Potential Mechanisms for the Ketamine-Induced Reduction of P3b Amplitudes.

Timm Rosburg,André Schmidt

doi:10.3389/fnbeh.2018.00308

Timm Rosburg, André Schmidt

Open Access

https://doi.org/10.3389/fnbeh.2018.00308

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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.

Highlights

Various studies have administered subanesthetic doses of ketamine, an N-methyl-D-aspartate receptor (NMDA) antagonist, to model psychotic symptoms and psychosislike experiences in healthy individuals. Krystal et al (1994) were one of the first research groups who experimentally investigated these effects
Some of the studies used event-related potentials (ERPs) in order to test whether such subanesthetic doses of ketamine lead to processing deficits in healthy individuals similar to those observed in patients with schizophrenia and to reveal the neurocognitive consequence of the drug administration
In the first result section, we present a selective review of previous studies showing how the ERP components P3a and P3b, P1, N1, and Processing Negativity (PN) of healthy individuals are modulated by an increased task difficulty in active oddball tasks

Summary

Introduction

Various studies have administered subanesthetic doses of ketamine, an N-methyl-D-aspartate receptor (NMDA) antagonist, to model psychotic symptoms and psychosislike experiences in healthy individuals. Krystal et al (1994) were one of the first research groups who experimentally investigated these effects. Some of the studies used event-related potentials (ERPs) in order to test whether such subanesthetic doses of ketamine lead to processing deficits in healthy individuals similar to those observed in patients with schizophrenia and to reveal the neurocognitive consequence of the drug administration (van Berckel et al, 1998; Oranje et al, 2000, 2009; Umbricht et al, 2000; Kreitschmann-Andermahr et al, 2001; Ahn et al, 2003; Boeijinga et al, 2007; Heekeren et al, 2008; Watson et al, 2009; Musso et al, 2011; Gunduz-Bruce et al, 2012; Schmidt et al, 2012, 2013; Mathalon et al, 2014; Koychev et al, 2017) In many of these ERP studies, ketamine effects were investigated in passive and active oddball experiments. The very same stimulation protocol might be used for both active and passive conditions, with only varying in instruction (Figure 1)

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