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Pharmacopsychiatry 2006; 39: 54-64
DOI: 10.1055/s-2006-931496
Original Paper
© Georg Thieme Verlag KG Stuttgart · New York

Using a Speech Perception Neural Network Computer Simulation to Contrast Neuroanatomic versus Neuromodulatory Models of Auditory Hallucinations

R. E. Hoffman1 , T. H. McGlashan1
  • 1Department of Psychiatry, Yale University School of Medicine, Yale-New Haven Psychiatric Hospital, New Haven, USA
Support for research described in this article has been provided by NIMH grants RO1-MH50557 (REH), a Dana Foundation grant (REH) a NARSAD Independent Investigator Award, Peterson 50th Anniversary Research Partner (REH), NMH grants R21MH63326 and R01MH067073 (REH) and KO5-MH01654 (THM). Some portions of this article will appear shortly in a book chapter entitled, ”Using a speech perception neural network simulation to study normal neurodevelopment and auditory hallucinations in schizophrenia,” in Advances in Clinical Cognitive Science: Formal Modeling and Assessment of Processes and Symptoms. (Neufeld, R.W.J., ed), American Psychological Association Publications, Washington, D.C., in press.
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Publication History

Publication Date:
01 March 2006 (online)

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A number of studies suggest that schizophrenia may arise from overzealous pruning of synapses that are an extension of normal developmental pruning during adolescence. Moreover, there has been a long history of studies suggesting that this disorder arises from alterations in the dopaminergic neuromodulatory systems. In order to further assess and compare these two hypotheses, a computer simulation of some aspects of speech perception was developed utilizing a recurrent, backpropagation model of working memory previously reported by Elman [13]. This system was found to produce spontaneous percepts simulating hallucinated speech when the working memory component either was excessively pruned or when neuronal responses were modulated to simulatea hyperdopaminergic system. These hallucinogenic systems also demonstrated disruptions in processing input information when ”phonetic information” was degraded. The perceptual performance of these systems were compared to that of actual hallucinating patients and normal controls while tracking (repeating while simultaneously listening to) speech that was phonetically degraded. We found that the neural network simulation producing the best match to speech tracking performance of human hallucinators was an overpruned system with compensatory hypodopaminergic adjustments. These data suggest that the primary pathophysiology of schizophrenia arises from curtailed connectivity in working memory systems and that dopaminergic alterations reflect secondary compensatory adjustments.

References

  • 1 Aboitz F, Garcia R. The anatomy of language revisited.  Biological Research. 1997;  30 171-83
    PubMedGoogle Scholar
  • 2 Akil M, Edgar C L, Pierri J N, Casali S, Lewis D A. Decreased density of tyrosine hydroxylase-immunoreactive axons in the entorhinal cortex of schizophrenic subjects.  Biological Psychiatry. 2000;  47 361-70
    CrossrefPubMedGoogle Scholar
  • 3 Akil M, Pierri J N, Whitehead R E, Edgar C L, Mohila C, Sampson A R, Lewis D A. Lamina-specific alterations in the dopamine innervation of the prefrontal cortex in schizophrenic subjects.  American Journal of Psychiatry. 1999;  156 1580-9
    PubMedGoogle Scholar
  • 4 Andreasen N C, Flaum M. Schizophrenia: The characteristic symptoms.  Schizophrenia Bulletin. 1991;  17(1) 27-49
    PubMedGoogle Scholar
  • 5 Arnold S E. Cellular and molecular neuropathology of the parahippocampal region in schizophrenia.  Annals of the New York Academy of Sciences.. 2000;  911 275-92
    PubMedGoogle Scholar
  • 6 Blennow K, Bogdanovic N, Gottfries C G, Davidsson P. The growth-associated protein GAP-43 is increased in the hippocampus and in the gyrus cinguli in schizophrenia.  Journal of Molecular Neuroscience. 1999;  13 101-9
    CrossrefPubMedGoogle Scholar
  • 7 Braff D L, Swerdlow N R, Geyer M A. Symptom correlates of prepulse inhibition deficits in male schizophrenic patients.  American Journal of Psychiatry. 1999;  156 596-602
    PubMedGoogle Scholar
  • 8 Buchanan R W, Vladar K, Barta P E, Pearlson G D. Structural evaluation of the prefrontal cortex in schizophrenia.  American Journal of Psychiatry.. 1998;  155 1049-55
    PubMedGoogle Scholar
  • 9 Chaturvedi S, Sinha V D. Recurrence of hallucinations in consecutive episodes of schizophrenia and affective disorder.  Schizophrenia Research. 1990;  3 103-106
    CrossrefPubMedGoogle Scholar
  • 10 Dierks T, Linden D EJ, Jandl M, Formisano E, Goebel R, Lanfermann H, Singer W. Activation of Heschl’s gyrus during auditory hallucinations.  Neuron. 1999;  22 615-621
    CrossrefPubMedGoogle Scholar
  • 11 Eastwood S L, Harrison P J. Decreased synaptophysin in the medial temporal lobe in schizophrenia demonstrated using immunoautoradiography.  Neuroscience. 1999;  69 339-43
    PubMedGoogle Scholar
  • 12 Edelman G M. Neural Darwinism: The Theory of Neural Group Selection. NY; Basic Books 1987
    Google Scholar
  • 13 Elman J L. Finding structure in time.  Cognitive Science. 1990;  14 179-211
    CrossrefPubMedGoogle Scholar
  • 14 Feinberg I. Schizophrenia caused by a fault in programmed synaptic elimination during adolescence?.  Journal of Psychiatric Research. 1982/1983;  17 319-334
    PubMedGoogle Scholar
  • 15 Friston K J, Frith C D. Schizophrenia: a disconnection syndrome?.  Clinical Neuroscience. 1995;  3 89-97
    PubMedGoogle Scholar
  • 16 Frith C D, Done D J. Experiences of alien control in schizophrenia reflect a disorder in the central monitoring of action.  Psychological Medicine. 1989;  19 359-63
    PubMedGoogle Scholar
  • 17 Garey L J, Ong W Y, Patel T S, Kanani M, Davis A, Mortimer A M, Barnes T R, Hirsch S R. Reduced dendritic spine density on cerebral cortical pyramidal neurons in schizophrenia.  Journal of Neurology, Neurosurgery and Psychiatry. 1998;  65 446-53
    PubMedGoogle Scholar
  • 18 Garrett M, Silva R. Auditory hallucinations, source monitoring and the belief that ”voices” are real.  Schizophrenia Bulletin. 2003;  29 445-457
    PubMedGoogle Scholar
  • 19 Glantz L A, Lewis D A. Reduction of synaptophysin immunoreactivity in the prefrontal cortex of subjects with schizophrenia. Regional and diagnostic specificity.  Archives of General Psychiatry. 1997;  54 943-52
    PubMedGoogle Scholar
  • 20 Glantz L A, Lewis D A. Decreased dendritic spine density on prefrontal cortical pyramidal neurons in schizophrenia.  Archives of General Psychiatry. 2000;  57 65-73
    PubMedGoogle Scholar
  • 21 Gold J M, Carpenter C, Randolph C, Goldberg T E, Weinberger D R. Auditory working memory and Wisconsin Card Sorting Test Performance in schizophrenia.  Archives of General Psychiatry. 1997;  54 159-165
    CrossrefPubMedGoogle Scholar
  • 22 Goldman-Rakic P S, Friedman H R. The circuitry of working memory revealed by anatomy and metabolic imaging. in Frontal Lobe Function and Injury. Edited by Leven H, Eisenberg HM New York; Oxford University Press 1991
    Google Scholar
  • 23 Gorelova N, Seamans J K, Yang C R. Mechanisms of dopamine activation of fast-spiking interneurons that exert inhibition in rat prefrontal cortex.  Journal of Neurophysiology. 2002;  88 3150-66
    PubMedGoogle Scholar
  • 24 Gur R E, Cowell P E, Latshaw A, Turetsky B I, Grossman R I, Arnold S E, Bilker W B, Gur R C. Reduced dorsal and orbital prefrontal gray matter volumes in schizophrenia.  Archives of General Psychiatry. 2000;  57 761-8
    CrossrefPubMedGoogle Scholar
  • 25 Gur R E, Turetsky B I, Cowell P E, Finkelman C, Maany V, Grossman R I, Arnold S E, Bilker W B, Gur R C. Temporolimbic volume reductions in schizophrenia. Archives of General Psychiatry.  . 2000;  57 769-75
    PubMedGoogle Scholar
  • 26 Heckers S, Rauch S L, Goff D, Savage C R, Schacter D L, Fischman A J, Alpert N M. Impaired recruitment of the hippocampus during conscious recollection in schizophrenia.  Nature Neuroscience.. 1998;  1 318-23
    CrossrefPubMedGoogle Scholar
  • 27 Hoffman R E, Boutros N N, Hu S, Berman R M, Krystal J H, Charney D S. Transcranial magnetic stimulation and auditory hallucinations in schizophrenia.  Lancet. 2000;  355 1073-5
    CrossrefPubMedGoogle Scholar
  • 28 Hoffman R E, Cavus I. Slow transcranial magnetic stimulation, long-term depotentiation, and brain hyperexcitability disorders.  American Journal of Psychiatry. 2002;  159 1093-1102
    CrossrefPubMedGoogle Scholar
  • 29 Hoffman R E, Dobscha S K. Cortical pruning and the development of schizophrenia: a computer model.  Schizophr Bull. 1989;  15 477-490
    PubMedGoogle Scholar
  • 30 Hoffman R E, Hawkins K A, Gueorguieva R, Boutros N N, Rachid F, Carroll K, Krystal J H. transcranial magnetic stimulation of left temporoparietal cortex and medication-resistant auditory hallucinations.  Archives of General Psychiatry. 2003;  60 49-56
    CrossrefPubMedGoogle Scholar
  • 31 Hoffman R E, Hampson , Wu K, Anderson A, Gore J, Buchanan R J, Varanko M, Constable T, Hawkins K, Sahay N, Krystal J H. Mapping the pathophysiology of auditory hallucinations by combining functional magnetic resonance imaging and trancranial magnetic stimulation. Under review
    Google Scholar
  • 32 Hoffman R E, McGlashan T H. Synaptic elimination, neurodevelopment and the mechanism of hallucinated ‘voices’ in schizophrenia.  American Journal of Psychiatry. 1997;  154 1683-1689
    PubMedGoogle Scholar
  • 33 Hoffman R E, McGlashan T H. Neural network models of schizophrenia.  Neuroscientist. 2001;  7 441-454
    PubMedGoogle Scholar
  • 34 Hoffman R E, Rapaport J, Ameli R, McGlashan T H, Harcherik D, Servan-Schreiber D. A neural network model of hallucinated ‘voices’ and associated speech perception impairments in schizophrenic patients.  Journal of Cognitive Neuroscience. 1995;  7 479-496
    PubMedGoogle Scholar
  • 35 Hoffman R E, Rapaport J, Mazure C, Quinlan D. Schizophrenic patients reporting hallucinated ”voices” demonstrate selective speech perception alterations.  American Journal of Psychiatry. 1999;  56 393-399
    PubMedGoogle Scholar
  • 36 Honer W G, Falkai P, Chen C, Arango V, Mann J J, Dwork A J. Synaptic and plasticity-associated proteins in anterior frontal cortex in severe mental illness.  Neuroscience. 1999;  9 1247-55
    PubMedGoogle Scholar
  • 37 Hubl D, Koenig T, Strik W, Federspiel A, Kreis R, Boesch C, Maier SE, Schroth G, Lovblad K, Dierks T. Pathways that make voices: white matter changes in auditory hallucinations.  Archives of General Psychiatry. 2004;  61 658-68
    Google Scholar
  • 38 Huttenlocher P R. Synaptic density in the human frontal cortex-developmental changes and effects of aging.  Brain Research. 1979;  163 195-205
    CrossrefPubMedGoogle Scholar
  • 39 Huttenlocher P R, Dabholkar A S. Regional differences in synaptogenesis in human cerebral cortex.  Journal of Comparative Neurology. 1997;  387 167-178
    PubMedGoogle Scholar
  • 40 Jonsson E G, Flyckt L, Burgert E, Crocq M A, Forslund K, Mattila-Evenden M, Rylander G, Asberg M, Nimgaonkar V L, Edman G, Bjerkenstedt L, Wiesel F A, Sedvall G C. Dopamine D3 receptor gene Ser9Gly variant and schizophrenia: association study and meta-analysis.  Psychiatric Genetics. 2003;  13 1-12
    CrossrefPubMedGoogle Scholar
  • 41 Kalikow D N, Stevens K N. Development of a test of speech intelligibility in noise using sentence materials with controlled word predictability.  Journal of the Acoustic Society of America. 1977;  5 1337-1351
    PubMedGoogle Scholar
  • 42 Kapur S, Seeman P. Does fast dissociation from the dopamine d(2) receptor explain the action of atypical antipsychotics? A new hypothesis.  American Journal of Psychiatry. 2001;  158 360-9
    Google Scholar
  • 43 Karson C N, Mrak R E, Schluterman K O, Sturner W Q, Sheng J G, Griffin W S. Alterations in synaptic proteins and their encoding mRNAs in prefrontal cortex in schizophrenia: a possible neurochemical basis for ‘hypofrontality’.  Molecular Psychiatry. 1999;  4 39-45
    CrossrefPubMedGoogle Scholar
  • 44 Laakso A, Vilkman H, Alakare B, Haaparanta M, Bergman J, Solin O, Peurasaari J, Rakkolainen V, Syvalahti E, Hietala J. Striatal dopamine transporter binding in neuroleptic-naive patients with schizophrenia studied with positron emission tomography.  American Journal of Psychiatry. 2000;  157 269-71.
    CrossrefPubMedGoogle Scholar
  • 45 Laruelle M. The role of endogenous sensitization in the pathophysiology of schizophrenia: implications from recent brain imaging studies.  Brain Research - Brain Research Reviews. 2000;  31 371-84
    CrossrefPubMedGoogle Scholar
  • 46 Le Cun Y, Denker J S, Solla S A. Optimal brain damage, in Advances in Neural Information Processing Systems. vol 2 Edited by Touretsky DS San Francisco; Morgan Kauffmann 1990: pp 598-605
    Google Scholar
  • 47 Lim K O, Hedehus M, Moseley M, de Crespigny A, Sullivan E V, Pfefferbaum A. Compromised white matter tract integrity in schizophrenia inferred diffusion tensor imaging.  Archives of General Psychiatry. 1999;  56 367-74
    CrossrefPubMedGoogle Scholar
  • 48 Margolis R L, Chuang D -M, Post R M. Programmed cell death: Implications for neuropsychiatric disorders.  Biological Psychiatry. 1995;  35 946-956
    PubMedGoogle Scholar
  • 49 McGlashan T H, Hoffman R E. Schizophrenia as a disorder of developmentally reduced synaptic connectivity.  Archives of General Psychiatry. 2000;  57 637-648
    PubMedGoogle Scholar
  • 50 McGuire P K, Shah G MS, Murray R M. Increased blood flow in Broca’s area during auditory hallucinations in schizophrenia.  Lancet. 1993;  342 703-06
    CrossrefPubMedGoogle Scholar
  • 51 Miikkulainen R. Subsymbolic natural language processing: An integrated model of scripts, lexicon and memory. Cambridge Mass; MIT Press 1993
    Google Scholar
  • 52 Munoz-Cueto A, Garcia-Segura M, Ruiz-Marcos A. Developmental sex differences and effect of ovariectomy on the number of cortical pyramidal cell dendritic spines.  Brain Research. 1990;  515 64-68
    CrossrefPubMedGoogle Scholar
  • 53 Naftolin F, Garcia-Segura L M, Keefe D, Leranth C, Maclusky N J, Brawer J R. Estrogen effects on the synaptology and neural membranes of the rat hypothalamic arcuate nucleus.  Biological Reprodruction. 1990;  42 21-28
    PubMedGoogle Scholar
  • 54 Olney J W, Farber N B. Glutamate receptor dysfunction and schizophrenia.  Archives of General Psychaitry. 1995;  52 998-1007
    PubMedGoogle Scholar
  • 55 Pakkenberg B. Total nerve cell number in neocortex in chronic schizophrenics and controls estimated using optical disectors.  Biological Psychiatry. 1993;  34 768-772
    CrossrefPubMedGoogle Scholar
  • 56 Park S, Holzman P S. Schizophrenics show spatial working memory deficits.  Archives of General Psychiatry. 1992;  49 975-982
    PubMedGoogle Scholar
  • 57 Sartorious N, Shapiro R, Jablonsky A. The international pilot study of schizophrenia.  Schizophrenia Bulletin. 1974;  1 21-35
    PubMedGoogle Scholar
  • 58 Scheich H, Wallhausseer-Franke E, Braun K. Does synaptic selection explain auditory imprinting. In Memory: Organization and locus of change. Edited by LR Squire, NM Weinberger, G Lynch, JL McGaugh New York; Oxford University Press 1991
    Google Scholar
  • 59 Selemon L D, Rajkowski G, Goldman-Rakic P S. Abnormally high neuronal density in schizophrenic cortex: A morphometric analysis of prefrontal area 9 and occipatal cortex area 17.  Archives of General Psychiatry. 1995;  52 805-818
    PubMedGoogle Scholar
  • 60 Selemon L D, Rajkowski G, Goldman-Rakic P S. Abnormally high neuronal density in prefrontal area 46 in brains from schizophrenic patients: Application of 3-dimensional stereologic counting method.  Journal of Comparative Neurology. 1998;  392 402-412
    PubMedGoogle Scholar
  • 61 Shergill S S, Brammer M J, Williams S CR, Murray R M, McGuire P K. Mapping auditory hallucinations in schizophrenia using functional magnetic resonance imaging.  Arch Gen Psychiatry. 2000;  57 1033-1038
    CrossrefPubMedGoogle Scholar
  • 62 Tamminga C A, Vogel M, Gao X, Lahti A C, Holcomb H H. The limbic cortex in schizophrenia: focus on the anterior cingulate.  Brain Research Brain Research Reviews. 2000;  31 364-70
    CrossrefPubMedGoogle Scholar
  • 63 Thierry G, Boulanouar K, Kherif F, Ranjeva J P, Demonet J F. Temporal sorting of neural components underlying phonological processing.  Neuroreport. 1999;  10 2599-603
    PubMedGoogle Scholar
  • 64 Tiihonen J, Hari R, Naukkarinen H, Rimon R, Jousmaki V, Kajoli M. Modified activity of the human auditory cortex during auditory hallucinations.  American Journal of Psychiatry. 1992;  149 255-257
    PubMedGoogle Scholar
  • 65 Velakoulis D, Pantelis C, McGorry P D, Dudgeon P, Brewer W, Cook M, Desmond P, Bridle N, Tierney P, Murrie V, Singh B, Copolov D. Hippocampal volume in first-episode psychoses and chronic schizophrenia: a high-resolution magnetic resonance imaging study.  Archives of General Psychiatry. 1999;  56 133-41
    PubMedGoogle Scholar
  • 66 Wang Y, Goldman-Rakic  S. D2 receptor regulation of synaptic burst firing in prefrontal cortical pyramidal neurons.  Proceedings of the National Academy of Sciences of the United States of America. 2004;  101 5093-8
    CrossrefPubMedGoogle Scholar
  • 67 Warren R M, Warren R P. Auditory illusions and confusions.  Scientific American. 1970;  223 30-36
    PubMedGoogle Scholar
  • 68 Weinberger D R. Implications of normal brain development for the pathogenesis of schizophrenia.  Archives of General Psychiatry. 1987;  44 660-669
    PubMedGoogle Scholar
  • 69 Weinberger D R, Berman K F, Suddath R, Torrey E F. Evidence of dysfunction of a prefrontal-limbic network in schizophrenia: a magnetic resonance imaging and regional cerebral blood flow study of discordant monozygotic twins.  American Journal of Psychiatry. 1992;  149 890-7
    CrossrefPubMedGoogle Scholar
  • 70 Woolley C S, Wenzel H J, Schwartzkroin P A. Estradiol increases the frequency of multiple synapse boutons in the hippocampal CA1 region of the adult female rat.  Journal of Comparative Neurology. 1996;  373 108-117
    PubMedGoogle Scholar
  • 71 Young C E, Arima K, Xie J, Hu L, Beach T G, Falkai P, Honer W G. SNAP-25 deficit and hippocampal connectivity in schizophrenia.  Cerebral Cortex. 1998;  8 261-8
    CrossrefPubMedGoogle Scholar

Prof. Ralph E. Hoffman, M.D.

Department of Psychiatry

Yale University School of Medicine

Yale-New Haven Psychiatric Hospital

184 Liberty Street LV108

New Haven CT 06519

USA

Phone: 203-688-9734

Email: ralph.hoffman@yale.edu

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