Ketamine Affects Prediction Errors about Statistical Regularities: A Computational Single-Trial Analysis of the Mismatch Negativity
Lilian Weber, Andreea O. Diaconescu, Christoph Mathys, André Schmidt, Michael Kometer, Franz X. Vollenweider, Klaas Ε. Stephan
Journal of Neuroscience June 19, 2020 DOI: 10.1523/jneurosci.3069-19.2020 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Randomized controlled trial Placebo-controlled Double-blind Peer reviewed |
|---|---|
| Population | Healthy human volunteers of either sex |
| Intervention | S-ketamine |
| Topics | Ketamine Esketamine |
| Keywords | Mismatch negativity Negativity effect Cognitive psychology Electroencephalography |
| Citations | 82 |
| Key findings | Ketamine significantly diminished high-level prediction error responses, indicating that NMDAR antagonism disrupts inference on abstract statistical regularities and impairs hierarchical Bayesian inference. |
Abstract
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 (102-207 ms poststimulus), while high-level PEs (about transition probability) are reflected by later components (152-199 and 215-277 ms) of single-trial responses. Furthermore, we find that ketamine significantly diminished the expression of high-level PE responses, implying that NMDAR antagonism disrupts the 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.
Comparable studies
Other randomized controlled trials on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Subanesthetic Effects of the Noncompetitive NMDA Antagonist, Ketamine, in Humans Healthy human subjects recruited from the community | 1994 | Randomized controlled trial | n = 19 |
| Antidepressant Efficacy of Ketamine in Treatment-Resistant Major Depression: A Two-Site Randomized Controlled Trial Patients with treatment-resistant major depression experiencing a major depressive episode | 2013 | Randomized controlled trial | n = 73 |
| Remifentanil-induced Postoperative Hyperalgesia and Its Prevention with Small-dose Ketamine Patients undergoing major abdominal surgery | 2005 | Randomized controlled trial | n = 75 |
| Efficacy of Intravenous Ketamine for Treatment of Chronic Posttraumatic Stress Disorder Patients with chronic PTSD related to a range of trauma exposures | 2014 | Randomized controlled trial | n = 41 |
| Ketamine-Induced Deficits in Auditory and Visual Context-Dependent Processing in Healthy Volunteers Healthy volunteers | 2000 | Single-blind placebo-controlled study | n = 20 |
Citations in the library
Cited by 16
- Classic Psychedelic Drugs: Update on Biological Mechanisms Pharmacopsychiatry January 25, 2022
- Evaluation of Early Ketamine Effects on Belief-Updating Biases in Patients With Treatment-Resistant Depression JAMA Psychiatry September 28, 2022
- Stronger Top-Down and Weaker Bottom-Up Frontotemporal Connections During Sensory Learning Are Associated With Severity of Psychotic Phenomena Schizophrenia Bulletin December 7, 2020
- Ketamine reduces the neural distinction between self- and other-produced affective touch: a randomized double-blind placebo-controlled study. Neuropsychopharmacology October 1, 2024
- Suicide prevention and ketamine: insights from computational modeling Frontiers in Psychiatry June 30, 2023
and 11 more in the library
Cites 12
- The Predictive Coding Account of Psychosis. Biological Psychiatry May 25, 2018
- Ketamine-Induced Deficits in Auditory and Visual Context-Dependent Processing in Healthy Volunteers Archives of General Psychiatry December 1, 2000
- Mismatch negativity generation in the human 5HT2A agonist and NMDA antagonist model of psychosis Psychopharmacology May 16, 2008
- Modeling Ketamine Effects on Synaptic Plasticity During the Mismatch Negativity Cerebral Cortex August 8, 2012
- Inhibition of cerebral type 1 cannabinoid receptors is associated with impaired auditory mismatch negativity generation in the ketamine model of schizophrenia Pharmacopsychiatry September 1, 2011
and 7 more in the library