In this double-blind, placebo-controlled study, we examined the effects of subanaesthetic doses of ketamine (an NMDA glutamate receptor antagonist) and thiopental (a GABA-A receptor agonist) on the event-related potential (ERP) correlates of deviant stimulus processing in 24 healthy adults. Participants completed three separate pharmacological challenge sessions (ketamine, thiopental, saline) in a counterbalanced order. EEG data were recorded both before and during each challenge while participants performed a visual ‘oddball’ task consisting of infrequent ‘target’ and ‘novel’ stimuli intermixed with frequent ‘standard’ stimuli. We examined drug effects on the amplitude and latency of the P300 (P3) component of the ERP elicited by target (P3b) and novel stimuli (P3a), as well as the N200 (N2) component elicited by both target and novel stimuli, and the N100 (N1) elicited by standard stimuli. Relative to placebo, both drugs reduced the amplitude of parietal P3b. While both drugs reduced parietal P3a and Novelty N2, ketamine also shortened P3a latency, reduced Novelty N2 amplitude more than thiopental, and increased frontal P3a amplitude relative to placebo. Overall, the data suggest that both the GABA-A and NMDA receptor systems modulate P3b and P3a. NMDA antagonism appears to lead to more varied effects on the neural correlates of novelty processing.

We used event-related functional magnetic resonance imaging (erfMRI) techniques to examine the cerebral sites involved with target detection and novelty processing of auditory stimuli. Consistent with the results from a recent erfMRI study in the visual modality, target processing was associated with activation bilaterally in the anterior superior temporal gyrus, inferior and middle frontal gyrus, inferior and superior parietal lobules, anterior and posterior cingulate, thalamus, caudate, and the amygdala/hippocampal complex. Analyses of the novel stimuli revealed activation bilaterally in the inferior frontal gyrus, insula, inferior parietal lobule, and in the inferior, middle, and superior temporal gyri. These data suggest that the scalp recorded event-related potentials (e.g., N2 and P3) elicited during similar tasks reflect an ensemble of neural generators located in spatially remote cortical areas.

This study investigated the functional significance of the N2 response to novel stimuli. In one condition, background, target, and deviant stimuli were simple geometric figures. In a second condition, all stimulus types were unfamiliar/unusual figures. In a third condition, background and target stimuli were unusual figures and deviant stimuli were simple shapes. Unusual figures, whether they were deviant, target, or background stimuli, evoked larger N2 responses than their simple, familiar counterparts. N2 elicited by an unusual background stimulus was larger than that evoked by simple, deviant stimuli, a pattern opposite that exhibited by the subsequent P3. Deviance from immediate context had limited influence over N2 amplitude. The results suggest that novelty N2 and novelty P3 reflect the processing of different aspects of “novel” visual stimuli. The novelty P3 is particularly sensitive to deviation from immediate context. In contrast, the novelty N2 is sensitive to deviation from long-term context that renders a stimulus unfamiliar and difficult to encode.