NMDA antagonist ketamine reduces task selectivity in macaque dorsolateral prefrontal neurons and impairs performance of randomly interleaved prosaccades and antisaccades

Abstract

Ketamine, an NMDA receptor antagonist, has been shown to induce behavioral abnormalities in humans that mimic the positive, negative, and most importantly cognitive deficits observed in schizophrenia. Similar cognitive deficits have been observed in nonhuman primates after a subanesthetic dose of ketamine, including an impairment in their ability to perform the antisaccade task, which requires the suppression of a prosaccade toward a flashed stimulus and the generation of a saccade in the opposite direction. The neural basis underlying these cognitive impairments remains unknown. Here, we recorded single-neuron activity in the lateral prefrontal cortex of macaque monkeys before and after the administration of subanesthetic doses of ketamine during the performance of randomly interleaved prosaccade and antisaccade trials. Ketamine impeded the monkeys' ability to maintain and apply the correct task rule and increased reaction times of prosaccades and antisaccades. These behavioral changes were associated with an overall increase in activity of PFC neurons and a reduction in their task selectivity. Our results suggest that the mechanism underlying ketamine-induced cognitive abnormalities may be the nonspecific increase in PFC activity and the associated reduction of task selectivity.

Figure 1.

Experimental paradigm. A, Rule-visible task. Each trial began with a fixation point (FP) signaling, by its color, a prosaccade or antisaccade trial. A stimulus then appeared either 8° to either the left or right. B, Rule-memorized task. Same as A, but the color of the FP changed to white 800–1000 ms before stimulus presentation. This required the monkey to memorize the task rule.

Figure 2.

Behavioral effects of ketamine administration. A, Effect of ketamine on the directional error rates (blue bars), response rates (green bars), and fixation error rates (red bars). The darker shaded foreground bars represent preinjection values, and the lighter background bars are postinjection values. Data for monkey O were averaged from 8 experiment sessions; data for monkey W were averaged from 10 experiment sessions. B, Effect of ketamine on saccade reaction times. The format is the same as in A, with blue bars representing saccade reaction times on correct trials and red bars representing saccade reaction times on (directional) error trials. Error bars indicate SEM. *p < 0.05, **p < 0.01, ***p < 0.001.

Figure 3.

MRI reconstruction of recording locations. L, Left hemisphere; R, right hemisphere; m, medial; a, anterior; p, posterior; l, lateral.

Figure 4.

Effect of ketamine on a single PFC neuron. The neuron was recorded from monkey O in the dorsal bank of the principal sulcus in the right hemisphere. A, Activity on rule-visible trials. B, Activity on rule-memorized trials. The top panel shows a raster plot with each dot indicating the time of an action potential relative to stimulus presentation, and each row represents one trial.

Figure 5.

Effect of ketamine on change in discharge rate and change in task selectivity. Scatter plot depicts the change in discharge rates of neurons (interval from 1000 ms before to 500 ms after stimulus onset) after ketamine injection on the x-axis and the change in task selectivity (same analysis interval as x-axis) on the y-axis. The circles indicate neurons recorded from monkey O, the squares indicate neurons recorded from monkey W, filled represent narrow-spiking neurons, and hollow points represent broad-spiking neurons.

Figure 6.

Results of three-way ANOVA on differences in neural activity. A, Results during prestimulus epoch. B, Results during stimulus/response epoch. RUL, Rule (prosaccade vs antisaccade); MEM, memory condition (rule-visible vs rule-memorized condition); DIR, direction (ipsilateral vs contralateral stimulus location); DRUG, ketamine status (preinjection vs postinjection).

Figure 7.

Time course of ketamine administration. A, Transient increase of error rates in prosaccade (thin lines) and antisaccade trials (thick lines) in rule-visible (solid lines) and rule-memorized (dashed lines) conditions. B, Transient increase in saccade reaction times, same format as A. C, Reduction of task selectivity following ketamine administration. Task selectivity was calculated for significant neurons for the prestimulus (dashed line) and stimulus/response (solid line) epochs. The time of ketamine injection is indicated by a vertical dashed line.

Figure 8.

Effects of ketamine on task selectivity. A, Task selectivity for the individual 35 neurons is plotted during the preinjection period against task selectivity during the postinjection period. Rule indicates neurons (squares) that showed maximal task selectivity between prosaccades and antisaccades. Memory indicates neurons (circles) that showed maximal task selectivity between the rule-visible and rule-memorized conditions. Dashed line, Unity line (slope = 1). B, Same as A, but for the 49 neurons in the stimulus/response epoch. Rule indicates neurons (squares) that showed maximal task selectivity between prosaccades and antisaccades. Direction indicates neurons (circles) that showed maximal task selectivity between ipsilateral and contralateral stimulus presentations. The solid points in both plots represent narrow-spiking neurons, and the hollow points represent broad-spiking neurons.

Figure 9.

Changes in task selectivity for error trials and correct trials. Change in task selectivity of neurons during trials completed correctly after ketamine administration is plotted on the x-axis, while change in task selectivity of neurons during error trials is plotted on the y-axis. A, Differences of correct trials versus error trials during the prestimulus epoch. Data points below the unity line (dashed line) indicate a greater loss in task selectivity during error trials. B, Differences of correct trials versus error trials during the stimulus/response epoch (same format as A). The solid points in both plots represent narrow-spiking neurons; the hollow points represent broad-spiking neurons.

Figure 10.

Effects of ketamine on population activity of task-selective neurons. In both rule-visible (A) and rule-memorized (B) conditions, the population activity shows a large separation between the preferred and nonpreferred condition before ketamine administration. This selectivity is reduced after ketamine.

Figure 11.

ROC curve of task selectivity before and after ketamine administration. A, ROC values for rule-visible trials. Preinjection (blue solid line) and postinjection (red solid line) task selectivity ROC values with accompanying 2.5 and 97.5% (dashed lines) significance cutoff values as calculated by bootstrap analysis. B, ROC values for rule-memorized trials (same format as A).