GABAergic inhibition shapes behavior and neural dynamics in human visual working memory

Abstract

Neuronal inhibition, primarily mediated by GABAergic neurotransmission, is crucial for brain development and healthy cognition. Gamma-aminobutyric acid concentration levels in sensory areas have been shown to correlate with hemodynamic and oscillatory neuronal responses. How these measures relate to one another during working memory, a higher-order cognitive process, is still poorly understood. We address this gap by collecting magnetoencephalography, functional magnetic resonance imaging, and Flumazenil positron emission tomography data within the same subject cohort using an n-back working-memory paradigm. By probing the relationship between GABAA receptor distribution, neural oscillations, and Blood Oxygen Level Dependent (BOLD) modulations, we found that GABAA receptor density in higher-order cortical areas predicted the reaction times on the working-memory task and correlated positively with the peak frequency of gamma power modulations and negatively with BOLD amplitude. These findings support and extend theories linking gamma oscillations and hemodynamic responses to gamma-aminobutyric acid neurotransmission and to the excitation-inhibition balance and cognitive performance in humans. Considering the small sample size of the study, future studies should test whether these findings also hold for other, larger cohorts as well as to examine in detail how the GABAergic system and neural fluctuations jointly support working-memory task performance.

Keywords: functional magnetic resonance imaging; magnetoencephalography; n-back; neurotransmission; positron emission tomography.

Fig. 1

The study consisted of the collection of multimodal neuroimaging data during an n-back task and the determination of the relationship between the neuroimaging signals and their link to WM task performance. (A) MEG and fMRI data were collected during the experimental task which consisted of 1-, 2-, and 3-back tasks of visually presented letters, while FMZ-PET data were collected during rest. (B) From the experimental data, we determined (C) the WM task performance measures (reaction times, accuracy, sensitivity, and specificity) as well as measures of oscillatory (peak frequency and amplitude) and hemodynamic (BOLD signal amplitude) activity, whereas the FMZ-PET data collected during rest were used to determine GABA_A-receptor densities across the brain.

Fig. 2

Brain areas showing significant modulation of activity as a function of memory load for MEG and fMRI (P < 0.05). Areas showing more neural/hemodynamic activity during conditions with a higher memory load are shown in red/yellow and areas showing less activity in blue. For visualization purposes, the volumetric data are projected to the surface of the brain.

Fig. 3

Group- (first three panels) and individual-level (last two panels) gamma-band spectra in the two MEG clusters of interest for the different WM comparisons. In the group-level spectra, confidence intervals represent the grand average ± SEM values. The vertical dashed line in the individual-level spectra represents the identified peak modulation frequencies, shown next to the peaks. GABA_A-receptor densities in the graphs represent the average values within the MEG clusters for each of the example subjects.

Fig. 4

Correlation (Spearman’s rho) between GABA_A-receptor density and gamma-band peak amplitude and frequency in brain areas showing significant modulation of activity as a function of memory load. The x-axis portrays the mean receptor density (A.U.). The correlations were examined in two ROIs (MEG1: Cuneus; MEG2: Medial/Middle Frontal Gyrus). See Table 1 for the sizes, Brodmann areas, and Talairach coordinates of the ROIs.

Fig. 5

Correlation (Spearman’s rho) between GABA_A-receptor density and BOLD amplitude in brain areas showing significant modulation of activity as a function of memory load. The x-axis portrays the mean receptor density (A.U.). The correlations were examined in five ROIs (fMRI1: precentral/middle frontal gyrus; fMRI2: precuneus; fMRI3: inferior parieral lobule; fMRI4: superior frontal gyrus; fMRI5: temporo-parietal junction). See Table 1 for the sizes, Brodmann areas, and Talairach coordinates of the ROIs.

Fig. 6

Correlation (Spearman’s rho) between GABA_A-receptor density and reaction times during the WM tasks in the ROIs identified based modulation of activity as a function of memory load. The tested reaction-time measures represent the correct responses in the 3-back task (RT) and the difference between the correct responses in 3- and 1-back tasks (RT difference). See Table 1 for the anatomical descriptions, sizes, Brodmann areas, and Talairach coordinates of the ROIs. For visualization purposes, the volumetric data are projected to the surface of the brain.