N-methyl-d-aspartate receptor hypofunction causes recurrent and transient failures of perceptual inference.
Veith Weilnhammer, Marcus Rothkirch, Deniz Yilmaz, Merve Fritsch, Lena Esther Ptasczynski, Katrin Reichenbach, Lukas Roediger, Philip R. Corlett, Philipp Sterzer
Brain May 13, 2025 DOI: 10.1093/brain/awaf011 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Double-blind, placebo-controlled, cross-over experiment; case-control study Peer reviewed |
|---|---|
| Population | Healthy human participants; individuals with paranoid schizophrenia |
| Intervention | S-ketamine |
| Topics | Ketamine |
| Keywords | Bistable perception Predictive processing Psychosis Schizophrenia Visual perception Psychopharmacology Perception disorders Mental health research Cognitive science |
| Citations | 11 |
| Key findings | S-ketamine shifts perception toward the external mode, and individuals with paranoid schizophrenia also spend more time in the external mode, suggesting schizophrenia symptoms may stem from perception dissociating from prior knowledge. |
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.
Comparable studies
Other randomized controlled trials on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Subanesthetic Effects of the Noncompetitive NMDA Antagonist, Ketamine, in Humans Healthy human subjects recruited from the community | 1994 | Randomized controlled trial | n = 19 |
| Antidepressant Efficacy of Ketamine in Treatment-Resistant Major Depression: A Two-Site Randomized Controlled Trial Patients with treatment-resistant major depression experiencing a major depressive episode | 2013 | Randomized controlled trial | n = 73 |
| Remifentanil-induced Postoperative Hyperalgesia and Its Prevention with Small-dose Ketamine Patients undergoing major abdominal surgery | 2005 | Randomized controlled trial | n = 75 |
| Efficacy of Intravenous Ketamine for Treatment of Chronic Posttraumatic Stress Disorder Patients with chronic PTSD related to a range of trauma exposures | 2014 | Randomized controlled trial | n = 41 |
| Ketamine-Induced Deficits in Auditory and Visual Context-Dependent Processing in Healthy Volunteers Healthy volunteers | 2000 | Single-blind placebo-controlled study | n = 20 |
Citations in the library
Cited by 3
- From Body to Brain and Back: Multimodal Evidence for Interoceptive Alterations in Schizophrenia Spectrum Disorders medRxiv Preprint Server January 13, 2026
- Ketamine disrupts consciousness in healthy participants in relation with psychotic-like symptoms. bioRxiv : the preprint server for biology November 8, 2025
- Anterior insular activity signals perceptual conflicts induced by temporal and spatial context. Neuroscience of Consciousness 2025
Cites 8
- The Predictive Coding Account of Psychosis. Biological Psychiatry May 25, 2018
- Ketamine use: a review Addiction July 21, 2011
- Linking Microcircuit Dysfunction to Cognitive Impairment: Effects of Disinhibition Associated with Schizophrenia in a Cortical Working Memory Model Cerebral Cortex November 29, 2012
- Evidence that Subanesthetic Doses of Ketamine Cause Sustained Disruptions of NMDA and AMPA-Mediated Frontoparietal Connectivity in Humans Journal of Neuroscience August 19, 2015
- An active role of inferior frontal cortex in conscious experience. Current Biology July 12, 2021
and 3 more in the library