Subanaesthetic doses of ketamine reduce but do not eliminate predictive coding responses: implications for mechanisms of sensory disconnection

Abstract

Background: Sensory disconnection is a key feature of sleep and anaesthesia. We have proposed that predictive coding offers a framework for understanding the mechanisms of disconnection. Low doses of ketamine that do not induce disconnection should thus diminish predictive coding, but not abolish it.

Methods: Ketamine was administered to 14 participants up to a blood concentration of 0.3 μg ml^-1 Participants were played a series of tones comprising a roving oddball sequence while electroencephalography evoked response potentials were recorded. We fit a Bayesian observer model to the tone sequence, correlating neural activity with the prediction errors generated by the model using linear mixed effects models and cluster-based statistics.

Results: Ketamine modulated prediction errors associated with the transition of one tone to the next (transitional probability), but not how often tones changed (environmental volatility), of the system. Transitional probability was reduced when blood concentrations of ketamine were increased to 0.2-0.3 μg ml^-1 (96-208 ms, P=0.003); however, correlates of prediction error were still evident in the electroencephalogram (124-168 ms, P=0.003). Prediction errors related to environmental volatility were associated with electroencephalographic activity before ketamine (224-284 ms, P=0.028) and during 0.2-0.3 μg ml^-1 ketamine (108-248 ms, P=0.003). At this subanaesthetic dose, ketamine did not exert a dose-dependent modulation of prediction error.

Conclusions: Subanaesthetic dosing of ketamine reduced correlates of predictive coding but did not eliminate them. Future studies should evaluate whether states of sensory disconnection, including anaesthetic doses of ketamine, are associated with a complete absence of predictive coding responses.

Clinical trial registration: NCT03284307.

Keywords: NMDA; electroencephalography; hierarchical Gaussian filter; ketamine; mismatch negativity; predictive coding; sensory disconnection.