Novel MRS methods for measuring brain energetics and neurotransmitter cycling

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DESCRIPTION (provided by applicant): Understanding neuronal metabolism is critical for studies of brain function, and magnetic resonance spectroscopy (MRS) of infused 13C-labeled substrates is well established as the only noninvasive in-vivo technique capable of measuring glutamate neurotransmitter cycling and cell-specific neuroenergetics in both normal and diseased states. Using metabolic modeling, in vivo 13C MRS studies have successfully compared neuronal and glial energy metabolism, elucidated the linkage between neuroenergetics and neurotransmitter cycling, and identified altered brain metabolism in multiple neurological and psychiatric diseases. In vivo human studies, however, are technically challenging due to low sensitivity and complex overlapping spectra arising from J-coupling between 1H and 13C nuclei. Although the use of decoupling, a well-known NMR method to simplify spectra, has been critical to the success of in vivo studies, associated Specific Absorption Rate (SAR) limits currently restrict human studies to the occipital brain (distal to the highly heat-sensitive eyes) and to field strengths d 4T. As described in our preliminary data, we have developed a novel family of MRS pulse sequences that simultaneously generate both in-phase and anti-phase magnetization the sum of which result in a single peak, obviating the need for high-power decoupling. This presents a major new opportunity to significantly extend current in vivo human 13C MRS brain studies. The goal of this two-year technical development R21 project is to develop optimized these new 1H-13C MRS methods for the in vivo measurement of neuronal and glial TCA fluxes and glutamate/glutamine cycling rates. The focus is on ultra-high field (e7 T) indirect detection methods that maximize sensitivity in order t enable interrogating small tissue regions (~1 cc) throughout the human brain within acceptable scan times. The resulting pulse sequence(s) will be evaluated in vitro, in phantoms, and using a rat animal model, with the successful completion of the research plan producing the critical preliminary data needed to justify transitioning to human studies.