Alterations in High-Frequency Neuronal Oscillations in a Cynomolgus Macaque Test of Sustained Attention Following NMDA Receptor Antagonism

Abstract

A growing body of evidence indicates that neuronal oscillations in the gamma frequency range are disturbed in schizophrenic patients during cognitive processes and may represent an endophenotype of the disease. N-methyl-D-aspartate (NMDA) receptor antagonists have been used experimentally to induce schizophrenia-like symptoms including cognitive deficits in animals and humans. Here we characterized neuronal oscillations and event-related potentials (ERPs) in Cynomolgus macaques fully trained to perform a continuous performance test (CPT) in the presence and absence of the NMDA antagonist phencyclidine (PCP). Macaques (n = 8) were trained to touch 'target' stimuli and ignore 'distractor' stimuli presented randomly on a touchscreen. Subsequently, all subjects were implanted with epidural EEG electrodes over frontal (FC) and parietal cortices (PC) and later tested under vehicle (saline, i.m.) or acute PCP (0.1-0.3 mg/ kg, i.m.) conditions. Compared with vehicle treatment, PCP produced a significant dose-dependent decrease in CPT performance accuracy and increased reaction times. Furthermore, PCP elevated the amplitudes of 'low' (30-50 Hz) and 'high' (51-80 Hz) gamma oscillations in FC and PC around target presentations for all correct responses. The CPT accuracy was inversely correlated with the gamma band amplitude in the presence of PCP. Additionally, PCP delayed the N100 peak latency in FC, and prolonged and suppressed the cognitively relevant P300 component of mean ERPs in FC and PC, respectively. The NMDA receptor antagonist-induced alteration in neuronal oscillations and ERPs may contribute to the observed cognitive deficits in macaques, and enhance our understanding of EEG recordings as a translatable biomarker.

The serotonin hallucinogen 5-MeO-DMT alters cortico-thalamic activity in freely moving mice: Regionally-selective involvement of 5-HT1A and 5-HT2A receptors

“…In agreement with these observations, here we found an increase in mPFC-gamma band power after 5-MeO-DMT. Increases in gamma power have been also reported in freely-moving animals after NMDA-R antagonist administration (Goonawardena et al, 2016;Wood et al, 2012). On the contrary, the 5-HT2A/2C-R agonist DOI decreases gamma power in freely-moving rats (Wood et al, 2012).…”

The qEEG Signature of Selective NMDA NR2B Negative Allosteric Modulators; A Potential Translational Biomarker for Drug Development

“…One limitation of the present studies was the relatively small number of subjects. While 5–6 macaques is similar in size to many nonhuman primate EEG studies previously published [ 15 , 16 , 18 ], relatively small variation between subjects can influence statistical significance of the analysis. For instance traxoprodil increased delta power with relatively large effects in all subjects; however, differences in the sensitivity of individual animals to different doses (e.g.…”

“…Subanesthetic doses of NMDA receptor channel blockers such as ketamine, phencyclidine or MK-801 produce very similar changes in qEEG measures in rodents and humans, whether in basal power spectra, or evoked potential procedures [ 13 , 14 ]. The effects of NMDA antagonists on evoked potentials typically align well with rodents, nonhuman primates and humans, an indication of cross-species translatability of these measures [ 15 – 19 ]. However, there is a paucity of data describing the effects of NMDA antagonists and in particular, ketamine, on qEEG power spectra in nonhuman primates.…”

Electrophysiological characterization of sleep/wake, activity and the response to caffeine in adult cynomolgus macaques

“…We have recently identified EEG correlates for correct responses during a sustained attention task in adult cynomolgus macaques (Goonawardena et al, 2016). Although NMDA receptor antagonists were used in that particular study, we have also assessed the EEG in conjunction with the improved performance produced by CAF on sustained attention tasks, which has led us to examine the effects on CAF on sleep/wake and EEG characteristics in greater detail.…”