Acute ketamine dysregulates task-related gamma-band oscillations in thalamo-cortical circuits in schizophrenia.
Tineke Grent-'t-Jong, Davide Rivolta, Joachim Gross, Ruchika Gajwani, Stephen M. Lawrie, Matthias Schwannauer, Tonio Heidegger, Michael Wibral, Wolf Singer, Andreas Sauer, Bertram Scheller, Peter J Uhlhaas
Brain August 1, 2018 DOI: 10.1093/brain/awy175 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Single-blind crossover study with clinical comparison groups Peer reviewed |
|---|---|
| Sample size | 40 |
| Population | 14 healthy volunteers, 10 unmedicated first-episode psychosis patients, and 16 patients with chronic schizophrenia |
| Intervention | S-ketamine |
| Dose | 0.006 mg/kg/min |
| Measures | Positive and Negative Syndrome Scale |
| Topics | Ketamine Esketamine |
| Keywords | Brain Thalamus Cerebral cortex Humans Receptors, n-methyl-d-aspartate Electroencephalography Magnetoencephalography Cross-over studies Single-blind method Schizophrenia Adult Female Gamma rhythm |
| Key points | Acute ketamine administration in healthy volunteers produced cognitive and psychopathological effects similar to those in first-episode and chronic schizophrenia patients, but the magnetoencephalographic effects differed: ketamine increased occipital gamma (63-80 Hz) and low-frequency (5-28 Hz) activity and disrupted thalamo-cortical feedforward/feedback signalling, whereas patients showed decreased task-induced high-gamma oscillations and predominantly increased Granger causality connectivity. The authors conclude that acute NMDAR hypofunction does not recreate the neural oscillatory alterations observed in schizophrenia during visual processing. |
Abstract
Hypofunction of the N-methyl-d-aspartate receptor (NMDAR) has been implicated as a possible mechanism underlying cognitive deficits and aberrant neuronal dynamics in schizophrenia. To test this hypothesis, we first administered a sub-anaesthetic dose of S-ketamine (0.006 mg/kg/min) or saline in a single-blind crossover design in 14 participants while magnetoencephalographic data were recorded during a visual task. In addition, magnetoencephalographic data were obtained in a sample of unmedicated first-episode psychosis patients (n = 10) and in patients with chronic schizophrenia (n = 16) to allow for comparisons of neuronal dynamics in clinical populations versus NMDAR hypofunctioning. Magnetoencephalographic data were analysed at source-level in the 1-90 Hz frequency range in occipital and thalamic regions of interest. In addition, directed functional connectivity analysis was performed using Granger causality and feedback and feedforward activity was investigated using a directed asymmetry index. Psychopathology was assessed with the Positive and Negative Syndrome Scale. Acute ketamine administration in healthy volunteers led to similar effects on cognition and psychopathology as observed in first-episode and chronic schizophrenia patients. However, the effects of ketamine on high-frequency oscillations and their connectivity profile were not consistent with these observations. Ketamine increased amplitude and frequency of gamma-power (63-80 Hz) in occipital regions and upregulated low frequency (5-28 Hz) activity. Moreover, ketamine disrupted feedforward and feedback signalling at high and low frequencies leading to hypo- and hyper-connectivity in thalamo-cortical networks. In contrast, first-episode and chronic schizophrenia patients showed a different pattern of magnetoencephalographic activity, characterized by decreased task-induced high-gamma band oscillations and predominantly increased feedforward/feedback-mediated Granger causality connectivity. Accordingly, the current data have implications for theories of cognitive dysfunctions and circuit impairments in the disorder, suggesting that acute NMDAR hypofunction does not recreate alterations in neural oscillations during visual processing observed in schizophrenia.
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 12
- Association of Ketamine With Psychiatric Symptoms and Implications for Its Therapeutic Use and for Understanding Schizophrenia JAMA Network Open May 1, 2020
- ( 2R,6R )-hydroxynorketamine exerts mGlu 2 receptor-dependent antidepressant actions Proceedings of the National Academy of Sciences March 13, 2019
- The neurophysiology of ketamine: an integrative review Reviews in the Neurosciences May 5, 2020
- Gamma Oscillations and Excitation/Inhibition Imbalance: Parallel Effects of NMDA Receptor Antagonism and Psychosis. Biological Psychiatry: Cognitive Neuroscience and Neuroimaging January 18, 2025
- Computational modeling of ketamine-induced changes in gamma-band oscillations: The contribution of parvalbumin and somatostatin interneurons. PLoS Computational Biology June 9, 2025
and 7 more in the library
Cites 10
- A default mode of brain function Proceedings of the National Academy of Sciences January 16, 2001
- 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
- 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
- Disruption of Prefrontal Cortex Large Scale Neuronal Activity by Different Classes of Psychotomimetic Drugs Journal of Neuroscience February 29, 2012
and 5 more in the library