Optimizing detection of glutamate functional magnetic resonance spectroscopy signals in the human brain

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INTRO - Proton Magnetic Resonance Spectroscopy (1H-MRS) has been a valuable tool allowing the non-invasive study of in vivo human brain glutamate. Up to now, measurements of glutamate with 1H-MRS at rest have been interpreted as a direct reflection of excitatory neurotransmission. Unfortunately, this interpretation has not been evidence-based. Observations show that glutamate varies among brain regions, different arousal/functional state and in disease states and our group showed dynamic changes during performance of a cognitive task (a method we call glutamate fMRS). This important advance strengthens the interpretation of glutamate levels as proxy to neural activity. Glutamate fMRS is still an immature tool and requires much development to enter main stream neuroscience. OBJECTIVES - Our long term goal is to determine the biological underpinnings of glutamate 1H-MRS signals at rest and during brain activation. Our short term goal will be to identify, localize and quantify the pools of glutamate contributing to the signal during functional activation. HYPOTHESIS - The glutamate signal from 1H-MRS volumes of interest (1.0-8.0ml) originates from molecules within several millions of cells (neuron, glia, etc.) in different tissue types (grey, white matter). We hypothesize that glutamate 1H-MRS signals responding to neuronal activation originate from a separate physiological pool than resting signals and that their relative signal contributions can be quantified. APPROACH - 1) Demonstrate how glutamate 1H-MRS signals vary linearly with neural activation at the single-subject level. We will adapt our glutamate fMRS cognitive paradigm to include a variable level of difficulty by increasing levels of stimulus encoding load. 2) Determine relative signal contributions from active/inactive glutamate pools by analyzing fMRS time courses using independent component analysis. 3) Develop a method to assess whole-brain glutamate during performance of a task rather using chemical exchange saturation transfer (CEST), an imaging method signal-to-noise ratio 700 times greater than 1H-MRS so that whole-brain maps can be obtained repeatedly. We will use custom pulse sequences and the only 7.0 Tesla human scanner in Canada. NOVELTY/SIGNIFICANCE - The research will provide a solid basis on which to physiologically interpret sources of variability in brain glutamate levels obtained with 1H-MRS at rest and during neural activation. This opens a new era of non-invasive functional brain activity measurement more directly related to neuronal firing rate than the traditional BOLD fMRI method. The work will establish the normal variance in healthy individuals for relative sizes of the active vs inactive glutamate pools. We will train medical biophysics students to design and implement glutamate fMRS and CEST pulse sequences and to develop data analysis tools supporting this nascent field of study.