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Cited by 157Hallucinations in medical conditionsSchizophrenia research and treatmentNeural dynamics and brain function

Are hallucinations due to an imbalance between excitatory and inhibitory influences on the brain?

Open access
Jardri, Renaud, Hugdahl, Kenneth, Hughes, Matthew, Brunelin, Jérôme, Waters, Flavie, Alderson-Day, Ben, Smailes, Dave, Sterzer, Philipp +5 more·2016·Schizophrenia Bulletin
DOI 10.1093/schbul/sbw075PMC PMC4988749
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Abstract

This review from the International Consortium on Hallucinations Research intends to question the pertinence of the excitatory-to-inhibitory (E/I) imbalance hypothesis as a model for hallucinations. A large number of studies suggest that subtle impairments of the E/I balance are involved in neurological and psychiatric conditions, such as schizophrenia. Emerging evidence also points to a role of the E/I balance in maintaining stable perceptual representations, suggesting it may be a plausible model for hallucinations. In support, hallucinations have been linked to inhibitory deficits as shown with impairment of gamma-aminobutyric acid transmission, N-methyl-d-aspartate receptor plasticity, reductions in gamma-frequency oscillations, hyperactivity in sensory cortices, and cognitive inhibition deficits. However, the mechanisms by which E/I dysfunctions at the cellular level might relate to clinical symptoms and cognitive deficits remain unclear. Given recent data advances in the field of clinical neuroscience, it is now possible to conduct a synthesis of available data specifically related to hallucinations. These findings are integrated with the latest computational frameworks of hallucinations, and recommendations for future research are provided.

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Written from the paper’s full text.

TL;DR

This review from the International Consortium on Hallucinations Research evaluates whether hallucinations arise from an excitatory-to-inhibitory (E/I) imbalance, reviewing molecular, imaging, neurophysiological, cognitive, and computational evidence. It concludes that inhibitory deficits are linked to hallucinations but that cellular E/I mechanisms remain unclear and require multiscale, transdiagnostic testing.

Key findings

  • Hallucinations are linked to inhibitory deficits across scales, including impaired GABA transmission, NMDA receptor plasticity, reduced gamma-frequency oscillations, sensory cortex hyperactivity, and cognitive inhibition deficits.
  • Neurophysiological evidence includes reduced short-interval cortical inhibition (SICI) in schizophrenia versus healthy subjects (d = 0.476), larger P50 gating ratios in acutely psychotic and nonpsychotic schizophrenia patients (especially at SOA = 500 ms), and P50 gating deficits in about half of schizophrenia relatives.
  • In cognitive studies, hallucination frequency in schizophrenia was associated with difficulties on intentional inhibition tasks such as ICIM, HSCT, directed forgetting, and dichotic listening, but not with delusions or other symptom dimensions; in nonclinical participants, ICIM scores correlated with Cardiff Anomalous Percepts Scale scores (r = .38) but not with Launay-Slade Hallucination Scale scores (r = .10).
  • Computational frameworks, especially Bayesian predictive coding and circular inference, are proposed to integrate micro- and macroscale findings; scaling down inhibition or up excitation in such models produces “circular belief propagation,” which can generate strong perceptual beliefs and hallucinations.

Methods

  • Narrative review and synthesis by the International Consortium on Hallucinations Research working group, using published evidence rather than new empirical data.
  • Evidence is reviewed across molecular/pharmacological, brain imaging, MR spectroscopy, neurophysiological, neuromodulation, cognitive, and computational levels, with attention to auditory and visual hallucinations in schizophrenia and other conditions.
  • Findings are integrated with computational models of hallucinations, mainly Bayesian inference, predictive coding, and circular inference, and recommendations for future research are provided.

Limitations

  • Stated: the mechanisms by which E/I dysfunctions at the cellular level relate to clinical symptoms and cognitive deficits remain unclear; there is a specific lack of empirical evidence, and neurophysiological validation of computational approaches is urgently needed.
  • Stated: several studies did not directly investigate the link with auditory hallucinations, such as TMS-EEG evidence of gamma inhibition deficits in dorsolateral prefrontal cortex, and the relationship between cerebellar inhibition deficit severity and auditory hallucination severity has yet to be explored.
  • Evident from the text: as a narrative review, it does not report a systematic search or meta-analytic quantification, and the evidence spans heterogeneous scales, paradigms, and populations, leaving causal direction and specificity to hallucinations unresolved.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1093/schbul/sbw075

Cites

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Statistics

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Claims the paper makes

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  • Premisecitation

    Phase synchronization depends critically on E/I balance.

    “This phenomenon depends critically on E/I balance and is thought to provide a temporal code that underpins coherent perception, thought, and action (the “binding problem”), which has now been observed within and between distributed brain structures during rest, encoding, and higher-order cognition.[54][55][56]”
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  • Premisecitation

    Neural circuits are regulated by activity-dependent feedback systems that maintain a precise excitatory-to-inhibitory (E/I) balance.

    “Neural circuits are regulated by activity-dependent feedback systems that act to maintain a precise excitatory-toinhibitory (E/I) balance. 1”
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  • Premisecitation

    Not all cognitive mechanisms under the rubric of inhibition are meaningfully related to hallucinations.

    “For example, not all the cognitive mechanisms falling under the rubric of inhibition may be meaningfully related to hallucinations.3”
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  • Premisecitation

    Metabolic and functional changes in speech-related areas are widely reported in functional brain imaging studies of schizophrenia patients with hallucinations.

    “Consistent with the notion of an E/I imbalance, metabolic and functional changes in speech-related areas have been widely reported in functional brain imaging studies of SCZ patients with hallucinations.26”
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  • Premisecitation

    Ketamine does not routinely induce hallucinations, but rather illusory percepts.

    “Furthermore, ketamine does not routinely induce hallucinations, rather illusory percepts-alterations of stimuli that are actually present.19”
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    Premisecitation

    Decreased inhibition or increased excitation is a consistent finding in schizophrenia.

    “Decreased inhibition or increased excitation is now a consistent finding in SCZ.”
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    Interpretationreasoning

    Computational scale-free frameworks can provide powerful models for understanding hallucinations by integrating macroscale findings with microscale factors that dictate E/I balance.

    “Computational scale-free frameworks can provide powerful models for understanding hallucinations by allowing the integration of macroscale findings with microscale factors that dictate the E/I balance.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    Frontal-temporal Glx levels positively correlate with hallucination severity, but not with negative symptoms.

    “A significant positive correlation was also found between frontal-temporal Glx levels and hallucination severity (assessed with item P3 from the Positive and Negative Syndrome Scale, PANSS), while correlations with negative symptoms were close to zero.”
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    Premisecitation

    LSD and other serotonergic hallucinogens induce profound visual hallucinations, altered sense of self and time, but no consistent delusions.

    “Contrary to ketamine, LSD and other serotonergic hallucinogens induce profound visual hallucinations, together with altered sense of self and time 21 but no consistent delusions.22”
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    Interpretationnone given

    GABA measures from the same brain regions as are targeted for measures of Glu could allow to sort out the specificity of E/I interactions for the initiation and maintenance of hallucinations.

    “Indeed, GABA measures from the same brain regions as are targeted for measures of Glu could allow to sort out the specificity of E/I interactions for the initiation and maintenance of hallucinations.”
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    • Rests on an assumption: GABA and Glu can be measured from the same brain regions using MRS.

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    Premisecitation

    Disrupted predictive coding has been invoked as a mechanism underlying hallucinations.

    “Disrupted predictive coding has also been invoked as a mechanism underlying hallucinations per se.122-124”
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    Interpretationnone given

    Validation of experimental data through computational model fitting, based on predictive coding and circular inference frameworks, should reinforce the biological plausibility of the computational approach.

    “The validation of these experimental data through computational model fitting, based on predictive coding and circular inference frameworks, should finally reinforce the biological plausibility of the computational approach.”
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    • Rests on an assumption: Computational model fitting based on predictive coding and circular inference frameworks can validate experimental data.

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    Interpretationcitation

    Ketamine and phencyclidine disturb the feed-forward mechanism through AMPA upregulation and the feedback constraint through NMDA blockade.

    “This suggests that ketamine and phencyclidine (PCP) disturb the feed-forward mechanism (prediction error signal) through AMPA upregulation and the feedback constraint (priors) through NMDA blockade.”
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  • Classified as probably not a substantial claim.

    Premisecitation

    Hallucinations have been proposed to originate primarily from the reverberation of bottom-up messages, leading to an overinterpretation of sensory evidence.

    “In this line, hallucinations have been proposed to originate primarily from the reverberation of “bottomup” messages, leading to an overinterpretation of the sensory evidence.145”
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    Premisecitation

    Recent theories propose that hallucinations could be due to altered inference mechanisms.

    “Recent theories propose that hallucinations could be due to altered inference mechanisms.[122][123][124]”
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    Premisecitation

    Corlett et al. suggested that under ketamine, the subject may experience both perceptual aberrations due to AMPA upregulation and a reduced capacity to accommodate and ignore these aberrations due to NMDA blockade.

    “Corlett et al suggested that under ketamine, the subject may experience both perceptual aberrations (due to AMPA [α-amino-3-hydroxyl-5-methyl-4-isoxazolepropionate receptor] upregulation) and a reduced capacity to accommodate and ignore these aberrations (due to NMDA blockade).123”
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    Interpretationreasoning

    Circular propagation generates strong perceptual beliefs even when facing weak sensory evidence, so that hallucinations occur where nothing relevant should have been inferred.

    “Even when facing weak sensory evidence, circular propagation generates strong perceptual beliefs: hallucinations occur where nothing relevant should have been inferred.”
    Quote in the paperSubstantial claim

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    Premisecitation

    LSD alters glutamatergic function but does not impair NMDA signaling and may actually enhance it.

    “Intriguingly, contrary to ketamine, LSD alters glutamatergic function but it does not impair NMDA signaling 23 and may actually enhance it.152”
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    Premisecitation

    Others have linked hallucinations to a failure to attenuate the sensory consequences of inner speech, analogous to the mechanism thought to underlie delusions of control.

    “Others have linked hallucinations to a failure to attenuate the sensory consequences of inner speech, in analogy to the mechanism that is thought to underlie delusions of control.42,124,135”
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    Premisecitation

    One possibility is that hallucinations result from an overly strong effect of top-down predictive signals on neural activity in sensory cortices.

    “One possibility is that hallucinations result from an overly strong effect of top-down predictive signals on neural activity in sensory cortices.133,134”
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    Interpretationnone given

    Bayesian inference frameworks are particularly efficient for integrating various degrees of understanding, from the molecular to anatomo-functional or behavioral levels.

    “Bayesian inference frameworks were shown to be particularly efficient for integrating various degrees of understanding, from the molecular to anatomo-functional or behavioral levels.”
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    Interpretationcitation

    LSD induces more visual hallucinations, a phenomenon that can be captured by circular inferences.

    “Thus, LSD induces more visual hallucinations, a phenomenon that can be captured by circular inferences.121”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [121] Jardri R Deneve S . Computational models of hallucinations. In: Jardri R Cachia A Thomas P Pins D , eds. The Neuroscience of Hallucinations. New York, NY: Springer; 2013:289–313. source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Psychosis is linked to increased prediction error signaling, which in turn leads to aberrant salience and the formation of delusions.

    “It has been proposed that psychosis is linked to increased prediction error signaling 122 which in turn leads to aberrant salience and the formation of delusions, as proposed earlier.123,124,[130][131][132]”
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    Premisecitation

    E/I balance is tightly maintained in cortical networks and is affected in schizophrenia.

    “Indeed such balance is tightly maintained in cortical networks, and was shown affected in SCZ.144”
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19 of 19

  • The paper relies on this without support.

    Long-range connections in the brain are overwhelmingly excitatory.

    “Since long-range connections in the brain are overwhelmingly excitatory, these messages would be reverberated endlessly through feedforward/feedback excitatory loops if they were not controlled by the presence of equivalently strong inhibitory connections.”

  • The paper relies on this without support.

    Belief propagation relies on local inhibitory control to avoid circular inference.

    “Regardless of its specific implementation, it is important to consider that belief propagation relies on local inhibitory control to avoid circular inference.”

  • The paper relies on this without support.

    Both the prior and the sensory evidence are weighted by their precisions, which define their relative contributions on the posterior.

    “Importantly, both the prior and the sensory evidence are weighted by their precisions, which define their relative contributions on the “posterior.””

  • The paper relies on this without support.

    An internal model that represents knowledge about the outer world serves to generate a stable perceptual experience despite noisy sensory data.

    “The core idea is that an internal model that represents the knowledge about the outer world serves to generate a stable perceptual experience despite noisy sensory data.”

  • The paper relies on this without support.

    Predictive signals are fed back from higher to lower levels of the cortical hierarchy.

    “Predictive signals are thought to be fed back from higher to lower levels of the cortical hierarchy.”

  • The paper relies on this without support.

    GABA and Glu can be measured from the same brain regions using MRS.

    “GABA measures from the same brain regions as are targeted for measures of Glu”

  • The paper relies on this without support.

    Computational model fitting based on predictive coding and circular inference frameworks can validate experimental data.

    “The validation of these experimental data through computational model fitting, based on predictive coding and circular inference frameworks”

  • The paper relies on this without support.

    Transdiagnostic comparisons can adequately control for SCZ as an independent factor.

    “exploring these hypotheses transdiagnostically, to adequately control for SCZ as an independent factor”
8 of 8

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Many findings in psychotic or psychosis-prone individuals point to weak priors that are implemented at low levels.

    “Many findings in psychotic or psychosis-prone individuals point to weak priors that are implemented at low levels (e.g. visual illusions; see above and (24, 59, 63)).”

    From The Predictive Coding Account of Psychosis (2018) · cites this paper as [63]

    The Circular Inference Framework (page not provided) reports that patients with psychosis are less sensitive to many perceptual illusions, which the authors say is inconsistent with strong priors driving those illusions. This supports the visual-illusion example, but the passage does not establish weak priors specifically at low levels or extend that finding to psychosis-prone individuals. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • The main neurotransmitter alterations thought to underlie the predictive coding abnormality in psychosis are hypofunction of cortical NMDA receptors and GABAergic neurons as well as elevated striatal dopamine D2 receptor activity.

    “The main neurotransmitter alterations that are thought to underlie this predictive coding abnormality are hypofunction of cortical NMDA receptors and GABAergic neurons as well as elevated striatal dopamine D2 receptor activity, as reviewed elsewhere (24, 59, 63).”

    From The Predictive Coding Account of Psychosis (2018) · cites this paper as [63]

    The Molecular and Pharmacological Evidence section (page not provided) describes impaired GABA transmission in schizophrenia and NMDA-receptor hypofunction in animal models. Further Experimental Support links NMDA blockade and local inhibitory control to altered inference. The paper does not identify elevated striatal D2 receptor activity as an underlying alteration in psychosis: it says ketamine induces striatal dopamine release and binds D2 receptors, while D2 blockade does not prevent ketamine-induced symptoms. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Predictive coding provides a plausible explanation for delusional mood and paranoid delusions, hallucinations, and passivity phenomena.

    “It not only provides a plausible explanation for delusional mood and paranoid delusions, akin to the aberrant salience account (47, 48), but also for hallucinations (61, 63) and passivity phenomena (13, 59).”

    From The Predictive Coding Account of Psychosis (2018) · cites this paper as [63]

Cites

Flagged first, then by citations

Research works printed but not linked: 2

  1. Bishop FR . Graphical models. In: Bishop FR , ed. Pattern Recognition and Machine Learning. Cambridge, UK: Springer; 2006:359–418.
  2. Deneve, 2004, Bayesian inference with recurrent spiking networks, 17, 353

Cited by

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Related

Authors
Jardri, R., Hugdahl, K., Hughes, M., Brunelin, J., Waters, F., Alderson-Day, B., Smailes, D., Sterzer, P., Corlett, P. R., Leptourgos, P., Debbané, M., Cachia, A., & Denève, S.
Affiliations
  • Centre National de la Recherche Scientifique (FR)
  • Haukeland University Hospital (NO)
  • Swinburne University of Technology (AU)
  • Lyon 1 Université (FR)
  • The University of Western Australia (AU)
  • Stiftung Charité (DE)
  • Yale University (US)
  • Inserm (FR)
  • University of Geneva (CH)
Corresponding author
Jardri, Renaud
ORCID
Venue
Schizophrenia Bulletin
Publisher
Oxford University Press (OUP)
Published
2016-06-03
Volume
42
Issue
5
Pages
1124-1134
ISSN
  • 0586-7614 (ISSN-L)
  • 1745-1701
DOI
10.1093/schbul/sbw075
PMC
PMC4988749
OpenAlex
W2410658921
Cited by
157
References
152
Citations by year
2026: 9 · 2025: 18 · 2024: 7 · 2023: 8 · 2022: 17 · 2021: 19 · 2020: 23 · 2019: 16 · 2018: 17 · 2017: 21 · 2016: 2
FWCI
1.96
Type
journal article
Language
en
Open access
Locations
  • Schizophrenia Bulletin (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Sunderland Repository (University of Sunderland) (acceptedVersion)
  • HAL (submittedVersion)
  • Northumbria Research Link (Northumbria University) (submittedVersion)
  • HighWire Press Open Archive (submittedVersion)
  • Swinburne figshare (Swinburne University of Technology) (submittedVersion)
  • Archive ouverte UNIGE (University of Geneva) (submittedVersion, cc-by)
Funders
Wellcome Trust (WT098455)
Topics
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Hallucinations in medical conditions
  • Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Neural dynamics and brain function
Keywords
hallucinations, excitation-inhibition balance
MeSH terms
Brain, Hallucinations, Humans, Neural Inhibition

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