GABA content within the ventromedial prefrontal cortex is related to trait anxiety

Abstract

The ventromedial prefrontal cortex (vmPFC) plays a key role in emotion processing and regulation. vmPFC dysfunction may lead to disinhibition of amygdala causing high anxiety levels. γ-Aminobutyric acid (GABA) inter-neurons within vmPFC shape the information flow to amygdala. Thus, we hypothesize that GABA content within vmPFC could be relevant to trait anxiety. Forty-three healthy volunteers aged between 20 and 88 years were assessed for trait anxiety with the Subscale-2 of the State-Trait-Anxiety Inventory (STAI-Y2) and were studied with proton magnetic resonance spectroscopy to investigate GABA and Glx (glutamate+glutamine) contents within vmPFC. Total creatine (tCr) was used as internal reference. Partial correlations assessed the association between metabolite levels and STAI-Y2 scores, removing the effect of possible nuisance factors including age, educational level, volumes of gray matter and white matter within magnetic resonance spectroscopy voxel. We observed a positive relationship between GABA/tCr and STAI-Y2 scores. No significant relationships were found between Glx/tCr and STAI-Y2 and between tCr/water and STAI-Y2. No differences were found between males and females as regards to age, STAI-Y2, GABA/tCr, Glx/tCr, tCr/water, gray matter and white matter volumes. We suggest a close relationship between GABA content within vmPFC and trait anxiety providing new insights in the physiology of emotional brain.

Keywords: anxiety; glutamate; ventromedial prefrontal cortex; γ-aminobutyric acid.

Fig. 1.

Proton magnetic resonance spectroscopy (¹H-MRS). (Panel A) A voxel of 3.0 × 3.0 × 2.0 mm³ was placed into the ventromedial prefrontal cortex (vmPFC) by using T¹-weighted image as anatomical reference. (Panel B) Representative GANNET-edited MR spectra for assessing GABA/tCr and Glx/tCr. (Panel C) Representative GANNET-edited spectra (in blue) with estimated Glx model indicated in red. (Panel D) Representative GANNET-edited spectra (in blue) with estimated GABA model indicated in red. For panels C and D, residue was shown in black. GABA, γ-aminobutyric acid (3.02 ppm); Glx, glutamate + glutamine (pseudo-doublet peaks at 3.65–3.75 ppm).

Fig. 2.

Absolute quantification of tCr. Representative PRESS spectra acquired with (upper panel) and without (lower panel) water suppression for assessing tCr and water concentrations, respectively. Estimated signals (red) were reported on original signals (blue). Residue was shown in black.

Fig. 3.

Scatterplots displaying the correlations between STAI-Y2 scores and the metabolites (GABA/tCr, Glx/tCr and tCr/water).

Fig. 4.

GABA-mediated circuit between the vmPFC and the amygdala. The basolateral nucleus of amygdale (BLA) receives incoming information on potentially negative emotional signals from the thalamus and the sensory association cortex. The bottom-up glutamatergic projections send excitatory input from the BLA to GABAergic interneurons and glutamatergic fibers in the vmPFC. (Panel A) In normal functioning, the activation of the glutamatergic ‘top-down’ control restores the normal activity of the amygdala by increasing the activity of the GABAergic interneurons within the BLA and within the central medial nucleus of amygdala (CeA). (Panel B) In anxious subjects, the primary activations of the BLA and the CeA, which are caused by incoming information on potentially negative emotional stimulus, could be not adequately compensated by the top–down control system. Specifically, the high GABA content in the vmPFC reduces the top–down control and down-regulates the GABA-mediated inhibition on the BLA and the CeA. Thus, the resulting over-activation of the GABAergic neurons projecting from CeA to hypothalamus- brainstem and of the glutamatergic projections from BLA to and bed nucleus of the stria terminalis (BNST) leads to somatic manifestation of anxiety.