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

Perception normally balances external sensory signals with internal predictions based on prior knowledge. In a double-blind, placebo-controlled, cross-over experiment with healthy participants, the N-methyl-D-aspartate receptor (NMDAR) antagonist S-ketamine shifted perception toward the external mode, favoring sensory input over prior knowledge. A case-control study found that people with paranoid schizophrenia, a condition linked to NMDAR hypofunction, also spend more time in the external mode. This NMDAR-dependent shift suggests that schizophrenia symptoms may arise from recurring disconnections between perception and prior knowledge about the world.

Study at a glance

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.