Skip to main content Accessibility help

Electrophysiological and diffusion tensor imaging evidence of delayed corollary discharges in patients with schizophrenia

  • T. J. Whitford (a1) (a2), D. H. Mathalon (a3) (a4), M. E. Shenton (a1) (a5), B. J. Roach (a3) (a4), R. Bammer (a6), R. A. Adcock (a7), S. Bouix (a1), M. Kubicki (a1) (a5), J. De Siebenthal (a1), A. C. Rausch (a1), J. S. Schneiderman (a1) and J. M. Ford (a3) (a4)...



Patients with schizophrenia (SZ) characteristically exhibit supranormal levels of cortical activity to self-induced sensory stimuli, ostensibly because of abnormalities in the neural signals (corollary discharges, CDs) normatively involved in suppressing the sensory consequences of self-generated actions. The nature of these abnormalities is unknown. This study investigated whether SZ patients experience CDs that are abnormally delayed in their arrival at the sensory cortex.


Twenty-one patients with SZ and 25 matched control participants underwent electroencephalography (EEG). Participants' level of cortical suppression was calculated as the amplitude of the N1 component evoked by a button press-elicited auditory stimulus, subtracted from the N1 amplitude evoked by the same stimulus presented passively. In the three experimental conditions, the auditory stimulus was delivered 0, 50 or 100 ms subsequent to the button-press. Fifteen SZ patients and 17 healthy controls (HCs) also underwent diffusion tensor imaging (DTI), and the fractional anisotropy (FA) of participants' arcuate fasciculus was used to predict their level of cortical suppression in the three conditions.


While the SZ patients exhibited subnormal N1 suppression to undelayed, self-generated auditory stimuli, these deficits were eliminated by imposing a 50-ms, but not a 100-ms, delay between the button-press and the evoked stimulus. Furthermore, the extent to which the 50-ms delay normalized a patient's level of N1 suppression was linearly related to the FA of their arcuate fasciculus.


These data suggest that SZ patients experience temporally delayed CDs to self-generated auditory stimuli, putatively because of structural damage to the white-matter (WM) fasciculus connecting the sites of discharge initiation and destination.


Corresponding author

*Address for correspondence: Dr T. J. Whitford, Psychiatry Neuroimaging Laboratory, 1249 Boylston Street, Boston, MA 02215, USA. (Email:


Hide All
Aliu, S, Houde, J, Nagarajan, S (2009). Motor-induced suppression of the auditory cortex. Journal of Cognitive Neuroscience 21, 791802.
Bartzokis, G (2002). Schizophrenia: breakdown in the well-regulated lifelong process of brain development and maturation. Neuropsychopharmacology 27, 672683.
Basser, PJ, Pierpaoli, C (1996). Microstructural and physiological features of tissues elucidated by quantitative-diffusion-tensor MRI. Journal of Magnetic Resonance, Series B 111, 209219.
Baumann, N, Pham-Dinh, D (2001). Biology of oligodendrocyte and myelin in the mammalian central nervous system. Physiological Reviews 81, 871927.
Beaulieu, C (2002). The basis of anisotropic water diffusion in the nervous system: a technical review. NMR in Biomedicine 15, 435455.
Blakemore, S, Smith, J, Steel, R, Johnstone, C, Frith, C (2000 a). The perception of self-produced sensory stimuli in patients with auditory hallucinations and passivity experiences: evidence for a breakdown in self-monitoring. Psychological Medicine 30, 11311139.
Blakemore, SJ, Wolpert, D, Frith, C (2000 b). Why can't you tickle yourself? Neuroreport 11, R11R16.
Blakemore, SJ, Wolpert, DM, Frith, CD (1998). Central cancellation of self-produced tickle sensation. Nature Neuroscience 1, 635640.
Brusa, A, Jones, S, Plant, G (2001). Long-term remyelination after optic neuritis: a 2-year visual evoked potential and psychophysical serial study. Brain 124, 468479.
Catani, M, Howard, RJ, Pajevic, S, Jones, DK (2002). Virtual in vivo interactive dissection of white matter fasciculi in the human brain. NeuroImage 17, 7794.
Catani, M, Thiebaut de Schotten, M (2008). A diffusion tensor imaging tractography atlas for virtual in vivo dissections. Cortex 44, 11051132.
Cowan, J, Rothwell, J, Dick, J, Thompson, P, Day, B, Marsden, C (1984). Abnormalities in central motor pathway conduction in multiple sclerosis. Lancet 2, 304307.
Crapse, T, Sommer, M (2008 a). Corollary discharge across the animal kingdom. Nature Reviews Neuroscience 9, 587600.
Crapse, T, Sommer, M (2008 b). Corollary discharge circuits in the primate brain. Current Opinion in Neurobiology 18, 552557.
Cuypers, M, Dickson, K, Pinckers, A, Thijssen, J, Hommes, O (1995). Discriminative power of visual evoked potential characteristics in multiple sclerosis. Documenta Ophthalmologica 90, 247257.
Dong, X, Jia, Y, Lu, S, Zhou, X, Cohen-Williams, M, Hodgson, R, Li, H, Priestley, T (2008). The antipsychotic drug, fluphenazine, effectively reverses mechanical allodynia in rat models of neuropathic pain. Psychopharmacology 195, 559568.
Edgerton, B, Danhauer, J, Beattie, R (1977). Bone conduction speech audiometry in normal subjects. Journal of the American Audiology Society 3, 8487.
Eliades, S, Wang, X (2003). Sensory-motor interaction in the primate auditory cortex during self-initiated vocalizations. Journal of Neurophysiology 89, 21942207.
Faravelli, C, Di Bernardo, M, Ricca, V, Benvenuti, P, Bartelli, M, Ronchi, O (1999). Effects of chronic lithium treatment on the peripheral nervous system. Journal of Clinical Psychiatry 60, 306310.
Feinberg, I (1978). Efference copy and corollary discharge: implications for thinking and its disorders. Schizophrenia Bulletin 4, 636640.
First, M, Spitzer, R, Gibbon, M, Williams, J (1997). Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I), Clinician Version. American Psychiatric Press: Washington, DC.
First, MB, Spitzer, RL, Gibbon, M, Williams, BJ (2002). Structured Clinical Interview for DSM-IV-TR Axis I Disorders, Research Version, Non-Patient Edition (SCID-I/NP). Biometrics Research, New York State Psychiatric Institute: New York.
Fletcher, P, Frith, C (2009). Perceiving is believing: a Bayesian approach to explaining the positive symptoms of schizophrenia. Nature Reviews Neuroscience 10, 4858.
Ford, J, Gray, M, Faustman, W, Roach, B, Mathalon, D (2007). Dissecting corollary discharge dysfunction in schizophrenia. Psychophysiology 44, 522529.
Ford, J, Mathalon, D, Kalba, S, Whitfield, S, Faustman, W, Roth, W (2001 a). Cortical responsiveness during talking and listening in schizophrenia: an event-related brain potential study. Biological Psychiatry 50, 540549.
Ford, JM, Mathalon, DH, Heinks, T, Kalba, S, Faustman, WO, Roth, WT (2001 b). Neurophysiological evidence of corollary discharge dysfunction in schizophrenia. American Journal of Psychiatry 158, 20692071.
Friston, KJ (1999). Schizophrenia and the disconnection hypothesis. Acta Psychiatrica Scandanavica. Supplementum 395, 6879.
Frith, CD (1992). The Cognitive Neuropsychology of Schizophrenia. Lawrence Erlbaum Associates: Hove, UK.
Gratton, G, Coles, M, Donchin, E (1983). A new method for the off-line removal of ocular artifact. Electroencephalography and Clinical Neurophysiology 55, 468484.
Gruzelier, J (2000). Self regulation of electrocortical activity in schizophrenia and schizotypy: a review. Clinical Electroencephalography 31, 2329.
Heinks-Maldonado, T, Mathalon, D, Houde, J, Gray, M, Faustman, W, Ford, J (2007). Relationship of imprecise corollary discharge in schizophrenia to auditory hallucinations. Archives of General Psychiatry 64, 286296.
Jones, S (1993). Visual evoked potentials after optic neuritis. Effect of time interval, age and disease dissemination. Journal of Neurology 240, 489494.
Kanaan, R, Kim, J, Kaufmann, W, Pearlson, G, Barker, G, McGuire, P (2005). Diffusion tensor imaging in schizophrenia. Biological Psychiatry 58, 921929.
Kesselring, J (1997). Multiple Sclerosis. Cambridge University Press: New York.
Konopaske, G, Dorph-Petersen, K, Sweet, R, Pierri, J, Zhang, W, Sampson, A, Lewis, D (2008). Effect of chronic antipsychotic exposure on astrocyte and oligodendrocyte numbers in macaque monkeys. Biological Psychiatry 63, 759765.
Kubicki, M, McCarley, R, Westin, C, Park, H, Maier, S, Kikinis, R, Jolesz, F, Shenton, M (2007). A review of diffusion tensor imaging studies in schizophrenia. Journal of Psychiatry Research 41, 1530.
Martikainen, M, Kaneko, K, Hari, R (2005). Suppressed responses to self-triggered sounds in the human auditory cortex. Cerebral Cortex 15, 299302.
McCarthy, G, Donchin, E (1976). The effects of temporal and event uncertainty in determining the waveforms of the auditory event related potential (ERP). Psychophysiology 13, 581590.
Neuweiler, G (2003). Evolutionary aspects of bat echolocation. Journal of Comparative Physiology A 189, 245256.
Pantev, C, Bertrand, O, Eulitz, C, Verkindt, C, Hampson, S, Schuierer, G, Elbert, T (1995). Specific tonotopic organizations of different areas of the human auditory cortex revealed by simultaneous magnetic and electric recordings. Electroencephalography and Clinical Neurophysiology 94, 2640.
Parker, G, Luzzi, S, Alexander, D, Wheeler-Kingshott, C, Ciccarelli, O, Lambon Ralph, M (2005). Lateralization of ventral and dorsal auditory-language pathways in the human brain. NeuroImage 24, 656666.
Paus, T, Perry, D, Zatorre, R, Worsley, K, Evans, A (1996). Modulation of cerebral blood flow in the human auditory cortex during speech: role of motor-to-sensory discharges. European Journal of Neuroscience 8, 22362246.
Petrides, M, Pandya, DN (1988). Association fiber pathways to the frontal cortex from the superior temporal region in the rhesus monkey. Journal of Comparative Neurology 273, 5266.
Poulet, J, Hedwig, B (2007). New insights into corollary discharges mediated by identified neural pathways. Trends in Neuroscience 30, 1421.
Reznik, I, Volchek, L, Mester, R, Kotler, M, Sarova-Pinhas, I, Spivak, B, Weizman, A (2000). Myotoxicity and neurotoxicity during clozapine treatment. Clinical Neuropharmacology 23, 276280.
Rosenberger, G, Kubicki, M, Nestor, P, Connor, E, Bushell, G, Markant, D, Niznikiewicz, M, Westin, C, Kikinis, R, Saykin, AJ, McCarley, R, Shenton, M (2008). Age-related deficits in fronto-temporal connections in schizophrenia: a diffusion tensor imaging study. Schizophrenia Research 102, 181188.
Schafer, E, Marcus, M (1973). Self-stimulation alters human sensory brain responses. Science 181, 175177.
Schneider, K (1957). Primary and secondary symptoms in schizophrenia. Fortschritte der Neurologie-Psychiatrie 25, 487490.
Shelley, A, Silipo, G, Javitt, D (1999). Diminished responsiveness of ERPs in schizophrenic subjects to changes in auditory stimulation parameters: implications for theories of cortical dysfunction. Schizophrenia Research 37, 6579.
Taub, H, Raab, D (1969). Fluctuations of N1 amplitude in relation to click-intensity discrimination. Journal of the Acoustical Society of America 46, 969978.
Uranova, N, Vostrikov, V, Vikhreva, O, Zimina, I, Kolomeets, N, Orlovskaya, D (2007). The role of oligodendrocyte pathology in schizophrenia. International Journal of Neuropsychopharmacology 10, 537545.
Whitford, TJ, Kubicki, M, Shenton, ME (in press). The neuroanatomical underpinnings of schizophrenia and their implications as to the cause of the disorder: a review of the structural MR and diffusion literature. In Understanding Neuropsychiatric Disorders: Insights from Neuroimaging (ed. Shenton, M. E. and Turetsky, B.). Cambridge University Press: New York.


Electrophysiological and diffusion tensor imaging evidence of delayed corollary discharges in patients with schizophrenia

  • T. J. Whitford (a1) (a2), D. H. Mathalon (a3) (a4), M. E. Shenton (a1) (a5), B. J. Roach (a3) (a4), R. Bammer (a6), R. A. Adcock (a7), S. Bouix (a1), M. Kubicki (a1) (a5), J. De Siebenthal (a1), A. C. Rausch (a1), J. S. Schneiderman (a1) and J. M. Ford (a3) (a4)...


Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed