title: Frontal Glutamate and γ-Aminobutyric Acid Levels and Their Associations With Mismatch Negativity and Digit Sequencing Task Performance in Schizophrenia.
abstract: OBJECTIVE
  Auditory mismatch negativity (MMN) is a biomarker for schizophrenia thought to reflect glutamatergic N-methyl-d-aspartate receptor function and excitatory-inhibitory neurotransmission balance. However, the association of glutamate level with MMN has not been directly examined in patients with schizophrenia, to our knowledge.
  
  
  OBJECTIVE
  To investigate the contributions of glutamate and γ-aminobutyric acid (GABA) to MMN and digit sequencing task (DST) performance, an assessment of verbal working memory, in schizophrenia.
  
  
  METHODS
  Fifty-three control participants from the community and 45 persons with schizophrenia from outpatient clinics completed an electroencephalographic session for MMN, magnetic resonance spectroscopy for glutamate and GABA, and a DST. The study dates were July 2011 to May 2014, and the dates of our analysis were May 2014 to August 2015.
  
  
  METHODS
  Glutamate, GABA, the ratio of glutamine to glutamate, MMN amplitude, and DST. Structural equation modeling was used to test the effects of neurochemistry and MMN amplitude on DST performance.
  
  
  RESULTS
  The 45 persons with schizophrenia were a mean (SD) of 37.7 (12.8) years and the control participants were 37.1 (13.1) years. The schizophrenia group had a mean (SD) of 14.7 (12.1) years of illness. Mismatch negativity amplitude (F = 4.39, P = .04) and glutamate (F = 9.69, P = .002) were reduced in the schizophrenia group. Smaller MMN amplitude was significantly associated with lower GABA level (P = .008), lower glutamate level (P = .05), and higher ratio of glutamine to glutamate (P = .003). Reduced MMN amplitude was linked to poor verbal working memory in schizophrenia (P = .002). Modeling revealed that a proxy of glutamatergic function, indexed by the ratio of glutamine to glutamate, influenced a path from the ratio of glutamine to glutamate to MMN to verbal working memory (P = .38 [root-mean-square error of approximation, P < .001] by χ2 test), supporting the contention that MMN serves as an intermediate biomarker linking glutamatergic function to DST performance in schizophrenia.
  
  
  CONCLUSIONS
  The role of glutamate and GABA in MMN and verbal working memory deficits in schizophrenia has been frequently debated. These data provide in vivo evidence that support glutamatergic and GABAergic regulation of MMN and verbal working memory function in schizophrenia.
authors.affiliation: Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore2Department of Radiology and Radiological Sciences, the Johns Hopkins University School of Medicine, Baltimore, Maryland3Department of Psyc.
authors.forename: Laura M
authors.initials: LM
authors.lastname: Rowland
authors.affiliation: Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore.
authors.forename: Ann
authors.initials: A
authors.lastname: Summerfelt
authors.affiliation: Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore.
authors.forename: S Andrea
authors.initials: SA
authors.lastname: Wijtenburg
authors.affiliation: Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Du
authors.affiliation: Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore.
authors.forename: Joshua J
authors.initials: JJ
authors.lastname: Chiappelli
authors.affiliation: Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore.
authors.forename: Nithin
authors.initials: N
authors.lastname: Krishna
authors.affiliation: Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: West
authors.affiliation: Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore.
authors.forename: Florian
authors.initials: F
authors.lastname: Muellerklein
authors.affiliation: Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore3Department of Psychology, University of Maryland, Baltimore County, Baltimore4Department of Physics, University of Maryland, Baltimore Cou.
authors.forename: Peter
authors.initials: P
authors.lastname: Kochunov
authors.affiliation: Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore.
authors.forename: L Elliot
authors.initials: LE
authors.lastname: Hong
mesh_terms: D000328:Adult; D001303:Auditory Cortex / Q000378:metabolism / Q000503:physiopathology; D001307:Auditory Perception / Q000502:physiology; D004569:Electroencephalography; D005071:Evoked Potentials / Q000502:physiology*; D005260:Female; D005625:Frontal Lobe / Q000378:metabolism / Q000503:physiopathology; D018698:Glutamic Acid / Q000378:metabolism*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008570:Memory, Short-Term / Q000502:physiology*; D008875:Middle Aged; D011597:Psychomotor Performance / Q000502:physiology*; D012559:Schizophrenia / Q000378:metabolism / Q000503:physiopathology; D055815:Young Adult; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid