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

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 data was 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.

114. Electrophysiological, Cognitive and Clinical Profiles of At-Risk Mental State: The Longitudinal Minds in Transition (MinT) Study

“…In line with this, pharmacological studies suggest MMN reflects glutamatergic processes [60,61], whereas P3a amplitude is modulated by dopamine (and hence current anti-psychotic medications) [62,63]. Consistent with the findings for MMN, P3a amplitude correlates with cognitive and psychosocial functioning [59,64,65], and is reduced in schizophrenia [59,66], first episode psychosis [37, 41,64,67], and in at risk samples [36,37,39,41]. Thus P3a might provide an additional biomarker for psychosis but targeting different disease processes, and can be readily measured concurrently with MMN.…”

“…MMN and P3a amplitude increased and latency decreased with age most likely due to maturational changes during the teenage years. Other studies in healthy adolescents have found similar age effects for frequency MMN [110,111], but in older age groups there are consistent reports of MMN amplitude reductions with age [29,59] with maximal amplitudes seen in 20-30 year old adults. Within the UHR literature, age effects have been poorly reported, but some studies have reported adjusted MMN effects assuming a linear relationship between age and MMN amplitude [33, 41,43].…”

“…More recently, experimental manipulations have demonstrated dissociations between MMN and P3a, which suggest P3a may be initiated independently of MMN by lower-level change detection/salience processes [55,56], and query whether P3a actually indexes a shift of attention [56,57]. Studies of individual differences in patient cohorts with established schizophrenia [58,59] further support the dissociation of MMN and P3a, and argue that deficits in these reflect distinct physiological abnormalities. In line with this, pharmacological studies suggest MMN reflects glutamatergic processes [60,61], whereas P3a amplitude is modulated by dopamine (and hence current anti-psychotic medications) [62,63].…”

Electroencephalographic Biomarkers of Psychosis: Present and Future

“…To this end, we recently found that the auditory mismatch negativity and later peak features of responses to unattended auditory oddball stimuli predict response to initial exposure to auditory training and are sensitive and early indices of sensory "engagement." We can envision a future in which EEG information in conjunction with other demographic, clinical, and genetic predictors may be used both to improve the identification of individuals at clinical risk for developing psychosis and to inform assignment of interventions that are most likely to provide therapeutic benefits (6,8,11).…”

“…Beyond the substantial validation required for large-scale deployment, instrumentation will need to be simplified to allow administration by nonspecialists in real-world community treatment centers. To this end, the Consortium on the Genetics of Schizophrenia recently demonstrated that neural responses to deviant auditory oddball stimuli can be reliably measured in settings without extensive technician training or expertise in EEG assessment and analysis (11). Such ready "scalability" should also be a development goal for studies using future, more sensitive, source-resolved EEG biomarkers.…”