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. 2016 Nov 16;36(46):11788-11794.
doi: 10.1523/JNEUROSCI.1970-16.2016.

Dorsolateral Prefrontal Cortex GABA Concentration in Humans Predicts Working Memory Load Processing Capacity

Jong H Yoon  1 , Anthony Grandelis  2 , Richard J Maddock  2
Affiliations

Dorsolateral Prefrontal Cortex GABA Concentration in Humans Predicts Working Memory Load Processing Capacity

Jong H Yoon et al. J Neurosci. .

Abstract

The discovery of neural mechanisms of working memory (WM) would significantly enhance our understanding of complex human behaviors and guide treatment development for WM-related impairments found in neuropsychiatric conditions and aging. Although the dorsolateral prefrontal cortex (DLPFC) has long been considered critical for WM, we still know little about the neural elements and pathways within the DLPFC that support WM in humans. In this study, we tested whether an individual's DLPFC gamma-aminobutryic acid (GABA) content predicts individual differences in WM task performance using a novel behavioral approach. Twenty-three healthy adults completed a task that measured the unique contribution of major WM components (memory load, maintenance, and distraction resistance) to performance. This was done to address the possibility that components have differing GABA dependencies and the failure to parse WM into components would lead to missing true associations with GABA. The subjects then had their DLPFC GABA content measured by single-voxel proton magnetic spectroscopy. We found that individuals with lower DLPFC GABA showed greater performance degradation with higher load, accounting for 31% of variance, p(corrected) = 0.015. This relationship was component, neurochemical, and brain region specific. DLPFC GABA content did not predict performance sensitivity to other components tested; DLPFC glutamate + glutamine and visual cortical GABA content did not predict load sensitivity. These results confirm the involvement of DLPFC GABA in WM load processing in humans and implicate factors controlling DLPFC GABA content in the neural mechanisms of WM and its impairments.

Significance statement: This study demonstrated for the first time that the amount of gamma-aminobutryic acid (GABA), the major inhibitory neurotransmitter of the brain, in an individual's prefrontal cortex predicts working memory (WM) task performance. Given that WM is required for many of the most characteristic cognitive and behavioral capabilities in humans, this finding could have a significant impact on our understanding of the neural basis of complex human behavior. Furthermore, this finding suggests that efforts to preserve or increase brain GABA levels could be fruitful in remediating WM-related deficits associated with neuropsychiatric conditions.

Keywords: GABA; magnetic resonance spectroscopy; prefrontal cortex; working memory.

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Figures

Figure 1.
Figure 1.
WM paradigm. The general trial structure shared by all trial types and examples of face stimuli are displayed. A trial starts with the presentation of face cue, which had to be maintained across a delay period to make a match discrimination with the probe face presented at the end of the delay period. This paradigm was designed to allow for the manipulation of specific WM components and the measurement of their effect on task performance. For example, the number of cue faces varied between 1 and 2 faces and the delay period varied between either 1 or 9 s so that we could measure the effect of longer maintenance requirements and memory load on task performance, respectively. In conditions involving distraction, a single face was presented in the middle of the delay period for 1 s. The effect of manipulating WM subcomponents was quantified by contrasting task performance (% correct accuracy) between conditions that differed only in the subcomponent of interest. See text for details on task manipulations in each of the five conditions and planned contrasts between conditions.
Figure 2.
Figure 2.
Task performance results. A, Group means of percentage task accuracy for the five conditions in the WM paradigm. B, Group means of the change in task accuracy with manipulation of the three WM components, ΔL, ΔM, and ΔD. Error bars indicate SEM.
Figure 3.
Figure 3.
GABA spectroscopy. A, Example of the voxel position within the left middle frontal gyrus in a representative subject. The irregular shape of the in-plane section (green lines) of the voxel is the result of having to rotate the voxel obliquely in reference to the slice plane of the structural images. SFS, Superior frontal sulcus; PCS, precentral sulcus. B, Group-averaged edited spectra from the middle frontal gyrus show the characteristic pseudo-doublet peak of the GABA line graph at ∼3.0 ppm and the doublet peak of Glx at ∼3.7 ppm.
Figure 4.
Figure 4.
Specificity of subjects' DLPFC GABA content correlation with task performance sensitivity to memory load. Scatter plot of individual subject's DLPFC GABA content (x-axis) plotted against ΔL (y-axis), change in task accuracy across levels of memory load (A); visual cortex GABA content plotted against ΔL (B); and DLPFC Glx plotted against ΔL (C).
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