Potential Mechanisms for the Ketamine-Induced Reduction of P3b Amplitudes

Abstract

In specific dosages, the N-methyl-D-aspartate receptor (NMDA) antagonist ketamine can be used to model transient psychotic symptoms in healthy individuals that resemble those of schizophrenia. Ketamine administration also temporarily impairs cognitive functions, which can be studied by event-related potentials (ERPs). ERPs also allow dissecting what stages of information processing are affected by ketamine and what stages remain functional. For tasks requiring the differentiation of targets and non-targets, it has repeatedly been shown that ketamine administration in healthy individuals leads to decreased amplitudes of the ERP component P3b in response to target stimuli. However, it could be argued that this ketamine-induced P3b reduction is the consequence of an increased difficulty to differentiate targets from non-targets, primarily mediated by ketamine's psychotomimetic rather than pharmacological effects. The current review of ERP studies seeks to clarify the issue whether P3b effects of ketamine may indeed be explained as the consequence of an experienced increase in task difficulty or whether alternative mechanisms are perhaps more plausible. The review first summarizes the effects of task difficulty on ERP components related to intentional stimulus categorization (P3b), involuntary attention switches to distractors (P3a), as well as sensory processing (P1, N1). Secondly, the ERP effects of task difficulty are contrasted with those observed in ketamine studies in healthy individuals. Findings show that P3b amplitudes are consistently diminished by an increased task difficulty, as well as after ketamine administration. In contrast and as most important difference, increased task difficulty leads to increased P3a amplitudes to distractors presented in same modality as targets, whereas ketamine leads to reduced P3a amplitudes for such distractors. This dissociation indicates that the decreased P3b amplitudes after ketamine cannot be explained by a drug-induced increase in task difficulty. The conjoint reductions of P3a and P3b amplitudes instead suggest that working memory operations, in particular working memory updating are impaired after ketamine, which is in line with previous behavioral findings.

Neurochemistry of Visual Attention

“…Most of this evidence comes from EEG studies demonstrating ketamine effects on several attention-related EEG components. In contrast to previous interpretations ( Schwertner et al, 2018 ), Rosburg and Schmidt (2018) suggested that the reduced P3 amplitudes found after ketamine treatment are better explained by working memory impairments than by a drug-related increase in task difficulty due to alterations of perceived stimulus salience. On the other hand, the influence of ketamine on high frequency oscillations does suggest a connection between glutamate, bottom-up attentional processing and selective attention ( Thiebes et al, 2018 ).…”

“…Thus, NMDA blockade affects early attentional processes as well as later voluntary control mechanisms ( Watson et al, 2009 ). Schwertner et al (2018) assumed that ketamine modulates EEG components by influencing stimulus discriminability (but see Rosburg and Schmidt (2018) for a different interpretation). This is in line with other research demonstrating that ketamine impairs the ability to both effectively gate the processing of sensory stimuli and process salient stimuli ( Krystal et al, 1999 ; Umbricht et al, 2002 ).…”