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

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.

Influence of diazepam on clinically designed FMRI.

The authors investigated the effect of diazepam on clinically relevant measures from functional magnetic resonance imaging (fMRI) examinations. Twenty volunteers were scanned twice. Using a double-blind randomized study design, the volunteers received placebo on one occasion, and on the other, 5 mg of diazepam. Three functional tests were used: motor, word generation, and working memory. Images were analyzed individually for each subject and the number of activated voxels and the laterality index were calculated. No significant effects related to the drug were detected. In contrast, the motor and working memory tasks showed a significant decrease in the number of activated voxels between Sessions 1 and 2, independently of diazepam administration. These results indicate that diazepam may be administered for premedication prior to fMRI investigations.