Effects of Acute Ketamine Infusion on Visual Working Memory: Event-Related Potentials

Abstract

This is the accepted version of the paper.This version of the publication may differ from the final published version. ABSTRACT BACKGROUND: Working memory (WM) deficits are a core feature of schizophrenia. Electrophysiological studies suggest that impaired early visual processing may contribute to impaired WM in the visual domain. Abnormal N-methyl-D-aspartate (NMDA) receptor function has been implicated both in WM and in early visual processing deficits in schizophrenia. We investigated whether ketamine, a noncompetitive NMDA antagonist, would replicate in healthy volunteers the WM performance and early visual processing abnormalities we and others have reported in patients with schizophrenia. METHODS: Forty-four healthy volunteers were randomly assigned to receive intravenous ketamine or placebo. During infusion, the effects of ketamine were recorded using standardized psychiatric scales. Visual evoked potentials (P100 and P300 components) were recorded during performance of a delayed matching to sample task. RESULTS: Ketamine induced mild psychosis-like symptoms and impaired WM performance. It also significantly increased the P100 amplitude, while P300 amplitude decreased in a load-dependent manner. Amplitudes of P100 during retrieval correlated with cognitive performance only in the placebo group. CONCLUSIONS: We confirmed previous studies showing that ketamine reproduces the impairment of WM performance and smaller P300 amplitudes observed in schizophrenia. However, ketamine increased visual P100 amplitude in contrast to our observation of reduced P100 amplitudes in established schizophrenia. The effects of ketamine on WM and P300 are likely to involve impaired NMDA function, as these receptors are implicated in changes of synaptic strength underlying associative learning and memory. Increased P100 amplitude may reflect the secondary disinhibition of cortical glutamate release that occurs after NMDA blockade. Permanent repository link

DISC1 regulates N-methyl-D-aspartate receptor dynamics: abnormalities induced by a Disc1 mutation modelling a translocation linked to major mental illness

“…We therefore propose that the deleterious effects of DISC1 disruption upon excitatory synapses, identified here using the Der1 mutant mouse, contribute substantially to risk of major mental illness in t(1;11) carriers, but can be influenced by the genetic modifiers and/or environmental factors, leading to differing outcomes. This is consistent with a previous observation that, irrespective of diagnosis, all tested t(1;11) carriers exhibit an abnormal schizophrenia endophenotype, the P300 event-related potential 6 , and that P300 abnormalities are linked to NMDAR dysfunction 56 .…”

DISC1 regulates N-Methyl-D-Aspartate receptor dynamics: Abnormalities induced by a Disc1 mutation modelling a translocation linked to major mental illness

“…We therefore propose that the deleterious effects of DISC1 disruption upon excitatory synapses, identified here using the Der1 mutant mouse, contribute substantially to risk of major mental illness in t(1;11) carriers, but can be influenced by the genetic modifiers and/or environmental factors, leading to differing outcomes. This is consistent with a previous observation that, irrespective of diagnosis, all tested t(1;11) carriers exhibit an abnormal schizophrenia endophenotype, the 20 P300 event-related potential 6 , and that P300 abnormalities are linked to NMDAR dysfunction 56 .…”

Effects of Subanesthetic Ketamine Administration on Visual and Auditory Event-Related Potentials (ERP) in Humans: A Systematic Review

“…According to our evaluation, most of the studies reached good methodological quality, indicating the reported results are quite reliable (Table 2 ). It was specially observed for reports on P300 complex (Watson et al, 2009 ; Mathalon et al, 2014 ), P100 (Koychev et al, 2017 ), N100 (Oranje et al, 2000 , 2002 ; Kort et al, 2017 ), and PPI (van Berckel et al, 1998 ; Heekeren et al, 2007 ). The study of Kreitschmann-Andermahr et al ( 2001 ) could be ranked as having the poorest methodological quality among the included studies, although they report the same null effects of ketamine as Heekeren et al ( 2007 ) using a very similar cognitive task.…”

“…Only three studies have assessed the effects of ketamine on N100 and P100. A recent study has shown that ketamine increased visual P100 potentials during encoding and retrieval phases of a working memory task (Koychev et al, 2017 ), whereas another study did not find any effect of ketamine on P100 in a visual emotional-face recognition task (Schmidt et al, 2013 ). However, a prior study reported that ketamine increased N100 amplitudes in an auditory paradigm (Umbricht et al, 2000 ).…”

“…The effects of ketamine on P300 were studied using varied tasks and contexts. Visual evoked P300s were evaluated using different kinds of stimulation, such as concrete geometrical forms (Watson et al, 2009 ), black and white checkerboard reversals (Musso et al, 2011 ), digits (Ahn et al, 2003 ; Knott et al, 2011 ), and abstract forms (Koychev et al, 2017 ). However, the result is similar, regardless of the stimulus category: ketamine consistently attenuated parietal P300 amplitudes without changing P300 latencies.…”