Modulation of resting human electroencephalographic dynamics by N-methyl-D-aspartate antagonist nitrous oxide

During anaesthesia electrocortical activity as observed by the human electroencephalogram (EEG) is subject to a host of quantitative changes which coincide with the selective actions of anaesthetic agents at gamma aminobutyric acid (GABA) inhibitory synapses. Through potentiation of GABAA receptor based inhibitory currents, inhaled volatile anaesthetics shift the EEG through a range of states yet to be fully understood, resulting in a large amplitude and low frequency EEG signal. Paradoxically, one class of anaesthetics/analgesics know as dissociative agents, target excitatory N-methyl-D-aspartate (NMDA) receptors, impeding their function and producing EEG patterns similar to alert and aroused states. Consequently, dissociative anaesthetics, especially the commonly used nitrous oxide (N2O) fail to be characterised by clinical EEG monitors of anaesthetic depth. To date, the effects of N2O on the EEG have yet to be adequately characterised, even though it has received extensive medical use for well over 100 years. The following investigation sought to clearly quantify the effects of N2O on the EEG in healthy male participants. It was found that during N2O inhalation the EEG underwent broadband attenuation but otherwise remained spectrally similar to resting EEG. Conversely, during the withdrawal of N2O, the EEG showed a strong rebound effect which produced large amplitude delta/theta oscillations, more typically associated with sedation and anaesthesia. The combination of these effects may help explain previously reported difficulties in attempting to monitor patient state with the EEG during anaesthesia involving N2O. Given the invariance of several standard linear measures, nonlinear analysis of the EEG was employed to investigate any higher order effects of N2O. However, a multivariate method showed nonlinearity of the EEG to be marginally altered by N2O. In general a central limiting factor was the insufficient number of participants administered higher concentrations of N2O, due to attrition. In light of previous theoretical attempts to simulate the EEG during anaesthesia, N2O is inferred to chiefly target cell populations that interact via NMDA synapses, which contribute less to the periodicity of the EEG. Contrasting this action with the standard GABAA based anaesthetics, where interacting inhibitory populations thought to be crucial in resting EEG rhythmogenesis are perturbed. These findings will assist in future attempts at monitoring dissociative anaesthesia and more generally contribute to understanding the brain dynamics associated with the NMDA receptor system.