High Frequency Neuronal Oscillations in a Cynomologus Macaque Test of Sustained Attention Following Nmda Receptor Antagonism

Abstract

Cognitive impairments associated with schizophrenia (CIAS) remain a large unmet clinical need. A growing body of evidence indicates that neuronal oscillations in the gamma frequency range (30-80 Hz) are disturbed in schizophrenic patients during cognitive processes (e.g., sustained attention, working memory) and may represent an endophenotype in CIAS. Alterations in gamma oscillations as well as other schizophrenia-like symptoms including cognitive impairments can be induced experimentally with NMDA receptor antagonists (e.g., ketamine) in humans and rodents; however, this correlation between gamma rhythms and cognition has not yet been demonstrated in non-human primates (NHPs). Given that NHPs and humans have a similar homology of prefrontal cortical structures that mediate attentional and working memory processes, our objective was to characterize neuronal oscillations in cynomologus macaques performing a continuous performance test (CPT) of sustained attention. Macaques (n=8) were trained to touch ‘target’ stimuli (hits) and ignore ‘distractor’ stimuli (correct rejections) presented randomly on a touchscreen in exchange for food rewards. Subsequently, all subjects were implanted with EEG electrodes [placed on the dura mater above the frontal cortex (FC) and primary visual cortex (V1)]. Thereafter, all animals were given acute doses of either PCP (0.1, 0.18, 0.3 mg/kg) or ketamine (0.3, 1.0, 1.8 mg/kg) to assess their effect on CPT performance and high frequency brain oscillations. As compared to vehicle treatment, PCP and ketamine significantly decreased CPT performance accuracy. EEG analyses during CPT performance demonstrated that PCP enhanced the amplitude of low (30-50Hz) and high (50-80Hz) gamma oscillations while suppressing alpha (8-12Hz) and beta (16-24Hz) in both the FC and V1 around stimulus presentations versus vehicle. Moreover, PCP-treated animals showed a significant enhancement in amplitude of high gamma oscillations following the stimulus presentation for ‘hits’ (i.e. correct responses) in comparison to ‘misses’ (i.e. error responses) and ‘correct rejections’ in the FC. In contrast, both PCP and ketamine-treated animals showed a suppression of beta oscillations following stimuli presentation for hits vs misses/correct rejections in the V1. Overall, our results suggest that acute administration of NMDA receptor antagonists impairs cognitive performance and disrupts neuronal oscillations in macaques. These studies may help to define the role of high frequency oscillations in cognitive processes in higher order species, and to enhance our understanding of EEG recordings as a translatable biomarker for CIAS.