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

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.

Glutamatergic modulation of auditory cortex connectivity with attentional brain networks in unpredictable perceptual environment

“… 44 ), which in turn are related to reduced ability to process deviating or unpredictable information 45 . However, the data on schizophrenia patients suggests an imbalance in regional metabolite concentration 46 , 47 , with dynamic changes over the course of the illness 48 , emphasizing that the dysfunction in the glutamate system may manifest as a dysregulation due to impaired NMDA receptors, leading to various effects throughout the brain, rather than reduction of glutamatergic signaling. Further studies are required to establish the relationship between in vivo measurements of glutamate and stimulus processing in schizophrenia; improved measurement techniques such as rapid event-related MRS combined with fMRI and EEG may help to provide the important data needed for fuller understanding of the glutamatergic system in psychiatric disorders.…”

Local and Interregional Neurochemical Associations Measured by Magnetic Resonance Spectroscopy for Studying Brain Functions and Psychiatric Disorders

“…The coordinated variations of glutamate and GABA across the brain can be assessed using chemical shift images of spectrally resolved glutamate and GABA. The absolute strengths of interregional correlations of spectrally resolved glutamate and GABA have the exciting potential for characterizing excitatory-inhibitory connections among the nodes of neural networks, therefore providing novel parameters for gauging interregional excitation-inhibition balance, the disruption of which is implicated in many neuropsychiatric disorders [e.g., (33,103,117,129,130)].…”

“…Glutamatergic neurons (e.g., cortical pyramidal neurons) receive a significant degree of GABA A -mediated inhibition through interneurons ( 83 ). Balanced excitation and inhibition facilitate normal brain functions, and failure to maintain excitation–inhibition balance underlies dysfunction in many brain disorders ( 32 , 33 , 84 ). Many studies have also revealed altered glutamate and GABA.…”

“…We hope that these discussions will spur interest in developing MRS techniques for mapping neurochemical associations across the brain to facilitate a variety of clinical investigations. In particular, since glutamate and GABA play dominant roles in the excitation–inhibition balance ( 28 , 29 ) and in many neuropsychiatric disorders ( 30 – 33 ), MRS characterization of glutamate–GABA associations among the nodes of neural networks may provide considerable insight into the interactions between glutamatergic and GABAergic systems and their abnormalities.…”

Glutamate- and GABA-Modulated Connectivity in Auditory Hallucinations—A Combined Resting State fMRI and MR Spectroscopy Study

“…Glu and GABA were measured with hydrogen magnetic resonance spectroscopy ( 1 H-MRS). Regions of interest for Glu and GABA measurements were the left STG in the temporal lobe and the anterior cingulate cortex (ACC) in the frontal lobe ( 10 , 14 , 22 ). Glu and GABA were hypothesized to modulate interhemispheric STG functional connectivity, as predicted by the interhemispheric miscommunication theory ( 10 ).…”