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. 2020 Apr 10;46(3):633-642.
doi: 10.1093/schbul/sbz099.

Intra-Regional Glu-GABA vs Inter-Regional Glu-Glu Imbalance: A 1H-MRS Study of the Neurochemistry of Auditory Verbal Hallucinations in Schizophrenia

Helene Hjelmervik  1   2 , Alexander R Craven  1   2 , Igne Sinceviciute  2   3 , Erik Johnsen  2   3   4 , Kristiina Kompus  1   2 , Josef J Bless  1 , Rune A Kroken  2   3   4 , Else-Marie Løberg  2   3   5   6 , Lars Ersland  1   2   7 , Renate Grüner  2   8   9 , Kenneth Hugdahl  1   2   3   8
Affiliations

Intra-Regional Glu-GABA vs Inter-Regional Glu-Glu Imbalance: A 1H-MRS Study of the Neurochemistry of Auditory Verbal Hallucinations in Schizophrenia

Helene Hjelmervik et al. Schizophr Bull. .

Abstract

Glutamate (Glu), gamma amino-butyric acid (GABA), and excitatory/inhibitory (E/I) imbalance have inconsistently been implicated in the etiology of schizophrenia. Elevated Glu levels in language regions have been suggested to mediate auditory verbal hallucinations (AVH), the same regions previously associated with neuronal hyperactivity during AVHs. It is, however, not known whether alterations in Glu levels are accompanied by corresponding GABA alterations, nor is it known if Glu levels are affected in brain regions with known neuronal hypo-activity. Using magnetic resonance spectroscopy (MRS), we measured Glx (Glu+glutamine) and GABA+ levels in the anterior cingulate cortex (ACC), left and right superior temporal gyrus (STG), and left inferior frontal gyrus (IFG), in a sample of 77 schizophrenia patients and 77 healthy controls. Two MRS-protocols were used. Results showed a marginally significant positive correlation in the left STG between Glx and AVHs, whereas a significant negative correlation was found in the ACC. In addition, high-hallucinating patients as a group showed decreased ACC and increased left STG Glx levels compared to low-hallucinating patients, with the healthy controls in between the 2 hallucinating groups. No significant differences were found for GABA+ levels. It is discussed that reduced ACC Glx levels reflect an inability of AVH patients to cognitively inhibit their "voices" through neuronal hypo-activity, which in turn originates from increased left STG Glu levels and neuronal hyperactivity. A revised E/I-imbalance model is proposed where Glu-Glu imbalance between brain regions is emphasized rather than Glu-GABA imbalance within regions, for the understanding of the underlying neurochemistry of AVHs.

Keywords: GABA; Glx; MR spectroscopy (MRS); Magnetic resonance imaging (MRI); auditory verbal hallucinations; excitatory; glutamate; hallucinations; inhibitory (E/I) imbalance model; schizophrenia.

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Figures

Fig. 1.
Fig. 1.
Placement of voxels in the left STG, ACC (across midline), right STG, and left IFG shown in horizontal views. Center-of-mass for the voxel localization, given in MNI space x, y, z coordinates for the left IFG: −36.8, 18.9, 11.9, left STG: −48.3, −35.9, 6.02, right STG: 50.2, −34.2, 6.11, and for the ACC: 0.389, 25.4, 33.9. The orange box illustrates the placement for a single representative subject. The red contours indicate 95%, and the green contours indicate 65% confidence regions for placement across the entire group (when mapped to a standard template). LSTG, left superior temporal gyrus; LIFG, left inferior frontal gyrus; ACC, anterior cingulate cortex; RSTG, right superior temporal gyrus.
Fig. 2.
Fig. 2.
Glutamate and GABA concentration levels are shown on the y-axes for healthy controls, low-hallucinating patients (AVH-), and high-hallucinating patients (AVH+) in the 4 brain regions. Error bars indicate standard error. * indicates significant post hoc comparisons at P < .05, conducted to explore the significant interaction of Group and Region. STG, superior temporal gyrus; IFG, inferior frontal gyrus; ACC, anterior cingulate cortex; IU, institutional units.
Fig. 3.
Fig. 3.
Graphs illustrating relations between glutamate or GABA levels (y-axis) and AVHs (x-axis) in left STG and ACC. Note that fixed predicted, not raw, values are used (y-axis). LSTG, left superior temporal gyrus; ACC, anterior cingulate cortex; IU, institutional units.
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