Magnetic Resonance Spectroscopy and Imaging Studies of Brain Functions

National Institute Of Mental Health

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Abstract

The goal of this research is to develop advanced magnetic resonance spectroscopy (MRS) and imaging techniques and to apply them and other complementary methods to study brain metabolism, neurotransmission, and enzyme activity. MRS allows in vivo measurement of the neurotransmission of glutamate and GABA, which play important roles in many major psychiatric diseases, including depression and schizophrenia. One of the central themes of our research is to remove the technical barriers to clinical application of carbon-13 MRS techniques. Conventional carbon-13 MRS approaches require scanners with a broadband channel and specialized or custom-made hardware. Furthermore, the requirements of high radiofrequency power broadband heteronuclear decoupling make it impossible to apply conventional carbon-13 MRS to study the frontal cortex, which is involved in a variety of higher functioning processing, such as regulating emotions, social interactions, and personality. We have been searching for proton-only MRS approaches to detect carbon-13 labeling of glutamate and GABA indirectly by measuring the changes in the spectral pattern of proton MRS caused by incorporation of carbon-13 labels into amino acids. To this end, we have developed novel proton MRS techniques that enhance both the signal intensity and spectral resolution of glutamate, glutamine and GABA at the high magnetic field of 7 Tesla using standard commercially available hardware (See, for example: L. An, M. Ferraris Araneta, M. Victorino, and J. Shen, Signal enhancement of glutamine and glutathione by single-step spectral editing, J. Magn. Reson., 316:106756 (2020), and L. An, J.W. Evans, C. Burton, J.S. Tomar, M. Ferraris Araneta, C.A. Zarate Jr., and J. Shen, Roles of strong scalar couplings in maximizing glutamate, glutamine and glutathione pseudo singlets at 7 Tesla, Front. Phys., 10:927162 (2022).). We have subsequently detected carbon-13 labeling of glutamate and glutamine at the high sensitivity and spatial resolution of proton MRS (L. An, S. Li, M. Ferraris Araneta, C.S. Johnson, and J. Shen, Detection of 13C labeling of glutamate and glutamine in human brain by proton magnetic resonance spectroscopy, Sci. Rep., 12:8729 (2022).). In addition to carbon-13 studies, we are also conducting proton and phosphorus-31 MRS research. Building upon our previous research in neurochemical correlations originating from spectral overlap (S. Hong, L. An, and J. Shen, Monte Carlo study of metabolite correlations originating from spectral overlap, J. Magn. Reson., 341:107257 (2022).) we have mapped the landscape of pre-existing spectral correlations in short echo time proton MRS and characterized the influence of static magnetic field strength on spectral correlations in phosphorus-31 MRS (S. Hong, and J. Shen, Neurochemical correlations in short echo time proton magnetic resonance spectroscopy, NMR Biomed., 36:e4910 (2023) and S. Hong, and J. Shen, Magnetic field dependence of spectral correlations between 31P-containing metabolites in brain, Metabolites, 13:211 (2023).). We found not only extensive spectral correlations among neurochemicals but also highly significant influence of background signals on spectral correlations among neurochemicals. These results have prompted us to develop 7 Tesla as well as 3 Tesla MRS strategies that suppress spectral correlations. In particular, we have been making progress in developing new MRS strategies for characterizing glutamatergic and GABAergic function and dysfunction using MRS with minimized spectral correlations. Cell pathology in neuropsychiatric disorders has mainly been accessible by analyzing postmortem tissue samples. Although molecular transverse relaxation informs local cellular microenvironment via molecule-environment interactions, precise determination of the transverse relaxation times of molecules with scalar couplings, such as glutamate and glutamine, has been difficult using conventional MRS technologies. We have developed a novel 2D MRS technique that turns targeted multiplets into high-intensity pseudo singlets in each column of the acquired 2D dataset, freeing up the entire row dimension for transverse relaxation encoding. This results in increased spectral resolution, minimized background signals, and markedly broadened dynamic range for transverse relaxation encoding. Since glutamate predominantly resides in glutamatergic neurons and glutamine in glia in the brain, we expect this noninvasive technique to provide a way to probe cellular pathophysiology in neuropsychiatric disorders, to characterize disease progression, and to monitor treatment response in a cell type-specific manner in vivo (L. An, and J. Shen, In vivo magnetic resonance spectroscopy by transverse relaxation encoding with narrowband decoupling, Sci. Rep., 13:12211 (2023).).