Prediction of Psychosis by Mismatch Negativity

doi:10.1016/j.biopsych.2010.09.057

Biological Psychiatry

Volume 69, Issue 10, 15 May 2011, Pages 959-966

https://doi.org/10.1016/j.biopsych.2010.09.057 Get rights and content

Background

To develop risk-adapted prevention of psychosis, an accurate estimation of the individual risk of psychosis at a given time is needed. Inclusion of biological parameters into multilevel prediction models is thought to improve predictive accuracy of models on the basis of clinical variables. To this aim, mismatch negativity (MMN) was investigated in a sample clinically at high risk, comparing individuals with and without subsequent conversion to psychosis.

Methods

At baseline, an auditory oddball paradigm was used in 62 subjects meeting criteria of a late risk at-state who remained antipsychotic-naive throughout the study. Median follow-up period was 32 months (minimum of 24 months in nonconverters, n = 37). Repeated-measures analysis of covariance was employed to analyze the MMN recorded at frontocentral electrodes; additional comparisons with healthy controls (HC, n = 67) and first-episode schizophrenia patients (FES, n = 33) were performed. Predictive value was evaluated by a Cox regression model.

Results

Compared with nonconverters, duration MMN in converters (n = 25) showed significantly reduced amplitudes across the six frontocentral electrodes; the same applied in comparison with HC, but not FES, whereas the duration MMN in in nonconverters was comparable to HC and larger than in FES. A prognostic score was calculated based on a Cox regression model and stratified into two risk classes, which showed significantly different survival curves.

Conclusions

Our findings demonstrate the duration MMN is significantly reduced in at-risk subjects converting to first-episode psychosis compared with nonconverters and may contribute not only to the prediction of conversion but also to a more individualized risk estimation and thus risk-adapted prevention.

Section snippets

Subjects

The study was approved by the local ethics committee. Written informed consent was obtained after complete description of the study to the subjects.

Subjects were recruited as part of the prospective early detection and intervention studies of the German Research Network on Schizophrenia (GNRS) (41, 42) and had to fulfill the criteria for a late at-risk state of psychosis (8), that is, presence of attenuated positive symptoms (APS) and/or brief limited intermittent positive symptoms (BLIPS)

Comparisons of MMN Amplitudes: Conversion Versus Nonconversion

AR-C subjects showed significantly reduced dMMN amplitudes over the six frontocentral electrodes compared with AR-NC subjects [F(1,52) = 5.16, p < .05]. The respective amplitude values are shown in Figure 1, Table 2; grand averages are shown in Figure 2. No site × group interactions [left midline right: F(2,52) = .66, p = .42, frontocentral: F(1,52) = .04, p = .84] were observed. Further, the average amplitude values of fMMN did not significantly differ between groups [F(1,52) = .42, p = .52]

Discussion

This study investigated the psychosis-predictive value of auditory MMN in subjects at high risk of psychosis by comparing individuals with and without subsequent conversion to psychosis. Compared with AR-NC subjects, AR-C subjects showed significantly reduced dMMN but not fMMN peak amplitudes in baseline recordings, even though these groups were thought to share a similar clinical risk of psychosis at baseline. In contrast, a recent magnetoencephalographic study (18) based on UHR criteria

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This study examined whether mismatch negativity (MMN) responses are impaired in participants at clinical high risk for psychosis (CHR-P) and patients with first-episode psychosis (FEP) and whether MMN deficits predict clinical outcomes in CHR-Ps.
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Mismatch negativity reductions are among the most reliable biomarkers for schizophrenia and have been associated with increased risk for conversion to psychosis in individuals who are at clinical high risk for psychosis (CHR-P). Here, we adopted a computational approach to develop a mechanistic model of mismatch negativity reductions in CHR-P individuals and patients early in the course of schizophrenia.
Electroencephalography was recorded in 38 CHR-P individuals (15 converters), 19 patients early in the course of schizophrenia (≤5 years), and 44 healthy control participants during three different auditory oddball mismatch negativity paradigms including 10% duration, frequency, or double deviants, respectively. We modeled sensory learning with the hierarchical Gaussian filter and extracted precision-weighted prediction error trajectories from the model to assess how the expression of hierarchical prediction errors modulated electroencephalography amplitudes over sensor space and time.
Both low-level sensory and high-level volatility precision-weighted prediction errors were altered in CHR-P individuals and patients early in the course of schizophrenia compared with healthy control participants. Moreover, low-level precision-weighted prediction errors were significantly different in CHR-P individuals who later converted to psychosis compared with nonconverters.
Our results implicate altered processing of hierarchical prediction errors as a computational mechanism in early psychosis consistent with predictive coding accounts of psychosis. This computational model seems to capture pathophysiological mechanisms that are relevant to early psychosis and the risk for future psychosis in CHR-P individuals and may serve as predictive biomarkers and mechanistic targets for the development of novel treatments.
Mismatch Negativity and Theta Oscillations Evoked by Auditory Deviance in Early Schizophrenia
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Amplitude reduction of mismatch negativity (MMN), an event-related potential component indexing NMDA receptor–dependent auditory echoic memory and predictive coding, is widely replicated in schizophrenia. Time-frequency analyses of single-trial electroencephalography epochs suggest that theta oscillation abnormalities underlie MMN deficits in schizophrenia. However, this has received less attention in early schizophrenia (ESZ).
Patients with ESZ (n = 89), within 5 years of illness onset, and healthy control subjects (n = 105) completed an electroencephalography MMN paradigm (duration-deviant, pitch-deviant, duration + pitch double-deviant). Repeated measures analyses of variance assessed group differences in MMN, theta intertrial phase coherence (ITC), and theta total power from frontocentral electrodes, after normal age adjustment. Group differences were retested after covarying MMN and theta measures.
Relative to healthy control subjects, patients with ESZ showed auditory deviance deficits. Patients with ESZ had MMN deficits for duration-deviants (p = .041), pitch-deviants (ps = .007), and double-deviants (ps < .047). Patients with ESZ had reduced theta ITC for standards (ps < .040) and duration-deviants (ps < .030). Furthermore, patients with ESZ had reduced theta power across deviants at central electrodes (p = .013). MMN group deficits were not fully accounted for by theta ITC and power, and neither were theta ITC group deficits fully accounted for by MMN. Group differences in theta total power were no longer significant after covarying for MMN.
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Reduced auditory mismatch negativity (MMN) is robustly impaired in schizophrenia. However, mechanisms underlying dysfunctional MMN generation remain incompletely understood. This study aimed to examine the role of evoked spectral power and phase-coherence towards deviance detection and its impairments in schizophrenia.
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Research increasingly implicates glutamatergic dysfunction in the pathophysiologies of psychotic disorders. Auditory mismatch negativity (MMN) is an electroencephalography (EEG) waveform linked to glutamatergic neurotransmission and is consistently attenuated in schizophrenia (SCZ). MMN consists of two subcomponents, the repetition positivity (RP) and deviant negativity (DN) possibly reflecting different neural mechanisms. However, whether MMN reduction is present across different psychotic disorders, linked to distinct symptom clusters, or related to sex remain to be clarified.
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: Authors MB and SR contributed equally to this work.

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Archival ReportPrediction of Psychosis by Mismatch Negativity

Background

Methods

Results

Conclusions

Section snippets

Subjects

Comparisons of MMN Amplitudes: Conversion Versus Nonconversion

Discussion

Schizophr Res

Schizophr Res

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Schizophr Res

Biol Psychiatry

Schizophr Res

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Neuroimage

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Neuropsychopharmacology

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Schizophr Res

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Schizophr Res

Electroencephalogr Clin Neurophysiol

Clin Neurophysiol

Clin Neurophysiol

Biol Psychiatry

Biol Psychiatry

Psychiatry Res

Int J Radiat Oncol Biol Phys

Diagnosing schizophrenia in the initial prodromal phase

Arch Gen Psychiatry

Risk and protection in prodromal schizophrenia: Ethical implications for clinical practice and future research

Schizophr Bull

Predicting first-episode psychosis by basic symptom criteria

Clin Neuropsychiatr

Validity of the prodromal risk syndrome for first psychosis: Findings from the North American Prodrome Longitudinal Study

Schizophr Bull

Prediction of psychosis in adolescents and young adults at high risk: results from the prospective European prediction of psychosis study

Arch Gen Psychiatry

Clinical staging of psychiatric disorders: a heuristic framework for choosing earlier, safer and more effective interventions

Aust N Z J Psychiatry

Archival Report
Prediction of Psychosis by Mismatch Negativity