Positive Allosteric Modulator of GABA Lowers BOLD Responses in the Cingulate Cortex

Abstract

Knowledge about the neural underpinnings of the negative blood oxygen level dependent (BOLD) responses in functional magnetic resonance imaging (fMRI) is still limited. We hypothesized that pharmacological GABAergic modulation attenuates BOLD responses, and that blood concentrations of a positive allosteric modulator of GABA correlate inversely with BOLD responses in the cingulate cortex. We investigated whether or not pure task-related negative BOLD responses were co-localized with pharmacologically modulated BOLD responses. Twenty healthy adults received either 5 mg diazepam or placebo in a double blind, randomized design. During fMRI the subjects performed a working memory task. Results showed that BOLD responses in the cingulate cortex were inversely correlated with diazepam blood concentrations; that is, the higher the blood diazepam concentration, the lower the BOLD response. This inverse correlation was most pronounced in the pregenual anterior cingulate cortex and the anterior mid-cingulate cortex. For subjects with diazepam plasma concentration > 0.1 mg/L we observed negative BOLD responses with respect to fixation baseline. There was minor overlap between cingulate regions with task-related negative BOLD responses and regions where the BOLD responses were inversely correlated with diazepam concentration. We interpret that the inverse correlation between the BOLD response and diazepam was caused by GABA-related neural inhibition. Thus, this study supports the hypothesis that GABA attenuates BOLD responses in fMRI. The minimal overlap between task-related negative BOLD responses and responses attenuated by diazepam suggests that these responses might be caused by different mechanisms.

Fig 1. Positive and negative BOLD responses during executive processing.

The sagittal brain images show whole brain group activation during the working memory task. Areas in orange/red denote positive BOLD responses, which were mainly found in the executive network. Areas in green/blue denote negative BOLD responses, which were mainly found in the default mode network. The coronal image shows the position of visualized sagittal slices.

Fig 2. Task- and DZ-related BOLD responses in the cingulate cortex.

The sagittal brain images show regions with task-related positive (red) and negative (blue) BOLD responses in the cingulate cortex in the whole group during the working memory task. Regions where the BOLD responses correlated inversely to diazepam plasma concentration are visualized in green. Task-negative and diazepam-attenuated responses were significant after family wise error (FWE) correction for multiple comparisons. Task-positive responses in the cingulate cortex were not significant after FWE correction.

Fig 3. DZ dose-response curve.

(A) Panel A shows the predicted diazepam-dose-fMRI response curve. The normalized response is shown on the left y-axis and the actual BOLD response on the right y-axis. The mean prediction and a range of prediction confidence bands are also shown in panel A. (B) Panel B shows the standardized residual of the model fit.

Fig 4. DZ-related negative BOLD responses.

The figure shows mean BOLD responses in the anterior midcingulate cortex [0, 18, 21] for three subjects with DZ plasma concentration > 0.1 mg/L during the 2-back, 1-back, and 0-back tasks. The BOLD responses are normalized to baseline defined as the fixation period immediately before the 2-back task. The figure shows that the BOLD responses are negative with respect to baseline during the DZ session and positive during the placebo session.