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Multicenter Study
. 2015 Apr;163(1-3):63-72.
doi: 10.1016/j.schres.2014.09.042. Epub 2014 Oct 23.

Validation of mismatch negativity and P3a for use in multi-site studies of schizophrenia: characterization of demographic, clinical, cognitive, and functional correlates in COGS-2

Gregory A Light  1 , Neal R Swerdlow  2 , Michael L Thomas  2 , Monica E Calkins  3 , Michael F Green  4 , Tiffany A Greenwood  2 , Raquel E Gur  3 , Ruben C Gur  3 , Laura C Lazzeroni  5 , Keith H Nuechterlein  6 , Marlena Pela  2 , Allen D Radant  7 , Larry J Seidman  8 , Richard F Sharp  2 , Larry J Siever  9 , Jeremy M Silverman  9 , Joyce Sprock  2 , William S Stone  8 , Catherine A Sugar  10 , Debby W Tsuang  7 , Ming T Tsuang  11 , David L Braff  2 , Bruce I Turetsky  3
Affiliations
Multicenter Study

Validation of mismatch negativity and P3a for use in multi-site studies of schizophrenia: characterization of demographic, clinical, cognitive, and functional correlates in COGS-2

Gregory A Light et al. Schizophr Res. 2015 Apr.

Abstract

Mismatch negativity (MMN) and P3a are auditory event-related potential (ERP) components that show robust deficits in schizophrenia (SZ) patients and exhibit qualities of endophenotypes, including substantial heritability, test-retest reliability, and trait-like stability. These measures also fulfill criteria for use as cognition and function-linked biomarkers in outcome studies, but have not yet been validated for use in large-scale multi-site clinical studies. This study tested the feasibility of adding MMN and P3a to the ongoing Consortium on the Genetics of Schizophrenia (COGS) study. The extent to which demographic, clinical, cognitive, and functional characteristics contribute to variability in MMN and P3a amplitudes was also examined. Participants (HCS n=824, SZ n=966) underwent testing at 5 geographically distributed COGS laboratories. Valid ERP recordings were obtained from 91% of HCS and 91% of SZ patients. Highly significant MMN (d=0.96) and P3a (d=0.93) amplitude reductions were observed in SZ patients, comparable in magnitude to those observed in single-lab studies with no appreciable differences across laboratories. Demographic characteristics accounted for 26% and 18% of the variance in MMN and P3a amplitudes, respectively. Significant relationships were observed among demographically-adjusted MMN and P3a measures and medication status as well as several clinical, cognitive, and functional characteristics of the SZ patients. This study demonstrates that MMN and P3a ERP biomarkers can be feasibly used in multi-site clinical studies. As with many clinical tests of brain function, demographic factors contribute to MMN and P3a amplitudes and should be carefully considered in future biomarker-informed clinical studies.

Keywords: Cognition; EEG; Function; Mismatch negativity; P300; P3a; Schizophrenia.

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Conflict of interest statement

Conflicts of Interest:

Dr. Light reports having been a consultant to EnVivo/Forum and Astellas and serves on an advisory board for Neuroverse. Dr. Green has been a consultant to AbbVie, Biogen, DSP, EnVivo/Forum and Roche, and he is on the scientific advisory board of Mnemosyne. He has received research funds from Amgen. Dr. Lazzeroni is an inventor on a patent application filed by Stanford University on genetic polymorphisms associated with depression. Dr. Nuechterlein has received unrelated research support from Janssen Scientific Affairs, Genentech, and Brain Plasticity, Inc., and has consulted to Genentech, Otsuka, Janssen, and Brain Plasticity, Inc. Dr. Swerdlow has been a consultant for Genco Sciences, Ltd. All other authors declare that they have no conflict of interest.

Figures

Figure 1
Figure 1. MMN/P3a Paradigm and Group Averages
Participants are presented with stimuli consisting of frequently presented Standard stimuli (90% of trails, red box labeled “s”) interspersed with infrequent Deviant stimuli (10% of trials, blue box labeled “deviant”). ERP waves to Standard and Deviant stimuli are calculated by averaging EEG responses to each stimulus type. Deviant – Standard difference waves are generated for calculating MMN and P3a components (black lines). For all waveforms, solid lines represent Healthy Comparison Subjects (n=753) dotted lines are used for Schizophrenia Patients (n=877).
Figure 2
Figure 2. Individual subject and group averaged waveforms
Individual subject Deviant-Standard difference wave averages (color coded by amplitude) are shown in the upper portion of the figure for Healthy Comparison Subjects (n=753) and Schizophrenia Patients (n=877). Group grandaverage waveforms are shown in the lower portion of the figure.
Figure 3
Figure 3. Mean mismatch negativity (MMN) and P3a amplitude plotted for Healthy Comparison Subjects (HCS) and Schizophrenia Patients (SZ) by age
MMN and P3a values by site are corrected for sex and race. Errors bars indicate 1 SE.
Figure 4
Figure 4. Mean mismatch negativity (MMN) and P3a amplitude plotted for Healthy Comparison Subjects (HCS) and Schizophrenia Patients (SZ) by sex
MMN and P3a values by site are corrected for age and race. Errors bars indicate 1 SE.
Figure 5
Figure 5. Mean mismatch negativity (MMN) and P3a amplitude plotted for Healthy Comparison Subjects (HCS) and Schizophrenia Patients (SZ) by site
MMN and P3a values by site are corrected for age, sex, and race. UCSD=University of California, San Diego; UCLA=University of California, Los Angeles; MSSM=Mount Sinai School of Medicine; PENN=University of Pennsylvania; UW=University of Washington. Errors bars indicate 1 SE.
Figure 6
Figure 6. Mean mismatch negativity (MMN) and P3a amplitude plotted for Healthy Comparison Subjects (HCS) and Schizophrenia Patients (SZ) by antipsychotic medication type
MMN and P3a values are corrected for age, sex, and race. Errors bars indicate 1 SE.
Figure 7
Figure 7. Mean mismatch negativity (MMN) and P3a amplitude plotted Healthy Comparison Subjects (HCS) and Schizophrenia Patients (SZ) by use of anticholinergic medication
MMN and P3a values are corrected for age, sex, and race. Errors bars indicate 1 SE.
Figure 8
Figure 8. Mean mismatch negativity (MMN) and P3a amplitude plotted Healthy Comparison Subjects (HCS) and Schizophrenia Patients (SZ) by smoking status
MMN and P3a values are corrected for age, sex, and race. Errors bars indicate 1 SE.
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