Mismatch negativity (MMN) has gained attention as a biomarker for psychosis and a translational intermediate phenotype in animal models of psychosis, including rodents and non-human primates. MMN has been linked to global functioning (Global Assessment of Functioning [GAF] score) and prognosis (psychosis onset or remission), suggesting that MMN reflects activities beyond auditory processing alone. This review examines the 45-year history of MMN from the perspective of psychiatric researchers and discusses current advances in computational and translational research on MMN, summarizing the current understanding of the MMN generation mechanism. We then address the essential question, “What do we observe through MMN?” Currently, we regard the relationship between global functioning in the real world and MMN as the key to answering this question. As a preliminary investigation, we analyzed the relationship between GAF as an objective variable and MMN, diagnosis, and basic epidemiological factors (age, sex, premorbid intelligence quotient) as explanatory variables (total n = 201, healthy controls: n = 41, patients with psychiatric disorders: n = 160) without assuming diagnostic categories. The relationship between functional outcomes and MMN was confirmed without a case-control design. Finally, we propose that new neurophysiological studies should acknowledge psychophysiological responses such as emotion, intention, and autonomic responses, as well as behavioral differences among participants beyond the dichotomy between healthy controls and patients. Measurements could be conducted in various settings from the participant's perspective. We discuss the potential for research investigating psychosis based on the interaction between individuals and the environment, using MMN as an illustrative model.
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