TY - JOUR T1 - Ketamine Affects Prediction Errors about Statistical Regularities: A Computational Single-Trial Analysis of the Mismatch Negativity JF - The Journal of Neuroscience JO - J. Neurosci. DO - 10.1523/JNEUROSCI.3069-19.2020 SP - JN-RM-3069-19 AU - Lilian A. Weber AU - Andreea O. Diaconescu AU - Christoph Mathys AU - André Schmidt AU - Michael Kometer AU - Franz Vollenweider AU - Klaas E. Stephan Y1 - 2020/06/19 UR - http://www.jneurosci.org/content/early/2020/06/19/JNEUROSCI.3069-19.2020.abstract N2 - The auditory mismatch negativity (MMN) is significantly reduced in schizophrenia. Notably, a similar MMN reduction can be achieved with NMDA receptor (NMDAR) antagonists. Both phenomena have been interpreted as reflecting an impairment of predictive coding or, more generally, the “Bayesian brain” notion that the brain continuously updates a hierarchical model to infer the causes of its sensory inputs. Specifically, neurobiological interpretations of predictive coding view perceptual inference as an NMDAR-dependent process of minimizing hierarchical precision-weighted prediction errors (PEs), and disturbances of this putative process play a key role in hierarchical Bayesian theories of schizophrenia. Here, we provide empirical evidence for this theory, demonstrating the existence of multiple, hierarchically related PEs in a “roving MMN” paradigm.We applied a hierarchical Bayesian model to single-trial EEG data from healthy human volunteers of either sex who received the NMDAR antagonist S-ketamine in a placebo-controlled, double-blind, within-subject fashion. Using an unrestricted analysis of the entire time-sensor space, our trial-by-trial analysis indicated that low-level PEs (about stimulus transitions) are expressed early (102-207ms post-stimulus), while high-level PEs (about transition probability) are reflected by later components (152-199ms, 215-277ms) of single-trial responses. Furthermore, we find that ketamine significantly diminished the expression of high-level PE responses, implying that NMDAR antagonism disrupts inference on abstract statistical regularities.Our findings suggest that NMDAR dysfunction impairs hierarchical Bayesian inference about the world’s statistical structure. Beyond the relevance of this finding for schizophrenia, our results illustrate the potential of computational single-trial analyses for assessing potential pathophysiological mechanisms.Significance StatementThe NMDA receptor antagonist ketamine induces psychosis-like experiences in healthy individuals, consistent with the notion that the pathophysiology of schizophrenia involves NMDAR dysfunction. On the cognitive level, the stark misrepresentations of reality during psychosis suggest a dysfunction at high levels of belief hierarchies, where general and stable features of the environment are represented. Here, we investigate physiological indices of altered perception under ketamine – the reduction of the auditory “mismatch negativity” – based on their algorithmic interpretation as hierarchical belief updates. We find that ketamine indeed impacts cortical signaling of higher-level belief updates about environmental volatility. This finding bridges physiological and computational concepts of NMDAR dysfunction and offers a novel mechanistic perspective on a central element of pathophysiological theories of schizophrenia. ER -