NMDA Receptor Antagonist Effects on Speech-Related Mismatch Negativity and Its Underlying Oscillatory and Source Activity in Healthy Humans

Abstract

Background: Previous studies in schizophrenia have consistently shown that deficits in the generation of the auditory mismatch negativity (MMN)-a pre-attentive, eventrelated 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 psychosislike 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.

Reduced Auditory Mismatch Negativity Reflects Impaired Deviance Detection in Schizophrenia

“… 10 , 11 Prior studies showed that ketamine, an antagonist of NMDA receptors, induces schizophrenia-like symptoms in healthy volunteers. 12 , 13 MMN-like responses have been demonstrated in various animals, including mice, rats, and nonhuman primates. 14–17 Thus, it may be possible to investigate the neural mechanisms underlying the MMN in animal studies for translation to clinical settings, which might facilitate better treatments of schizophrenia.…”

Change in the Neural Response to Auditory Deviance Following Cognitive Therapy for Hallucinations in Patients With Schizophrenia

“…Possibly reflecting contributions from bilateral prefrontal cortices, the auditory MMN response to both simple sound and speech deviants is mainly dependent on synaptic plasticity mediated by glutamatergic N-methyl-D-aspartate (NMDA) receptors in the auditory cortex (115)(116)(117). Although also shown with the detection of duration deviants in our combined group analysis, the more reliable improvements in deviance detection with CBTv were observed in response to the pitch deviant, with pMMN being shown to be increased in both sets of analyses along with pitch CD in auditory cortices.…”

“…In order to reduce Type 1 error rates our source analysis with eLORETA was limited to two ROI, and additional studies are required to examine CBTv effects on non-auditory brain regions, especially frontal areas which are thought to contribute to MMN generation during deviance detection and to interact with auditory cortices in producing AVHs. External auditory stimulation for MMN generation was limited to pure tone deviants and additional studies need to examine CBTv effects on the processing of complex natural sounds including MMN response to speech deviants, which appear to be particularly sensitive to EAIP dysfunction in patients with SZ (21,152) and as with MMN to response to pure tone deviants are reflective of NMDA receptor-mediated neurotransmission in auditory cortices (117). Functional neuroimaging has shown that the neural encoding of natural sounds (e.g., speech, voice) entails the formation of multiple representations of sound spectrograms with different degrees of spectral and temporal resolution (152)(153)(154).…”

Interaction of Background Noise and Auditory Hallucinations on Phonemic Mismatch Negativity (MMN) and P3a Processing in Schizophrenia

“…In addition, greater reductions of MMN amplitudes have been observed in later stages of illness (47)(48)(49). The reduction of MMN amplitudes can in part be attributed to the deficient functioning of N-methyl-D-aspartate (NMDA) glutamate receptor (50)(51)(52).…”

“…While pure tone stimuli are typically used to elicit the MMN and P3a, both can be elicited by any auditory deviant, including spectrally-complex phonetic stimuli ( 76 – 78 ). Numerous studies have examined MMNs elicited by speech sounds to probe language-based processes in healthy and clinical populations ( 52 , 74 , 74 , 76 , 79 , 80 ), with many employing phonemes (i.e., the simplest unit of speech with linguistic meaning) as standard and deviant stimuli. The earliest study to use a phonemic paradigm to investigate the MMN in SZ reported significant deficits in MMN amplitudes elicited by a cross-phoneme change in SZ patients [vs. HCs; ( 81 )].…”