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Auditory dysfunction in schizophrenia: integrating clinical and basic features

Key Points

  • Individuals with schizophrenia show deficits in auditory sensory processing that represent a core feature of the disorder.

  • At the behavioural level, patients are impaired in the ability to match tones or to detect the 'musicality' of speech (prosody). Deficits in the ability to correctly detect non-verbal elements of speech (for example, emotion and attitude) contributes greatly to the social disability associated with schizophrenia.

  • Impaired auditory processing also leads to degeneration of phonological reading ability that first becomes manifest during the early stages of the disorder and which contributes to educational and occupational impairment.

  • At the neurophysiological level, deficits are reflected in impaired generation of mismatch negativity and other event-related potentials that are generated primarily within the auditory sensory cortex. These deficits, in turn, are linked to dysfunction in NMDA receptor-mediated neurotransmission.

  • The deficits in auditory processing are mirrored by objective histological changes observed in the post-mortem auditory cortex in schizophrenia. Histological changes show reductions in spine density and alterations in glutamatergic transmission, which is consistent with the pattern of functional impairment.

  • Overall, these findings encourage the use of auditory neurophysiological measures for cross-species aetiological and pharmacological research into schizophrenia.

Abstract

Schizophrenia is a complex neuropsychiatric disorder that is associated with persistent psychosocial disability in affected individuals. Although studies of schizophrenia have traditionally focused on deficits in higher-order processes such as working memory and executive function, there is an increasing realization that, in this disorder, deficits can be found throughout the cortex and are manifest even at the level of early sensory processing. These deficits are highly amenable to translational investigation and represent potential novel targets for clinical intervention. Deficits, moreover, have been linked to specific structural abnormalities in post-mortem auditory cortex tissue from individuals with schizophrenia, providing unique insights into underlying pathophysiological mechanisms.

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Figure 1: Anatomy of the auditory pathway and the auditory cortex.
Figure 2: Tone matching deficits in schizophrenia.
Figure 3: Translational utility of auditory neurophysiological responses.
Figure 4: Contributions of auditory sensory dysfunction to higher-order cognitive impairments.
Figure 5: Impaired delta entrainment during auditory processing in schizophrenia.
Figure 6: Auditory cortical circuitry: neurophysiological and histological findings in schizophrenia.

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References

  1. Insel, T. R. Rethinking schizophrenia. Nature 468, 187–193 (2010). This study illustrates the developmental course of neural changes in schizophrenia.

    Article  CAS  PubMed  Google Scholar 

  2. Javitt, D. C., Spencer, K. M., Thaker, G. K., Winterer, G. & Hajos, M. Neurophysiological biomarkers for drug development in schizophrenia. Nat. Rev. Drug Discov. 7, 68–83 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Javitt, D. C. & Freedman, R. Sensory processing dysfunction in the personal experience and neuronal machinery of schizophrenia. Am. J. Psychiatry 172, 17–31 (2015). This paper describes the clinical implications of auditory and visual sensory processing dysfunction in schizophrenia.

    Article  PubMed  Google Scholar 

  4. Javitt, D. C. Neurophysiological models for new treatment development in schizophrenia: early sensory approaches. Ann. NY Acad. Sci. 1344, 92–104 (2015).

    Article  CAS  PubMed  Google Scholar 

  5. Hu, W., MacDonald, M. L., Elswick, D. E. & Sweet, R. A. The glutamate hypothesis of schizophrenia: evidence from human brain tissue studies. Ann. NY Acad. Sci. 1338, 38–57 (2015).

    Article  CAS  PubMed  Google Scholar 

  6. Javitt, D. C. & Zukin, S. R. Recent advances in the phencyclidine model of schizophrenia. Am. J. Psychiatry 148, 1301–1308 (1991). This paper describes the historical and pharmacological basis of NMDAR models of schizophrenia.

    Article  CAS  PubMed  Google Scholar 

  7. Javitt, D. C. et al. Translating glutamate: from pathophysiology to treatment. Sci. Transl Med. 3, 102mr2 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  8. Sweet, R. A., Dorph-Petersen, K. A. & Lewis, D. A. Mapping auditory core, lateral belt, and parabelt cortices in the human superior temporal gyrus. J. Comp. Neurol. 491, 270–289 (2005).

    Article  PubMed  Google Scholar 

  9. Hill, J. et al. Similar patterns of cortical expansion during human development and evolution. Proc. Natl Acad. Sci. USA 107, 13135–13140 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  10. Javitt, D. C. When doors of perception close: bottom-up models of disrupted cognition in schizophrenia. Annu. Rev. Clin. Psychol. 5, 249–275 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  11. Harrington, I. A., Heffner, R. S. & Heffner, H. E. An investigation of sensory deficits underlying the aphasia-like behavior of macaques with auditory cortex lesions. Neuroreport 12, 1217–1221 (2001).

    Article  CAS  PubMed  Google Scholar 

  12. Talwar, S. K., Musial, P. G. & Gerstein, G. L. Role of mammalian auditory cortex in the perception of elementary sound properties. J. Neurophysiol. 85, 2350–2358 (2001).

    Article  CAS  PubMed  Google Scholar 

  13. Tramo, M. J., Shah, G. D. & Braida, L. D. Functional role of auditory cortex in frequency processing and pitch perception. J. Neurophysiol. 87, 122–139 (2002).

    Article  PubMed  Google Scholar 

  14. Dykstra, A. R., Koh, C. K., Braida, L. D. & Tramo, M. J. Dissociation of detection and discrimination of pure tones following bilateral lesions of auditory cortex. PLoS ONE 7, e44602 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Sanchez, J. T., Ghelani, S. & Otto-Meyer, S. From development to disease: diverse functions of NMDA-type glutamate receptors in the lower auditory pathway. Neuroscience 285, 248–259 (2015).

    Article  CAS  PubMed  Google Scholar 

  16. Tarasenko, M. A., Swerdlow, N. R., Makeig, S., Braff, D. L. & Light, G. A. The auditory brain-stem response to complex sounds: a potential biomarker for guiding treatment of psychosis. Front. Psychiatry 5, 142 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  17. Iversen, S. D. & Mishkin, M. Comparison of superior temporal and inferior prefrontal lesions on auditory and non-auditory tasks in rhesus monkeys. Brain Res. 55, 355–367 (1973).

    Article  CAS  PubMed  Google Scholar 

  18. Heffner, H. E. & Heffner, R. S. Temporal lobe lesions and perception of species-specific vocalizations by macaques. Science 226, 75–76 (1984).

    Article  CAS  PubMed  Google Scholar 

  19. Chao, L. L. & Knight, R. T. Human prefrontal lesions increase distractability to irrelevant sensory inputs. Neuroreport 6, 1605–1610 (1995).

    Article  CAS  PubMed  Google Scholar 

  20. Strous, R. D., Cowan, N., Ritter, W. & Javitt, D. C. Auditory sensory (“echoic”) memory dysfunction in schizophrenia. Am. J. Psychiatry 152, 1517–1519 (1995).

    Article  CAS  PubMed  Google Scholar 

  21. March, L. et al. Normal time course of auditory recognition in schizophrenia, despite impaired precision of the auditory sensory (“echoic”) memory code. J. Abnorm. Psychol. 108, 69–75 (1999).

    Article  CAS  PubMed  Google Scholar 

  22. Gold, R. et al. Auditory emotion recognition impairments in schizophrenia: relationship to acoustic features and cognition. Am. J. Psychiatry 169, 424–432 (2012). This report describes the relationship between sensory processing deficits and disordered social cognition in schizophrenia.

    Article  PubMed  Google Scholar 

  23. Rabinowicz, E. F., Silipo, G., Goldman, R. & Javitt, D. C. Auditory sensory dysfunction in schizophrenia: imprecision or distractibility? Arch. Gen. Psychiatry 57, 1149–1155 (2000).

    Article  CAS  PubMed  Google Scholar 

  24. Javitt, D. C., Strous, R. D., Grochowski, S., Ritter, W. & Cowan, N. Impaired precision, but normal retention, of auditory sensory (“echoic”) memory information in schizophrenia. J. Abnorm. Psychol. 106, 315–324 (1997).

    Article  CAS  PubMed  Google Scholar 

  25. Lakatos, P. et al. An oscillatory hierarchy controlling neuronal excitability and stimulus processing in the auditory cortex. J. Neurophysiol. 94, 1904–1911 (2005).

    Article  PubMed  Google Scholar 

  26. Javitt, D. C. Intracortical mechanisms of mismatch negativity dysfunction in schizophrenia. Audiol. Neurootol. 5, 207–215 (2000).

    Article  CAS  PubMed  Google Scholar 

  27. Rosburg, T. et al. Subdural recordings of the mismatch negativity (MMN) in patients with focal epilepsy. Brain 128, 819–828 (2005).

    Article  PubMed  Google Scholar 

  28. El Karoui, I. et al. Event-related potential, time-frequency, and functional connectivity facets of local and global auditory novelty processing: an intracranial study in humans. Cereb. Cortex http://dx.doi.org/10.1093/cercor/bhu143 (2014).

  29. Javitt, D. C., Steinschneider, M., Schroeder, C. E. & Arezzo, J. C. Role of cortical N-methyl-d-aspartate receptors in auditory sensory memory and mismatch negativity generation: implications for schizophrenia. Proc. Natl Acad. Sci. USA 93, 11962–11967 (1996). This report describes the role of NMDARs in the generation of MMNs in an intracortical study in non-human primates.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Leitman, D. I. et al. Sensory deficits and distributed hierarchical dysfunction in schizophrenia. Am. J. Psychiatry 167, 818–827 (2010).

    Article  PubMed  Google Scholar 

  31. Light, G. A. et al. Characterization of neurophysiologic and neurocognitive biomarkers for use in genomic and clinical outcome studies of schizophrenia. PLoS ONE 7, e39434 (2012). This paper describes the magnitude of neurophysiological deficits relative both to each other and to behavioural (neuropsychological) measures in a large, multicentre cohort of patients with schizophrenia.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Friedman, T., Sehatpour, P., Dias, E., Perrin, M. & Javitt, D. C. Differential relationships of mismatch negativity and visual P1 deficits to premorbid characteristics and functional outcome in schizophrenia. Biol. Psychiatry 71, 521–529 (2012).

    Article  PubMed  Google Scholar 

  33. Todd, J. et al. Deviant matters: duration, frequency, and intensity deviants reveal different patterns of mismatch negativity reduction in early and late schizophrenia. Biol. Psychiatry 63, 58–64 (2008).

    Article  PubMed  Google Scholar 

  34. Hay, R. A. et al. Equivalent mismatch negativity deficits across deviant types in early illness schizophrenia-spectrum patients. Biol. Psychol. 105, 130–137 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  35. Bodatsch, M. et al. Prediction of psychosis by mismatch negativity. Biol. Psychiatry 69, 959–966 (2011).

    Article  PubMed  Google Scholar 

  36. Perez, V. B. et al. Automatic auditory processing deficits in schizophrenia and clinical high-risk patients: forecasting psychosis risk with mismatch negativity. Biol. Psychiatry 75, 459–469 (2014). This paper describes the importance of auditory sensory processing measures for prediction of outcome in individuals with potential early symptoms of schizophrenia.

    Article  PubMed  Google Scholar 

  37. Corcoran, C. M. et al. Emotion recognition deficits as predictors of transition in individuals at clinical high risk for schizophrenia: a neurodevelopmental perspective. Psychol. Med. http://dx.doi.org/10.1017/S0033291715000902 (2015).

  38. Naatanen, R. & Picton, T. The N1 wave of the human electric and magnetic response to sound: a review and an analysis of the component structure. Psychophysiology 24, 375–425 (1987).

    Article  CAS  PubMed  Google Scholar 

  39. Shelley, A. M., Silipo, G. & Javitt, D. C. Diminished responsiveness of ERPs in schizophrenic subjects to changes in auditory stimulation parameters: implications for theories of cortical dysfunction. Schizophr. Res. 37, 65–79 (1999).

    Article  CAS  PubMed  Google Scholar 

  40. Light, G. A. et al. Gamma band oscillations reveal neural network cortical coherence dysfunction in schizophrenia patients. Biol. Psychiatry 60, 1231–1240 (2006).

    Article  PubMed  Google Scholar 

  41. Krishnan, G. P. et al. Steady state and induced auditory gamma deficits in schizophrenia. Neuroimage 47, 1711–1719 (2009).

    Article  CAS  PubMed  Google Scholar 

  42. Gonzalez-Burgos, G. & Lewis, D. A. NMDA receptor hypofunction, parvalbumin-positive neurons, and cortical gamma oscillations in schizophrenia. Schizophr. Bull. 38, 950–957 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  43. Kirli, K. K., Ermentrout, G. B. & Cho, R. Y. Computational study of NMDA conductance and cortical oscillations in schizophrenia. Front. Comput. Neurosci. 8, 133 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  44. Vohs, J. L., Chambers, R. A., O'Donnell, B. F., Krishnan, G. P. & Morzorati, S. L. Auditory steady state responses in a schizophrenia rat model probed by excitatory/inhibitory receptor manipulation. Int. J. Psychophysiol 86, 136–142 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  45. Sivarao, D. V. et al. MK-801 disrupts and nicotine augments 40 Hz auditory steady state responses in the auditory cortex of the urethane-anesthetized rat. Neuropharmacology 73, 1–9 (2013).

    Article  CAS  PubMed  Google Scholar 

  46. Javitt, D. C., Shelley, A. & Ritter, W. Associated deficits in mismatch negativity generation and tone matching in schizophrenia. Clin. Neurophysiol. 111, 1733–1737 (2000).

    Article  CAS  PubMed  Google Scholar 

  47. Lakatos, P., Schroeder, C. E., Leitman, D. I. & Javitt, D. C. Predictive suppression of cortical excitability and its deficit in schizophrenia. J. Neurosci. 33, 11692–11702 (2013). This paper describes neural mechanisms underlying deficits in delta entrainment and predictive gamma modulation in schizophrenia, relative to findings in non-human primates.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Womelsdorf, T., Valiante, T. A., Sahin, N. T., Miller, K. J. & Tiesinga, P. Dynamic circuit motifs underlying rhythmic gain control, gating and integration. Nat. Neurosci. 17, 1031–1039 (2014). This paper describes the relationship between GABA interneuron populations and specific ERSP frequency bands.

    Article  CAS  PubMed  Google Scholar 

  49. Blatow, M. et al. A novel network of multipolar bursting interneurons generates theta frequency oscillations in neocortex. Neuron 38, 805–817 (2003).

    Article  CAS  PubMed  Google Scholar 

  50. Umbricht, D. et al. Ketamine-induced deficits in auditory and visual context-dependent processing in healthy volunteers: implications for models of cognitive deficits in schizophrenia. Arch. Gen. Psychiatry 57, 1139–1147 (2000).

    Article  CAS  PubMed  Google Scholar 

  51. Heekeren, K. et al. Mismatch negativity generation in the human 5HT2A agonist and NMDA antagonist model of psychosis. Psychopharmacology (Berl.) 199, 77–88 (2008).

    Article  CAS  Google Scholar 

  52. Gunduz-Bruce, H. et al. Glutamatergic modulation of auditory information processing in the human brain. Biol. Psychiatry 71, 969–977 (2012).

    Article  CAS  PubMed  Google Scholar 

  53. Schmidt, A. et al. Mismatch negativity encoding of prediction errors predicts S-ketamine-induced cognitive impairments. Neuropsychopharmacology 37, 865–875 (2012).

    Article  CAS  PubMed  Google Scholar 

  54. Knott, V. et al. Nicotine, auditory sensory memory, and sustained attention in a human ketamine model of schizophrenia: moderating influence of a hallucinatory trait. Front. Pharmacol. 3, 172 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Kreitschmann-Andermahr, I. et al. Effect of ketamine on the neuromagnetic mismatch field in healthy humans. Brain Res. Cogn. Brain Res. 12, 109–116 (2001).

    Article  CAS  PubMed  Google Scholar 

  56. Gil-da-Costa, R., Stoner, G. R., Fung, R. & Albright, T. D. Nonhuman primate model of schizophrenia using a noninvasive EEG method. Proc. Natl Acad. Sci. USA 110, 15425–15430 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  57. Ehrlichman, R. S., Maxwell, C. R., Majumdar, S. & Siegel, S. J. Deviance-elicited changes in event-related potentials are attenuated by ketamine in mice. J. Cogn. Neurosci. 20, 1403–1414 (2008).

    Article  PubMed  Google Scholar 

  58. Tikhonravov, D. et al. Effects of an NMDA-receptor antagonist MK-801 on an MMN-like response recorded in anesthetized rats. Brain Res. 1203, 97–102 (2008).

    Article  CAS  PubMed  Google Scholar 

  59. Mathalon, D. H. et al. Effects of nicotine on the neurophysiological and behavioral effects of ketamine in humans. Front. Psychiatry 5, 3 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  60. Oranje, B. et al. The effects of a sub-anaesthetic dose of ketamine on human selective attention. Neuropsychopharmacology 22, 293–302 (2000).

    Article  CAS  PubMed  Google Scholar 

  61. Umbricht, D., Koller, R., Vollenweider, F. X. & Schmid, L. Mismatch negativity predicts psychotic experiences induced by NMDA receptor antagonist in healthy volunteers. Biol. Psychiatry 51, 400–406 (2002).

    Article  CAS  PubMed  Google Scholar 

  62. Umbricht, D. et al. Effects of the 5-HT2A agonist psilocybin on mismatch negativity generation and AX-continuous performance task: implications for the neuropharmacology of cognitive deficits in schizophrenia. Neuropsychopharmacology 28, 170–181 (2003).

    Article  CAS  PubMed  Google Scholar 

  63. Kasai, K. et al. Do high or low doses of anxiolytics and hypnotics affect mismatch negativity in schizophrenic subjects? An EEG and MEG study. Clin. Neurophysiol. 113, 141–150 (2002).

    Article  CAS  PubMed  Google Scholar 

  64. Javitt, D. C., Jayachandra, M., Lindsley, R. W., Specht, C. M. & Schroeder, C. E. Schizophrenia-like deficits in auditory P1 and N1 refractoriness induced by the psychomimetic agent phencyclidine (PCP). Clin. Neurophysiol. 111, 833–836 (2000).

    Article  CAS  PubMed  Google Scholar 

  65. Laroi, F. et al. The characteristic features of auditory verbal hallucinations in clinical and nonclinical groups: state-of-the-art overview and future directions. Schizophr. Bull. 38, 724–733 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  66. Brunoni, A. R. et al. Understanding tDCS effects in schizophrenia: a systematic review of clinical data and an integrated computation modeling analysis. Expert Rev. Med. Devices 11, 383–394 (2014).

    Article  CAS  PubMed  Google Scholar 

  67. Gaser, C., Nenadic, I., Volz, H. P., Buchel, C. & Sauer, H. Neuroanatomy of “hearing voices”: a frontotemporal brain structural abnormality associated with auditory hallucinations in schizophrenia. Cereb. Cortex 14, 91–96 (2004).

    Article  PubMed  Google Scholar 

  68. Modinos, G. et al. Neuroanatomy of auditory verbal hallucinations in schizophrenia: a quantitative meta-analysis of voxel-based morphometry studies. Cortex 49, 1046–1055 (2013).

    Article  PubMed  Google Scholar 

  69. Kompus, K., Westerhausen, R. & Hugdahl, K. The “paradoxical” engagement of the primary auditory cortex in patients with auditory verbal hallucinations: a meta-analysis of functional neuroimaging studies. Neuropsychologia 49, 3361–3369 (2011). A comprehensive review of fMRI studies of AVHs in schizophrenia.

    Article  PubMed  Google Scholar 

  70. Ford, J. M. et al. Tuning in to the voices: a multisite FMRI study of auditory hallucinations. Schizophr. Bull. 35, 58–66 (2009).

    Article  PubMed  Google Scholar 

  71. Schulman, C. A., Richlin, M. & Weinstein, S. Hallucinations and disturbances of affect, cognition, and physical state as a function of sensory deprivation. Percept. Mot. Skills 25, 1001–1024 (1967).

    Article  CAS  PubMed  Google Scholar 

  72. Ford, J. M. et al. Neurophysiological evidence of corollary discharge function during vocalization in psychotic patients and their nonpsychotic first-degree relatives. Schizophr. Bull. 39, 1272–1280 (2013).

    Article  PubMed  Google Scholar 

  73. Fisher, D. J. et al. Effects of auditory hallucinations on the mismatch negativity (MMN) in schizophrenia as measured by a modified 'optimal' multi-feature paradigm. Int. J. Psychophysiol 81, 245–251 (2011).

    Article  PubMed  Google Scholar 

  74. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Perrin, M. A. et al. Spatial localization deficits and auditory cortical dysfunction in schizophrenia. Schizophr. Res. 124, 161–168 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  76. Krystal, J. H. et al. Comparative and interactive human psychopharmacologic effects of ketamine and amphetamine: implications for glutamatergic and dopaminergic model psychoses and cognitive function. Arch. Gen. Psychiatry 62, 985–994 (2005).

    Article  CAS  PubMed  Google Scholar 

  77. Ellison, G. D. & Eison, M. S. Continuous amphetamine intoxication: an animal model of the acute psychotic episode. Psychol. Med. 13, 751–761 (1983).

    Article  CAS  PubMed  Google Scholar 

  78. Nielsen, E. B., Lyon, M. & Ellison, G. Apparent hallucinations in monkeys during around-the-clock amphetamine for seven to fourteen days. Possible relevance to amphetamine psychosis. J. Nerv. Ment. Dis. 171, 222–233 (1983).

    Article  CAS  PubMed  Google Scholar 

  79. Linn, G. S., O'Keeffe, R. T., Schroeder, C. E., Lifshitz, K. & Javitt, D. C. Behavioral effects of chronic phencyclidine in monkeys. Neuroreport 10, 2789–2793 (1999).

    Article  CAS  PubMed  Google Scholar 

  80. Linn, G. S., O'Keeffe, R. T., Lifshitz, K., Schroeder, C. & Javitt, D. C. Behavioral effects of orally administered glycine in socially housed monkeys chronically treated with phencyclidine. Psychopharmacology (Berl.) 192, 27–38 (2007).

    Article  CAS  Google Scholar 

  81. Hoffman, R. E. et al. Probing the pathophysiology of auditory/verbal hallucinations by combining functional magnetic resonance imaging and transcranial magnetic stimulation. Cereb. Cortex 17, 2733–2743 (2007).

    Article  PubMed  Google Scholar 

  82. Brunelin, J. et al. Examining transcranial direct-current stimulation (tDCS) as a treatment for hallucinations in schizophrenia. Am. J. Psychiatry 169, 719–724 (2012).

    Article  PubMed  Google Scholar 

  83. Zhang, Y. et al. Repetitive transcranial magnetic stimulation for hallucination in schizophrenia spectrum disorders: a meta-analysis. Neural Regen. Res. 8, 2666–2676 (2013).

    PubMed  PubMed Central  Google Scholar 

  84. Maiza, O. et al. Impact of repetitive transcranial magnetic stimulation (rTMS) on brain functional marker of auditory hallucinations in schizophrenia patients. Brain Sci. 3, 728–743 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  85. Kindler, J. et al. Reduced neuronal activity in language-related regions after transcranial magnetic stimulation therapy for auditory verbal hallucinations. Biol. Psychiatry 73, 518–524 (2013).

    Article  PubMed  Google Scholar 

  86. Homan, P., Kindler, J., Hauf, M., Hubl, D. & Dierks, T. Cerebral blood flow identifies responders to transcranial magnetic stimulation in auditory verbal hallucinations. Transl Psychiatry 2, e189 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Sommer, I. E. et al. Can fMRI-guidance improve the efficacy of rTMS treatment for auditory verbal hallucinations? Schizophr. Res. 93, 406–408 (2007).

    Article  CAS  PubMed  Google Scholar 

  88. Leitman, D. I. et al. Sensory contributions to impaired prosodic processing in schizophrenia. Biol. Psychiatry 58, 56–61 (2005).

    Article  PubMed  Google Scholar 

  89. Kantrowitz, J. T. et al. Reduction in tonal discriminations predicts receptive emotion processing deficits in schizophrenia and schizoaffective disorder. Schizophr. Bull. 39, 86–93 (2013).

    Article  PubMed  Google Scholar 

  90. Leitman, D. I. et al. The neural substrates of impaired prosodic detection in schizophrenia and its sensorial antecedents. Am. J. Psychiatry 164, 474–482 (2007).

    Article  PubMed  Google Scholar 

  91. Kantrowitz, J. T., Hoptman, M. J., Leitman, D. I., Silipo, G. & Javitt, D. C. The 5% difference: early sensory processing predicts sarcasm perception in schizophrenia and schizo-affective disorder. Psychol. Med. 44, 25–36 (2014).

    Article  CAS  PubMed  Google Scholar 

  92. Yang, L. et al. Schizophrenia, culture and neuropsychology: sensory deficits, language impairments and social functioning in Chinese-speaking schizophrenia patients. Psychol. Med. 42, 1485–1494 (2012).

    Article  CAS  PubMed  Google Scholar 

  93. Revheim, N. et al. Reading deficits in schizophrenia and individuals at high clinical risk: relationship to sensory function, course of illness, and psychosocial outcome. Am. J. Psychiatry 171, 949–959 (2014). This paper describes the contributions of sensory processing deficits to degeneration of reading ability ('acquired dyslexia') in patients with schizophrenia.

    Article  PubMed  PubMed Central  Google Scholar 

  94. Gaebler, A. J. et al. Auditory mismatch impairments are characterized by core neural dysfunctions in schizophrenia. Brain 138, 1410–1423 (2015). This report describes contributions of MMN dysfunction to impaired modulation of network-level function in schizophrenia.

    Article  PubMed  PubMed Central  Google Scholar 

  95. Lakatos, P. et al. The spectrotemporal filter mechanism of auditory selective attention. Neuron 77, 750–761 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Carracedo, L. M. et al. A neocortical delta rhythm facilitates reciprocal interlaminar interactions via nested theta rhythms. J. Neurosci. 33, 10750–10761 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Honea, R. A. et al. Is gray matter volume an intermediate phenotype for schizophrenia? A voxel-based morphometry study of patients with schizophrenia and their healthy siblings. Biol. Psychiatry 63, 465–474 (2008).

    Article  PubMed  Google Scholar 

  98. Hirayasu, Y. et al. Lower left temporal lobe MRI volumes in patients with first-episode schizophrenia compared with psychotic patients with first-episode affective disorder and normal subjects. Am. J. Psychiatry 155, 1384–1391 (1998).

    Article  CAS  PubMed  Google Scholar 

  99. Hirayasu, Y. et al. Planum temporale and Heschl gyrus volume reduction in schizophrenia: a magnetic resonance imaging study of first-episode patients. Arch. Gen. Psychiatry 57, 692–699 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Kasai, K. et al. Progressive decrease of left superior temporal gyrus gray matter volume in patients with first-episode schizophrenia. Am. J. Psychiatry 160, 156–164 (2003).

    Article  PubMed  PubMed Central  Google Scholar 

  101. Rajarethinam, R., Sahni, S., Rosenberg, D. R. & Keshavan, M. S. Reduced superior temporal gyrus volume in young offspring of patients with schizophrenia. Am. J. Psychiatry 161, 1121–1124 (2004).

    Article  PubMed  Google Scholar 

  102. Mathalon, D. H., Pfefferbaum, A., Lim, K. O., Rosenbloom, M. J. & Sullivan, E. V. Compounded brain volume deficits in schizophrenia-alcoholism comorbidity. Arch. Gen. Psychiatry 60, 245–252 (2003).

    Article  PubMed  Google Scholar 

  103. Sullivan, E. V., Mathalon, D. H., Lim, K. O., Marsh, L. & Pfefferbaum, A. Patterns of regional cortical dysmorphology distinguishing schizophrenia and chronic alcoholism. Biol. Psychiatry 43, 118–131 (1998).

    Article  CAS  PubMed  Google Scholar 

  104. Barta, P. E. et al. Planum temporale asymmetry reversal in schizophrenia: replication and relationship to gray matter abnormalities. Am. J. Psychiatry 154, 661–667 (1997).

    Article  CAS  PubMed  Google Scholar 

  105. Salisbury, D. F., Kuroki, N., Kasai, K., Shenton, M. E. & McCarley, R. W. Progressive and interrelated functional and structural evidence of post-onset brain reduction in schizophrenia. Arch. Gen. Psychiatry 64, 521–529 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  106. Takahashi, T. et al. Progressive gray matter reduction of the superior temporal gyrus during transition to psychosis. Arch. Gen. Psychiatry 66, 366–376 (2009).

    Article  PubMed  Google Scholar 

  107. Pantelis, C. et al. Structural brain imaging evidence for multiple pathological processes at different stages of brain development in schizophrenia. Schizophr. Bull. 31, 672–696 (2005).

    Article  PubMed  Google Scholar 

  108. Vogeley, K. et al. Compartmental volumetry of the superior temporal gyrus reveals sex differences in schizophrenia — a post-mortem study. Schizophr. Res. 31, 83–87 (1998).

    Article  CAS  PubMed  Google Scholar 

  109. Falkai, P. et al. Disturbed planum temporale asymmetry in schizophrenia. A quantitative post-mortem study. Schizophr. Res. 14, 161–176 (1995).

    Article  CAS  PubMed  Google Scholar 

  110. Highley, J. R., McDonald, B., Walker, M. A., Esiri, M. M. & Crow, T. J. Schizophrenia and temporal lobe asymmetry. A post-mortem stereological study of tissue volume. Br. J. Psychiatry 175, 127–134 (1999).

    Article  CAS  PubMed  Google Scholar 

  111. Smiley, J. F. et al. Altered volume and hemispheric asymmetry of the superficial cortical layers in the schizophrenia planum temporale. Eur. J. Neurosci. 30, 449–463 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  112. Smiley, J. F. et al. Hemispheric comparisons of neuron density in the planum temporale of schizophrenia and nonpsychiatric brains. Psychiatry Res. 192, 1–11 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  113. Sweet, R. A., Henteleff, R. A., Zhang, W., Sampson, A. R. & Lewis, D. A. Reduced dendritic spine density in auditory cortex of subjects with schizophrenia. Neuropsychopharmacology 34, 374–389 (2009).

    Article  PubMed  Google Scholar 

  114. Moyer, C. E. et al. Intracortical excitatory and thalamocortical boutons are intact in primary auditory cortex in schizophrenia. Schizophr. Res. 149, 127–134 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  115. Fish, K. N., Sweet, R. A. & Lewis, D. A. Differential distribution of proteins regulating GABA synthesis and reuptake in axon boutons of subpopulations of cortical interneurons. Cereb. Cortex 21, 2450–2460 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  116. Rocco, B. R., Sweet, R. A., Lewis, D. A. & Fish, K. N. GABA-synthesizing enzymes in calbindin and calretinin neurons in monkey prefrontal cortex. Cereb. Cortex http://dx.doi.org/10.1093/cercor/bhv051 (2015).

  117. MacDonald, M. L. et al. Altered glutamate protein co-expression network topology linked to spine loss in the auditory cortex of schizophrenia. Biol. Psychiatry 77, 959–968 (2014). This paper describes the role of impaired glutamatergic function in histological changes associated with schizophrenia.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Liu, B. H., Wu, G. K., Arbuckle, R., Tao, H. W. & Zhang, L. I. Defining cortical frequency tuning with recurrent excitatory circuitry. Nat. Neurosci. 10, 1594–1600 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Kaur, S., Rose, H. J., Lazar, R., Liang, K. & Metherate, R. Spectral integration in primary auditory cortex: laminar processing of afferent input, in vivo and in vitro. Neuroscience 134, 1033–1045 (2005).

    Article  CAS  PubMed  Google Scholar 

  120. Chen, X., Leischner, U., Rochefort, N. L., Nelken, I. & Konnerth, A. Functional mapping of single spines in cortical neurons in vivo. Nature 475, 501–505 (2011).

    Article  CAS  PubMed  Google Scholar 

  121. Shelton, M. A. et al. Schizophrenia-associated alterations of microtubule-associated protein 2 in human auditory cortex. Soc. Neurosci. [online], (2013).

  122. Dorph-Petersen, K. A. et al. Pyramidal neuron number in layer 3 of primary auditory cortex of subjects with schizophrenia. Brain Res. 1285, 42–57 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Mateos, J. M. et al. Synaptic modifications at the CA3-CA1 synapse after chronic AMPA receptor blockade in rat hippocampal slices. J. Physiol. 581, 129–138 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Woods, G. F., Oh, W. C., Boudewyn, L. C., Mikula, S. K. & Zito, K. Loss of PSD-95 enrichment is not a prerequisite for spine retraction. J. Neurosci. 31, 12129–12138 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Barksdale, K. A., Roche, J. K., Lahti, A. C. & Roberts, R. C. Synaptic and mitochondrial changes in the postmortem anterior cingulate cortex in schizophrenia. Soc. Neurosci. [online], (2012).

  126. Harnett, M. T., Makara, J. K., Spruston, N., Kath, W. L. & Magee, J. C. Synaptic amplification by dendritic spines enhances input cooperativity. Nature 491, 599–602 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Quinlan, E. M. & Halpain, S. Postsynaptic mechanisms for bidirectional control of MAP2 phosphorylation by glutamate receptors. Neuron 16, 357–368 (1996).

    Article  CAS  PubMed  Google Scholar 

  128. Mirnics, K., Middleton, F. A., Marquez, A., Lewis, D. A. & Levitt, P. Molecular characterization of schizophrenia viewed by microarray analysis of gene expression in prefrontal cortex. Neuron 28, 53–67 (2000).

    Article  CAS  PubMed  Google Scholar 

  129. Mirnics, K., Middleton, F. A., Lewis, D. A. & Levitt, P. Analysis of complex brain disorders with gene expression microarrays: schizophrenia as a disease of the synapse. Trends Neurosci. 24, 479–486 (2001).

    Article  CAS  PubMed  Google Scholar 

  130. Sweet, R. A. et al. Anatomical evidence of impaired feedforward auditory processing in schizophrenia. Biol. Psychiatry 61, 854–864 (2007).

    Article  PubMed  Google Scholar 

  131. Navone, F. et al. Protein p38: an integral membrane protein specific for small vesicles of neurons and neuroendocrine cells. J. Cell Biol. 103, 2511–2527 (1986).

    Article  CAS  PubMed  Google Scholar 

  132. Kwon, S. E. & Chapman, E. R. Synaptophysin regulates the kinetics of synaptic vesicle endocytosis in central neurons. Neuron 70, 847–854 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Gitler, D. et al. Different presynaptic roles of synapsins at excitatory and inhibitory synapses. J. Neurosci. 24, 11368–11380 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Cheng, H. W. et al. Differential spine loss and regrowth of striatal neurons following multiple forms of deafferentation: a Golgi study. Exp. Neurol. 147, 287–298 (1997).

    Article  CAS  PubMed  Google Scholar 

  135. McKinney, R. A., Capogna, M., Durr, R., Gahwiler, B. H. & Thompson, S. M. Miniature synaptic events maintain dendritic spines via AMPA receptor activation. Nat. Neurosci. 2, 44–49 (1999).

    Article  CAS  PubMed  Google Scholar 

  136. Sa, S. I., Pereira, P. A., Paula-Barbosa, M. M. & Madeira, M. D. Role of neural afferents as mediators of estrogen effects on the hypothalamic ventromedial nucleus. Brain Res. 1366, 60–70 (2010).

    Article  CAS  PubMed  Google Scholar 

  137. Matthews, D. A., Cotman, C. & Lynch, G. An electron microscopic study of lesion-induced synaptogenesis in the dentate gyrus of the adult rat. II. Reappearance of morphologically normal synaptic contacts. Brain Res. 115, 23–41 (1976).

    Article  CAS  PubMed  Google Scholar 

  138. Balu, D. T., Basu, A. C., Corradi, J. P., Cacace, A. M. & Coyle, J. T. The NMDA receptor co-agonists, D-serine and glycine, regulate neuronal dendritic architecture in the somatosensory cortex. Neurobiol. Dis. 45, 671–682 (2012).

    Article  CAS  PubMed  Google Scholar 

  139. Gonzalez-Burgos, G. & Lewis, D. A. GABA neurons and the mechanisms of network oscillations: implications for understanding cortical dysfunction in schizophrenia. Schizophr. Bull. 34, 944–961 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  140. Sohal, V. S., Zhang, F., Yizhar, O. & Deisseroth, K. Parvalbumin neurons and gamma rhythms enhance cortical circuit performance. Nature 459, 698–702 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Moyer, C. E. et al. Reduced glutamate decarboxylase 65 protein within primary auditory cortex inhibitory boutons in schizophrenia. Biol. Psychiatry 72, 734–743 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Behrens, M. M. & Sejnowski, T. J. Does schizophrenia arise from oxidative dysregulation of parvalbumin-interneurons in the developing cortex? Neuropharmacology 57, 193–200 (2009). This paper describes the potential role of NMDAR dysfunction in the pathogenesis of GABAergic pathology and PV downregulation in schizophrenia.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Belforte, J. E. et al. Postnatal NMDA receptor ablation in corticolimbic interneurons confers schizophrenia-like phenotypes. Nat. Neurosci. 13, 76–83 (2010).

    Article  CAS  PubMed  Google Scholar 

  144. Javitt, D. C. Sensory processing in schizophrenia: neither simple nor intact. Schizophr. Bull. 35, 1059–1064 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  145. Javitt, D. C., Liederman, E., Cienfuegos, A. & Shelley, A. M. Panmodal processing imprecision as a basis for dysfunction of transient memory storage systems in schizophrenia. Schizophr. Bull. 25, 763–775 (1999).

    Article  CAS  PubMed  Google Scholar 

  146. Martinez, A. et al. Magnocellular pathway impairment in schizophrenia: evidence from functional magnetic resonance imaging. J. Neurosci. 28, 7492–7500 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Dorph-Petersen, K. A., Pierri, J. N., Wu, Q., Sampson, A. R. & Lewis, D. A. Primary visual cortex volume and total neuron number are reduced in schizophrenia. J. Comp. Neurol. 501, 290–301 (2007).

    Article  PubMed  Google Scholar 

  148. Butler, P. D. et al. Early-stage visual processing and cortical amplification deficits in schizophrenia. Arch. Gen. Psychiatry 62, 495–504 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  149. Kern, R. S. et al. The MCCB impairment profile for schizophrenia outpatients: results from the MATRICS psychometric and standardization study. Schizophr. Res. 126, 124–131 (2011).

    Article  PubMed  Google Scholar 

  150. Delay, J., Deniker, P. & Harl, J. M. Utilisation en thérapeutique d'une phénothiazine d'action centrale selective. Ann. Médico-Psychol. 110, 112–117 (in French) (1952).

    CAS  Google Scholar 

  151. Seeman, P. & Lee, T. Antipsychotic drugs: direct correlation between clinical potency and presynaptic action on dopamine neurons. Science 188, 1217–1219 (1975).

    Article  CAS  PubMed  Google Scholar 

  152. Carlsson, A. Basic actions of psychoactive drugs. Int. J. Neurol. 6, 27–45 (1967).

    CAS  PubMed  Google Scholar 

  153. Howes, O. D. & Kapur, S. The dopamine hypothesis of schizophrenia: version III — the final common pathway. Schizophr. Bull. 35, 549–562 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  154. Miyamoto, S., Miyake, N., Jarskog, L. F., Fleischhacker, W. W. & Lieberman, J. A. Pharmacological treatment of schizophrenia: a critical review of the pharmacology and clinical effects of current and future therapeutic agents. Mol. Psychiatry 17, 1206–1227 (2012).

    Article  CAS  PubMed  Google Scholar 

  155. Krystal, J. H. et al. Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch. Gen. Psychiatry 51, 199–214 (1994).

    Article  CAS  PubMed  Google Scholar 

  156. Moghaddam, B. & Krystal, J. H. Capturing the angel in “angel dust”: twenty years of translational neuroscience studies of NMDA receptor antagonists in animals and humans. Schizophr. Bull. 38, 942–949 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  157. Kantrowitz, J. & Javitt, D. C. Glutamatergic transmission in schizophrenia: from basic research to clinical practice. Curr. Opin. Psychiatry 25, 96–102 (2012).

    PubMed  PubMed Central  Google Scholar 

  158. Kantrowitz, J. T. et al. D-serine for the treatment of negative symptoms in individuals at clinical high risk of schizophrenia: a pilot, double-blind, placebo-controlled, randomised parallel group mechanistic proof-of-concept trial. Lancet Psychiatry 2, 403–412 (2015).

    Article  PubMed  Google Scholar 

  159. Goff, D. C. Drug development in schizophrenia: are glutamatergic targets still worth aiming at? Curr. Opin. Psychiatry 28, 207–215 (2015).

    Article  PubMed  Google Scholar 

  160. Buchanan, R. W. et al. A randomized clinical trial of MK-0777 for the treatment of cognitive impairments in people with schizophrenia. Biol. Psychiatry 69, 442–449 (2011).

    Article  CAS  PubMed  Google Scholar 

  161. Sanchez-Blazquez, P., Rodriguez-Munoz, M. & Garzon, J. The cannabinoid receptor 1 associates with NMDA receptors to produce glutamatergic hypofunction: implications in psychosis and schizophrenia. Front. Pharmacol. 4, 169 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Gouzoulis-Mayfrank, E. et al. Psychological effects of S-ketamine and N,N-dimethyltryptamine (DMT): a double-blind, cross-over study in healthy volunteers. Pharmacopsychiatry 38, 301–311 (2005).

    Article  CAS  PubMed  Google Scholar 

  163. Schizophrenia Working Group of the Psychiatric Genomics Consortium Biological insights from 108 schizophrenia-associated genetic loci. Nature 511, 421–427 (2014).

  164. Dalmau, J., Lancaster, E., Martinez-Hernandez, E., Rosenfeld, M. R. & Balice-Gordon, R. Clinical experience and laboratory investigations in patients with anti-NMDAR encephalitis. Lancet Neurol. 10, 63–74 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Chao, L. L. & Knight, R. T. Contribution of human prefrontal cortex to delay performance. J. Cogn. Neurosci. 10, 167–177 (1998).

    Article  CAS  PubMed  Google Scholar 

  166. Javitt, D. C., Steinschneider, M., Schroeder, C. E., Vaughan, H. G. Jr & Arezzo, J. C. Detection of stimulus deviance within primate primary auditory cortex: intracortical mechanisms of mismatch negativity (MMN) generation. Brain Res. 667, 192–200 (1994).

    Article  CAS  PubMed  Google Scholar 

  167. Carrión, R. E. et al. Contributions of early cortical processing and reading ability to functional status in individuals at clinical high risk for psychosis. Schizophr. Res. 164, 1–7 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

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Correspondence to Daniel C. Javitt.

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Competing interests

D.C. J. has acted as a consultant for Forum and Takeda, has received a grant from Roche and has been part of an advisory board for Promentis and NeuroRx. He also holds stock in Glytech and NeuroRx and has patents for D-serine in the treatment of schizophrenia and d-cycloserine in the treatment of depression. R.A.S. declares no competing interests.

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Glossary

Event-related potential

(ERP). An alteration in ongoing electroencephalographic activity that is elicited by specific sensory, motor or cognitive events, and is measured as a function of mean amplitude over time ('time domain' response).

Event-related spectral perturbation

(ERSP). An alteration in ongoing electroencephalographic activity that is elicited by specific sensory, motor or cognitive events, and is measured as a function of mean alteration in spectral amplitude and inter-trial coherence over time ('frequency domain' response).

Tone matching

The ability to compare the physical properties between successively presented stimuli. It is disrupted by auditory cortical lesions in both humans and non-human primates.

Mismatch negativity

(MMN). A component of an event-related potential that reflects NMDA receptor-mediated information processing within the auditory sensory cortex, permitting its use as a translational biomarker of NMDA receptor dysfunction in schizophrenia research.

Gating

The reduction in the amplitude of the response to a second stimulus compared with amplitude to the first stimulus in a paired auditory stimulus.

Antipsychotics

Medications typically used in the treatment of schizophrenia that primarily act through dopamine D2- and 5-hydroxytryptamine 2A-type receptors.

Ketamine

A well-studied non-competitive NMDA receptor antagonist that induces transient schizophrenia-like symptoms in healthy human volunteers and schizophrenia-like event-related potential abnormalities in non-human primates.

Prosody

The 'musicality' of speech, which is used to convey non-verbal information such as emotion or attitude.

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Javitt, D., Sweet, R. Auditory dysfunction in schizophrenia: integrating clinical and basic features. Nat Rev Neurosci 16, 535–550 (2015). https://doi.org/10.1038/nrn4002

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