Automatic auditory processing deficits in schizophrenia and clinical high-risk patients: forecasting psychosis risk with mismatch negativity

Abstract

Background: Only about one third of patients at high risk for psychosis based on current clinical criteria convert to a psychotic disorder within a 2.5-year follow-up period. Targeting clinical high-risk (CHR) individuals for preventive interventions could expose many to unnecessary treatments, underscoring the need to enhance predictive accuracy with nonclinical measures. Candidate measures include event-related potential components with established sensitivity to schizophrenia. Here, we examined the mismatch negativity (MMN) component of the event-related potential elicited automatically by auditory deviance in CHR and early illness schizophrenia (ESZ) patients. We also examined whether MMN predicted subsequent conversion to psychosis in CHR patients.

Methods: Mismatch negativity to auditory deviants (duration, frequency, and duration + frequency double deviant) was assessed in 44 healthy control subjects, 19 ESZ, and 38 CHR patients. Within CHR patients, 15 converters to psychosis were compared with 16 nonconverters with at least 12 months of clinical follow-up. Hierarchical Cox regression examined the ability of MMN to predict time to psychosis onset in CHR patients.

Results: Irrespective of deviant type, MMN was significantly reduced in ESZ and CHR patients relative to healthy control subjects and in CHR converters relative to nonconverters. Mismatch negativity did not significantly differentiate ESZ and CHR patients. The duration + frequency double deviant MMN, but not the single deviant MMNs, significantly predicted the time to psychosis onset in CHR patients.

Conclusions: Neurophysiological mechanisms underlying automatic processing of auditory deviance, as reflected by the duration + frequency double deviant MMN, are compromised before psychosis onset and can enhance the prediction of psychosis risk among CHR patients.

Keywords: Auditory cortex; clinical high-risk for psychosis; event-related potential; longitudinal; mismatch negativity; psychosis; schizophrenia.

Conflict of interest statement

Financial Disclosures. Drs. Perez, Woods, Ford, McGlashan, Srihari, and Mr. Roach report no biomedical financial interests or poten tial conflicts of interest. Dr. Mathalon is a consultant for Bristol-Myers Squibb and Amgen.

Copyright © 2014 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1. Mismatch Negativity (MMN) for each Group and Deviant Type

On the left, scalp voltage topography maps of MMN amplitudes are shown for each group and deviant type. MMN topography maps show the group means of MMN amplitudes associated with subject-specific median peak latency across the six fronto-central leads (F3, Fz, F4, C3, Cz, C4). All maps are plotted on the same voltage scale (µV) as indicated in the legend. In the center, ear-referenced ERP difference waveforms averaged across the six fronto-central leads for Duration, Frequency, and Double-Deviant MMN are shown for each group. On the right, line graphs show group means and standard errors for raw MMN amplitude in microvolts (top) and MMN age-corrected z-scores (bottom). Healthy Controls are shown in red, Clinical High Risk patients in blue, and Early Illness Schizophrenia (SZ) patients in green. MMN is reduced in Early Illness SZ and Clinical High Risk patients relative to Healthy Controls across deviant type.

Figure 2. Mismatch Negativity (MMN) for each Clinical High-Risk Conversion Group and Deviant Type

On the left, scalp voltage topography maps of MMN amplitudes are shown for each group and deviant type. MMN topography maps show the group means of MMN amplitudes associated with subject-specific median peak latency across the six fronto-central leads (F3, Fz, F4, C3, Cz, C4). In the center, ear-referenced ERP difference waveforms averaged across the six fronto-central leads for Duration, Frequency, and Double-Deviant MMN are shown for both groups. On the right, line graphs show (top) group means and standard errors for raw MMN amplitude in microvolts and (bottom) MMN age-corrected z-scores. Converters to psychosis are shown in magenta and non-converters are shown in black. MMN is reduced in converters relative to non-converters across deviant type. Individual subject butterfly plots are shown in Figure S3 of the Supplementary Materials.

Figure 3. Estimated Survival Functions for Quartiles of the Double-Deviant Mismatch Negativity (MMN) in Clinical High-Risk Patients Showing Psychosis Conversion Risk

A Cox regression analysis shows that a greater Double-Deviant MMN deficit in CHR patients is associated with an earlier transition to psychosis. To illustrate this finding, estimated cumulative survival functions are plotted for the amplitude values corresponding to the quartiles of the double-deviant MMN in the CHR group: Lower quartile (25th percentile) of MMN = −4.8 µV (blue line); Middle quartile (50th percentile) of MMN = −6.1 µV (red line); Upper quartile (75th percentile) of MMN = −7.2 µV (gray line).