Determinants of brain glutamate functional magnetic resonance spectroscopy response

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Studying the living healthy human brain non-invasively is important in understanding the dynamic interaction between connected brain regions part of a network involved in performing a given task. Functional Magnetic Resonance Spectroscopy (fMRS) of the human brain has been a useful way to study dynamic changes in brain chemicals involved in brain excitation (glutamate), inhibition (GABA) and oxidative stress (glutathione). Using fMRS, levels of individual brain chemicals have now been published, but there is currently no single theoretical framework that allows a satisfactory explanation of the wide range of glutamatergic metabolite responses observed in various functional stimulation types or tasks. This limited understanding of how the healthy brain performs tasks ultimately limits our ability to interpret chemical responses in unhealthy brains. We previously developed optimized fMRS measurement protocols for the observation of brain glutamate, the brain's main excitatory neurotransmitter. We now propose detailed observations of a more complete array of glutamatergic metabolites markers of excitation (glutamate, glutamine), inhibition (GABA) and oxidative stress (glutathione) in basic tasks aimed at understanding the effect of stimuli intensity, duration, timing and nature to provide the data necessary to construct more broadly valid models of brain region interactions. This is a critical step in the maturing of fMRS techniques that will deepen our understanding of normal glutamatergic brain responses beyond what has already been learned from hemodynamic investigations using blood oxygenation-dependent functional MRI (fMRI), the original MRI-based approach that has powered the neuroscience revolution of the last 3 decades. To reach this objective, however, fMRS data acquisition techniques and data analysis tools still require much development and a new generation of scientist familiar with these approach needs to be trained if fMRS is to achieve the same level of scientific sophistication as functional MRI. We propose to train highly qualified personnel pursuing the following three aims of our research program: 1) Optimize the fMRS data acquisition of glutamatergic metabolites by implementing metabolite-selective fMRS methods that isolate the MRS signals of up to 3 metabolites of interest in a single-shot acquisition, extending our current metabolite-selective work in resting MRS. 2) Characterize how glutamatergic fMRS signals vary in connected brain regions of the visual network via temporally interleaved fMRS measurements of glutamatergic metabolite in response to simple photic stimulation tasks of varying duration and intensity. 3) Develop multi-voxel fMRS analysis methods to identify the portion of the fMRS signal that participates to the connection between the selected brain regions by analyzing fMRS time courses using independent component analysis agnostic of the stimulation paradigm used.