Biol Psychiatry
May 25, 2018
Philipp Sterzer, Rick A. Adams, Paul Fletcher et al.
901 citations
Psychosis may stem from altered predictive coding in the brain, where prior beliefs are combined with sensory signals to interpret the world. The canonical account suggests that weakened prior beliefs relative to sensory data lead to maladaptive inferences. However, evidence is mixed: some studies find weakened priors, others stronger priors. Hallucinations and delusions may involve distinct predictive coding alterations. Challenges include non-uniform deficits across sensory modalities, hierarchical processing where lower and higher levels interact non-linearly, and the role of active inference—anticipating how actions affect sensations. Considering these complexities could reconcile conflicting findings and yield a more comprehensive framework for psychosis.
Cerebral Cortex
November 29, 2012
John D. Murray, Alan Anticevic, Mark G. Gancsos et al.
278 citations
Disruption of the balance between excitation and inhibition in the prefrontal cortex is thought to underlie cognitive problems in schizophrenia. A computational model of spatial working memory showed that disinhibition—caused by perturbing NMDA receptors on interneurons—broadens the tuning of memory-related neural activity, leading to more variable and less precise stored information and a reduced ability to filter out distractions. This prediction was tested with behavioral data from humans given ketamine, which induces disinhibition, and ketamine increased errors as the model predicted. The model also showed that restoring excitation-inhibition balance could reverse these working memory deficits, pointing to new experimental approaches for studying memory problems in schizophrenia.
Proceedings of the National Academy of Sciences
September 25, 2012
Alan Anticevic, Mark G. Gancsos, John D. Murray et al.
260 citations
Glutamate signaling through NMDA receptors is essential for brain computations that support cognition, and its disruption may contribute to schizophrenia. Using ketamine, an NMDA receptor antagonist, the study found that the normal anticorrelation between the default-mode and task-positive brain systems was disrupted during a working memory task. The degree of this disruption predicted task performance and produced schizophrenia-like symptoms. A computational model suggests that cortical disinhibition underlies this effect, linking glutamate's role in large-scale brain organization to cognition and psychiatric symptoms.
PLoS ONE
June 12, 2013
Philip R. Corlett, Victoria C. Cambridge, Jennifer M. Gardner et al.
104 citations
Delusions, the persistent bizarre beliefs characteristic of psychosis, may arise from disturbances in prediction error-dependent learning. In a placebo-controlled study with 18 human subjects, ketamine—an NMDA receptor antagonist that induces aberrant prediction error signals—was administered during re-exposure to a conditioned fear stimulus. This led to stronger subsequent fear memory compared to placebo, with the degree of strengthening correlating with individual vulnerability to ketamine's psychotogenic effects and with prediction error brain signals. A partial replication in an independent sample with an appetitive learning procedure (8 subjects) supported these findings. The results suggest a link between altered prediction error, memory strength, and psychosis, potentially explaining both the emergence and persistence of delusional beliefs.
Schizophrenia Bulletin
August 5, 2020
Pantelis Leptourgos, Martin Fortier-Davy, Robin Carhart‐Harris et al.
88 citations
A multidisciplinary working group reviewed evidence on the similarities and differences between hallucinations induced by psychedelics and those occurring in schizophrenia-spectrum disorders, examining data from pharmacology, brain imaging, phenomenology, and anthropology. The authors highlight both shared features and distinct characteristics across these scales, and attempt to integrate findings using computational approaches. They conclude with recommendations for future research, emphasizing the need for further study to clarify the relationship between these types of hallucinations.
Schizophrenia Bulletin
August 8, 2018
T. M. Luhrmann, Ben Alderson‐day, Vaughan Bell et al.
74 citations
Trauma can contribute to voice-hearing but is not necessary for it. This article uses ethnographic and other data to show multiple pathways to voice-hearing in both clinical and nonclinical populations, excluding known causes like drugs or epilepsy. Trauma sometimes plays a major role, sometimes a minor role, and sometimes no role at all. Distinct phenomenological patterns in voice-hearing may reflect different salience of trauma for those who hear voices.
Cogn Neuropsychiatry
February 6, 2011
James W. Moore, Danielle C. Turner, Philip R. Corlett et al.
64 citations
Ketamine, a drug that induces temporary psychosis-like symptoms, increased the sense of agency in healthy adults, mimicking the exaggerated action-effect binding seen in schizophrenia. In a small experiment, 14 participants given low-dose ketamine showed greater compression of time between their actions and outcomes compared to placebo. The size of this effect correlated with unusual bodily experiences caused by the drug. The findings suggest ketamine can reproduce certain agency disturbances characteristic of schizophrenia, and that these changes are linked to broader alterations in body awareness.
ACS Chemical Neuroscience
August 24, 2022
Manoj K. Doss, Frederick S. Barrett, Philip R. Corlett
21 citations
A critique of a Nature Medicine paper claiming psilocybin therapy reduces brain network modularity in depressed patients, an effect not seen with the SSRI S-citalopram. The authors identify multiple problems: inconsistent reporting of the primary clinical outcome, statistical flaws including a one-tailed test and a nonsignificant interaction, regression to the mean, ambiguous interpretation of resting-state fMRI data, and a missing reference to a similar study that undermines the justification for a one-tailed test. These issues cast doubt on the uniqueness and impact of the original findings and the media hype they generated.
July 3, 2023
Hugh McGovern, Hilary Jane Grimmer, Manoj K. Doss et al.
12 citations
preprint
Psychedelics can reorient beliefs, but they may also lead to false insights and false beliefs. A review of laboratory research on false insights and false memories is connected to belief formation under psychedelics through the active inference framework. Psychedelics increase both the quantity and subjective intensity of insights and beliefs, including false ones. Future research should aim to minimize the risk of false and potentially harmful beliefs arising from psychedelics. Understanding this risk is crucial for safely leveraging the therapeutic potential of psychedelics.
Journal of Psychopharmacology
November 30, 2016
Benjamin Kelmendi, Philip R. Corlett, Mohini Ranganathan et al.
11 citations
No Summary
Am J Psychiatry
March 26, 2025
Philip R. Corlett, Kurt M. Fraser
9 citations
The salience hypothesis of psychosis, which links dopamine dysfunction to delusion formation, is critically evaluated against newer evidence. The hypothesis's specific predictions about dopamine dysfunction's neural and behavioral loci in psychosis are found lacking. Advances in tools for measuring and manipulating dopamine circuits inform this critique. Contemporary theories proposing dopamine's role in belief formation, belief updating under uncertainty, and abductive inference are argued to better explain patient behavior and dopamine function. While influential for uniting neurochemistry with clinical phenomenology, the original hypothesis faces challenges, and the authors highlight novel predictions for future research.
September 15, 2021
Hugh McGovern, Pantelis Leptourgos, Brendan Hutchinson et al.
4 citations
preprint
Renewed interest in psychedelics has sparked debate about whether and how they alter human beliefs. In clinical and social-cognitive contexts, psychedelic use may lead to profound and sometimes lasting belief changes. Rather than creating entirely new beliefs, psychedelics may instead shift how affect and others' suggestions influence the way beliefs are formed. Baseline beliefs, such as expectations about psychedelics' effects, might color both acute experiences and longer-term changes. To harness psychedelics' potential for clinical use and human flourishing, these possibilities require empirical investigation.
April 28, 2022
Manoj K. Doss, Frederick S. Barrett, Philip R. Corlett
1 citation
preprint
A critical commentary identifies problems in a previously published study on psilocybin therapy. The authors argue that the original paper drew unsupported causal conclusions from correlational data, failed to account for placebo effects and participant expectations, and used statistical methods that inflated the apparent strength of the findings. The commentary suggests the original study's claims about psilocybin's therapeutic mechanisms are not justified by the evidence presented.
Nature Mental Health
June 1, 2026
George E. Chapman, Philip R. Corlett, Stephen M. Fleming et al.
Fixed, false beliefs called delusions are a core feature of psychotic disorders, but why they remain fixed is not well understood. This review proposes a clearer vocabulary for describing delusion fixity—using the terms conviction, incorrigibility, persistence, and stability—and examines factors from diagnosis, psychopathology, psychodynamics, social context, cognition, metacognition, and cognitive neuroscience that may influence fixity. The authors present a working model of delusion fixity and call for interdisciplinary longitudinal studies to better understand it and to improve therapeutic strategies.