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.
Highlights
Blood oxygen level dependent (BOLD) responses in functional magnetic resonance imaging reflect hemodynamic responses to neural activation [1, 2], and the responses can become either positive or negative in relation to baseline activity
In follow-up analyses, we investigated these effects in cingulate subregions by making statistical analyses in predefined regions of interest (ROI) in the cingulate cortex based on cytoarchitecture and functional studies
Our interpretation is that the inverse correlation between DZ and the BOLD response was caused by gamma-aminobutyric acid (GABA)-related neural inhibition
Summary
Blood oxygen level dependent (BOLD) responses in functional magnetic resonance imaging (fMRI) reflect hemodynamic responses to neural activation [1, 2], and the responses can become either positive or negative in relation to baseline activity. A few studies indicate an association between BOLD responses and the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) [8, 10,11,12]. In these studies, GABA concentrations were measured during rest with magnetic resonance spectroscopy (MRS), and the BOLD responses were measured subsequently during visual or emotional processing. It has been shown that a positive allosteric modulator of GABA (GABA-PAM) further lowers the negative BOLD response during emotional processing [13]. Other studies have reported dose-dependent relations between GABA-PAMs and decreased cerebral blood flow [14,15], and dosedependent attenuation of BOLD responses during emotional processing [16]. Pharmacodynamics vary widely between individuals, and the relationship between the effective plasma concentrations of GABA-PAMs and BOLD responses has not been investigated yet
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