The excitatory and inhibitory amino acid neurotransmitter systems of glutamate (Glu) and GABA, respectively, are critical for normal brain function. As dysregulation of glutamatergic and/or GABAergic neurotransmission has been implicated in a variety of neurological and neuropsychiatric disorders, significant advances toward a better understanding of the pathophysiology of such disorders can be achieved through in vivo investigations of the function of these neurotransmitter systems. However, there is currently a paucity of effective methods for in vivo GABA and Glu detection. In this Neurotechnology Research, Development and Enhancement grant request the applicants propose to develop a novel noninvasive proton magnetic resonance spectroscopy (1H MRS) technology that would enable robust in vivo detection and functional studies of GABA and Glu in human brain. Specifically, this research will aim (a) to develop and validate of a family of novel volume-selective, """"""""single-shot"""""""" selective homonuclear multiple quantum coherence (sh-MQC) transfer techniques for the efficient and unambiguous detection of either GABA or Glu alone, or of the two compounds simultaneously, in vivo in human brain;(b) to enhance sensitivity and detection ease by implementing the developed sequences with a phased-array multichannel receiver coil, and homonuclear single-frequency decoupling techniques in vivo, which would minimize spectral overlap and increase spectral purity;(c) to estimate the reliability of the developed technology by performing test-retest reliability measurements and computing the coefficient of variation;and (d) to conduct a pilot clinical research study in which the new technology would be implemented to measure and compare baseline levels of prefrontal cortical Glu and GABA in schizophrenics and in healthy subjects. If successfully developed, the proposed GABA and Glu detection technology would be highly significant in that 1H MRS is currently the only noninvasive technique that offers the possibility to directly measure these two amino acid neurotransmitters in vivo. Thus, while this research will emphasize the utility of the proposed technology in the study of schizophrenia, it should be stressed that this will be a widely applicable technology that will find use in the study of any brain disorder (e.g.,epilepsy, substance abuse, anxiety disorder, major depression disorder) in which GABA and/or Glu function may be dysregulated.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Medical Imaging Study Section (MEDI)
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Freund, Michelle
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Weill Medical College of Cornell University
Schools of Medicine
New York
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Pereira, Ana C; Mao, Xiangling; Jiang, Caroline S et al. (2017) Dorsolateral prefrontal cortex GABA deficit in older adults with sleep-disordered breathing. Proc Natl Acad Sci U S A 114:10250-10255
de la Fuente-Sandoval, Camilo; Reyes-Madrigal, Francisco; Mao, Xiangling et al. (2017) Prefrontal and Striatal Gamma-Aminobutyric Acid Levels and the Effect of Antipsychotic Treatment in First-Episode Psychosis Patients. Biol Psychiatry :
Shungu, Dikoma C; Mao, Xiangling; Gonzales, Robyn et al. (2016) Brain ?-aminobutyric acid (GABA) detection in vivo with the J-editing (1) H MRS technique: a comprehensive methodological evaluation of sensitivity enhancement, macromolecule contamination and test-retest reliability. NMR Biomed 29:932-42
Milak, M S; Proper, C J; Mulhern, S T et al. (2016) A pilot in vivo proton magnetic resonance spectroscopy study of amino acid neurotransmitter response to ketamine treatment of major depressive disorder. Mol Psychiatry 21:320-7
de la Fuente-Sandoval, Camilo; Reyes-Madrigal, Francisco; Mao, Xiangling et al. (2015) Cortico-Striatal GABAergic and Glutamatergic Dysregulations in Subjects at Ultra-High Risk for Psychosis Investigated with Proton Magnetic Resonance Spectroscopy. Int J Neuropsychopharmacol 19:pyv105
Lapidus, Kyle A B; Gabbay, Vilma; Mao, Xiangling et al. (2014) In vivo (1)H MRS study of potential associations between glutathione, oxidative stress and anhedonia in major depressive disorder. Neurosci Lett 569:74-9
Chen, Chi-Ming A; Stanford, Arielle D; Mao, Xiangling et al. (2014) GABA level, gamma oscillation, and working memory performance in schizophrenia. Neuroimage Clin 4:531-9
Weiduschat, Nora; Kaufmann, Petra; Mao, Xiangling et al. (2014) Cerebral metabolic abnormalities in A3243G mitochondrial DNA mutation carriers. Neurology 82:798-805
Gabbay, Vilma; Ely, Benjamin A; Li, Qingyang et al. (2013) Striatum-based circuitry of adolescent depression and anhedonia. J Am Acad Child Adolesc Psychiatry 52:628-41.e13
Kegeles, Lawrence S; Mao, Xiangling; Stanford, Arielle D et al. (2012) Elevated prefrontal cortex ?-aminobutyric acid and glutamate-glutamine levels in schizophrenia measured in vivo with proton magnetic resonance spectroscopy. Arch Gen Psychiatry 69:449-59

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