Ketamine Alters Functional Gamma and Theta Resting-State Connectivity in Healthy Humans: Implications for Schizophrenia Treatment Targeting the Glutamate System.
Stjepan Curic, Christina Andreou, Guido Nolte, Saskia Steinmann, Stephanie Thiebes, Nenad Polomac, Moritz Haaf, Jonas Rauh, Gregor Leicht, Christoph Mulert
Frontiers in Psychiatry 2021 DOI: 10.3389/fpsyt.2021.671007 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Placebo-controlled crossover study Peer reviewed |
|---|---|
| Sample size | 25 |
| Population | Healthy volunteers |
| Intervention | Ketamine |
| Measures | Positive and Negative Syndrome Scale (PANSS), 5-Dimensional Altered States of Consciousness Rating Scale (5D-ASC), 64-channel-electroencephalography (EEG), Multivariate Interaction Measure (MIM) |
| Topics | Esketamine Ketamine |
| Keywords | Functional connectivity Gamma-band oscillations Glutamate hypothesis Negative-symptoms Resting state Theta-band oscillations |
| Key points | Ketamine increased PANSS and 5D-ASC psychopathology scores and resting-state gamma and theta power, and produced two networks of increased gamma- and theta-band functional connectivity in healthy volunteers. Gamma-band current source density correlated negatively with PANSS negative symptom scores, and gamma-network activity correlated negatively with the 5D-ASC changed meaning of percepts subscale. The authors argue these resting-state patterns resemble those seen in schizophrenia and support a role for the glutamate system in dysfunctional gamma- and theta-band connectivity. |
Abstract
Disturbed functional connectivity is assumed to cause neurocognitive deficits in patients suffering from schizophrenia. A Glutamate N-methyl-D-aspartate receptor (NMDAR) dysfunction has been suggested as a possible mechanism underlying altered connectivity in schizophrenia, especially in the gamma- and theta-frequency range. The present study aimed to investigate the effects of the NMDAR-antagonist ketamine on resting-state power, functional connectivity, and schizophrenia-like psychopathological changes in healthy volunteers. In a placebo-controlled crossover design, 25 healthy subjects were recorded using resting-state 64-channel-electroencephalography (EEG) (eyes closed). The imaginary coherence-based Multivariate Interaction Measure (MIM) was used to measure gamma and theta connectivity across 80 cortical regions. The network-based statistic was applied to identify involved networks under ketamine. Psychopathology was assessed with the Positive and Negative Syndrome Scale (PANSS) and the 5-Dimensional Altered States of Consciousness Rating Scale (5D-ASC). Ketamine caused an increase in all PANSS (p < 0.001) as well as 5D-ASC scores (p < 0.01). Significant increases in resting-state gamma and theta power were observed under ketamine compared to placebo (p < 0.05). The source-space analysis revealed two distinct networks with an increased mean functional gamma- or theta-band connectivity during the ketamine session. The gamma-network consisted of midline regions, the cuneus, the precuneus, and the bilateral posterior cingulate cortices, while the theta-band network involved the Heschl gyrus, midline regions, the insula, and the middle cingulate cortex. The current source density (CSD) within the gamma-band correlated negatively with the PANSS negative symptom score, and the activity within the gamma-band network correlated negatively with the subjective changed meaning of percepts subscale of the 5D-ASC. These results are in line with resting-state patterns seen in people who have schizophrenia and argue for a crucial role of the glutamate system in mediating dysfunctional gamma- and theta-band-connectivity in schizophrenia. Resting-state networks could serve as biomarkers for the response to glutamatergic drugs or drug development efforts within the glutamate system.
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
- The Altered States Database: Psychometric data from a systematic literature review. Scientific Data November 23, 2022
- Opposite Modulation of the NMDA Receptor by Glycine and S-Ketamine and the Effects on Resting State EEG Gamma Activity: New Insights into the Glutamate Hypothesis of Schizophrenia International Journal of Molecular Sciences January 18, 2023
- Is the antidepressant effect of ketamine separate from its psychotomimetic effect? A review of rodent models. Neuropharmacology November 1, 2024
- Effects of NMDA receptor antagonists on working memory and gamma oscillations, and the mediating role of the GluN2D subunit. Neuropsychopharmacology May 15, 2025
- Effects of acute and chronic ketamine administration on spontaneous and evoked brain activity. Brain Research 2025
and 11 more in the library
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