Ketamine and Psilocybin Differentially Impact Sensory LearningDuring the Mismatch Negativity

Ketamine and psilocybin affect sensory learning in the brain through different neural mechanisms. By combining computational modeling with EEG data from a previous study, researchers analyzed how these drugs alter the brain's processing of prediction errors during an auditory task. Ketamine produced a larger reduction in sensory precision from 207 to 316 milliseconds after sounds, peaking at 277 milliseconds in frontal central brain regions, while psilocybin showed no significant effect on this measure. Both drugs reduced belief precision between 160 to 184 milliseconds, peaking at 172 milliseconds. For higher-level volatility prediction errors, ketamine reduced expression while psilocybin had no effect at 312 milliseconds. These distinct effects could inform tailored therapies for major depressive disorder.

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Abstract

Abstract Ketamine and psilocybin show potential as therapies for various mental illnesses, including major depressive disorder. However, further investigation into their neural mechanisms is required to understand their effects on the brain. By combining computational modelling with electroencephalography (EEG), we examine the effects of ketamine and psilocybin on hierarchical sensory precision-weighted prediction error (pwPE) learning in the context of the auditory mismatch negativity, an event-related potential consistently shown to be reduced under psychotomimetic interventions. We employed a Bayesian framework and re-analyzed a previously acquired EEG dataset (Schmidt et al., 2012) by modelling single-trial EEG data using the Hierarchical Gaussian Filter. Using a placebo-controlled within-subject crossover design, healthy subjects were administered either S-ketamine or psilocybin during an auditory roving paradigm of pure sinusoidal tones. Our findings elucidate distinct neural impacts of ketamine and psilocybin on sensory learning: ketamine led to a larger reduction in the effect of sensory precision compared to placebo from 207 to 316 ms peaking at 277 ms in the frontal central channels, while psilocybin showed no significant effect. Both drugs reduced the expression of belief precision between 160 to 184 ms, peaking at 172 ms. For higher-level volatility pwPEs, ketamine reduced the expression while psilocybin had null effect at 312 ms. For perception of elementary imagery, ketamine had a greater effect than psilocybin on sensory and volatility precision, while psilocybin had a greater effect on volatility pwPEs. Our findings suggest hallucinogens have distinct effects on sensory learning that could inform tailored therapies for major depression.