Frontal Glutamate and γ-Aminobutyric Acid Levels and Their Associations With Mismatch Negativity and Digit Sequencing Task Performance in Schizophrenia

Abstract

Importance: 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.

Design, setting, and participants: 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.

Main outcomes and measures: 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 and relevance: 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.

Figure 1. Voxel Location, Representative Spectra, and Mismatch Negativity (MMN) Waveforms

A, Shown is the medial frontal and anterior cingulate voxel (white rectangle). The lines indicate the center of the voxel. B, Spectra (gray line) and spectral fit (red line) for glutamine and glutamate acquisition are shown. Residual is seen at the top. Cho indicates choline; Cr, creatine; Glu, glutamate; Gln, glutamine; NAA, N-acetylaspartate; mI, myo-inositol; and mm, macromolecule. C, GABA indicates γ-aminobutyric acid. D, The total mean values are shown.

Figure 2. Correlations Between Mismatch Negativity (MMN) and Ratio of Glutamine to Glutamate, γ-Aminobutyric Acid (GABA), and Glutamate

Figure 3. Structural Equation Modeling of γ-Aminobutyric Acid (GABA) and Glutamine and Glutamate Contributions to Digit Sequencing Task (DST) Performance Through Mismatch Negativity (MMN) Mediation

A, Mismatch negativity was a significant mediator of glutamine and glutamate contribution to DST performance. B, Although both GABA and glutamine and glutamate contributed to MMN, they were not related to DST performance. ^a The letter a and the thick lines indicate statistical significance.