Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

An integrative framework for perceptual disturbances in psychosis

A Publisher Correction to this article was published on 10 March 2020

This article has been updated

Abstract

Perceptual disturbances in psychosis, such as auditory verbal hallucinations, are associated with increased baseline activity in the associative auditory cortex and increased dopamine transmission in the associative striatum. Perceptual disturbances are also associated with perceptual biases that suggest increased reliance on prior expectations. We review theoretical models of perceptual inference and key supporting physiological evidence, as well as the anatomy of associative cortico–striatal loops that may be relevant to auditory perceptual inference. Integrating recent findings, we outline a working framework that bridges neurobiology and the phenomenology of perceptual disturbances via theoretical models of perceptual inference.

Your institute does not have access to this article

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Fig. 1: Examples of perceptual decision making without and with an expectation bias that is contextually appropriate and adaptive.
Fig. 2: Bayesian model of perceptual inference, illustrating the expectation biases related to common perceptual distortions and pathological hallucinations.
Fig. 3: Neural implementation of perceptual decision making in the saccade generation system.
Fig. 4: Circuitry of associative auditory cortex and basal ganglia relevant to perceptual disturbances in psychosis.

Change history

  • 10 March 2020

    An amendment to this paper has been published and can be accessed via a link at the top of the paper.

References

  1. Fletcher, P. C. & Frith, C. D. Perceiving is believing: a Bayesian approach to explaining the positive symptoms of schizophrenia. Nat. Rev. Neurosci. 10, 48–58 (2009). This in-depth review proposes an influential framework based on Bayesian inference to bridge the known dopamine dysregulation and individual experiential aspects associated with psychosis.

    CAS  PubMed  Google Scholar 

  2. Weinstein, J. J. et al. Pathway-specific dopamine abnormalities in schizophrenia. Biol. Psychiatry 81, 31–42 (2017). This study reviews the literature on dopamine alterations in schizophrenia with special emphasis on the distinct anatomical pathways that comprise the dopamine system.

    CAS  PubMed  Google Scholar 

  3. Powers, A. R. III, Kelley, M. & Corlett, P. R. Hallucinations as top-down effects on perception. Biol. Psychiatry Cogn. Neurosci. Neuroimaging 1, 393–400 (2016).

    PubMed  PubMed Central  Google Scholar 

  4. Adams, R. A., Stephan, K. E., Brown, H. R., Frith, C. D. & Friston, K. J. The computational anatomy of psychosis. Front. Psychiatry 4, 47 (2013). This report provides a comprehensive computational account of various phenomenological and neurophysiological aspects of schizophrenia.

    PubMed  PubMed Central  Google Scholar 

  5. Sterzer, P. et al. The predictive coding account of psychosis. Biol. Psychiatry 84, 634–643 (2018).

    PubMed  PubMed Central  Google Scholar 

  6. Heinz, A. Dopaminergic dysfunction in alcoholism and schizophrenia—psychopathological and behavioral correlates. Eur. Psychiatry 17, 9–16 (2002).

    CAS  PubMed  Google Scholar 

  7. Kapur, S. Psychosis as a state of aberrant salience: a framework linking biology, phenomenology, and pharmacology in schizophrenia. Am. J. Psychiatry 160, 13–23 (2003).

    PubMed  Google Scholar 

  8. Glimcher, P. W. Understanding dopamine and reinforcement learning: the dopamine reward prediction error hypothesis. Proc. Natl Acad. Sci. USA 108 (Suppl. 3), 15647–15654 (2011).

    CAS  PubMed  Google Scholar 

  9. Schultz, W. Predictive reward signal of dopamine neurons. J. Neurophysiol. 80, 1–27 (1998).

    CAS  PubMed  Google Scholar 

  10. Schultz, W. Getting formal with dopamine and reward. Neuron 36, 241–263 (2002).

    CAS  PubMed  Google Scholar 

  11. Schultz, W. Multiple dopamine functions at different time courses. Annu. Rev. Neurosci. 30, 259–288 (2007).

    CAS  PubMed  Google Scholar 

  12. Yung, A. R. & McGorry, P. D. The prodromal phase of first-episode psychosis: past and current conceptualizations. Schizophr. Bull. 22, 353–370 (1996).

    CAS  PubMed  Google Scholar 

  13. Lim, A., Hoek, H. W., Deen, M. L., Blom, J. D. & GROUP Investigators. Prevalence and classification of hallucinations in multiple sensory modalities in schizophrenia spectrum disorders. Schizophr. Res. 176, 493–499 (2016).

    PubMed  Google Scholar 

  14. Waters, F. & Fernyhough, C. Hallucinations: a systematic review of points of similarity and difference across diagnostic classes. Schizophr. Bull. 43, 32–43 (2017).

    PubMed  Google Scholar 

  15. Andreasen, N. C. & Flaum, M. Schizophrenia: the characteristic symptoms. Schizophr. Bull. 17, 27–49 (1991).

    CAS  PubMed  Google Scholar 

  16. Nayani, T. H. & David, A. S. The auditory hallucination: a phenomenological survey. Psychol. Med. 26, 177–189 (1996).

    CAS  PubMed  Google Scholar 

  17. Llorca, P. M. et al. Hallucinations in schizophrenia and Parkinson’s disease: an analysis of sensory modalities involved and the repercussion on patients. Sci. Rep. 6, 38152 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Lehembre-Shiah, E. et al. Distinct relationships between visual and auditory perceptual abnormalities and conversion to psychosis in a clinical high-risk population. JAMA Psychiatry 74, 104–106 (2017).

    PubMed  PubMed Central  Google Scholar 

  19. Emsley, R., Rabinowitz, J., Torreman, M. & RIS-INT-35 Early Psychosis Global Working Group. The factor structure for the Positive and Negative Syndrome Scale (PANSS) in recent-onset psychosis. Schizophr. Res. 61, 47–57 (2003).

    PubMed  Google Scholar 

  20. Freedman, R. Schizophrenia. N. Engl. J. Med. 349, 1738–1749 (2003).

    CAS  PubMed  Google Scholar 

  21. De Keyser, J., De Backer, J. P., Ebinger, G. & Vauquelin, G. Regional distribution of the dopamine D2 receptors in the mesotelencephalic dopamine neuron system of human brain. J. Neurol. Sci. 71, 119–127 (1985).

    PubMed  Google Scholar 

  22. Palacios, J. M., Camps, M., Cortes, R. & Probst, A. Mapping dopamine receptors in the human brain. J. Neural. Transm. Suppl. 27, 227–235 (1988).

    CAS  PubMed  Google Scholar 

  23. Agid, O., Seeman, P. & Kapur, S. The ‘delayed onset’ of antipsychotic action—an idea whose time has come and gone. J. Psychiatry Neurosci. 31, 93–100 (2006).

    PubMed  PubMed Central  Google Scholar 

  24. Emsley, R., Rabinowitz, J. & Medori, R. Time course for antipsychotic treatment response in first-episode schizophrenia. Am. J. Psychiatry 163, 743–745 (2006).

    PubMed  Google Scholar 

  25. Rector, N. A. & Beck, A. T. Cognitive behavioral therapy for schizophrenia: an empirical review. J. Nerv. Ment. Dis. 189, 278–287 (2001).

    CAS  PubMed  Google Scholar 

  26. Slotema, C. W., Aleman, A., Daskalakis, Z. J. & Sommer, I. E. Meta-analysis of repetitive transcranial magnetic stimulation in the treatment of auditory verbal hallucinations: update and effects after one month. Schizophr. Res. 142, 40–45 (2012).

    CAS  PubMed  Google Scholar 

  27. Pruessner, J. C., Champagne, F., Meaney, M. J. & Dagher, A. Dopamine release in response to a psychological stress in humans and its relationship to early life maternal care: a positron emission tomography study using [11C]raclopride. J. Neurosci. 24, 2825–2831 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Volkow, N. D., Fowler, J. S., Wang, G. J. & Swanson, J. M. Dopamine in drug abuse and addiction: results from imaging studies and treatment implications. Mol. Psychiatry 9, 557–569 (2004).

    CAS  PubMed  Google Scholar 

  29. Jardri, R. et al. Are hallucinations due to an imbalance between excitatory and inhibitory influences on the brain? Schizophr. Bull. 42, 1124–1134 (2016).

    PubMed  PubMed Central  Google Scholar 

  30. Krystal, J. H. et al. impaired tuning of neural ensembles and the pathophysiology of schizophrenia: a translational and computational neuroscience perspective. Biol. Psychiatry 81, 874–885 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Bohlken, M. M., Hugdahl, K. & Sommer, I. E. Auditory verbal hallucinations: neuroimaging and treatment. Psychol. Med. 47, 199–208 (2017).

    CAS  PubMed  Google Scholar 

  32. Goghari, V. M., Harrow, M., Grossman, L. S. & Rosen, C. A 20-year multi-follow-up of hallucinations in schizophrenia, other psychotic, and mood disorders. Psychol. Med. 43, 1151–1160 (2013).

    CAS  PubMed  Google Scholar 

  33. Marshall, M. et al. Association between duration of untreated psychosis and outcome in cohorts of first-episode patients: a systematic review. Arch. Gen. Psychiatry 62, 975–983 (2005).

    PubMed  Google Scholar 

  34. Summerfield, C. & de Lange, F. P. Expectation in perceptual decision making: neural and computational mechanisms. Nat. Rev. Neurosci. 15, 745–756 (2014). This review integrates non-primate electrophysiology and human neuroimaging findings that represent possible neural implementations of expectation effects in perceptual decision-making in the brain.

    CAS  PubMed  Google Scholar 

  35. Bitzer, S., Park, H., Blankenburg, F. & Kiebel, S. J. Perceptual decision making: drift-diffusion model is equivalent to a Bayesian model. Front. Hum. Neurosci. 8, 102 (2014).

    PubMed  PubMed Central  Google Scholar 

  36. Friston, K. & Kiebel, S. Predictive coding under the free-energy principle. Philos Trans. R. Soc. Lond. B. Biol. Sci. 364, 1211–1221 (2009).

    PubMed  PubMed Central  Google Scholar 

  37. Rao, R. P. & Ballard, D. H. Predictive coding in the visual cortex: a functional interpretation of some extra-classical receptive-field effects. Nat. Neurosci. 2, 79–87 (1999).

    CAS  PubMed  Google Scholar 

  38. Friston, K. Hallucinations and perceptual inference. Behavioral and Brain Sciences 28, 764–766 (2005). In this short commentary, Karl Friston delineates for the first time a perceptual-inference model of hallucinations.

    Google Scholar 

  39. Benrimoh, D., Parr, T., Vincent, P., Adams, R. A. & Friston, K. Active inference and auditory hallucinations. Comput. Psychiatr. 2, 183–204 (2018).

    PubMed  PubMed Central  Google Scholar 

  40. Bentall, R. P. & Slade, P. D. Reality testing and auditory hallucinations: a signal detection analysis. Br. J. Clin. Psychol. 24 (Pt 3), 159–169 (1985).

    PubMed  Google Scholar 

  41. Brookwell, M. L., Bentall, R. P. & Varese, F. Externalizing biases and hallucinations in source-monitoring, self-monitoring and signal detection studies: a meta-analytic review. Psychol. Med. 43, 2465–2475 (2013).

    CAS  PubMed  Google Scholar 

  42. Varese, F., Barkus, E. & Bentall, R. P. Dissociation mediates the relationship between childhood trauma and hallucination-proneness. Psychol. Med. 42, 1025–1036 (2012).

    CAS  PubMed  Google Scholar 

  43. Vercammen, A., de Haan, E. H. & Aleman, A. Hearing a voice in the noise: auditory hallucinations and speech perception. Psychol. Med. 38, 1177–1184 (2008).

    CAS  PubMed  Google Scholar 

  44. Powers, A. R., Mathys, C. & Corlett, P. R. Pavlovian conditioning-induced hallucinations result from overweighting of perceptual priors. Science 357, 596–600 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. O’Callaghan, C. et al. Visual hallucinations are characterized by impaired sensory evidence accumulation: insights from hierarchical drift diffusion modeling in Parkinson’s Disease. Biol. Psychiatry Cogn. Neurosci. Neuroimaging 2, 680–688 (2017).

    PubMed  Google Scholar 

  46. Limongi, R., Bohaterewicz, B., Nowicka, M., Plewka, A. & Friston, K. J. Knowing when to stop: aberrant precision and evidence accumulation in schizophrenia. Schizophr. Res. 197, 386–391 (2018).

    PubMed  PubMed Central  Google Scholar 

  47. Teufel, C. et al. Shift toward prior knowledge confers a perceptual advantage in early psychosis and psychosis-prone healthy individuals. Proc. Natl Acad. Sci. USA 112, 13401–13406 (2015). This behavioural human study provided a first demonstration of exaggerated expectation biases specifically relevant to perceptual disturbances in populations at risk for psychosis.

    CAS  PubMed  Google Scholar 

  48. Cassidy, C. M. et al. A perceptual inference mechanism for hallucinations linked to striatal dopamine. Curr. Biol. 28, 503–514 (2018). This study is the first demonstration of a correlation between striatal dopamine excess and altered expectation biases in relation to hallucinations in patients with schizophrenia.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Gold, J. I. & Shadlen, M. N. The neural basis of decision making. Annu. Rev. Neurosci. 30, 535–574 (2007). This general review delves into the electrophysiology literature on perceptual decision making and its links to computational models of evidence accumulation.

    CAS  PubMed  Google Scholar 

  50. Dehaene, S. & Changeux, J. P. Experimental and theoretical approaches to conscious processing. Neuron 70, 200–227 (2011).

    CAS  PubMed  Google Scholar 

  51. Maia, T. V. & Cleeremans, A. Consciousness: converging insights from connectionist modeling and neuroscience. Trends Cogn. Sci. 9, 397–404 (2005).

    PubMed  Google Scholar 

  52. de Lafuente, V. & Romo, R. Neuronal correlates of subjective sensory experience. Nat. Neurosci. 8, 1698–1703 (2005).

    PubMed  Google Scholar 

  53. de Lafuente, V. & Romo, R. Neural correlate of subjective sensory experience gradually builds up across cortical areas. Proc. Natl Acad. Sci. USA 103, 14266–14271 (2006).

    PubMed  Google Scholar 

  54. Van Vugt, B. et al. The threshold for conscious report: signal loss and response bias in visual and frontal cortex. Science 360, 537–542 (2018).

    PubMed  Google Scholar 

  55. Kaas, J. H. & Hackett, T. A. Subdivisions of auditory cortex and processing streams in primates. Proc. Natl Acad. Sci. USA 97, 11793–11799 (2000).

    CAS  PubMed  Google Scholar 

  56. Tang, C., Hamilton, L. S. & Chang, E. F. Intonational speech prosody encoding in the human auditory cortex. Science 357, 797–801 (2017).

    CAS  PubMed  Google Scholar 

  57. Penfield, W. & Perot, P. The brain’s record of auditory and visual experience: a final summary and discussion. Brain 86, 595–696 (1963).

    CAS  PubMed  Google Scholar 

  58. Kobayashi, E. et al. Magnetic resonance imaging abnormalities in familial temporal lobe epilepsy with auditory auras. Arch. Neurol. 60, 1546–1551 (2003).

    PubMed  Google Scholar 

  59. Winawer, M. R., Ottman, R., Hauser, W. A. & Pedley, T. A. Autosomal dominant partial epilepsy with auditory features: defining the phenotype. Neurology 54, 2173–2176 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Yeterian, E. H. & Pandya, D. N. Corticostriatal connections of the superior temporal region in rhesus monkeys. J. Comp. Neurol. 399, 384–402 (1998). This tracing study in non-human primates describes the anatomical downstream connections of the superior temporal cortex.

    CAS  PubMed  Google Scholar 

  61. Hackett, T. A., Stepniewska, I. & Kaas, J. H. Thalamocortical connections of the parabelt auditory cortex in macaque monkeys. J. Comp. Neurol. 400, 271–286 (1998).

    CAS  PubMed  Google Scholar 

  62. Middleton, F. A. & Strick, P. L. The temporal lobe is a target of output from the basal ganglia. Proc. Natl Acad. Sci. USA 93, 8683–8687 (1996).

    CAS  PubMed  Google Scholar 

  63. Shammah-Lagnado, S. J., Alheid, G. F. & Heimer, L. Efferent connections of the caudal part of the globus pallidus in the rat. J. Comp. Neurol. 376, 489–507 (1996).

    CAS  PubMed  Google Scholar 

  64. Horga, G., Schatz, K. C., Abi-Dargham, A. & Peterson, B. S. Deficits in predictive coding underlie hallucinations in schizophrenia. J. Neurosci. 34, 8072–8082 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Jardri, R., Pouchet, A., Pins, D. & Thomas, P. Cortical activations during auditory verbal hallucinations in schizophrenia: a coordinate-based meta-analysis. Am. J. Psychiatry 168, 73–81 (2011).

    PubMed  Google Scholar 

  66. Diederen, K. M. et al. Deactivation of the parahippocampal gyrus preceding auditory hallucinations in schizophrenia. Am. J. Psychiatry 167, 427–435 (2010).

    PubMed  Google Scholar 

  67. Hoffman, R. E., Pittman, B., Constable, R. T., Bhagwagar, Z. & Hampson, M. Time course of regional brain activity accompanying auditory verbal hallucinations in schizophrenia. Br. J. Psychiatry 198, 277–283 (2011).

    PubMed  PubMed Central  Google Scholar 

  68. Gerfen, C. R. & Surmeier, D. J. Modulation of striatal projection systems by dopamine. Annu. Rev. Neurosci. 34, 441–466 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Maia, T. V. & Frank, M. J. An integrative perspective on the role of dopamine in schizophrenia. Biol. Psychiatry 81, 52–66 (2017). This article provides a comprehensive model of how dopamine dysregulation in schizophrenia may explain different symptom domains via reinforcement-learning theory.

    CAS  PubMed  Google Scholar 

  70. Alexander, G. E., DeLong, M. R. & Strick, P. L. Parallel organization of functionally segregated circuits linking basal ganglia and cortex. Annu. Rev. Neurosci. 9, 357–381 (1986).

    CAS  PubMed  Google Scholar 

  71. Haber, S. N. The primate basal ganglia: parallel and integrative networks. J. Chem. Neuroanat. 26, 317–330 (2003).

    PubMed  Google Scholar 

  72. Choi, E. Y., Tanimura, Y., Vage, P. R., Yates, E. H. & Haber, S. N. Convergence of prefrontal and parietal anatomical projections in a connectional hub in the striatum. Neuroimage 146, 821–832 (2017).

    PubMed  Google Scholar 

  73. Wickens, J. R., Reynolds, J. N. & Hyland, B. I. Neural mechanisms of reward-related motor learning. Curr. Opin. Neurobiol. 13, 685–690 (2003).

    CAS  PubMed  Google Scholar 

  74. Xiong, Q., Znamenskiy, P. & Zador, A. M. Selective corticostriatal plasticity during acquisition of an auditory discrimination task. Nature 521, 348–351 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Redgrave, P., Prescott, T. J. & Gurney, K. Is the short-latency dopamine response too short to signal reward error? Trends Neurosci. 22, 146–151 (1999).

    CAS  PubMed  Google Scholar 

  76. Horvitz, J. C., Stewart, T. & Jacobs, B. L. Burst activity of ventral tegmental dopamine neurons is elicited by sensory stimuli in the awake cat. Brain Res. 759, 251–258 (1997).

    CAS  PubMed  Google Scholar 

  77. de Lafuente, V. & Romo, R. Dopamine neurons code subjective sensory experience and uncertainty of perceptual decisions. Proc. Natl Acad. Sci. USA 108, 19767–19771 (2011). This non-human primate study shows that dopamine neurons encode perceptual uncertainty during a decision-making task.

    PubMed  Google Scholar 

  78. Lak, A., Nomoto, K., Keramati, M., Sakagami, M. & Kepecs, A. Midbrain dopamine neurons signal belief in choice accuracy during a perceptual decision. Curr. Biol. 27, 821–832 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Sarno, S., de Lafuente, V., Romo, R. & Parga, N. Dopamine reward prediction error signal codes the temporal evaluation of a perceptual decision report. Proc. Natl Acad. Sci. USA 114, E10494–E10503 (2017).

    CAS  PubMed  Google Scholar 

  80. Sharpe, M. J. et al. Dopamine transients are sufficient and necessary for acquisition of model-based associations. Nat. Neurosci. 20, 735–742 (2017). This rodent study uses a sensory preconditioning paradigm and optogenetics to show that dopamine is necessary for stimulus–stimulus learning, separate from reward learning.

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Menegas, W., Babayan, B. M., Uchida, N. & Watabe-Uchida, M. Opposite initialization to novel cues in dopamine signaling in ventral and posterior striatum in mice. eLife 6, e21886 (2017). This rodent study shows that, in contrast with dopamine signals in ventral striatum, those in dorsal striatum encode a type of sensory prediction error.

    PubMed  PubMed Central  Google Scholar 

  82. Wolpe, N. et al. Sensory attenuation in Parkinson’s disease is related to disease severity and dopamine dose. Sci. Rep. 8, 15643 (2018).

    PubMed  PubMed Central  Google Scholar 

  83. Vilares, I. & Kording, K. P. Dopaminergic medication increases reliance on current information in Parkinson’s Disease. Nat. Hum. Behav. 1, 0129 (2017).

    PubMed  PubMed Central  Google Scholar 

  84. Nour, M. M. et al. Dopaminergic basis for signaling belief updates, but not surprise, and the link to paranoia. Proc. Natl Acad. Sci. USA 115, E10167–E10176 (2018).

    CAS  PubMed  Google Scholar 

  85. Howes, O. D. et al. The nature of dopamine dysfunction in schizophrenia and what this means for treatment. Arch. Gen. Psychiatry 69, 776–786 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Laruelle, M. Imaging synaptic neurotransmission with in vivo binding competition techniques: a critical review. J. Cereb. Blood Flow Metab. 20, 423–451 (2000).

    CAS  PubMed  Google Scholar 

  87. Abi-Dargham, A. et al. Prefrontal dopamine D1 receptors and working memory in schizophrenia. J. Neurosci. 22, 3708–3719 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Abi-Dargham, A. et al. Increased prefrontal cortical D1 receptors in drug naive patients with schizophrenia: a PET study with [11C]NNC112. J. Psychopharmacol. 26, 794–805 (2012).

    PubMed  Google Scholar 

  89. Okubo, Y. et al. Decreased prefrontal dopamine D1 receptors in schizophrenia revealed by PET. Nature 385, 634–636 (1997).

    CAS  PubMed  Google Scholar 

  90. Okubo, Y., Suhara, T., Sudo, Y. & Toru, M. Possible role of dopamine D1 receptors in schizophrenia. Mol. Psychiatr. 2, 291–292 (1997).

    CAS  Google Scholar 

  91. Laruelle, M. et al. Single photon emission computerized tomography imaging of amphetamine-induced dopamine release in drug free schizophrenic subjects. Proc. Natl Acad. Sci. USA 93, 9235–9240 (1996).

    CAS  PubMed  Google Scholar 

  92. Abi-Dargham, A. et al. Increased striatal dopamine transmission in schizophrenia: confirmation in a second cohort. Am. J. Psychiatry 155, 761–767 (1998).

    CAS  PubMed  Google Scholar 

  93. Abi-Dargham, A. et al. Increased baseline occupancy of D2 receptors by dopamine in schizophrenia. Proc. Natl Acad. Sci. USA 97, 8104–8109 (2000).

    CAS  PubMed  Google Scholar 

  94. Kegeles, L. et al. Increased synaptic dopamine in associative regions of the striatum in schizophrenia. Archives of General Psychiatry 67, 231–239 (2010).

    CAS  PubMed  Google Scholar 

  95. Howes, O. D. et al. Dopamine synthesis capacity before onset of psychosis: a prospective [18f]-dopa pet imaging study. Am. J. Psychiatry 168, 1311–1317 (2011).

    PubMed  PubMed Central  Google Scholar 

  96. Howes, O. et al. Progressive increase in striatal dopamine synthesis capacity as patients develop psychosis: a PET study. Mol Psychiatry 16, 885–886 (2011).

    CAS  PubMed  Google Scholar 

  97. Howes, O. D. et al. Elevated striatal dopamine function linked to prodromal signs of schizophrenia. Arch. Gen. Psychiatry 66, 13–20 (2009).

    PubMed  Google Scholar 

  98. Laruelle, M., Abi-Dargham, A., Gil, R., Kegeles, L. & Innis, R. Increased dopamine transmission in schizophrenia: relationship to illness phases. Biol. Psychiatry 46, 56–72 (1999).

    CAS  PubMed  Google Scholar 

  99. Thompson, J. L. et al. Striatal dopamine release in schizophrenia comorbid with substance dependence. Mol. Psychiatry 18, 909–915 (2013).

    CAS  PubMed  Google Scholar 

  100. Jauhar, S. et al. A test of the transdiagnostic dopamine hypothesis of psychosis using positron emission tomographic imaging in bipolar affective disorder and schizophrenia. JAMA Psychiatry 74, 1206–1213 (2017).

    PubMed  PubMed Central  Google Scholar 

  101. Farde, L., Hall, H., Ehrin, E. & Sedvall, G. Quantitative analysis of D2 dopamine receptor binding in the living human brain by PET. Science 231, 258–261 (1986).

    CAS  PubMed  Google Scholar 

  102. Farde, L. et al. Positron emission tomographic analysis of central D1 and D2 dopamine receptor occupancy in patients treated with classical neuroleptics and clozapine: relation to extrapyramidal side effects. Arch. Gen. Psychiatry 49, 538–544 (1992).

    CAS  PubMed  Google Scholar 

  103. Farid, F. & Mahadun, P. Schizophrenia-like psychosis following left putamen infarct: a case report. J. Med. Case Rep. 3, 7337 (2009).

    PubMed  PubMed Central  Google Scholar 

  104. Kitabayashi, Y. et al. Schizophrenia-like psychosis following right putaminal infarction. J. Neuropsychiatry Clin. Neurosci. 18, 561–562 (2006).

    PubMed  Google Scholar 

  105. Cleghorn, J. M. et al. Toward a brain map of auditory hallucinations. Am. J. Psychiatry 149, 1062–1069 (1992).

    CAS  PubMed  Google Scholar 

  106. Horga, G. et al. Differential brain glucose metabolic patterns in antipsychotic-naive first-episode schizophrenia with and without auditory verbal hallucinations. J. Psychiatry Neurosci. 36, 312–321 (2011).

    PubMed  PubMed Central  Google Scholar 

  107. Zhuo, C. et al. Cerebral blood flow alterations specific to auditory verbal hallucinations in schizophrenia. Br. J. Psychiatry 210, 209–215 (2017).

    PubMed  Google Scholar 

  108. Samejima, K. & Doya, K. Multiple representations of belief states and action values in corticobasal ganglia loops. Ann. N. Y. Acad. Sci. 1104, 213–228 (2007).

    PubMed  Google Scholar 

  109. Ding, L. & Gold, J. I. Caudate encodes multiple computations for perceptual decisions. J. Neurosci. 30, 15747–15759 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Yartsev, M. M., Hanks, T. D., Yoon, A. M. & Brody, C. D. Causal contribution and dynamical encoding in the striatum during evidence accumulation. eLife 7, e34929 (2018).

    PubMed  PubMed Central  Google Scholar 

  111. Ding, L. & Gold, J. I. Separate, causal roles of the caudate in saccadic choice and execution in a perceptual decision task. Neuron 75, 865–874 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Znamenskiy, P. & Zador, A. M. Corticostriatal neurons in auditory cortex drive decisions during auditory discrimination. Nature 497, 482–485 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Guo, L., Walker, W. I., Ponvert, N. D., Penix, P. L. & Jaramillo, S. Stable representation of sounds in the posterior striatum during flexible auditory decisions. Nat. Commun. 9, 1534 (2018).

    PubMed  PubMed Central  Google Scholar 

  114. Forstmann, B. U., Brown, S., Dutilh, G., Neumann, J. & Wagenmakers, E. J. The neural substrate of prior information in perceptual decision making: a model-based analysis. Front. Hum. Neurosci. 4, 40 (2010).

    PubMed  PubMed Central  Google Scholar 

  115. Vilares, I., Howard, J. D., Fernandes, H. L., Gottfried, J. A. & Kording, K. P. Differential representations of prior and likelihood uncertainty in the human brain. Curr. Biol. 22, 1641–1648 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Horga, G. et al. Dopamine-related disruption of functional topography of striatal connections in unmedicated patients with schizophrenia. JAMA Psychiatry 73, 862–870 (2016).

    PubMed  PubMed Central  Google Scholar 

  117. Bateup, H. S. et al. Distinct subclasses of medium spiny neurons differentially regulate striatal motor behaviors. Proc. Natl Acad. Sci. USA 107, 14845–14850 (2010).

    CAS  PubMed  Google Scholar 

  118. Beeler, J. A. et al. A role for dopamine-mediated learning in the pathophysiology and treatment of Parkinson’s disease. Cell Rep. 2, 1747–1761 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Durieux, P. F., Schiffmann, S. N. & De Kerchove d’Exaerde, A. Differential regulation of motor control and response to dopaminergic drugs by D1R and D2R neurons in distinct dorsal striatum subregions. EMBO J. 31, 640–653 (2012).

    CAS  PubMed  Google Scholar 

  120. Mowery, T. M. et al. The sensory striatum is permanently impaired by transient developmental deprivation. Cell Rep. 19, 2462–2468 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Grace, A. A. Dysregulation of the dopamine system in the pathophysiology of schizophrenia and depression. Nat. Rev. Neurosci. 17, 524–532 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Howes, O. D. & Murray, R. M. Schizophrenia: an integrated sociodevelopmental–cognitive model. Lancet 383, 1677–1687 (2014).

    PubMed  Google Scholar 

  123. Baker, S. C., Konova, A. B., Daw, N. D. & Horga, G. A distinct inferential mechanism for delusions in schizophrenia. Brain 142, 1797–1812 (2019).

    PubMed  PubMed Central  Google Scholar 

  124. Corlett, P. R. et al. Disrupted prediction-error signal in psychosis: evidence for an associative account of delusions. Brain 130, 2387–2400 (2007).

    CAS  PubMed  Google Scholar 

  125. Davies, D. J., Teufel, C. & Fletcher, P. C. Anomalous perceptions and beliefs are associated with shifts toward different types of prior knowledge in perceptual inference. Schizophr. Bull. 44, 1245–1253 (2018).

    PubMed  Google Scholar 

  126. Corlett, P. R. et al. Hallucinations and strong priors. Trends Cogn. Sci. 23, 114–127 (2019).

    PubMed  Google Scholar 

  127. Javitt, D. C. & Sweet, R. A. Auditory dysfunction in schizophrenia: integrating clinical and basic features. Nat. Rev. Neurosci. 16, 535–550 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Hosoya, T., Baccus, S. A. & Meister, M. Dynamic predictive coding by the retina. Nature 436, 71–77 (2005).

    CAS  PubMed  Google Scholar 

  129. Singla, S., Dempsey, C., Warren, R., Enikolopov, A. G. & Sawtell, N. B. A cerebellum-like circuit in the auditory system cancels responses to self-generated sounds. Nat. Neurosci. 20, 943–950 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. Freedman, R. et al. Neurobiological studies of sensory gating in schizophrenia. Schizophr. Bull. 13, 669–678 (1987).

    CAS  PubMed  Google Scholar 

  131. Jensen, J. & Kapur, S. Salience and psychosis: moving from theory to practise. Psychol. Med. 39, 197–198 (2009).

    CAS  PubMed  Google Scholar 

  132. Feinberg, I. Efference copy and corollary discharge: implications for thinking and its disorders. Schizophr. Bull. 4, 636–640 (1978).

    CAS  PubMed  Google Scholar 

  133. Ford, J. M. & Mathalon, D. H. Corollary discharge dysfunction in schizophrenia: can it explain auditory hallucinations? Int. J. Psychophysiol. 58, 179–189 (2005).

    PubMed  Google Scholar 

  134. Frith, C. D. The positive and negative symptoms of schizophrenia reflect impairments in the perception and initiation of action. Psychol. Med. 17, 631–648 (1987).

    CAS  PubMed  Google Scholar 

  135. Leptourgos, P., Deneve, S. & Jardri, R. Can circular inference relate the neuropathological and behavioral aspects of schizophrenia? Curr. Opin. Neurobiol. 46, 154–161 (2017).

    CAS  PubMed  Google Scholar 

  136. Gold, J. I. & Shadlen, M. N. Banburismus and the brain: decoding the relationship between sensory stimuli, decisions, and reward. Neuron 36, 299–308 (2002).

    CAS  PubMed  Google Scholar 

  137. Schlack, A. & Albright, T. D. Remembering visual motion: neural correlates of associative plasticity and motion recall in cortical area MT. Neuron 53, 881–890 (2007).

    CAS  PubMed  Google Scholar 

  138. Hanks, T. D., Mazurek, M. E., Kiani, R., Hopp, E. & Shadlen, M. N. Elapsed decision time affects the weighting of prior probability in a perceptual decision task. J. Neurosci. 31, 6339–6352 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Kok, P., Brouwer, G. J., van Gerven, M. A. & de Lange, F. P. Prior expectations bias sensory representations in visual cortex. J. Neurosci. 33, 16275–16284 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. Summerfield, C. & Egner, T. Expectation (and attention) in visual cognition. Trends Cogn. Sci. 13, 403–409 (2009).

    PubMed  Google Scholar 

  141. Slifstein, M. et al. Deficits in prefrontal cortical and extrastriatal dopamine release in schizophrenia: a positron emission tomographic functional magnetic resonance imaging study. JAMA Psychiatry 72, 316–324 (2015).

    PubMed  PubMed Central  Google Scholar 

  142. Bao, S., Chan, V. T. & Merzenich, M. M. Cortical remodelling induced by activity of ventral tegmental dopamine neurons. Nature 412, 79–83 (2001).

    CAS  PubMed  Google Scholar 

  143. Chun, S. et al. Specific disruption of thalamic inputs to the auditory cortex in schizophrenia models. Science 344, 1178–1182 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  144. Gritton, H. J. et al. Cortical cholinergic signaling controls the detection of cues. Proc. Natl Acad. Sci. USA 113, E1089–E1097 (2016).

    CAS  PubMed  Google Scholar 

  145. Kilgard, M. P. & Merzenich, M. M. Cortical map reorganization enabled by nucleus basalis activity. Science 279, 1714–1718 (1998).

    CAS  PubMed  Google Scholar 

  146. Yu, A. J. & Dayan, P. Acetylcholine in cortical inference. Neural Netw. 15, 719–730 (2002).

    PubMed  Google Scholar 

  147. Iglesias, S. et al. Hierarchical prediction errors in midbrain and basal forebrain during sensory learning. Neuron 80, 519–530 (2013).

    CAS  PubMed  Google Scholar 

  148. Rowntree, D. W., Nevin, S. & Wilson, A. The effects of diisopropylfluorophosphonate in schizophrenia and manic depressive psychosis. J. Neurol. Neurosurg. Psychiatry 13, 47–62 (1950).

    CAS  PubMed  PubMed Central  Google Scholar 

  149. Perry, E. K. & Perry, R. H. Acetylcholine and hallucinations: disease-related compared to drug-induced alterations in human consciousness. Brain Cognit. 28, 240–258 (1995).

    CAS  Google Scholar 

  150. Buchanan, R. W. et al. Galantamine for the treatment of cognitive impairments in people with schizophrenia. Am. J. Psychiatry 165, 82–89 (2008).

    PubMed  Google Scholar 

  151. Keefe, R. S. et al. Efficacy and safety of donepezil in patients with schizophrenia or schizoaffective disorder: significant placebo/practice effects in a 12-week, randomized, double-blind, placebo-controlled trial. Neuropsychopharmacology 33, 1217–1228 (2008).

    CAS  PubMed  Google Scholar 

  152. Aston-Jones, G. & Cohen, J. D. An integrative theory of locus coeruleus–norepinephrine function: adaptive gain and optimal performance. Annu. Rev. Neurosci. 28, 403–450 (2005).

    CAS  PubMed  Google Scholar 

  153. Yu, A. J. & Dayan, P. Uncertainty, neuromodulation, and attention. Neuron 46, 681–692 (2005).

    CAS  PubMed  Google Scholar 

  154. Krishnamurthy, K., Nassar, M. R., Sarode, S. & Gold, J. I. Arousal-related adjustments of perceptual biases optimize perception in dynamic environments. Nat. Hum. Behav. 1, 0107 (2017).

    PubMed  PubMed Central  Google Scholar 

  155. Yates, J. L., Park, I. M., Katz, L. N., Pillow, J. W. & Huk, A. C. Functional dissection of signal and noise in MT and LIP during decision-making. Nat. Neurosci. 20, 1285–1292 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  156. Abi-Dargham, A. et al. Increased striatal dopamine transmission in schizophrenia: confirmation in a second cohort. Am. J. Psychiatry 155, 761–767 (1998).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank T. Maia, S. Haber and K. Schmack for insightful discussions on the ideas presented in this article. The authors acknowledge funding sources: G.H.: R01MH117323, R01MH114965;A.A-D.: R01MH109635.

Peer review information

Nature Reviews Neuroscience thanks P. Corlett, P. Fletcher and the other, anonymous, reviewer(s), for their contribution to the peer review of this work.

Author information

Authors and Affiliations

Authors

Contributions

G.H. researched data for the article, and both authors made substantial contributions to discussion of the content and writing, reviewing and editing the manuscript before submission.

Corresponding authors

Correspondence to Guillermo Horga or Anissa Abi-Dargham.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Glossary

Schizophrenia

A psychiatric illness characterized by a variety of symptoms, including positive symptoms, negative symptoms (for example, apathy and amotivation) and cognitive impairments (for example, memory deficits).

Psychotic disorders

A group of disorders, including schizophrenia and other disorders, such as bipolar disorder, with psychotic features, that present with psychotic or positive symptoms.

Auditory verbal hallucinations

(AVH). Percepts of speech or voices without corresponding speech stimuli.

Positive symptoms

Also known as psychotic symptoms or psychosis; symptoms that are added to the repertoire of usual experiences and that represent a loss of contact with reality (that is, subjective experiences that substantially deviate from what most perceive as objective evidence), including hallucinations and delusions.

Prodromal

Related to the psychosis prodrome or prodromal phase, terms that refer to the phase preceding the development of full-blown symptoms of a psychotic disorder; typically defined by the expression of attenuated forms of positive symptoms.

Marr’s three levels of analysis

A framework whereby information-processing systems can be understood at three distinct, complementary levels: computational (the problem that is solved), algorithmic (what representations and processes are used to solve this problem) and implementational (the physical and biological substrates through which the solution is realized).

Bayesian inference

A statistical algorithm for probabilistic estimation that relies on the optimal combination of prior knowledge and new data.

Inner speech

A person’s inner dialogue, expressed as a silent conscious stream of thoughts in a coherent linguistic form.

Gating

A process by which the passage of information is actively controlled, thereby facilitating or impeding information flow.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Horga, G., Abi-Dargham, A. An integrative framework for perceptual disturbances in psychosis. Nat Rev Neurosci 20, 763–778 (2019). https://doi.org/10.1038/s41583-019-0234-1

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41583-019-0234-1

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing