Effects of Ketamine on Frontoparietal Interactions in a Rule-Based Antisaccade Task in Macaque Monkeys.

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.

Study at a glance

Abstract

Cognitive control is engaged by working memory processes and high-demand situations like antisaccade, where one must suppress a prepotent response. While it is known to be supported by the frontoparietal control network, how intra- and interareal dynamics contribute to cognitive control processes remains unclear. N-Methyl-d-aspartate glutamate receptors (NMDARs) play a key role in prefrontal dynamics that support cognitive control. NMDAR antagonists, such as ketamine, are known to alter task-related prefrontal activities and impair cognitive performance. However, the role of NMDAR in cognitive control-related frontoparietal dynamics remains underexplored. Here, we simultaneously recorded local field potentials and single-unit activities from the lateral prefrontal (lPFC) and posterior parietal cortices (PPC) in two male macaque monkeys during a rule-based antisaccade task, with both rule-visible (RV) and rule-memorized (RM) conditions. In addition to altering the E/I balance in both areas, ketamine had a negative impact on rule coding in true oscillatory activities. It also reduced frontoparietal coherence in a frequency- and rule-dependent manner. Granger prediction analysis revealed that ketamine induced an overall reduction in bidirectional connectivity. Among antisaccade trials, a greater reduction in lPFC-PPC connectivity during the delay period preceded a greater delay in saccadic onset under the RM condition and a greater deficit in performance under the RV condition. Lastly, ketamine compromised rule coding in lPFC neurons in both RV and RM conditions and in PPC neurons only in the RV condition. Our findings demonstrate the utility of acute NMDAR antagonists in understanding the mechanisms through which frontoparietal dynamics support cognitive control processes.