Umbricht D, Koller R, Vollenweider FX, Schmid L. Mismatch negativity predicts psychotic experiences induced by NMDA receptor antagonist in healthy volunteers. Biol Psychiatry 51: 400-406

Psychiatry Research, University of Zurich, Zürich, Zurich, Switzerland
Biological Psychiatry (Impact Factor: 10.26). 04/2002; 51(5):400-6. DOI: 10.1016/S0006-3223(01)01242-2
Source: PubMed


Previous studies indicate that mismatch negativity (MMN)-a preattentive auditory event-related potential (ERP)-depends on NMDA receptor (NMDAR) functioning. To explore if the strength of MMN generation reflects the functional condition of the NMDAR system in healthy volunteers, we analyzed correlations between MMN recorded before drug administration and subsequent responses to the NMDAR antagonist ketamine or the 5-HT2a agonist psilocybin.
In two separate studies, MMN was recorded to both frequency and duration deviants prior to administration of ketamine or psilocybin. Behavioral and subjective effects of ketamine and psilocybin were assessed with the Brief Psychiatric Rating Scale and the OAV Scale-a rating scale developed to measure altered states of consciousness. Correlations between ERP amplitudes (MMN, N1, and P2) and drug-induced effects were calculated in each study group and compared between them.
Smaller MMN to both pitch and duration deviants was significantly correlated to stronger effects during ketamine, but not psilocybin administration. No significant correlations were observed for N1 and P2.
Smaller MMN indicates a NMDAR system that is more vulnerable to disruption by the NMDAR antagonist ketamine. MMN generation appears to index the functional state of NMDAR-mediated neurotransmission even in subjects who do not demonstrate any psychopathology.

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    • "Several clinical reports indicate a disruption of MMN in the presence of a non-selective antagonist like ketamine (29–33). Indeed, MMN has been argued as an index of NMDA receptor dysfunction in schizophrenia in part based on these findings (28, 32). However, NMDA receptors are heterotetramers made of two NR1 and two NR2 subunits with considerable heterogeneity in expression and distribution within the brain (34, 35). "
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    ABSTRACT: Schizophrenia patients exhibit a decreased ability to detect change in their auditory environ-ment as measured by auditory event-related potentials (ERP) such as mismatch negativity. This deficit has been linked to abnormal NMDA neurotransmission since, among other observations, non-selective channel blockers of NMDA reliably diminish automatic deviance detection in human subjects as well as in animal models. Recent molecular and functional evidence links NR2B receptor subtype to aberrant NMDA transmission in schizophrenia. However, it is unknown if NR2B receptors participate in pre-attentive deviance detec-tion. We recorded ERP from the vertex of freely behaving rats in response to frequency mismatch protocols. We saw a robust increase in N1 response to deviants compared to standard as well as control stimuli indicating true deviance detection. Moreover, the increased negativity was highly sensitive to deviant probability. Next, we tested the effect of a non-selective NMDA channel blocker (ketamine, 30 mg/kg) and a highly selective NR2B antagonist, CP-101,606 (10 or 30 mg/kg) on deviance detection. Ketamine attenu-ated deviance mainly by increasing the amplitude of the standard ERP. Amplitude and/or latency of several ERP components were also markedly affected. In contrast, CP-101,606 robustly and dose-dependently inhibited the deviant's N1 amplitude, and as a consequence, completely abolished deviance detection. No other ERPs or components were affected. Thus, we report first evidence that NR2B receptors robustly participate in processes of automatic deviance detection in a rodent model. Lastly, our model demonstrates a path forward to test specific pharmacological hypotheses using translational endpoints relevant to aberrant sensory processing in schizophrenia.
    Frontiers in Psychiatry 08/2014; 5. DOI:10.3389/fpsyt.2014.00096
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    • "Thus the finding of improved prediction of psychosis by the inclusion of auditory function assessment via MMN is promising (Kaur et al. 2013; Umbricht et al. 2002). Although the neural pathophysiology giving rise to schizophrenia remains unclear, recent theories suggest an imbalance in Glu and GABA. "
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    ABSTRACT: Cognition is often affected in a variety of neuropsychiatric, neurological, and neurodevelopmental disorders. The neural discriminative response, reflected in mismatch negativity (MMN) and its magnetoencephalographic equivalent (MMNm), has been used as a tool to study a variety of disorders involving auditory cognition. MMN/MMNm is an involuntary brain response to auditory change or, more generally, to pattern regularity violation. For a number of disorders, MMN/MMNm amplitude to sound deviance has been shown to be attenuated or the peak-latency of the component prolonged compared to controls. This general finding suggests that while not serving as a specific marker to any particular disorder, MMN may be useful for understanding factors of cognition in various disorders, and has potential to serve as an indicator of risk. This review presents a brief history of the MMN, followed by a description of how MMN has been used to index auditory processing capability in a range of neuropsychiatric, neurological, and neurodevelopmental disorders. Finally, we suggest future directions for research to further enhance our understanding of the neural substrate of deviance detection that could lead to improvements in the use of MMN as a clinical tool.
    Brain Topography 05/2014; 27(4). DOI:10.1007/s10548-014-0374-6 · 3.47 Impact Factor
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    • "In clinical studies, the aforementioned cognitive deficits have been demonstrated being predictive of future transition to psychosis in at-risk samples (30–33, 35–37). Finally, the MMN, which has been demonstrated to be predictive of psychosis development (55–58), is rather specifically affected by PCP/NMDA antagonists (9, 75) and altered MMN amplitudes in healthy individuals predicted the individual’s susceptibility to PCP induced psychotic experiences (98). The latter aspect suggests that vulnerability as well as resilience to psychotic experiences might be further understood by a detailed elucidation of NMDA antagonist actions in sensory domains. "
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    ABSTRACT: In the recent decades, a paradigmatic change in psychosis research and treatment shifted attention towards the early and particularly the prodromal stages of illness. Despite substantial progress with regard to the neuronal underpinnings of psychosis development, the crucial biological mechanisms leading to manifest illness are yet insufficiently understood. Until today, one significant approach to elucidate the neurobiology of psychosis has been the modeling of psychotic symptoms by psychedelic substances in healthy individuals. These models bear the opportunity to evoke particular neuronal aberrations and the respective psychotic symptoms in a controlled experimental setting. In the present paper, we hypothesize that experimental psychiatry bears unique opportunities in elucidating the biological mechanisms of the prodromal stages of psychosis. Psychosis risk symptoms are attenuated, transient, and often only retrospectively reported. The respective neuronal aberrations are thought being dynamic. The correlation of unstable psychopathology with observed, e. g., neurophysiological disturbances is thus yet largely unclear. In modeling psychosis, the experimental setting allows not only for evoking particular symptoms, but for the concomitant assessment of psychopathology, neurophysiology, and neuropsychology. Herein, the glutamatergic model will be highlighted exemplarily, with special emphasis on its potential contribution to the elucidation of psychosis development. This model of psychosis appears as candidate for modeling the prodrome since it induces psychopathological, neurocognitive and neurofunctional changes that are comparable to clinical features of the prodrome.As exemplarily illustrated by the PCP/NMDA model of psychosis many aspects advocate that prodromal stages might be validly mimicked by psychedelic substances. In summary, experimental psychiatry bears the potential to further elucidate the biological mechanisms of the psychosis prodrome.
    Frontiers in Psychiatry 12/2013; 4:170. DOI:10.3389/fpsyt.2013.00170
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