Acute ketamine administration alters the brain responses to executive demands in a verbal working memory task: an FMRI study

Abstract

We have used functional MRI to determine the effects of ketamine on brain systems activated in association with a working memory task. Healthy volunteers received intravenous infusions of placebo, ketamine at 50 ng/ml plasma concentration, and ketamine at 100 ng/ml. They were scanned while carrying out a verbal working memory task in which we varied the executive requirements (manipulation vs maintenance processes) and the mnemonic load (three vs five presented letters). We previously showed that ketamine produces a specific behavioral impairment in the manipulation task. In the current study, we modified tasks in order to match performance across drug and placebo conditions, and used an event-related fMRI design, allowing us to remove unsuccessful trials from the analysis. Our results suggest a task-specific effect of ketamine on working memory in a brain system comprising frontal cortex, parietal cortex, and putamen. When subjects are required to manipulate presented letters into alphabetical order, as opposed to maintaining them in the order in which they were presented, ketamine is associated with significantly greater activity in this system, even under these performance-matched conditions. No significant effect of ketamine was seen in association with increasing load. This suggests that our findings are not explicable in terms of a nonspecific effect of ketamine when task difficulty is increased. Rather, our findings provide evidence that the predominant effects of low, subdissociative doses of ketamine are upon the control processes engaged by the manipulation task. Furthermore, we have shown that ketamine's effects may be elucidated by fMRI even when overt behavioral measures show no evidence of impairment.

Figure 1

Experimental design. The two factors were load (high and low) and task (manipulation and maintenance) resulting in the four conditions shown. Following a 2.5 s presentation of the stimuli, subjects were given an instruction as to what was required. A 7 s delay period followed before the probe question appeared, requiring a yes/no (button push) response. The fMRI response to the instruction and delay period was modelled.

Figure 2

(a) SPM showing the contrast between manipulation and maintenance conditions collapsed across load for the placebo condition. ‘Glass brain’ images are presented showing coronal, sagittal, and axial views. In order to identify the localization of main frontal and parietal activations, these are mapped onto a standard anatomical image in the same space at 30 mm above the ac-pc line. Images are presented at p<0.05 (FDR corrected). Clusters less than 10 contiguous voxels have been excluded. (b) SPM showing the contrast between manipulation and maintenance conditions collapsed across load for the ketamine conditions. Images are prepared and represented as described above.

Figure 3

(a) SPM showing the contrast between high load and low load collapsed across task type (manipulation and maintenance) for the placebo condition. (b) SPM showing the contrast between high load and low load collapsed across task type (manipulation and maintenance) for the ketamine conditions. Images are prepared and represented as for Figure 2.

Figure 4

(a) SPM showing the drug by task interaction. This figure identifies regions in which the manipulation vs maintenance contrast (collapsed across load) is greater under ketamine (collapsed across doses) than placebo. Glass brain images were prepared and thresholded as for Figure 2. An axial slice at 30 mm above ac-pc line is presented with activations superimposed. (b) Drug by task interaction prepared as for (c) but showing the ketamine-related increase for high-load conditions only. (c) Drug by task interaction prepared as for (c) Figure 4c but showing the ketamine-related increase for low-load conditions only. NB. All images (Figure 4) are presented at p<0.05 (FDR) and with a threshold level of 10 voxels. All images presented are constrained by masks that were generated from the contrast between manipulation and maintenance conditions collapsed across load for all three drug conditions (placebo, lower dose, and higher dose). Thresholds defining this mask were set at p<0.005, uncorrected for multiple comparisons.