The impact of NMDA receptor blockade on human working memory-related prefrontal function and connectivity

Abstract

Preclinical research suggests that N-methyl-D-aspartate glutamate receptors (NMDA-Rs) have a crucial role in working memory (WM). In this study, we investigated the role of NMDA-Rs in the brain activation and connectivity that subserve WM. Because of its importance in WM, the lateral prefrontal cortex, particularly the dorsolateral prefrontal cortex and its connections, were the focus of analyses. Healthy participants (n=22) participated in a single functional magnetic resonance imaging session. They received saline and then the NMDA-R antagonist ketamine while performing a spatial WM task. Time-course analysis was used to compare lateral prefrontal activation during saline and ketamine administration. Seed-based functional connectivity analysis was used to compare dorsolateral prefrontal connectivity during the two conditions and global-based connectivity was used to test for laterality in these effects. Ketamine reduced accuracy on the spatial WM task and brain activation during the encoding and early maintenance (EEM) period of task trials. Decrements in task-related activation during EEM were related to performance deficits. Ketamine reduced connectivity in the DPFC network bilaterally, and region-specific reductions in connectivity were related to performance. These results support the hypothesis that NMDA-Rs are critical for WM. The knowledge gained may be helpful in understanding disorders that might involve glutamatergic deficits such as schizophrenia and developing better treatments.

Figure 1

(a) Spatial working memory (WM) task, 4-target version. (b) Regions of interests (ROIs) used for time-course analysis, SFG (blue), MFG (magenta), and IFG (green). Ketamine reduced task-related activation during the encoding and early maintenance (EEM) phase, [F(1,686)=9.48, p=0.0022. EEM (yellow), later maintence (LM) (green), and response (purple) analysis periods indicated by vertical bars. BOLD, blood oxygen level dependent; IFG, inferior frontal gyrus; MFG, middle frontal gyrus; SFG, superior frontal gyrus.

Figure 2

Blood oxygen level–dependent (BOLD) percent signal change (mean±SEM) in auditory cortex.

Figure 3

R-dlPFC functional connectivity with brain mean time course removed. Green shows task R-dlPFC connectivity under saline, blue are voxels that have higher correlation with R-dlPFC under saline than ketamine, yellow are voxels that have higher correlation with R-dlPFC under ketamine than saline. No other areas of the brain than those shown are significantly increased during ketamine. (a) right lateral saggital, (b) left lateral saggital, (c) axial (z=16).

Figure 4

Relationship between connectivity alterations and performance (each cluster is depicted with a different color). (a) Relationship between ketamine-related changes in percent correct and connectivity changes in the R-dlPFC network in the IFG observed during task. (b) Relationship between ketamine-related decreases in percent correct and connectivity changes in the thalamus. In blue, thalamic areas (anterior nuclei) correlated with L-dlPFC connectivity changes. In green, thalamic areas (medio-dorsal nucleus and anterior nuclei) correlated with R-dlPFC connectivity changes. In yellow, thalamic areas correlated with both R-dlPFC and L-dlPFC seeds (anterior nuclei). Red arrows indicate area shown in graph. All references to subareas within the thalamus are used for descriptive purposes only and are approximate. All clusters that appear on the slices pictured are shown and their co-ordinates and associated r-values are provided in Supplementary Information, Supplementary Tables 4 and 5.