Premature commitment to uncertain decisions during human NMDA receptor hypofunction

Abstract

Making accurate decisions based on unreliable sensory evidence requires cognitive inference. Dysfunction of n-methyl-d-aspartate (NMDA) receptors impairs the integration of noisy input in theoretical models of neural circuits, but whether and how this synaptic alteration impairs human inference and confidence during uncertain decisions remains unknown. Here we use placebo-controlled infusions of ketamine to characterize the causal effect of human NMDA receptor hypofunction on cognitive inference and its neural correlates. At the behavioral level, ketamine triggers inference errors and elevated decision uncertainty. At the neural level, ketamine is associated with imbalanced coding of evidence and premature response preparation in electroencephalographic (EEG) activity. Through computational modeling of inference and confidence, we propose that this specific pattern of behavioral and neural impairments reflects an early commitment to inaccurate decisions, which aims at resolving the abnormal uncertainty generated by NMDA receptor hypofunction.