Dorsolateral prefrontal γ-aminobutyric acid in men predicts individual differences in rash impulsivity

Abstract

Background: Impulsivity is a multifaceted personality construct associated with numerous psychiatric disorders. Recent research has characterized four facets of impulsivity: "urgency" (the tendency to act rashly especially in the context of distress or cravings); "lack of premeditation" (not envisaging the consequences of actions); "lack of perseverance" (not staying focused on a task); and "sensation seeking" (engaging in exciting activities). Urgency is particularly associated with clinical populations and problematic disinhibited behavior.

Methods: We used magnetic resonance spectroscopy to measure concentration of the inhibitory neurotransmitter γ-aminobutyric acid (GABA) in the dorsolateral prefrontal cortex (DLPFC) in two cohorts of 12 and 13 participants.

Results: We find that variation in trait urgency in healthy men correlates with GABA concentration in the DLPFC. The result was replicated in an independent cohort. More GABA predicted lower urgency scores, consistent with a role in self-control for GABA-mediated inhibitory mechanisms in DLPFC.

Conclusions: These findings help account for individual differences in self-control and thus clarify the relationship between GABA and a wide range of psychiatric disorders associated with impaired self-control.

Figure 1

Methodology for spectroscopy. (a, b) the MRS voxel (yellow, 3 cm × 3cm × 3cm voxel) was placed over the anatomical location of the dlPFC. Edited MR spectra (c) allow the quantification of GABA concentration by extracting the area under the GABA peak (39-41, 68). In a similar way, we extracted a measure of glutamate+glutamine, Glx, (also marked is the N-acetyl-aspartate peak, NAA). The GABA peak will contain signal from co-edited macromolecules, but although we do not know the exact contribution, we do not expect any individual differences in macromolecules to drive any correlation with our behavioural measures.

Figure 2

Urgency correlates with GABA in the dlPFC region. Higher dlPFC GABA predicted lower urgency score across individuals (a). This result was replicated in a second cohort (b). GABA concentration measurements are stated in institutional units (i.u.). The p-value for cohort 2 is given 1-tailed, and corrected for two comparisons, since there were two planned tests of replication that arose from cohort 1. Inserts show that the relation observed for GABA levels did not hold for glutamate+glutamine (Glx).

Figure 3

Reliable correlation between GABA and impulsivity was specific to the dlPFC region and the urgency component. GABA concentration measurements are stated in institutional units (i.u.).

Figure 4

The fraction of gray matter in the dlPFC MRS voxel, the participants’ age and Stop-signal reaction time do not correlate with GABA in the dlPFC region. (a) The fraction of gray matter in the dlPFC MRS voxel was assessed using Freesurfer (Martinos center for biomedical imaging, Cambridge, Mass, USA) and showed no correlation with dlPFC GABA – first cohort, r = 0.2, p < .5; second cohort, r= 0.07, p < .8. (b) Age in our sample was not related to GABA in the dlPFC region – first cohort, r = −0.1, p < .75; second cohort, r = 0.07, p < .8. (c) The experimental measure of response inhibition is not predicted by our neurochemical measurement. Both correlations were not significant – first cohort, r = −0.49, p < .1 (bootstrap 90% conf. int.: [−0.8, 0.0]); second cohort, r= 0.35, p < .3 (bootstrap 90% conf. int.: [−0.2, 0.7])– and even in opposite directions. The Stop-signal task (86), can be conceived as an enriched version of a Go/No-go task (e.g.,87), bringing detailed information about the timing of inhibitory motor processes by estimating a Stop-signal reaction time. In our case, participants made speeded button presses to a shape cue, but on a subset of trials a second stimulus was presented that instructed them to withhold their response. The interval between go and stop signals is modulated to find the interval at which participants successfully stop on 50% of the stop trials.