Relationship of resting brain hyperconnectivity and schizophrenia-like symptoms produced by the NMDA receptor antagonist ketamine in humans
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N-methyl-D-aspartate glutamate receptor (NMDA-R) antagonists produce schizophrenia-like positive and negative symptoms in healthy human subjects. Preclinical research suggests that NMDA-R antagonists interfere with the function of gamma-aminobutyric acid (GABA) neurons and alter the brain oscillations. These changes have been hypothesized to contribute to psychosis. In this investigation, we evaluated the hypothesis that the NMDA-R antagonist ketamine produces alterations in cortical functional connectivity during rest that are related to symptoms. We administered ketamine to a primary sample of 22 subjects and to an additional, partially overlapping, sample of 12 subjects. Symptoms before and after the experimental session were rated with the Positive and Negative Syndrome Scale (PANSS). In the primary sample, functional connectivity was measured via functional magnetic resonance imaging almost immediately after infusion began. In the additional sample, this assessment was repeated after 45 min of continuous ketamine infusion. Global, enhanced functional connectivity was observed at both timepoints, and this hyperconnectivity was related to symptoms in a region-specific manner. This study supports the hypothesis that pathological increases in resting brain functional connectivity contribute to the emergence of positive and negative symptoms associated with schizophrenia.
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Other studies have employed pharmacoimaging paradigms to demonstrate a relationship between ketamine-induced prefrontal activation/connectivity and its transient behavioral disturbances.
“Other studies have employed pharmacoimaging paradigms to demonstrate a relationship between ketamine-induced prefrontal activation/connectivity and its transient behavioral disturbances [29][30][31][32][33][34][35][36]”
From The effects of ketamine on prefrontal glutamate neurotransmission in healthy and depressed subjects (2018) · cites this paper as [30]
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“Ketamine has been repeatedly shown to increase GBCr in healthy individuals (194, 201, 202).”
BackgroundIhalainen, R., Gosseries, O., de Steen, F. V., Raimondo, F., Panda, R., Bonhomme, V. L., Marinazzo, D., Bowman, H., Laureys, S., & Chennu, S. (2021) · NeuroImage · doi:10.1016/j.neuroimage.2021.117841 · Cited by 31 · see citing works
- Authors
- Driesen, N. R., McCarthy, G., Bhagwagar, Z., Bloch, M., Calhoun, V, D'Souza, D. C., Gueorguieva, R., He, G., Ramachandran, R., Suckow, R. F., Anticevic, A., Morgan, P. T., & Krystal, J. H.
- Affiliations
- Yale University (US)
- University of New Mexico (US)
- New York State Psychiatric Institute (US)
- Corresponding author
- Driesen, N R
- Venue
- Molecular Psychiatry
- Published
- 2013-01-22
- Volume
- 18
- Issue
- 11
- Pages
- 1199-1204
- ISSN
- 1359-4184 (ISSN-L)
- 1476-5578
- PMC
- PMC3646075
- OpenAlex
- W2022888479
- Cited by
- 224
- References
- 64
- Citations by year
- 2026: 6 · 2025: 11 · 2024: 7 · 2023: 16 · 2022: 12 · 2021: 15 · 2020: 14 · 2019: 27 · 2018: 15 · 2017: 18 · 2016: 20 · 2015: 29 · 2014: 20 · 2013: 13
- FWCI
- 19.43
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Molecular Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (5k23mh077914-02, DP5OD012109)
- National Institute on Alcohol Abuse and Alcoholism (P50AA012870)
- National Institute of Mental Health (K23-MH077914, P50MH068789)
- National Center for Research Resources (UL1RR024139)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Neuroscience › Cognitive Neuroscience › Functional Brain Connectivity Studies
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- ketamine, NMDA receptor antagonists, resting-state functional connectivity, hyperconnectivity, schizophrenia-like symptoms, positive symptoms, negative symptoms, psychosis, cortical connectivity, GABAergic dysfunction, neural oscillations
- MeSH terms
- Adult, Brain Mapping, Cerebral Cortex, Female, Humans, Ketamine, Male, Middle Aged, Schizophrenia, Excitatory Amino Acid Antagonists, Diagnostic and Statistical Manual of Mental Disorders, Healthy Volunteers
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