Effects of ketamine on frontoparietal interactions in a rule-based antisaccade task in macaque monkeys.

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 inter-areal dynamics contribute to cognitive control processes remain unclear. N-Methyl-D-aspartate glutamate receptors (NMDARs) play a key role in prefrontal dynamics that support cognitive control, and its 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 remain underexplored. Here, we simultaneously recorded local field potentials and single unit activities from 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 NMDA receptor antagonist in understanding the mechanisms through which frontoparietal dynamics support cognitive control processes.Significance statement A low dose of ketamine is known to induce a transient cognitive control deficit in healthy humans and animals, but it remains unclear whether this deficit is related to a frontoparietal dysconnection. In macaque monkeys performing a rule-based pro- and anti-saccade task, we found that ketamine impaired information coding in frontoparietal neuron, local oscillations and inter-areal synchrony in a rule- and frequency-dependent manner. Notably, under the antisaccade rule, the amount of impairment in task performance could be predicted by the loss in fronto-parietal connectivity in the period just before the monkeys responded. The observations support the utility of NMDA receptor antagonists like ketamine as a tool to understand the role of frontoparietal dynamics in cognitive control.