Ketamine Alters Lateral Prefrontal Oscillations in a Rule-Based Working Memory Task

Acute administration of N-methyl-D-aspartate receptor (NMDAR) antagonists in healthy humans and animals produces working memory deficits similar to those observed in schizophrenia. However, it is unclear whether they also lead to altered low-frequency (≤60 Hz) neural oscillatory activities similar to those associated with schizophrenia during working memory processes. Here, we recorded local field potentials (LFPs) and single-unit activity from the lateral prefrontal cortex (LPFC) of three male rhesus macaque monkeys while they performed a rule-based prosaccade and antisaccade working memory task both before and after systemic injections of a subanesthetic dose (≤0.7 mg/kg) of ketamine. Accompanying working-memory impairment, ketamine enhanced the low-gamma-band (30–60 Hz) and dampened the beta-band (13–30 Hz) oscillatory activities in the LPFC during both delay periods and intertrial intervals. It also increased task-related alpha-band activities, likely reflecting compromised attention. Beta-band oscillations may be especially relevant to working memory processes because stronger beta power weakly but significantly predicted shorter saccadic reaction time. Also in beta band, ketamine reduced the performance-related oscillation as well as the rule information encoded in the spectral power. Ketamine also reduced rule information in the spike field phase consistency in almost all frequencies up to 60 Hz. Our findings support NMDAR antagonists in nonhuman primates as a meaningful model for altered neural oscillations and synchrony, which reflect a disorganized network underlying the working memory deficits in schizophrenia.

SIGNIFICANCE STATEMENT Low doses of ketamine, an NMDAR blocker, produce working memory deficits similar to those observed in schizophrenia. In the lateral prefrontal cortex, a key brain region for working memory, we found that ketamine altered neural oscillatory activities in similar ways that differentiate schizophrenic patients and healthy subjects during both task and nontask periods. Ketamine induced stronger gamma (30–60 Hz) and weaker beta (13–30 Hz) oscillations, reflecting local hyperactivity and reduced long-range communications. Furthermore, ketamine reduced performance-related oscillatory activities, as well as the rule information encoded in the oscillations and in the synchrony between single-cell activities and oscillations. The ketamine model helps link the molecular and cellular basis of neural oscillatory changes to the working memory deficit in schizophrenia.