Role of N-Methyl D-aspartate receptors in action-based predictive coding deficits in schizophrenia
Open accessAbstract
Background Recent theoretical models of schizophrenia posit that dysfunction of the neural mechanisms subserving predictive coding contributes to symptoms and cognitive deficits, and this dysfunction is further posited to result from N-methyl-D-aspartate glutamate receptor (NMDAR) hypofunction. Previously, by examining auditory cortical responses to self-generated speech sounds, we demonstrated that predictive coding during vocalization is disrupted in schizophrenia. To test the hypothesized contribution of NMDAR hypofunction to this disruption, we examined the effects of the NMDAR antagonist, ketamine, on predictive coding during vocalization in healthy volunteers and compared them with the effects of schizophrenia.Methods In two separate studies, the N1 component of the event-related potential elicited by speech sounds during vocalization (talk) and passive playback (listen) were compared to assess the degree of N1 suppression during vocalization, a putative measure of auditory predictive coding. In the crossover study, 31 healthy volunteers completed two randomly ordered test days, a saline day and a ketamine day. Event-related potentials during the talk/listen task were obtained before infusion and during infusion on both days, and N1 amplitudes were compared across days. In the case-control study, N1 amplitudes from 34 schizophrenia patients and 33 healthy control volunteers were compared.Results N1 suppression to self-produced vocalizations was significantly and similarly diminished by ketamine (Cohen's d = 1.14) and schizophrenia (Cohen's d = .85).Conclusions Disruption of NMDARs causes dysfunction in predictive coding during vocalization in a manner similar to the dysfunction observed in schizophrenia patients, consistent with the theorized contribution of NMDAR hypofunction to predictive coding deficits in schizophrenia.
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Administration of ketamine in healthy controls induces impairments similar to those observed in SCZ patients.
“The administration of ketamine in HC induced impairments similar to those observed in SCZ patients (Kort et al., 2017).”
From Predictive coding in neuropsychiatric disorders: a systematic transdiagnostic review. (2025) · cites this paper as Kort et al., 2017
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Wang, J., Mathalon, D., Roach, B., Reilly, J., Keedy, S., Sweeney, J., & Ford, J. (2014) · NeuroImage · doi:10.1016/j.neuroimage.2014.01.003 · Cited by 85 · see citing works
Self-citationWatson, T. D., Petrakis, I. L., Edgecombe, J., Perrino, A. C., Krystal, J. H., & Mathalon, D. H. (2008) · The International Journal of Neuropsychopharmacology · doi:10.1017/s1461145708009334 · Cited by 82 · see citing works
Self-citationLi, D., & He, L. (2007) · Genetics in Medicine · doi:10.1097/01.gim.0000250507.96760.4b · Cited by 79 · see citing works
A bilateral cortical network responds to pitch perturbations in speech feedback
Kort, N. S., Nagarajan, S. S., & Houde, J. F. (2013) · NeuroImage · doi:10.1016/j.neuroimage.2013.09.042 · Cited by 75 · see citing works
Self-citationFord, J., Mathalon, D., Roach, B., Keedy, S., Reilly, J., Gershon, E., & Sweeney, J. (2013) · Schizophrenia bulletin · doi:10.1093/schbul/sbs129 · Cited by 74 · see citing works
Self-citationSensory-Motor Interactions for Vocal Pitch Monitoring in Non-Primary Human Auditory Cortex
Greenlee, J. D. W., Behroozmand, R., Larson, C. R., Jackson, A. W., Chen, F., Hansen, D. R., Oya, H., Kawasaki, H., & Howard, M. A. (2013) · PLoS ONE · doi:10.1371/journal.pone.0060783 · Cited by 73 · see citing works
Perez, V. B., Ford, J. M., Roach, B. J., Loewy, R. L., Stuart, B. K., Vinogradov, S., & Mathalon, D. H. (2011) · Schizophrenia Bulletin · doi:10.1093/schbul/sbr124 · Cited by 69 · see citing works
Self-citationResponse-Locked Brain Dynamics of Word Production
Riès, S., Janssen, N., Burle, B., & Alario, F. ‐. (2013) · PLoS ONE · doi:10.1371/journal.pone.0058197 · Cited by 64 · see citing works
Turken, A. U., Vuilleumier, P. O., Mathalon, D. H., Diane Swick, A., & Ford, J. M. (2003) · American Journal of Psychiatry · doi:10.1176/appi.ajp.160.10.1881 · Cited by 63 · see citing works
Self-citationAuditory Cortex Processes Variation in Our Own Speech
Sitek, K. R., Mathalon, D. H., Roach, B. J., Houde, J. F., Niziolek, C. A., & Ford, J. M. (2013) · PLoS ONE · doi:10.1371/journal.pone.0082925 · Cited by 53 · see citing works
Self-citationGeddes, A. E., Huang, X., & Newell, K. A. (2011) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2011.02.017 · Cited by 48 · see citing works
Rentzsch, J., Shen, C., Jockers-Scherübl, M. C., Gallinat, J., & Neuhaus, A. H. (2015) · PLoS ONE · doi:10.1371/journal.pone.0126775 · Cited by 47 · see citing works
Song selectivity and sensorimotor signals in vocal learning and production
Solis, M. M., Brainard, M. S., Hessler, N. A., & Doupe, A. J. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.97.22.11836 · Cited by 46 · see citing works
Knott, V., Shah, D., Millar, A., McIntosh, J., Fisher, D., Blais, C., & Ilivitsky, V. (2012) · Frontiers in Pharmacology · doi:10.3389/fphar.2012.00172 · Cited by 44 · see citing works
When it’s time for a change: failures to track context in schizophrenia
Ford, J. M., Roach, B. J., Miller, R. M., Duncan, C. C., Hoffman, R. E., & Mathalon, D. H. (2010) · International Journal of Psychophysiology · doi:10.1016/j.ijpsycho.2010.05.005 · Cited by 43 · see citing works
Self-citationD’Souza, D. C., Ahn, K.-H., Bhakta, S. G., Elander, J., Singh, N. M., Nadim, H., Jatlow, P. I., Suckow, R. F., Pittman, B. P., & Ranganathan, M. (2012) · Biological Psychiatry · doi:10.1016/j.biopsych.2012.05.009 · Cited by 38 · see citing works
Strelnikov, K. (2007) · Brain and Cognition · doi:10.1016/j.bandc.2007.04.002 · Cited by 34 · see citing works
Antipsychotic medications, glutamate, and cell death: A hidden, but common medication side effect?
Isom, A. M., Gudelsky, G. A., Benoit, S. C., & Richtand, N. M. (2012) · Medical Hypotheses · doi:10.1016/j.mehy.2012.11.042 · Cited by 12 · see citing works
Curio (2000) · doi:10.1002/(sici)1097-0193(200004)9:4
Flagged first, then by citations
Research works printed but not linked: 1
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Cited by
Sorted by citations
Predictive coding in neuropsychiatric disorders: a systematic transdiagnostic review.
Qela, B., Damiani, S., De Santis, S., Groppi, F., Pichiecchio, A., Asteggiano, C., Brondino, N., Monteleone, A. M., Grassi, L., Politi, P., et al. (2025) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2025.106020 · Cited by 26 · see citing works
“The administration of ketamine in HC induced impairments similar to those observed in SCZ patients (Kort et al., 2017).”
- Authors
- Kort, N. S., Ford, J. M., Roach, B. J., Gunduz-Bruce, H., Krystal, J. H., Jaeger, J., Reinhart, R. M. G., & Mathalon, D. H.
- Affiliations
- University of California, San Francisco (US)
- San Francisco VA Medical Center (US)
- Northern California Institute for Research and Education (US)
- Yale University (US)
- AstraZeneca (United States) (US)
- Corresponding author
- Mathalon, Daniel H.
- ORCID
- Venue
- Biological Psychiatry
- Publisher
- Elsevier BV
- Published
- 2017-03
- Volume
- 81
- Issue
- 6
- Pages
- 514-524
- ISSN
- 0006-3223 (ISSN-L)
- PMC
- PMC5203970
- OpenAlex
- W2461047954
- Cited by
- 48
- References
- 108
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 7 · 2023: 8 · 2022: 3 · 2021: 5 · 2020: 6 · 2019: 3 · 2018: 6 · 2017: 6
- FWCI
- 4.44
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Biological Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- OpenBU (Boston University) (submittedVersion)
- Funders
- National Institutes of Health (5r01mh058262-17, UL1TR001863)
- National Institute on Alcohol Abuse and Alcoholism (R01AA012879, P50AA012870)
- National Institute of Mental Health (R01MH-058262, T32MH089920)
- National Center for Research Resources (UL1RR024139)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Social Sciences › Arts and Humanities › Philosophy › Mental Health and Psychiatry
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- schizophrenia, predictive coding, NMDA receptor hypofunction, ketamine, self-produced speech, auditory cortex, event-related potentials, vocalizations, glutamate receptor antagonism
- MeSH terms
- Acoustic Stimulation, Adult, Cerebral Cortex, Electroencephalography, Evoked Potentials, Female, Humans, Ketamine, Male, Schizophrenia, Schizophrenic Psychology, Speech Perception, Receptors, N-Methyl-D-Aspartate, Cross-Over Studies
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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