Journal of Computational Neuroscience

, Volume 43, Issue 3, pp 173–187 | Cite as

Disrupted cholinergic modulation can underlie abnormal gamma rhythms in schizophrenia and auditory hallucination

  • Jung Hoon Lee


The pathophysiology of auditory hallucination, a common symptom of schizophrenia, has yet been understood, but during auditory hallucination, primary auditory cortex (A1) shows paradoxical responses. When auditory stimuli are absent, A1 becomes hyperactive, while A1 responses to auditory stimuli are reduced. Such activation pattern of A1 responses during auditory hallucination is consistent with aberrant gamma rhythms in schizophrenia observed during auditory tasks, raising the possibility that the pathology underlying abnormal gamma rhythms can account for auditory hallucination. Moreover, A1 receives top-down signals in the gamma frequency band from an adjacent association area (Par2), and cholinergic modulation regulates interactions between A1 and Par2. In this study, we utilized a computational model of A1 to ask if disrupted cholinergic modulation could underlie abnormal gamma rhythms in schizophrenia. Furthermore, based on our simulation results, we propose potential pathology by which A1 can directly contribute to auditory hallucination.


Abnormal gamma rhythms, cholinergic modulation Computational models Schizophrenia Inhibitory cell types 


Compliance with ethical standards

Conflict of interest

The author declares that he has no conflict of interest.


  1. Alherz, F., Alherz, M., & Almusawi, H. (2017). NMDAR hypofunction and somatostatin-expressing GABAergic interneurons and receptors: a newly identified correlation and its effects in schizophrenia. Schizophrenia Research: Cognition, 8, 1–6. Scholar
  2. Allen, P., Modinos, G., Hubl, D., Shields, G., Cachia, A., Jardri, R., et al. (2012). Neuroimaging auditory hallucinations in schizophrenia: from neuroanatomy to neurochemistry and beyond. Schizophrenia Bulletin, 38(4), 695–703. Scholar
  3. Arnal, L. H., Wyart, V., & Giraud, A.-L. (2011). Transitions in neural oscillations reflect prediction errors generated in audiovisual speech. Nature Neuroscience, 14(6), 797–801. Scholar
  4. Battaglia, D., & Hansel, D. (2011). Synchronous chaos and broad band gamma rhythm in a minimal multi-layer model of primary visual cortex. PLoS Computational Biology, 7(10).
  5. Battaglia, D., Brunel, N., & Hansel, D. (2007). Temporal decorrelation of collective oscillations in neural networks with local inhibition and long-range excitation. Physical Review Letters, 99(23), 1–4. Scholar
  6. Cachia, A., Amad, A., Brunelin, J., Krebs, M.-O., Plaze, M., Thomas, P., & Jardri, R. (2015). Deviations in cortex sulcation associated with visual hallucinations in schizophrenia. Molecular Psychiatry, 20(9), 1101–1107. Scholar
  7. Chen, N., Sugihara, H., & Sur, M. (2015). An acetylcholine-activated microcircuit drives temporal dynamics of cortical activity. Nature Neuroscience, 18(6), 892–902. Scholar
  8. Couey, J. J., Meredith, R. M., Spijker, S., Poorthuis, R. B., Smit, A. B., Brussaard, A. B., & Mansvelder, H. D. (2007). Distributed network actions by nicotine increase the threshold for spike-timing-dependent plasticity in prefrontal cortex. Neuron, 54(1), 73–87. Scholar
  9. Curcic-Blake, B., Ford, J. M., Hubl, D., Orlov, N. D., Sommer, I. E., Waters, F., et al. (2017). Interaction of language, auditory and memory brain networks in auditory verbal hallucinations c, 148, 1–20.
  10. Destexhe, A., & Bedard, C. (2013). Local field potential. Scholarpedia, 8(8), 10183.CrossRefGoogle Scholar
  11. Dierks, T., Linden, D. E., Jandl, M., Formisano, E., Goebel, R., Lanfermann, H., & Singer, W. (1999). Activation of Heschl’s gyrus during auditory hallucinations. Neuron, 22(3), 615–621. Scholar
  12. Douglas, R. J., & Martin, K. A. (2004). Neuronal circuits of the neocortex. Annual Review of Neuroscience, 27, 419–451. Scholar
  13. Felleman, D. J., & Van Essen, D. C. (1991). Distributed hierarchical processing in the primate cerebral cortex. Cerebral cortex (New York, N.Y. : 1991), 1(1), 1–47 Scholar
  14. Flynn, G., Alexander, D., Harris, A., Whitford, T., Wong, W., Galletly, C., et al. (2008). Increased absolute magnitude of gamma synchrony in first-episode psychosis. Schizophrenia Research, 105(1–3), 262–271. Scholar
  15. Ford, J. M., & Mathalon, D. H. (2005). Corollary discharge dysfunction in schizophrenia: Can it explain auditory hallucinations? International Journal of Psychophysiology, 58(2–3 SPEC. ISS), 179–189. Scholar
  16. Fries, P. (2005). A mechanism for cognitive dynamics: neuronal communication through neuronal coherence. Trends in Cognitive Sciences, 9(10), 474–480. Scholar
  17. Fritz, J. B., David, S. V., Fritz, J. B., Elhilali, M., David, S. V., & Shamma, S. A. (2007). Auditory attention – Focusing the searchlight on sound auditory attention — focusing the searchlight on sound. Current Opinion in Neurobiology, 17, 1–19. Scholar
  18. Gewaltig, M.-O., & Diesmann, M. (2007). NEST (NEural simulation tool). Scholarpedia, 2(4), 1430.CrossRefGoogle Scholar
  19. Gibson, J. R., Beierlein, M., & Connors, B. W. (1999). Two networks of electrically coupled inhibitory neurons in neocortex. Nature, 402(6757), 75–79. Scholar
  20. Giraud, A.-L., & Poeppel, D. (2012). Cortical oscillations and speech processing: emerging computational principles and operations. Nature Neuroscience, 15(4), 511–517. Scholar
  21. Gulledge, A. T., Park, S. B., Kawaguchi, Y., & Stuart, G. J. (2007). Heterogeneity of phasic cholinergic signaling in neocortical neurons. 2215–2229.
  22. Hill, S., & Tononi, G. (2005). Modeling sleep and wakefulness in the thalamocortical system. Journal of Neurophysiology, 93(3), 1671–1698. Scholar
  23. Hirano, Y., Oribe, N., Kanba, S., Onitsuka, T., Nestor, P. G., & Spencer, K. M. (2015). Spontaneous gamma activity in schizophrenia. JAMA Psychiatry, 72(8), 813–821. Scholar
  24. Jadi, M. P., Margarita Behrens, M., & Sejnowski, T. J. (2015). Abnormal gamma oscillations in N-methyl-D-aspartate receptor Hypofunction models of schizophrenia. Biological Psychiatry, 79(9), 716–726. Scholar
  25. Jardri, R., Thomas, P., Delmaire, C., Delion, P., & Pins, D. (2013). The neurodynamic organization of modality-dependent hallucinations. Cerebral Cortex, 23(5), 1108–1117. Scholar
  26. Jardri, R., Hugdahl, K., Hughes, M., Brunelin, J., Waters, F., Alderson-Day, B., et al. (2016). Are hallucinations due to an imbalance between excitatory and inhibitory influences on the brain? Schizophrenia Bulletin, 42(5), 1124–1134. Scholar
  27. Jiang, X., Shen, S., Cadwell, C. R., Berens, P., Sinz, F., Ecker, A. S., et al. (2015). Principles of connectivity among morphologically defined cell types in adult neocortex. Science, 350(6264), aac9462–aac9462. Scholar
  28. Kawaguchi, Y., & Kubota, Y. (1997). GABAergic cell subtypes and their synaptic connections in rat frontal cortex. Cerebral cortex (New York, N.Y. : 1991), 7(6), 476–486 Scholar
  29. Kompus, K., Westerhausen, R., & Hugdah, I. K. (2011). The “paradoxical” engagement of the primary auditory cortex in patients with auditory verbal hallucinations: a meta-analysis of functional neuroimaging studies. Neuropsychologia, 49(12), 3361–3369.CrossRefPubMedGoogle Scholar
  30. Kompus, K., Falkenberg, L. E., Bless, J. J., Johnsen, E., & Kroken, R. A. (2013). The role of the primary auditory cortex in the neural mechanism of auditory verbal hallucinations, 7(April), 1–13.
  31. Kwon, J. S., O’Donnell, B. F., Wallenstein, G. V., Greene, R. W., Hirayasu, Y., Nestor, P. G., et al. (1999). Gamma frequency–range abnormalities to auditory stimulation in schizophrenia. Archives of General Psychiatry, 56(11), 1001. Scholar
  32. Lakatos, P., Shah, A. S., Knuth, K. H., Ulbert, I., Karmos, G., & Schroeder, C. E. (2005). An oscillatory hierarchy controlling neuronal excitability and stimulus processing in the auditory cortex. Journal of Neurophysiology, 94(3), 1904–1911. Scholar
  33. Lakatos, P., Chen, C. M., O’Connell, M. N., Mills, A., & Schroeder, C. E. (2007). Neuronal oscillations and multisensory interaction in primary auditory cortex. Neuron, 53(2), 279–292. Scholar
  34. Lakatos, P., O’Connell, M. N., Barczak, A., Mills, A., Javitt, D. C., & Schroeder, C. E. (2010). The leading sense: supramodal control of neurophysiological context by attention. Neuron, 42(2), 157–162.
  35. Lee, J. H., Whittington, M. A., & Kopell, N. J. (2015). Potential mechanisms underlying intercortical signal regulation via cholinergic neuromodulators. Journal of Neuroscience, 35(45), 15000–15014. Scholar
  36. Lewis, D. A., Hashimoto, T., & Volk, D. W. (2005). Cortical inhibitory neurons and schizophrenia. Nature Reviews. Neuroscience, 6(4), 312–324. Scholar
  37. Lisman, J. (2012). Excitation, inhibition, local oscillations, or large-scale loops: what causes the symptoms of schizophrenia? Current Opinion in Neurobiology, 22(3), 537–544.
  38. Markov, N. T., & Kennedy, H. (2013). The importance of being hierarchical. Current Opinion in Neurobiology, 23(2), 187–194. Scholar
  39. Mazzoni, A., Panzeri, S., Logothetis, N. K., & Brunel, N. (2008). Encoding of naturalistic stimuli by local field potential spectra in networks of excitatory and inhibitory neurons. PLoS Computational Biology, 4(12), e1000239. Scholar
  40. Mitchell, J. F., Sundberg, K. A., & Reynolds, J. H. (2007). Differential attention-dependent response modulation across cell classes in macaque visual area V4. Neuron, 55(1), 131–141. Scholar
  41. Mondino, M., Jardri, R., Suaud-Chagny, M.-F., Saoud, M., Poulet, E., & Brunelin, J. (2016). Effects of Fronto-temporal transcranial direct current stimulation on auditory verbal hallucinations and resting-state functional connectivity of the left temporo-parietal junction in patients with schizophrenia. Schizophrenia Bulletin, 42(2), 318–326. Scholar
  42. Mulert, C., Kirsch, V., Pascual-marqui, R., Mccarley, R. W., & Spencer, J. (2011). Long-range synchrony of gamma oscillations and auditory hallucination symptoms in schizophrenia. International Journal of Psychophysiology, 79(1), 55–63.
  43. Mulert, C., Kirsch, V., Whitford, T. J., Alvarado, J., Pelavin, P., McCarley, R. W., et al. (2012). Hearing voices: a role of interhemispheric auditory connectivity? World Journal of Biological Psychiatry, 13(2), 153–158. Scholar
  44. Palaniyappan, L., Simmonite, M., White, T. P., Liddle, E. B., & Liddle, P. F. (2013). Neural primacy of the salience processing system in schizophrenia. Neuron, 79(4), 814–828. Scholar
  45. Pfeffer, C. K., Xue, M., He, M., Huang, Z. J., & Scanziani, M. (2013). Inhibition of inhibition in visual cortex: the logic of connections between molecularly distinct interneurons. Nature Neuroscience, 16(8), 1068–1076. Scholar
  46. Pittman-Polletta, B. R., Kocsis, B., Vijayan, S., Whittington, M. A., & Kopell, N. J. (2015). Brain rhythms connect impaired inhibition to altered cognition in schizophrenia. Biological Psychiatry, 77(12), 1020–1030. Scholar
  47. Powers III, A. R., Kelley, M., & Corlett, P. R. (2016). Review hallucinations as top-down effects on perception. Biological Psychiatry: Cognitive Neuroscience and Neuroimaging, 1(5), 393–400. Scholar
  48. Powers, A. R., Mathys, C., & Corlett, P. R. (2017). Pavlovian conditioning–induced hallucinations result from overweighting of perceptual priors. Science, 357(August), 596–600. Scholar
  49. Roopun, A. K., Lebeau, F. E. N., Ramell, J., Cunningham, M. O., Traub, R. D., & Whittington, M. A. (2010). Cholinergic neuromodulation controls directed temporal communication in neocortex in vitro. Frontiers in Neural Circuits, 4(March), 8. Scholar
  50. Ross, R. G., Hunter, S. K., McCarthy, L., Beuler, J., Hutchison, A. K., Wagner, B. D., et al. (2013). Perinatal choline effects on neonatal pathophysiology related to later schizophrenia riskic access. The American Journal of Psychiatry, 170(3), 290–298. Scholar
  51. Rudy, B., Fishell, G., Lee, S., & Hjerling-Leffler, J. (2011). Three groups of interneurons account for nearly 100% of neocortical GABAergic neurons. Developmental Neurobiology, 71(1), 45–61. Scholar
  52. Sarter, M., Parikh, V., & Howe, W. M. (2009). Phasic acetylcholine release and the volume transmission hypothesis: time to move on. Nature Reviews. Neuroscience, 10(5), 383–390. Scholar
  53. Schneider, D., Nelson, A., & Moony, R. (2014). A synaptic and circuit basis for corollary discharge in the auditory cortex. Nature, 513, 189–194.CrossRefPubMedPubMedCentralGoogle Scholar
  54. Shergill, S. S., Brammer, M. J., Williams, S. C., Murray, R. M., & Mcguire, P. K. (2000). Mapping auditory hallucinations in schizophrenia using functional magnetic resonance imaging. Archives of General Psychiatry, 57(11), 1033–1038.CrossRefPubMedGoogle Scholar
  55. Sommer, I. E. C., Diederen, K. M. J., Blom, J. D., Willems, A., Kushan, L., Slotema, K., et al. (2008). Auditory verbal hallucinations predominantly activate the right inferior frontal area. Brain, 131(12), 3169–3177. Scholar
  56. Spencer, K. M. (2009). The functional consequences of cortical circuit abnormalities on gamma oscillations in schizophrenia: insights from computational modeling. Frontiers in Human Neuroscience, 3(October), 33. Scholar
  57. Spencer, K. M. (2011). Baseline gamma power during auditory steady-state stimulation in schizophrenia. Frontiers in Human Neuroscience, 5(January), 190. Scholar
  58. Spencer, K. M., Niznikiewicz, M. a., Nestor, P. G., Shenton, M. E., & McCarley, R. W. (2009a). Left auditory cortex gamma synchronization and auditory hallucination symptoms in schizophrenia. BMC Neuroscience, 10, 85. Scholar
  59. Spencer, K. M., Salisbury, D. F., Shenton, M. E., & Mccarley, R. W. (2009b). Gamma-band auditory steady-state responses are impared in first episode. Psychosis, 64(5), 369–375.
  60. Traub, R. D., Contreras, D., Cunningham, M. O., Murray, H., LeBeau, F. E. N., Roopun, A., et al. (2005). Single-column thalamocortical network model exhibiting gamma oscillations, sleep spindles, and epileptogenic bursts. Journal of Neurophysiology, 93(4), 2194–2232. Scholar
  61. Tsunada, J., Baker, A. E., Christison-Lagay, K. L., Davis, S. J., & Cohen, Y. E. (2011). Modulation of cross-frequency coupling by novel and repeated stimuli in the primate ventrolateral prefrontal cortex. Frontiers in Psychology, 2(SEP), 1–14. Scholar
  62. Urban-Ciecko, J., & Barth, A. L. (2016). Somatostatin-expressing neurons in cortical networks. Nature Reviews. Neuroscience, 17(7), 401–409. Scholar
  63. Van De Ven, V. G., Formisano, E., Röder, C. H., Prvulovic, D., Bittner, R. A., Dietz, M. G., et al. (2005). The spatiotemporal pattern of auditory cortical responses during verbal hallucinations. NeuroImage, 27(3), 644–655. Scholar
  64. Vercammen, A., Knegtering, H., Liemburg, E. J., Boer, J. A. d., & Aleman, A. (2010). Functional connectivity of the temporo-parietal region in schizophrenia: effects of rTMS treatment of auditory hallucinations. Journal of Psychiatric Research, 44(11), 725–731. Scholar
  65. Vierling-Claassen, D., Siekmeier, P., Stufflebeam, S., & Kopell, N. (2008). Modeling GABA alterations in schizophrenia: a link between impaired inhibition and altered gamma and beta range auditory entrainment. Journal of Neurophysiology, 99, 2656–2671. Scholar
  66. Wang, X. (2003). Cortical processing of temporal modulations. Speech Communication, 41(1), 107–121. Scholar
  67. Waters, F. A., Badcock, J. C., Michie, P. T., & Maybery, M. T. (2006). Auditory hallucinations in schizophrenia: intrusive thoughts and forgotten memories. Cognitive Neuropsychiatry, 11, 65–83.CrossRefPubMedGoogle Scholar
  68. Waters, F., Allen, P., Aleman, A., Fernyhough, C., Woodward, T. S., Badcock, J. C., et al. (2012). Auditory hallucinations in schizophrenia and nonschizophrenia populations: a review and integrated model of cognitive mechanisms. Schizophrenia Bulletin, 38(4), 683–692. Scholar
  69. Whittington, M. A., Traub, R. D., Kopell, N., Ermentrout, B., & Buhl, E. H. (2000). Inhibition-based rhythms: experimental and mathematical observations on network dynamics. International journal of psychophysiology : official journal of the International Organization of Psychophysiology, 38(3), 315–336 Scholar
  70. Xiang, Z., Huguenard, J. R., & Prince, D. A. (1998). Cholinergic switching within neocortical inhibitory networks. Science, 281(5379), 985–988. Scholar
  71. Zhang, S., Xu, M., Kamigaki, T., Hoang Do, J. P., Chang, W.-C., Jenvay, S., et al. (2014). Long-range and local circuits for top-down modulation of visual cortex processing. Science, 345(6197), 660–665. Scholar

Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  1. 1.Allen Institute for Brain ScienceSeattleUSA

Personalised recommendations