N-methyl-d-aspartate receptor hypofunction causes recurrent and transient failures of perceptual inference.

Deniz Yilmaz, Veith Weilnhammer, Marcus Rothkirch, Merve Fritsch, Lena Esther Ptasczynski, Katrin Reichenbach, Lukas Roediger, Philip Corlett, Philipp Sterzer

Journal: Brain : a journal of neurology 2025;148(5):1531-1539

PMID: 39821016

Abstract

Perception integrates external sensory signals with internal predictions that reflect prior knowledge about the world. Previous research suggests that this integration is governed by slow alternations between an external mode, driven by sensory signals, and an internal mode, shaped by prior knowledge. Using a double-blind, placebo-controlled, cross-over experiment in healthy human participants, we investigated the effects of the N-methyl-D-aspartate receptor (NMDAR) antagonist S-ketamine on the balance between external and internal modes. We found that S-ketamine causes a shift of perception towards the external mode. A case-control study revealed that individuals with paranoid schizophrenia, a disorder repeatedly associated with NMDAR hypofunction, spend more time in the external mode. This NMDAR-dependent increase in the external mode suggests that the symptoms of schizophrenia are caused by recurring dissociations of perception from prior knowledge about the world.

© The Author(s) 2025. Published by Oxford University Press on behalf of the Guarantors of Brain.

Address: Department of Psychiatry and Neurosciences, Charité-Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin 10117, Germany.; Berlin Institute of Health, Charité-Universitätsmedizin Berlin and Max Delbrück Center, Berlin 10178, Germany.; Helen Wills Neuroscience Institute, University of California Berkeley, Berkeley, CA 94720, USA.; Department of Psychiatry and Neurosciences, Charité-Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin 10117, Germany.; Medical School Berlin, Hochschule für Gesundheit und Medizin, Berlin 14197, Germany.; Department of Psychiatry and Neurosciences, Charité-Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin 10117, Germany.; Berlin School of Mind and Brain, Humboldt-Universität zu Berlin, Berlin 10117, Germany.; Max Planck School of Cognition, Department of Neurology, Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig 04103, Germany.; Department of Psychiatry and Psychotherapy, LMU University Hospital, Munich 80336, Germany.; Department of Psychiatry and Neurosciences, Charité-Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin 10117, Germany.; Department of Psychiatry and Neurosciences, Charité-Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin 10117, Germany.; Berlin School of Mind and Brain, Humboldt-Universität zu Berlin, Berlin 10117, Germany.; Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06511, USA.; Department of Psychiatry (UPK), University of Basel, Basel 4001, Switzerland.
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