Ketamine, an NMDAR antagonist, impairs cognitive control by disrupting frontoparietal dynamics. In macaques performing an antisaccade task, ketamine altered excitation/inhibition balance in the lateral prefrontal and posterior parietal cortices, reduced rule coding in neural oscillations, and lowered frontoparietal coherence in a frequency- and rule-dependent manner. It also decreased bidirectional connectivity between these areas. Greater reductions in connectivity during the delay period of antisaccade trials preceded larger delays in saccade onset under a rule-memorized condition and greater performance deficits under a rule-visible condition. Ketamine also compromised rule coding in prefrontal neurons under both conditions and in parietal neurons only under the rule-visible condition. These results demonstrate how acute NMDAR blockade can reveal mechanisms by which frontoparietal dynamics support cognitive control.
Schizophrenia involves disrupted communication between brain regions. Low doses of the NMDA receptor antagonist ketamine produce schizophrenia-like symptoms and cognitive deficits, including impaired working memory. This study recorded neural activity in the lateral prefrontal cortex and posterior parietal cortex of macaque monkeys performing a working memory task. Ketamine impaired rule coding in single neurons during the delay period, reduced low-frequency oscillations in the parietal cortex, and weakened task-related connectivity between frontal and parietal regions in both directions. It also reduced interareal coherence between spiking and low-frequency oscillations. The findings support the use of acute NMDA receptor antagonists to model dysconnection and explore new treatments for schizophrenia.