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    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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    Author
    Adams, Rick A
    Pinotsis, Dimitris
    Tsirlis, Konstantinos
    Unruh, Leonhardt
    Mahajan, Aashna
    Horas, Ana Montero
    Convertino, Laura
    Summerfelt, Ann
    Sampath, Hemalatha
    Du, Xiaoming Michael
    Kochunov, Peter
    Ji, Jie Lisa
    Repovs, Grega
    Murray, John D
    Friston, Karl J
    Hong, L Elliot
    Anticevic, Alan
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    Date
    2021-08-10
    Journal
    Biological Psychiatry
    Publisher
    Elsevier Inc.
    Type
    Article
    
    Metadata
    Show full item record
    See at
    https://doi.org/10.1016/j.biopsych.2021.07.024
    Abstract
    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.
    Rights/Terms
    Copyright © 2021 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
    Keyword
    Auditory steady-state
    Dynamic causal model
    Mismatch negativity
    Psychosis
    Resting state
    Schizophrenia
    Identifier to cite or link to this item
    http://hdl.handle.net/10713/16801
    ae974a485f413a2113503eed53cd6c53
    10.1016/j.biopsych.2021.07.024
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