Systematic regional variations of GABA, glutamine, and glutamate concentrations follow receptor fingerprints of human cingulate cortex

Abstract

Magnetic resonance spectroscopy (MRS) of glutamatergic or GABAergic measures in anterior cingulate cortex (ACC) was found altered in psychiatric disorders and predictive of interindividual variations of functional responses in healthy populations. Several ACC subregions have been parcellated into receptor-architectonically different portions with heterogeneous fingerprints for excitatory and inhibitory receptors. Similarly, these subregions overlap with functionally distinct regions showing opposed signal changes toward stimulation or resting conditions. We therefore investigated whether receptor-architectonical and functional segregation of the cingulate cortex in humans was also reflected in its local concentrations of glutamate (Glu), glutamine (Gln), and GABA. To accomplish a multiregion estimation of all three metabolites in one robust and reliable session, we used an optimized 7T-stimulated echo-acquisition mode method with variable-rate selective excitation pulses. Our results demonstrated that, ensuring high data retest reliability, four cingulate subregions discerning e.g., pregenual ACC (pgACC) from anterior mid-cingulate cortex showed different metabolite concentrations and ratios reflective of regionally specific inhibition/excitation balance. These findings could be controlled for potential influences of local gray matter variations or MRS voxel-placement deviations. Pregenual ACC was found to have significantly higher GABA and Glu concentrations than other regions. This pattern was not paralleled by Gln concentrations, which for both absolute and relative values showed a rostrocaudal gradient with highest values in pgACC. Increased excitatory Glu and inhibitory GABA in pgACC were shown to follow a regional segregation agreeing with recently shown receptor-architectonic GABAB receptor distribution in ACC, whereas Gln distribution followed a pattern of AMPA receptors.

Figure 1.

Voxel placement on four ROIs in representative 3D MPRAGE anatomical images (top, sagittal plane; bottom, transverse plane): pgACC (A), aMCC (B), rPCC (C), and cPCC (D).

Figure 2.

A, Landmarks for voxel placement in pgACC region: anterior border of genu of the corpus callosum perpendicular to AC–PC orientation and lower boundary of genu of the corpus callosum in AC–PC orientation. B, Landmarks for voxel placement in aMCC region: hippocampal axis and posterior border of genu of the corpus callosum perpendicular to AC–PC orientation.

Figure 3.

An exemplary cPCC spectrum with a flat baseline, SNR 51 and FWHM 6.8 Hz.

Figure 4.

Interregional differences in mean GM content with error bars indicating ± 2 standard error (SE) (***p < 0.001; **p < 0.01; *p < 0.05).

Figure 5.

ICCs of the metabolite concentrations (GABA, Gln, and Glu) before (A) and after (B) correction for GM content in pgACC, aMCC, rPCC, and cPCC regions.

Figure 6.

Mean levels of metabolite concentrations of GABA (top), Gln (middle), and Glu (bottom) before (A) and after (B) correction for the GM content in pgACC, aMCC, rPCC, and cPCC regions with error bars indicating ± 2 SE [**p < 0.01; * p < 0.05; (*)p < 0.1]. The metabolite concentrations are expressed in i.u.

Figure 7.

Mean levels of metabolite concentration ratios for inhibition/excitation balance (GABA/Glu, top) and indirect Gln cycling (Gln/Glu, bottom) by using metabolite concentrations before (A) and after (B) correction for the GM content in pgACC, aMCC, rPCC, and cPCC regions with error bars indicating ± 2 SE [**p < 0.01; *p < 0.05; (*)p < 0.1].