Selective Prefrontal Disinhibition in a Roving Auditory Oddball Paradigm Under N-Methyl-D-Aspartate Receptor Blockade.
Richard E Rosch, Ryszard Auksztulewicz, Pui Duen Leung, Karl Friston, Torsten Baldeweg
Biological Psychiatry: Cognitive Neuroscience and Neuroimaging February 2019 DOI: 10.1016/j.bpsc.2018.07.003 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Double-blind, placebo-controlled, crossover study Peer reviewed |
|---|---|
| Sample size | 18 |
| Population | Healthy human volunteers |
| Intervention | Ketamine |
| Topics | Ketamine |
| Keywords | Dynamic causal modeling EEG Erp Event-related potential Mismatch negativity Nmda receptor |
| Key points | Ketamine's effects on auditory event-related potentials were best explained by a selective reduction in intrinsic inhibitory interneuron connectivity, with a pronounced reduction in frontal sources compared with temporal sources. Simulations indicated this reduced superficial pyramidal cell activity, and the authors argue that inhibitory interneuron-specific NMDA receptor dysfunction may be sufficient to explain electrophysiological abnormalities from NMDA receptor blockade in humans. |
Abstract
Disturbances in N-methyl-D-aspartate receptors (NMDARs)-as implicated in patients with schizophrenia-can cause regionally specific electrophysiological effects. Both animal models of NMDAR blockade and clinical studies in patients with schizophrenia have suggested that behavioral phenotypes are associated with reduction in inhibition within the frontal cortex. Here we investigate event-related potentials to a roving auditory oddball paradigm under ketamine in healthy human volunteers (N= 18; double-blind, placebo-controlled, crossover design). Using recent advances in Bayesian modeling of group effects in dynamic causal modeling, we fit biophysically plausible network models of the auditory processing hierarchy to whole-scalp event-related potential recordings. This allowed us to identify regionally specific effects of ketamine in a distributed network of interacting cortical sources. We show that the effect of ketamine is best explained as a selective change in intrinsic inhibition, with a pronounced ketamine-induced reduction of inhibitory interneuron connectivity in frontal sources, compared with temporal sources. Simulations of these changes in an integrated microcircuit model shows that they are associated with a reduction in superficial pyramidal cell activity that can explain drug effects observed in the event-related potential. These results are consistent with findings from invasive recordings in animal models exposed to NMDAR blockers, and provide evidence that inhibitory interneuron-specific NMDAR dysfunction may be sufficient to explain electrophysiological abnormalities induced by NMDAR blockade in human subjects.
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 11
- Ketamine Affects Prediction Errors about Statistical Regularities: A Computational Single-Trial Analysis of the Mismatch Negativity Journal of Neuroscience June 19, 2020
- Ketamine and serotonergic psychedelics: An update on the mechanisms and biosignatures underlying rapid-acting antidepressant treatment Neuropharmacology January 13, 2023
- Stronger Top-Down and Weaker Bottom-Up Frontotemporal Connections During Sensory Learning Are Associated With Severity of Psychotic Phenomena Schizophrenia Bulletin December 7, 2020
- Predictive Feedback, Early Sensory Representations, and Fast Responses to Predicted Stimuli Depend on NMDA Receptors Journal of Neuroscience November 3, 2021
- Neurophysiological evidence that frontoparietal connectivity and GABA-A receptor changes underpin the antidepressant response to ketamine. Translational Psychiatry February 24, 2024
and 6 more in the library
Cites 10
- Subanesthetic Effects of the Noncompetitive NMDA Antagonist, Ketamine, in Humans Archives of General Psychiatry March 1, 1994
- Ketamine-Induced Deficits in Auditory and Visual Context-Dependent Processing in Healthy Volunteers Archives of General Psychiatry December 1, 2000
- Linking Microcircuit Dysfunction to Cognitive Impairment: Effects of Disinhibition Associated with Schizophrenia in a Cortical Working Memory Model Cerebral Cortex November 29, 2012
- NMDA receptor function in large-scale anticorrelated neural systems with implications for cognition and schizophrenia Proceedings of the National Academy of Sciences September 25, 2012
- Evidence that Subanesthetic Doses of Ketamine Cause Sustained Disruptions of NMDA and AMPA-Mediated Frontoparietal Connectivity in Humans Journal of Neuroscience August 19, 2015
and 5 more in the library