Skip to main content
SpringerLink
Log in

Not on speaking terms: hallucinations and structural network disconnectivity in schizophrenia

  • Original Article
  • Published:
Brain Structure and Function Aims and scope Submit manuscript

Abstract

Auditory verbal hallucinations (AVH) in schizophrenia have previously been associated with functional deficiencies in language networks, specifically with functional disconnectivity in fronto-temporal connections in the left hemisphere and in interhemispheric connections between frontal regions. Here, we investigate whether AVH are accompanied by white matter abnormalities in tracts connecting the frontal, parietal and temporal lobes, also engaged during language tasks. We combined diffusion tensor imaging with tract-based spatial statistics and found white matter abnormalities in patients with schizophrenia as compared with healthy controls. The patients showed reduced fractional anisotropy bilaterally: in the anterior thalamic radiation (ATR), body of the corpus callosum (forceps minor), cingulum, temporal part of the superior longitudinal fasciculus (SLF) and a small area in the inferior fronto-occipital fasciculus (IFOF); and in the right hemisphere: in the visual cortex, forceps major, body of the corpus callosum (posterior parts) and inferior parietal cortex. Compared to patients without current hallucinations, patients with hallucinations revealed decreased fractional anisotropy in the left IFOF, uncinate fasciculus, arcuate fasciculus with SLF, corpus callosum (posterior parts–forceps major), cingulate, corticospinal tract and ATR. The severity of hallucinations correlated negatively with white matter integrity in tracts connecting the left frontal lobe with temporal regions (uncinate fasciculus, IFOF, cingulum, arcuate fasciculus anterior and long part and superior long fasciculus frontal part) and in interhemispheric connections (anterior corona radiata). These findings support the hypothesis that hallucinations in schizophrenia are accompanied by a complex pattern of white matter alterations that negatively affect the language, emotion and attention/perception networks.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Abbreviations

ACC:

Anterior cingulate cortex

ACR:

Anterior corona radiata

AF:

Anterior fasciculus

ATR:

Anterior thalamic radiation

AVH:

Auditory verbal hallucinations

DTI:

Diffusion tensor imaging

IFG:

Inferior frontal gyrus

IFOF:

Inferior fronto-occipital fasciculus

ILF:

Inferior longitudinal fasciculus

FA:

Fractional anisotropy

ROI:

Region of interest

SLF:

Superior longitudinal fasciculus

TBSS:

Tract-based spatial statistics

TFCE:

Threshold-free cluster enhancement

UF:

Uncinate fasciculus

References

  • Aleman A, Larøi F (2008) Hallucinations: the science of idiosyncratic perception. American Psychological Association, Washington, DC

    Book  Google Scholar 

  • Alexander AL, Lee JE, Lazar M, Field AS (2007) Diffusion tensor imaging of the brain. Neurotherapeutics 4:316–329

    Article  PubMed Central  PubMed  Google Scholar 

  • Allen P, Larøi F, McGuire PK, Aleman A (2008) The hallucinating brain: a review of structural and functional neuroimaging studies of hallucinations. Neurosci Biobehav Rev 32:175–191

    Article  PubMed  Google Scholar 

  • Amad A, Cachia A, Gorwood P, Pins D, Delmaire C, Rolland B et al (2013) The multimodal connectivity of the hippocampal complex in auditory and visual hallucinations. Mol Psychiatry (in press)

  • Andreasen NC, Pressler M, Nopoulos P, Miller D, Ho BC (2010) Antipsychotic dose equivalents and dose-years: a standardized method for comparing exposure to different drugs. Biol Psychiatry 67:255–262

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Baggio HC, Segura B, Ibarretxe-Bilbao N, Valldeoriola F, Marti MJ, Compta Y et al (2012) Structural correlates of facial emotion recognition deficits in Parkinson’s disease patients. Neuropsychologia 50:2121–2128

    Article  CAS  PubMed  Google Scholar 

  • Barch DM, Dowd EC (2010) Goal representations and motivational drive in schizophrenia: the role of prefrontal–striatal interactions. Schizophr Bull 36:919–934

    Article  PubMed Central  PubMed  Google Scholar 

  • Bastin ME, Armitage PA, Marshall I (1998) A theoretical study of the effect of experimental noise on the measurement of anisotropy in diffusion imaging. Magn Reson Imaging 16:773–785

    Article  CAS  PubMed  Google Scholar 

  • Beaulieu C (2002) The basis of anisotropic water diffusion in the nervous system—a technical review. NMR Biomed 15:435–455

    Article  PubMed  Google Scholar 

  • Benedetti F, Yeh PH, Bellani M, Radaelli D, Nicoletti MA, Poletti S, Falini A, Dallaspezia S, Colombo C, Scotti G, Smeraldi E, Soares JC, Brambilla P (2011) Disruption of white matter integrity in bipolar depression as a possible structural marker of illness. Biol Psychiatry 69:309–317

    Article  PubMed  Google Scholar 

  • Brown GG, Thompson WK (2010) Functional brain imaging in schizophrenia: selected results and methods. Curr Top Behav Neurosci 4:181–214

    Article  PubMed  Google Scholar 

  • Catani M, Craig MC, Forkel SJ, Kanaan R, Picchioni M, Toulopoulou T, Shergill S, Williams S, Murphy DG, McGuire P (2011) Altered integrity of perisylvian language pathways in schizophrenia: relationship to auditory hallucinations. Biol Psychiatry 70:1143–1150

    Article  PubMed  Google Scholar 

  • Catani M, Mesulam M (2008) The arcuate fasciculus and the disconnection theme in language and aphasia: history and current state. Cortex 44:953–961

    Google Scholar 

  • Catani M, Mesulam MM, Jakobsen E, Malik F, Martersteck A, Wieneke C et al (2013) A novel frontal pathway underlies verbal fluency in primary progressive aphasia. Brain 136:2619–2628

    Article  PubMed Central  PubMed  Google Scholar 

  • Cercignani M, Horsfield MA (2001) The physical basis of diffusion-weighted MRI. J Neurol Sci 186(Suppl 1):S11–S14

    Article  PubMed  Google Scholar 

  • Chechlacz M, Rotshtein P, Hansen PC, Riddoch JM, Deb S, Humphreys GW (2012) The neural underpinnings of simultanagnosia: disconnecting the visuospatial attention network. J Cogn Neurosci 24:718–735

    Article  PubMed  Google Scholar 

  • Clark KA, Nuechterlein KH, Asarnow RF, Hamilton LS, Phillips OR, Hageman NS, Woods RP, Alger JR, Toga AW, Narr KL (2011) Mean diffusivity and fractional anisotropy as indicators of disease and genetic liability to schizophrenia. J Psychiatr Res 45:980–988

    Article  PubMed Central  PubMed  Google Scholar 

  • Ćurčić-Blake B, Liemburg E, Vercammen A, Swart M, Knegtering H, Bruggeman R, Aleman A (2012) When Broca goes uninformed: reduced information flow to Broca’s area in schizophrenia patients with auditory hallucinations. Schizophr Bull 39(5):1087–1095

    Article  PubMed Central  PubMed  Google Scholar 

  • de Weijer AD, Mandl RC, Diederen KM, Neggers SF, Kahn RS, Hulshoff Pol HE, Sommer IE (2011) Microstructural alterations of the arcuate fasciculus in schizophrenia patients with frequent auditory verbal hallucinations. Schizophr Res 130:68–77

    Article  PubMed  Google Scholar 

  • Duffau H (2008) The anatomo-functional connectivity of language revisited. New insights provided by electrostimulation and tractography. Neuropsychologia 46:927–934

    Article  PubMed  Google Scholar 

  • Duffau H, Gatignol P, Moritz-Gasser S, Mandonnet E (2009) Is the left uncinate fasciculus essential for language? A cerebral stimulation study. J Neurol 256:382–389

    Article  PubMed  Google Scholar 

  • Ellison-Wright I, Bullmore E (2009) Meta-analysis of diffusion tensor imaging studies in schizophrenia. Schizophr Res 108:3–10

    Article  PubMed  Google Scholar 

  • Feinberg I, Guazzelli M (1999) Schizophrenia—a disorder of the corollary discharge systems that integrate the motor systems of thought with the sensory systems of consciousness. Br J Psychiatry 174:196–204

    Article  CAS  PubMed  Google Scholar 

  • ffytche DH, Catani M (2005) Beyond localization: from hodology to function. Philos Trans R Soc Lond B Biol Sci 360:767–779

    Article  PubMed Central  PubMed  Google Scholar 

  • Forkel SJ, Thiebaut de SM, Kawadler JM, Dell’Acqua F, Danek A, Catani M (2012) The anatomy of fronto-occipital connections from early blunt dissections to contemporary tractography. Cortex. doi:10.1016/j.cortex.2012.09.005

  • Friston KJ, Frith CD (1995) Schizophrenia: a disconnection syndrome? Clin Neurosci 3:89–97

    CAS  PubMed  Google Scholar 

  • Frith C (1996) Neuropsychology of schizophrenia: what are the implications of intellectual and experimental abnormalities for the neurobiology of schizophrenia? Br Med Bull 52:618–626

    Article  CAS  PubMed  Google Scholar 

  • Frith C (2005) The neural basis of hallucinations and delusions. C R Biol 328:169–175

    Article  PubMed  Google Scholar 

  • Grossberg S (2000) How hallucinations may arise from brain mechanisms of learning, attention, and volition. J Int Neuropsychol Soc 6:583–592

    Article  CAS  PubMed  Google Scholar 

  • Highley JR, Walker MA, Esiri MM, Crow TJ, Harrison PJ (2002) Asymmetry of the uncinate fasciculus: a post-mortem study of normal subjects and patients with schizophrenia. Cereb Cortex 12:1218–1224

    Article  PubMed  Google Scholar 

  • Hoffman RE (2007) A social deafferentation hypothesis for induction of active schizophrenia. Schizophr Bull 33:1066–1070

    Article  PubMed Central  PubMed  Google Scholar 

  • Hoffman RE, Pittman B, Constable RT, Bhagwagar Z, Hampson M (2011) Time course of regional brain activity accompanying auditory verbal hallucinations in schizophrenia. Br J Psychiatry 198:277–283

    Article  PubMed Central  PubMed  Google Scholar 

  • Hubl D, Koenig T, Strik W, Federspiel A, Kreis R, Boesch C, Maier SE, Schroth G, Lovblad K, Dierks T (2004) Pathways that make voices: white matter changes in auditory hallucinations. Arch Gen Psychiatry 61:658–668

    Article  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  • Jones DK, Catani M, Pierpaoli C, Reeves SJ, Shergill SS, O’Sullivan M, Golesworthy P, McGuire P, Horsfield MA, Simmons A, Williams SC, Howard RJ (2006) Age effects on diffusion tensor magnetic resonance imaging tractography measures of frontal cortex connections in schizophrenia. Hum Brain Mapp 27:230–238

    Article  PubMed  Google Scholar 

  • Kay SR, Fiszbein A, Opler LA (1987) The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull 13:261–276

    Article  CAS  PubMed  Google Scholar 

  • Kemp R, David AS (1997) Insight and compliance. In: Blackwell B (ed) Compliance and the treatment alliance in serious mental illness. Hardwood Academic Publishers, Amsterdam, pp 61–86

    Google Scholar 

  • Knecht S, Drager B, Deppe M, Bobe L, Lohmann H, Floel A, Ringelstein EB, Henningsen H (2000) Handedness and hemispheric language dominance in healthy humans. Brain 123(Pt 12):2512–2518

    Article  PubMed  Google Scholar 

  • Knochel C, Oertel-Knochel V, Schonmeyer R, Rotarska-Jagiela A, van de Ven V, Prvulovic D, Haenschel C, Uhlhaas P, Pantel J, Hampel H, Linden DE (2012) Interhemispheric hypoconnectivity in schizophrenia: fiber integrity and volume differences of the corpus callosum in patients and unaffected relatives. NeuroImage 59:926–934

    Article  PubMed  Google Scholar 

  • Kubicki M, Westin CF, McCarley RW, Shenton ME (2005) The application of DTI to investigate white matter abnormalities in schizophrenia. Ann N Y Acad Sci 1064:134–148

    Article  PubMed Central  PubMed  Google Scholar 

  • Kuhn S, Gallinat J (2010) Quantitative meta-analysis on state and trait aspects of auditory verbal hallucinations in schizophrenia. Schizophr Bull 32:358–365

    Google Scholar 

  • Makris N, Kennedy DN, McInerney S, Sorensen AG, Wang R, Caviness VS Jr, Pandya DN (2005) Segmentation of subcomponents within the superior longitudinal fascicle in humans: a quantitative, in vivo, DT-MRI study. Cereb Cortex 15:854–869

    Article  PubMed  Google Scholar 

  • Mandonnet E, Nouet A, Gatignol P, Capelle L, Duffau H (2007) Does the left inferior longitudinal fasciculus play a role in language? A brain stimulation study. Brain 130:623–629

    Article  PubMed  Google Scholar 

  • Martino J, Brogna C, Robles SG, Vergani F, Duffau H (2010) Anatomic dissection of the inferior fronto-occipital fasciculus revisited in the lights of brain stimulation data. Cortex 46:691–699

    Article  PubMed  Google Scholar 

  • Mechelli A, Allen P, Amaro E, Fu CHY, Williams SCR, Brammer MJ, Johns LC, McGuire PK (2007) Misattribution of speech and impaired connectivity in patients with auditory verbal hallucinations. Hum Brain Mapp 28:1213–1222

    Article  PubMed  Google Scholar 

  • Mori T, Ohnishi T, Hashimoto R, Nemoto K, Moriguchi Y, Noguchi H, Nakabayashi T, Hori H, Harada S, Saitoh O, Matsuda H, Kunugi H (2007) Progressive changes of white matter integrity in schizophrenia revealed by diffusion tensor imaging. Psychiatry Res 154:133–145

    Article  PubMed  Google Scholar 

  • Niogi S, Mukherjee P, Ghajar J, McCandliss BD (2010) Individual differences in distinct components of attention are linked to anatomical variations in distinct white matter tracts. Front Neuroanat 4:2

    PubMed Central  PubMed  Google Scholar 

  • Parker GJ, Luzzi S, Alexander DC, Wheeler-Kingshott CA, Ciccarelli O, Lambon Ralph MA (2005) Lateralization of ventral and dorsal auditory-language pathways in the human brain. Neuroimage 24:656–666

    Article  PubMed  Google Scholar 

  • Ranson SW (1947) The anatomy of the nervous system: its development and function. W. B. Saunders company, London

    Google Scholar 

  • Rotarska-Jagiela A, Oertel-Knoechel V, DeMartino F, van de Ven V, Formisano E, Roebroeck A, Rami A, Schoenmeyer R, Haenschel C, Hendler T, Maurer K, Vogeley K, Linden DE (2009) Anatomical brain connectivity and positive symptoms of schizophrenia: a diffusion tensor imaging study. Psychiatry Res 174:9–16

    Article  PubMed  Google Scholar 

  • Rubin LH, Witkiewitz K, Andre JS, Reilly S (2007) Methods for handling missing data in the behavioral neurosciences: don’t throw the baby rat out with the bath water. J Undergrad Neurosci Educ 5:A71–A77

    PubMed Central  PubMed  Google Scholar 

  • Seok JH, Park HJ, Chun JW, Lee SK, Cho HS, Kwon JS, Kim JJ (2007) White matter abnormalities associated with auditory hallucinations in schizophrenia: a combined study of voxel-based analyses of diffusion tensor imaging and structural magnetic resonance imaging. Psychiatry Res 156:93–104

    Article  PubMed  Google Scholar 

  • Sheehan DV, Lecrubier Y, Sheehan KH, Amorim P, Janavs J, Weiller E, Hergueta T, Baker R, Dunbar GC (1998) The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry 59(Suppl 20):22–33

    PubMed  Google Scholar 

  • Shergill SS, Kanaan RA, Chitnis XA, O’Daly O, Jones DK, Frangou S, Williams SC, Howard RJ, Barker GJ, Murray RM, McGuire P (2007) A diffusion tensor imaging study of fasciculi in schizophrenia. Am J Psychiatry 164:467–473

    Article  PubMed  Google Scholar 

  • Smith SM, Nichols TE (2009) Threshold-free cluster enhancement: addressing problems of smoothing, threshold dependence and localisation in cluster inference. NeuroImage 44:83–98

    Article  PubMed  Google Scholar 

  • Smith SM, Jenkinson M, Johansen-Berg H, Rueckert D, Nichols TE, Mackay CE, Watkins KE, Ciccarelli O, Cader MZ, Matthews PM, Behrens TE (2006) Tract-based spatial statistics: voxelwise analysis of multi-subject diffusion data. NeuroImage 31:1487–1505

    Article  PubMed  Google Scholar 

  • Tang YY, Lu Q, Geng X, Stein EA, Yang Y, Posner MI (2010) Short-term meditation induces white matter changes in the anterior cingulate. Proc Natl Acad Sci USA 107:15649–15652

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Thiebaut de Schotten M, Ffytche DH, Bizzi A, Dell’Acqua F, Allin M, Walshe M, Murray R, Williams SC, Murphy DG, Catani M (2011) Atlasing location, asymmetry and inter-subject variability of white matter tracts in the human brain with MR diffusion tractography. Neuroimage 54:49–59

    Article  PubMed  Google Scholar 

  • van der Meer L, de Vos AE, Stiekema AP, Pijnenborg GH, van Tol MJ, Nolen WA, David AS, Aleman A (2012) Insight in schizophrenia: involvement of self-reflection networks? Schizophr Bull 39(6):1288–1295. doi:10.1093/schbul/sbs122

    Article  PubMed Central  PubMed  Google Scholar 

  • Vercammen A, Knegtering H, den Boer JA, Liemburg EJ, Aleman A (2010) Auditory hallucinations in schizophrenia are associated with reduced functional connectivity of the temporo-parietal area. Biol Psychiatry 67:912–918

    Article  PubMed  Google Scholar 

  • Von Der Heide RJ, Skipper LM, Klobusicky E, Olson IR (2013) Dissecting the uncinate fasciculus: disorders, controversies and a hypothesis. Brain 136:1692–1707

    Article  Google Scholar 

  • Wakana S, Jiang H, Nagae-Poetscher LM, van Zijl PC, Mori S (2004) Fiber tract-based atlas of human white matter anatomy. Radiology 230:77–87

    Article  PubMed  Google Scholar 

  • Wakana S, Caprihan A, Panzenboeck MM, Fallon JH, Perry M, Gollub RL, Hua K, Zhang J, Jiang H, Dubey P, Blitz A, van Zijl P, Mori S (2007) Reproducibility of quantitative tractography methods applied to cerebral white matter. Neuroimage 36:630–644

    Article  PubMed Central  PubMed  Google Scholar 

  • Whitford TJ, Mathalon DH, Shenton ME, Roach BJ, Bammer R, Adcock RA, Bouix S, Kubicki M, De Siebenthal J, Rausch AC, Schneiderman JS, Ford JM (2011) Electrophysiological and diffusion tensor imaging evidence of delayed corollary discharges in patients with schizophrenia. Psychol Med 41:959–969

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Xu J, Kober H, Carroll KM, Rounsaville BJ, Pearlson GD, Potenza MN (2012) White matter integrity and behavioral activation in healthy subjects. Hum Brain Mapp 33:994–1002

    Article  PubMed Central  PubMed  Google Scholar 

  • Zamm A, Schlaug G, Eagleman DM, Loui P (2013) Pathways to seeing music: enhanced structural connectivity in colored-music synesthesia. Neuroimage 74:359–366

    Article  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgments

The authors thank G.R. Blake for his comments on earlier versions of the manuscript. We thank psychiatrists Dr. R. Bruggeman and Dr. H. Knegtering for their help with patient inclusion. Our thanks are due especially to A. de Vos and J. van der Velde for help with data sorting and to S. Chalavi for discussions on analysis. L. Cerliani is supported by an NWO MaGW Open competition grant (grant number 400-08-089) and by an NIHC grant (grant number 056-13-017). This research was supported by a EURYI Award from the European Science Foundation (No. 044035001) awarded to A.A.

Conflict of interest

The authors declare that they have no competing financial interests in relation to the work described.

Author information

Authors and Affiliations

  1. Department of Neuroscience, Neuroimaging Center (NIC), University Medical Center Groningen, University of Groningen, A. Deusinglaan 2, 9713AW, Groningen, The Netherlands

    Branislava Ćurčić-Blake, Luca Nanetti, Lisette van der Meer, Leonardo Cerliani, Remco Renken, Gerdina H. M. Pijnenborg & André Aleman

  2. Department of Rehabilitation, Lentis, Zuidlaren, The Netherlands

    Lisette van der Meer

  3. Netherlands Institute for Neuroscience, Royal Netherlands Academy of Arts and Sciences (KNAW), Amsterdam, The Netherlands

    Leonardo Cerliani

  4. Department of Clinical Psychology & Experimental Psychopathalogy, University of Groningen, Grote Kruisstraat 2/1, 9712TS, Groningen, The Netherlands

    Gerdina H. M. Pijnenborg

  5. Rob Giel Research Centrum, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands

    Lisette van der Meer

  6. Department of Psychotic Disorders, GGZ-Drenthe, Dennenweg 9, 9404LA, Assen, The Netherlands

    Gerdina H. M. Pijnenborg

Authors
  1. Branislava Ćurčić-Blake
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Luca Nanetti
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lisette van der Meer
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Leonardo Cerliani
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Remco Renken
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Gerdina H. M. Pijnenborg
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. André Aleman
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Branislava Ćurčić-Blake.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (XLSX 21 kb)

Supplementary material 2 (XLSX 16 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ćurčić-Blake, B., Nanetti, L., van der Meer, L. et al. Not on speaking terms: hallucinations and structural network disconnectivity in schizophrenia. Brain Struct Funct 220, 407–418 (2015). https://doi.org/10.1007/s00429-013-0663-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00429-013-0663-y

Keywords

Search

Navigation