Mismatch Negativity in Response to Auditory Deviance and Risk for Future Psychosis in Youth at Clinical High Risk for Psychosis

Abstract

IMPORTANCEAlthough clinical criteria for identifying youth at risk for psychosis have been validated, they are not sufficiently accurate for predicting outcomes to inform major treatment decisions. The identification of biomarkers may improve outcome prediction among individuals at clinical high risk for psychosis (CHR-P).OBJECTIVE To examine whether mismatch negativity (MMN) event-related potential amplitude, which is deficient in schizophrenia, is reduced in young people with the CHR-P syndrome and associated with outcomes, accounting for effects of antipsychotic medication use.DESIGN, SETTING, AND PARTICIPANTS MMN data were collected as part of the multisite case-control North American Prodrome Longitudinal Study (NAPLS-2) from 8 university-based outpatient research programs. Baseline MMN data were collected from June 2009 through April 2013. Clinical outcomes were assessed throughout 24 months. Participants were individuals with the CHR-P syndrome and healthy controls with MMN data. Participants with the CHR-P syndrome who developed psychosis (ie, converters) were compared with those who did not develop psychosis (ie, nonconverters) who were followed up for 24 months. Analysis took place between December 2019 and December 2021. MAIN OUTCOMES AND MEASURESElectroencephalography was recorded during a passive auditory oddball paradigm. MMN elicited by duration-, pitch-, and duration + pitch double-deviant tones was measured. RESULTSThe CHR-P group (n = 580; mean [SD] age, 19.24 [4.39] years) included 247 female individuals (42.6%) and the healthy control group (n = 241; mean age, 20.33 [4.74] years) included 114 female individuals (47.3%). In the CHR-P group, 450 (77.6%) were not taking antipsychotic medication at baseline. Baseline MMN amplitudes, irrespective of deviant type, were deficient in future CHR-P converters to psychosis (n = 77, unmedicated n = 54) compared with nonconverters (n = 238, unmedicated n = 190) in both the full sample (d = 0.27) and the unmedicated subsample (d = 0.33). In the full sample, baseline medication status interacted with group and deviant type indicating that double-deviant MMN, compared with single deviants, was reduced in unmedicated converters compared with nonconverters (d = 0.43). Further, within the unmedicated subsample, deficits in double-deviant MMN were most strongly associated with earlier conversion to psychosis (hazard ratio, 1.40 [95% CI, 1.03-1.90]; P = .03], which persisted over and above positive symptom severity.CONCLUSIONS AND RELEVANCE This study found that MMN amplitude deficits were sensitive to future psychosis conversion among individuals at risk of CHR-P, particularly those not taking antipsychotic medication at baseline, although associations were modest. While MMN shows limited promise as a biomarker of psychosis onset on its own, it may contribute novel risk information to multivariate prediction algorithms and serve as a translational neurophysiological target for novel treatment development in a subgroup of at-risk individuals.

Reduced magnetic mismatch negativity: a shared deficit in psychosis and related risk

“…Presently, the lack of clinical follow-ups in the CHR population impedes determining the progression trajectory of our participants. A longitudinal study is required to establish whether the present effect was driven by those who will transition to SCZ or another chronic psychotic disorder (Fujioka et al, 2020; Hamilton et al, 2022; Perez et al, 2014; Shaikh et al, 2012). However, the observation of significant mMMN reduction in CHR, among whom only few are expected to progress to full-blown psychosis, suggests that MMN might be a potential neurobiological marker in people with a greater risk for psychosis, irrespective of clinical course.…”

“…Sparser findings show that MMN alterations are also present in other populations of patients with psychotic symptoms (Erickson, Ruffle, & Gold, 2016), like in bipolar disorder (BD) (Raggi, Lanza, & Ferri, 2021) and in first-episode psychosis (FEP) (Haigh, Coffman, & Salisbury, 2017), and in subjects at clinical high risk for psychosis (CHR) (Bodatsch, Brockhaus-Dumke, Klosterkotter, & Ruhrmann, 2015;Tada et al, 2019). A recent study with more than 500 CHR participants reported only limited evidence of significant MMN reduction in this population, whereas the MMN deficit was associated with future conversion and earlier onset of full-blown psychosis (Hamilton et al, 2022). Hence, the debate is still open about whether MMN alterations are peculiar to SCZ (Baldeweg & Hirsch, 2015;Erickson et al, 2016;Umbricht et al, 2003) or are instead shared by patients with a history of psychosis.…”

“…Hence, the debate is still open about whether MMN alterations are peculiar to SCZ (Baldeweg & Hirsch, 2015; Erickson et al, 2016; Umbricht et al, 2003) or are instead shared by patients with a history of psychosis. In such a scenario, MMN might be informative on disease onset (Hamilton et al, 2022; Naatanen, Shiga, Asano, & Yabe, 2015; Nagai et al, 2013), progress (Fujioka et al, 2020; Perez et al, 2014; Shaikh et al, 2012), or resilience (Hamilton, Roach, & Mathalon, 2021) in people at clinical risk of psychosis.…”

Musicians show more integrated neural processing of contextually relevant acoustic features

“…Some clinical studies have indeed measured neural responses to multiple co-occurring auditory feature deviants (e.g., Hay et al, 2015 ) and have found, for example, that MMNs from double deviants combining duration and frequency–but not their constitutive single-deviant MMNs–predict the time to psychosis onset in individuals at high risk for schizophrenia ( Perez et al, 2014 ; Hamilton et al, 2022 ). These studies have, however, not typically assessed MMN(m) additivity per se .…”

Why mismatch negativity continues to hold potential in probing altered brain function in schizophrenia

“…For example, in a large mega-analysis of magnetic resonance imaging data in CHR individuals, 61 253 out of 1487 CHR individuals followed up transitioned to psychosis (17%). In a recent multicenter study of MMN among CHR individuals, Hamilton et al 62 reported that 77/315 (24.4%) of followed-up individuals transitioned to psychosis. From the same multicenter study, Seidman et al 63 Although together these findings suggest that combined pitch and duration MMN could be more sensitive to deficits in truly prodromal CHR individuals, 67 as noted by the authors, the effect sizes for each type of MMN are too small to be useful as a risk biomarker.…”