallucinations

Abstract

Magnetic resonance imaging (MRI) may be considered one of the most useful technological developments in the field of cognitive neuroscience. Above the ability to provide detailed anatomical images, MRI has afforded researchers new insights into both the healthy brain and pathological states through the ability to map neural activity with blood-oxygen-level dependent functional MRI (BOLD-fMRI) and to perform quantitative analyses of biochemical compounds in vivo with magnetic resonance spectroscopy (MRS). Despite the usefulness of these methods, one of the limitations to BOLD-fMRI is that it does not reveal how changes in neural activity relate to excitation and inhibition in a neural circuit, commonly characterised as the excitation/inhibition balance. Similarly, while MRS may allow quantitative measurement of the primary excitatory and inhibitory neurotransmitters in the brain, namely glutamate and γ-aminobutyric acid (GABA), it may only reveal average levels over the course of an acquisition, and MRS alone provides no measure of neural activity. A number of studies have attempted to relate patterns of activity as measured with fMRI with metabolite levels acquired separately with MRS, and though this approach may be useful for investigating how metabolite levels may predict or influence patterns of activity, it does not allow detection and measurement of acute metabolic changes occurring over short time scales, or how changes correlate with neural activity. The motivation for this project was to investigate new approaches to performing MRS that would allow measurement of dynamic changes in the balance of excitatory and inhibitory neurotransmitter levels with high temporal resolution (i.e. functional MRS), as well as methods for simultaneous, functional imaging of both neural and metabolic activity. It is believed that these techniques may advance ongoing investigations within the research group into understanding of the pathophysiology of auditory-verbal hallucinations, one of the characteristic symptoms of schizophrenia. This project proceeded through three key stages. The first stage was to create an overview of key metabolites implicated in the pathophysiology of schizophrenia that may be measured with MRS. The first article in this thesis reviews current practice and new developments in the use of MRS in measuring metabolites in four categories: N-acetyl aspartate (NAA), glutamate and glutamine (or the composite “Glx” signal), GABA and glutathione (GSH). The second stage was to evaluate a method for analysing MR-spectra in a time-resolved manner at high temporal resolution. Using transcranial direct current stimulation (tDCS) to induce a change in local levels of Glx and GABA, MR-spectra were acquired continuously before, during, and after stimulation and analysed using a novel “time-windowing” approach presented in the second article in this thesis. Finally, the BOLD effect that provides the contrast used in BOLD-fMRI has been demonstrated to affect the linewidth of MR-Spectra. By acquiring spectra with interleaved frames without water suppression, changes in the linewidth of the unsuppressed water signal may be used as a measure of the BOLD effect, effectively permitting simultaneous measurement of neural and metabolic activity. The third article in this thesis was a feasibility study, determining whether this approach may be implemented using a MEGA-PRESS sequence at a field strength of 3 T in order to investigate how changes in local GABA and Glx levels relate to changes in the BOLD signal in response to visual stimulation. The methods presented in this thesis show great potential for measuring dynamic changes in GABA levels as well as simultaneous measurement of neural and metabolic activity at a field strength of 3 T. However, more work is required to evaluate their effectiveness conclusively. Further studies may benefit from judicious choice of stimulus and experimental design as well as the use of specialised sequences that do not rely on spectral editing.