Oscillatory, computational, and behavioral evidence for impaired gabaergic inhibition in schizophrenia
Open accessAbstract
The dysconnection hypothesis of schizophrenia (SZ) proposes that psychosis is best understood in terms of aberrant connectivity. Specifically, it suggests that dysconnectivity arises through aberrant synaptic modulation associated with deficits in GABAergic inhibition, excitation-inhibition balance and disturbances of high-frequency oscillations. Using a computational model combined with a graded-difficulty visual orientation discrimination paradigm, we demonstrate that, in SZ, perceptual performance is determined by the balance of excitation-inhibition in superficial cortical layers. Twenty-eight individuals with a DSM-IV diagnosis of SZ, and 30 age- and gender-matched healthy controls participated in a psychophysics orientation discrimination task, a visual grating magnetoencephalography (MEG) recording, and a magnetic resonance spectroscopy (MRS) scan for GABA. Using a neurophysiologically informed model, we quantified group differences in GABA, gamma measures, and the predictive validity of model parameters for orientation discrimination in the SZ group. MEG visual gamma frequency was reduced in SZ, with lower peak frequency associated with more severe negative symptoms. Orientation discrimination performance was impaired in SZ. Dynamic causal modeling of the MEG data showed that local synaptic connections were reduced in SZ and local inhibition correlated negatively with the severity of negative symptoms. The effective connectivity between inhibitory interneurons and superficial pyramidal cells predicted orientation discrimination performance within the SZ group; consistent with graded, behaviorally relevant, disease-related changes in local GABAergic connections. Occipital GABA levels were significantly reduced in SZ but did not predict behavioral performance or oscillatory measures. These findings endorse the importance, and behavioral relevance, of GABAergic synaptic disconnection in schizophrenia that underwrites excitation-inhibition balance.
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DCM analyses reveal that individuals with schizophrenia show diminished local synaptic connectivity, particularly between inhibitory interneurons and superficial pyramidal cells, with connectivity deficits correlating with negative symptom severity.
“DCM analyses reveal the circuit-level consequences of these abnormalities: individuals show diminished local synaptic connectivity, particularly between inhibitory interneurons and superficial pyramidal cells (the putative error units in predictive coding), with connectivity deficits correlating with negative symptom severity (36).”
From Predictive coding and neurocomputational psychiatry: a mechanistic framework for understanding mental disorders (2026) · cites this paper as [36]
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Experimental — accuracy not yet measuredGABAergic abnormalities-evidenced by decreased occipital GABA concentrations in patients-further disrupt the excitation-inhibition balance crucial for appropriate precision-weighting.
“Complementing this, GABAergic abnormalities-evidenced by decreased occipital GABA concentrations in patients-further disrupt the excitation-inhibition balance crucial for appropriate precision-weighting (36).”
From Predictive coding and neurocomputational psychiatry: a mechanistic framework for understanding mental disorders (2026) · cites this paper as [36]
The Abstract reports significantly reduced occipital GABA levels in patients with schizophrenia and links GABAergic synaptic disconnection to excitation–inhibition balance. It also says GABA levels did not predict behavioral or oscillatory measures; the paper does not establish that the reduced concentrations disrupt precision-weighting. (LLM, conf=0.88)
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Deakin, J. F. W., Liddle, E. B., Rathnaiah, M., Gregory, C., Katshu, M. Z. U. H., Williams, G., Conen, S., Smallman, R. P., Koelewijn, L. C., Anton, A., et al. (2024) · medRxiv · doi:10.1101/2024.06.26.24308831 · Cited by 1 · see citing works
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Trust your gut: the neuro-gastroenteric mechanics of prediction and expectation
Caccamo, A. (2026) · Frontiers in Human Neuroscience · doi:10.3389/fnhum.2026.1956182
Neurometabolic Differences in Psychosis Observed with 7 T Magnetic Resonance Spectroscopy
Schallmo, M., Demro, C., Killebrew, K. W., Sheldon, A. A., Olman, C. A., Sponheim, S. R., & Marjańska, M. (2026) · Schizophrenia Bulletin · doi:10.1093/schbul/sbag137
- Authors
- Shaw, A. D., Knight, L., Freeman, T. C. A., Williams, G. M., Moran, R. J., Friston, K. J., Walters, J. T. R., & Singh, K. D.
- Affiliations
- Cardiff University (GB)
- King's College London (GB)
- Wellcome Centre for Human Neuroimaging (GB)
- Corresponding author
- Singh, Krish D
- ORCID
- Venue
- Schizophrenia Bulletin
- Publisher
- Oxford University Press (OUP)
- Published
- 2019-06-20
- Volume
- 46
- Issue
- 2
- Pages
- 345-353
- ISSN
- 0586-7614 (ISSN-L)
- 1745-1701
- PMC
- PMC7442335
- OpenAlex
- W2952288277
- Cited by
- 54
- References
- 38
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 8 · 2023: 7 · 2022: 7 · 2021: 15 · 2020: 6 · 2019: 4
- FWCI
- 6.27
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Schizophrenia Bulletin (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- ORCA Online Research @Cardiff (Cardiff University) (acceptedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- CUBRIC
- Schools of Psychology and Medicine at Cardiff University
- MRC/EPSRC (MR/K005464/1)
- Wellcome Trust Strategic Award (104943/Z/14/Z)
- Wellcome Trust Principal Research Fellowship (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, GABAergic inhibition
- MeSH terms
- Adult, Cerebral Cortex, Discrimination, Psychological, Female, gamma-Aminobutyric Acid, Humans, Interneurons, Male, Middle Aged, Neural Inhibition, Schizophrenia, Space Perception, Visual Perception, Magnetoencephalography, Pyramidal Cells, Gamma Rhythm
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