Selective Prefrontal Disinhibition in a Roving Auditory Oddball Paradigm Under N-Methyl-D-Aspartate Receptor Blockade
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Abstract
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
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Reduced activity through glutamate receptors is proposed to induce a decrease in the inhibitory activity of the inhibitory interneurons.
“In this view, reduced activity through glutamate receptors is proposed to induce a decrease in the inhibitory activity of the inhibitory interneurons.”
From Deviations in effective connectivity explain different hallucination subtypes in Parkinson's disease psychosis (2026) · cites this paper as [52]
The Results (Effects of Ketamine on Model Parameters; page unavailable) report reduced inhibition from inhibitory interneurons in frontal regions under ketamine-induced NMDA receptor blockade. The claim generalizes this region-specific finding to reduced activity through glutamate receptors broadly; the paper does not establish a uniform decrease in interneuron inhibition across regions. (LLM, conf=0.86)
Experimental — accuracy not yet measuredSix of the eight regions are based on prior studies that established a frontotemporal network responsible for generating the mismatch negativity response.
“Six of these regions are based on a series of prior studies of mismatch negativity generation with healthy adults and those with non‐AD dementia, 4 , 18 , 24 , 25 which established a frontotemporal network (primary auditory, superior temporal, and inferior frontal regions) responsible for generating the mismatch negativity response.”
From Alzheimer's disease and its progression reduce pyramidal cell gain and connectivity (2025) · cites this paper as [24]
The second set of models with both exponential and phasic change embody the hypothesis of predictive coding for sequential neural responses to stimuli.
“The second set of models with both exponential and phasic change embody the hypothesis of predictive coding for sequential neural responses to stimuli, allowing extrinsic connections to show stimulus‐specific adaptation with exponential decrease with repetition; while intrinsic connections show a phasic response, reducing after the deviant tone and recovering with subsequent tones thereby refle”
From Alzheimer's disease and its progression reduce pyramidal cell gain and connectivity (2025) · cites this paper as [24]
The winning model's combination of exponential and phasic basis functions is in line with a predictive coding framework for the mismatch negativity task rather than stimulus-specific adaptation only.
“in accordance with previous studies, 4 , 24 and in line with a predictive coding framework for the mismatch negativity task, rather than stimulus‐specific adaptation only. 4”
From Alzheimer's disease and its progression reduce pyramidal cell gain and connectivity (2025) · cites this paper as [24]
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“4,24 The neuronal parameters for each participant’s dynamic causal model were inferred from their observed response fields of gra-diometers using a lead field informed by subject-specific T1 magnetic resonance images.”
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- Authors
- Rosch, R. E., Auksztulewicz, R., Leung, P. D., Friston, K. J., & Baldeweg, T.
- Affiliations
- Wellcome Centre for Human Neuroimaging (GB)
- University College London (GB)
- Corresponding author
- Rosch, Richard E.
- Venue
- Biological Psychiatry: Cognitive Neuroscience and Neuroimaging
- Publisher
- Elsevier BV
- Published
- 2019-02
- Volume
- 4
- Issue
- 2
- Pages
- 140-150
- ISSN
- 2451-9022 (ISSN-L)
- PMC
- PMC6374982
- OpenAlex
- W2885310232
- Cited by
- 56
- References
- 69
- Citations by year
- 2026: 1 · 2025: 6 · 2024: 9 · 2023: 6 · 2022: 8 · 2021: 4 · 2020: 14 · 2019: 5 · 2018: 2 · 2017: 1
- FWCI
- 4.88
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Biological Psychiatry Cognitive Neuroscience and Neuroimaging (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- CityU Scholars (submittedVersion, cc-by)
- Funders
- Wellcome Trust (088130/Z/09/Z, 106556/Z/14/Z)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cognitive Neuroscience › Neural dynamics and brain function
- Keywords
- NMDA receptor blockade, ketamine, inhibitory interneurons, event-related potentials, dynamic causal modeling, auditory cortex, schizophrenia
- MeSH terms
- Acoustic Stimulation, Adult, Auditory Perception, Bayes Theorem, Double-Blind Method, Evoked Potentials, Auditory, Humans, Ketamine, Male, Models, Neurological, Receptors, N-Methyl-D-Aspartate, Prefrontal Cortex, Cross-Over Studies, Excitatory Amino Acid Antagonists, Young Adult
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