Abstract
Background: Previous studies in schizophrenia have consistently shown that deficits in the generation of the auditory mismatch negativity (MMN) – a pre-attentive, event-related potential (ERP) typically elicited by changes to simple sound features – are linked to N-methyl-D-aspartate (NMDA) receptor hypofunction. Concomitant with extensive language dysfunction in schizophrenia, patients also exhibit MMN deficits to changes in speech but their relationship to NMDA-mediated neurotransmission is not clear. Accordingly, our study aimed to investigate speech MMNs in healthy humans and their underlying electrophysiological mechanisms in response to NMDA antagonist treatment. We also evaluated the relationship between baseline MMN/electrocortical activity and emergent schizophrenia-like symptoms associated with NMDA receptor blockade.Methods: In a sample of 18 healthy volunteers, a multi-feature Finnish language paradigm incorporating changes in syllables, vowels and consonant stimuli was used to assess the acute effects of the NMDA receptor antagonist ketamine and placebo on the MMN. Further, measures of underlying neural activity, including evoked theta power, theta phase locking and source-localized current density in cortical regions of interest were assessed. Subjective symptoms were assessed with the Clinician Administered Dissociative States Scale (CADSS).Results: Participants exhibited significant ketamine-induced increases in psychosis-like symptoms and depending on temporal or frontal recording region, co-occurred with reductions in MMN generation in response to syllable frequency/intensity, vowel duration, across vowel and consonant deviants. MMN attenuation was associated with decreases in evoked theta power, theta phase locking and diminished current density in auditory and inferior frontal (language-related cortical) regions. Baseline (placebo) MMN and underlying electrophysiological features associated with the processing of changes in syllable intensity correlated with the degree of psychotomimetic response to ketamine.Conclusion: Ketamine-induced impairments in healthy human speech MMNs and their underlying electrocortical mechanisms closely resemble those observed in schizophrenia and support a model of dysfunctional NMDA receptor-mediated neurotransmission of language processing deficits in schizophrenia.HIGHLIGHTS-Neural effects of NMDA receptor blockade on speech processing were assessed in a ketamine model.-Ketamine reduced MMN, theta power, theta phase locking factor and regional cortical current density.-Psychosis-like symptoms induced by ketamine were related to baseline (placebo) neural measures of speech processing.
Highlights
This electroencephalographic (EEG)-based research project aimed to advance our neural understanding of language processing by assessing the effects of ketamine-induced N-methyl-D-aspartate (NMDA) receptor hypofunction on mismatch negativity (MMN) responses to changes in speech stimuli
It is possible that our baseline MMNketamine response associations seen with intensity deviants may reflect the unique cortical recruitment pattern specific to changes in speech intensity and its disruption by NMDA receptor hypofunction. These results provide potential insight into some of the neural mechanisms underlying NMDA receptor-mediated impairments in the sensory processing of human speech, but there are limitations to the study
To the best of our knowledge, this is the first study assessing the effects of the NMDA receptor antagonist ketamine on speech MMNs, and their associated oscillatory activities and intra-cortical current densities in healthy humans
Summary
This electroencephalographic (EEG)-based research project aimed to advance our neural understanding of language processing by assessing the effects of ketamine-induced N-methyl-D-aspartate (NMDA) receptor hypofunction on mismatch negativity (MMN) responses to changes in speech stimuli (i.e., speech deviants). Addressing the clinical relevance of this work, as multiple lines of evidence have implicated NMDA receptor dysfunction in schizophrenia pathophysiology including impairments in MMN generation, this study examined the relationship of these neural measures to psychotomimetic symptoms produced by acute ketamine administration This is the first known human EEG study combining sensor- and sourcelevel approaches to assess the neural substrates of speech deviance detection modified by NMDA receptor antagonist treatment and their association with schizophrenia-like symptomatology. We evaluated the relationship between baseline MMN/electrocortical activity and emergent schizophrenia-like symptoms associated with NMDA receptor blockade Neurophysiological approaches such as EEG-derived averaged event-related potentials (ERP) are used increasingly as biomarkers for aiding our understanding the neural mechanisms underlying normal and abnormal information processing, and to monitor novel drug therapies for treatment of sensory and cognitive processing deficits (Javitt et al, 2008; Bickel and Javitt, 2009; Javitt, 2015). As MMN and its abnormality can be elicited by changes of an abstract nature such as a violation of a multi-stimulus pattern or regularity (Avissar et al, 2018; Salisbury et al, 2018), or that of a complex sequential stimulus rule, the MMN is thought to signal a prediction-error based on regularity-violation rather than just stimulus-change (Todd et al, 2013)
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