Computational Modeling of Electroencephalography and Functional Magnetic Resonance Imaging Paradigms Indicates a Consistent Loss of Pyramidal Cell Synaptic Gain in Schizophrenia
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BACKGROUND: Diminished synaptic gain-the sensitivity of postsynaptic responses to neural inputs-may be a fundamental synaptic pathology in schizophrenia. Evidence for this is indirect, however. Furthermore, it is unclear whether pyramidal cells or interneurons (or both) are affected, or how these deficits relate to symptoms. METHODS: People with schizophrenia diagnoses (PScz) (n = 108), their relatives (n = 57), and control subjects (n = 107) underwent 3 electroencephalography (EEG) paradigms-resting, mismatch negativity, and 40-Hz auditory steady-state response-and resting functional magnetic resonance imaging. Dynamic causal modeling was used to quantify synaptic connectivity in cortical microcircuits. RESULTS: Classic group differences in EEG features between PScz and control subjects were replicated, including increased theta and other spectral changes (resting EEG), reduced mismatch negativity, and reduced 40-Hz power. Across all 4 paradigms, characteristic PScz data features were all best explained by models with greater self-inhibition (decreased synaptic gain) in pyramidal cells. Furthermore, disinhibition in auditory areas predicted abnormal auditory perception (and positive symptoms) in PScz in 3 paradigms. CONCLUSIONS: First, characteristic EEG changes in PScz in 3 classic paradigms are all attributable to the same underlying parameter change: greater self-inhibition in pyramidal cells. Second, psychotic symptoms in PScz relate to disinhibition in neural circuits. These findings are more commensurate with the hypothesis that in PScz, a primary loss of synaptic gain on pyramidal cells is then compensated by interneuron downregulation (rather than the converse). They further suggest that psychotic symptoms relate to this secondary downregulation.
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Within the DCM framework, decreased self-inhibition represents an increase in excitability and an overweighting of sensory prediction errors.
“Within the DCM framework, decreased self-inhibition represents an increase in excitability and an overweighting of sensory prediction errors24,46.”
From Deviations in effective connectivity explain different hallucination subtypes in Parkinson's disease psychosis (2026) · cites this paper as [24]
The Results section ('Self-inhibition Findings in PScz Across Electroencephalography and rsfMRI Paradigms Are Similar'; page not provided) equates increased self-inhibition with reduced synaptic gain, supporting the inverse interpretation of decreased self-inhibition as increased gain or excitability. The Discussion (page not provided) also links disinhibition to rebalancing excitatory and inhibitory transmission. Neither passage establishes that decreased self-inhibition represents an overweighting of sensory prediction errors. (LLM, conf=0.84)
Experimental — accuracy not yet measuredThe result of increased activity from rV1 being associated to VH and VH severity aligns with the finding in schizophrenia of disinhibition in sensory areas (A1) predicting abnormal auditory perception in the aMMN and positive symptoms.
“The result of increased activity from rV1 being associated to VH and VH severity aligns with the finding in schizophrenia of disinhibition in sensory areas (A1) predicting abnormal auditory perception in the aMMN and positive symptoms24.”
From Deviations in effective connectivity explain different hallucination subtypes in Parkinson's disease psychosis (2026) · cites this paper as [24]
The Results sections on resting-state fMRI and 40-Hz ASSR associate A1 disinhibition with abnormal auditory percepts, and the resting-state fMRI results also associate it with positive symptoms. But the MMN Results locate the association with abnormal auditory percepts in the left inferior frontal gyrus, not A1. The paper reports associations rather than showing that A1 disinhibition predicts these outcomes in the MMN paradigm. (LLM, conf=0.85)
Experimental — accuracy not yet measuredDCM has proved instrumental in clarifying the disruption of MMN in people with schizophrenia-related psychosis.
“DCM has proved instrumental in clarifying the disruption of MMN in people with schizophrenia-related psychosis24”
From Deviations in effective connectivity explain different hallucination subtypes in Parkinson's disease psychosis (2026) · cites this paper as [24]
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- Authors
- Adams, R. A., Pinotsis, D., Tsirlis, K., Unruh, L., Mahajan, A., Horas, A. M., Convertino, L., Summerfelt, A., Sampath, H., Du, X. M., Kochunov, P., Ji, J. L., Repovs, G., Murray, J. D., Friston, K. J., Hong, L. E., & Anticevic, A.
- Affiliations
- Yale University (US)
- City, University of London (GB)
- University College London (GB)
- University of Maryland, Baltimore (US)
- Wellcome Centre for Human Neuroimaging (GB)
- Corresponding author
- Adams, Rick A.
- ORCID
- Venue
- Biological Psychiatry
- Publisher
- Elsevier BV
- Published
- 2022-01
- Volume
- 91
- Issue
- 2
- Pages
- 202-215
- ISSN
- 0006-3223 (ISSN-L)
- PMC
- PMC8654393
- OpenAlex
- W3159456120
- Cited by
- 98
- References
- 60
- Citations by year
- 2026: 15 · 2025: 23 · 2024: 18 · 2023: 21 · 2022: 17 · 2021: 4
- FWCI
- 10.76
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Biological Psychiatry (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Repository of the University of Ljubljana (University of Ljubljana) (publishedVersion, cc-by)
- City Research Online (City University London) (acceptedVersion)
- Funders
- National Institute for Health Research (CL-2013-18-003)
- Academy of Medical Sciences (AMS-SGCL13-Adams)
- University College London
- National Institutes of Health (MH112746)
- Javna Agencija za Raziskovalno Dejavnost RS (J7-8275, P3-0338)
- Medical Research Council (MR/S007806/1)
- Wellcome Trust (088130/Z/09/Z)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Neuroscience › Cognitive Neuroscience › Neural dynamics and brain function
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- schizophrenia, synaptic gain, pyramidal neurons, interneurons, autoinhibition, disinhibition, dynamic causal modeling, mismatch negativity, 40 Hz auditory steady-state response, resting-state EEG, theta power, positive symptoms, auditory perception, cortical microcircuits
- MeSH terms
- Computer Simulation, Electroencephalography, Evoked Potentials, Auditory, Humans, Magnetic Resonance Imaging, Schizophrenia, Pyramidal Cells
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.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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