Formal thought disorder is a feature schizophrenia that manifests as disorganized, incoherent speech, and is associated with a poor clinical outcome. The neurocognitive basis of this symptom is unclear but it is thought to involve an impairment in semantic processing classically described as a loosening of meaningful associations. Using a paradigm derived from the n400 event-related, potential, we examined the extent to which regional activation during semantic processing is altered in schizophrenic patients with formal thought disorder. Ten healthy control and 18 schizophrenic participants (9 with and 9 without formal thought disorder) performed a semantic decision sentence task during an event-related functional magnetic resonance imaging experiment. We employed analysis of variance to estimate the main effects of semantic congruency and groups on activation and specific effects of formal thought disorder were addressed using post-hoc comparisons. We found that the frontotemporal network, normally engaged by a semantic decision task, was underactivated in schizophrenia, particularly in patients with FTD. This network is implicated in the inhibition of automatically primed stimuli and impairment of its function interferes with language processing and contributes to the production of incoherent speech. 1. Introduction Bleuler’s work in psychosis continues to be highly influential in furthering understanding of the signs and symptoms of schizophrenia [1]. Nevertheless, one of his primary conceptual contributions in understanding schizophrenia, “disturbance of associations” [2, 3], remains to be explained in terms of underlying neural basis. In turn, Bleuler’s ideas were influenced by Jung’s word association task [4]. Regardless of the psychological or affective mechanisms that may influence the production of speech, Jungian word association is by nature a semantic association test. Interpretations of the broader meanings of “split mind” and “association”, arising from the psychoanalytical field, are not incompatible with an inbuilt characteristic of this test, which taps into the concept of semantic priming [5], extensively investigated in schizophrenia (see Minzenberg et al. [6] for a review in single-word semantic priming in schizophrenia). However, some studies do not take into account specific symptoms proposed by Bleuler, such as formal thought disorder, as an underlying factor that would interfere with task performance (e.g., [7]), mixing up performance of patients with a range of distinct symptoms. Of note, there is a line of investigation
References
[1]
V. Peralta and M. J. Cuesta, “Eugen bleuler and the schizophrenias: 100 Years after,” Schizophrenia Bulletin, vol. 37, no. 6, pp. 1118–1120, 2011.
[2]
S. Heckers, “Bleuler and the neurobiology of schizophrenia,” Schizophrenia Bulletin, vol. 37, no. 6, pp. 1131–1135, 2011.
[3]
M.-C. Hardy-Baylé, Y. Sarfati, and C. Passerieux, “The cognitive basis of disorganization symptomatology in Schizophrenia and its clinical correlates: toward a pathogenetic approach to disorganization,” Schizophrenia Bulletin, vol. 29, no. 3, pp. 459–471, 2003.
[4]
A. Moskowitz and G. Heim, “Eugen Bleuler's Dementia Praecox or the Group of Schizophrenias (1911): a centenary appreciation and reconsideration,” Schizophrenia Bulletin, vol. 37, no. 3, pp. 471–479, 2011.
[5]
M. Spitzer, “Associative networks, formal thought disorder and schizophrenia. On the experimental psychopathology of speech-dependent thought processes,” Nevernartz, vol. 64, no. 3, pp. 147–159, 1993.
[6]
M. J. Minzenberg, B. A. Ober, and S. Vinogradov, “Semantic priming in schizophrenia: a review and synthesis,” Journal of the International Neuropsychological Society, vol. 8, no. 5, pp. 699–720, 2002.
[7]
J. D. Ragland, R. C. Gur, J. Raz et al., “Effect of schizophrenia on frontotemporal activity during word encoding and recognition: a PET cerebral blood flow study,” American Journal of Psychiatry, vol. 158, no. 7, pp. 1114–1125, 2001.
[8]
M. Spitzer, U. Braun, L. Hermle, and S. Maier, “Associative semantic network dysfunction in thought-disordered schizophrenic patients: direct evidence from indirect semantic priming,” Biological Psychiatry, vol. 34, no. 12, pp. 864–877, 1993.
[9]
M. Spitzer, I. Weisker, M. Winter, S. Maier, L. Hermle, and B. A. Maher, “Semantic and phonological priming in schizophrenia,” Journal of Abnormal Psychology, vol. 103, no. 3, pp. 485–494, 1994.
[10]
M. Spitzer, “A cognitive neuroscience view of schizophrenic thought disorder,” Schizophrenia Bulletin, vol. 23, no. 1, pp. 29–50, 1997.
[11]
M. Kiefer and M. Spitzer, “Time course of conscious and unconscious semantic brain activation,” NeuroReport, vol. 11, no. 11, pp. 2401–2407, 2000.
[12]
M. Kiefer, U. Martens, M. Weisbrod, L. Hermle, and M. Spitzer, “Increased unconscious semantic activation in schizophrenia patients with formal thought disorder,” Schizophrenia Research, vol. 114, no. 1–3, pp. 79–83, 2009.
[13]
T. E. Goldberg, M. S. Aloia, M. L. Gourovitch, D. Missar, D. Pickar, and D. R. Weinberger, “Cognitive substrates of thought disorder, I: the semantic system,” American Journal of Psychiatry, vol. 155, no. 12, pp. 1671–1676, 1998.
[14]
J. G. Kerns and H. Berenbaum, “Cognitive impairments associated with formal thought disorder in people with schizophrenia,” Journal of Abnormal Psychology, vol. 111, no. 2, pp. 211–224, 2002.
[15]
T. H. McGlashan, “Eugen bleuler: centennial anniversary of his 1911 publication of dementia praecox or the group of schizophrenias,” Schizophrenia Bulletin, vol. 37, no. 6, pp. 1101–1103, 2011.
[16]
G. McCarthy, A. C. Nobre, S. Bentin, and D. D. Spencer, “Language-related field potentials in the anterior-medial temporal lobe: I. Intracranial distribution and neural generators,” The Journal of Neuroscience, vol. 15, no. 2, pp. 1080–1089, 1995.
[17]
A. C. Nobre and G. McCarthy, “Language-related field potentials in the anterior-medial temporal lobe: II. Effects of word type and semantic priming,” The Journal of Neuroscience, vol. 15, no. 2, pp. 1090–1098, 1995.
[18]
P. J. Holcomb, “Semantic priming and stimulus degradation: implications for the role of the N400 in language processing,” Psychophysiology, vol. 30, no. 1, pp. 47–61, 1993.
[19]
P. F. Mitchell, S. Andrews, A. M. Fox, S. V. Catts, P. B. Ward, and N. McConaghy, “Active and passive attention in schizophrenia: an ERP study of information processing in a linguistic task,” Biological Psychology, vol. 32, no. 2-3, pp. 101–124, 1991.
[20]
M. A. Niznikiewicz, B. F. O'Donnell, P. G. Nestor et al., “ERP assessment of visual and auditory language processing in schizophrenia,” Journal of Abnormal Psychology, vol. 106, no. 1, pp. 85–94, 1997.
[21]
S. Andrews, A. M. Shelley, P. B. Ward, A. Fox, S. V. Catts, and N. McConaghy, “Event-related potential indices of semantic processing in schizophrenia,” Biological Psychiatry, vol. 34, no. 7, pp. 443–458, 1993.
[22]
J. Adams, S. F. Faux, P. G. Nestor et al., “ERP abnormalities during semantic processing in schizophrenia,” Schizophrenia Research, vol. 10, no. 3, pp. 247–257, 1993.
[23]
M. Kutas and S. A. Hillyard, “Brain potentials during reading reflect word expectancy and semantic association,” Nature, vol. 307, no. 5947, pp. 161–163, 1984.
[24]
D. Salisbury, “N400 to lexical ambiguity and semantic incongruity in schizophrenia,” International Journal of Psychophysiology, vol. 75, no. 2, pp. 127–132, 2010.
[25]
M. Kostova, C. Passerieux, J. P. Laurent, and M. C. Hardy-Baylé, “N400 anomalies in schizophrenia are correlated with the severity of formal thought disorder,” Schizophrenia Research, vol. 78, no. 2-3, pp. 285–291, 2005.
[26]
J. P. Laurent, M. Kostova, and C. Passerieux, “N400 and P300 modulation as functions of processing level in schizophrenia patients exhibiting formal thought disorder,” International Journal of Psychophysiology, vol. 75, no. 2, pp. 177–182, 2010.
[27]
P. F. Liddle, K. J. Friston, C. D. Frith, S. R. Hirsch, T. Jones, and R. S. J. Frackowiak, “Patterns of cerebral blood flow in schizophrenia,” British Journal of Psychiatry, vol. 160, pp. 179–186, 1992.
[28]
P. K. McGuire, D. J. Quested, S. A. Spence, R. M. Murray, C. D. Frith, and P. F. Liddle, “Pathophysiology of “positive” thought disorder in schizophrenia,” British Journal of Psychiatry, vol. 173, pp. 231–235, 1998.
[29]
T. T. J. Kircher, E. T. Bulimore, M. J. Brammer et al., “Differential activation of temporal cortex during sentence completion in schizophrenic patients with and without formal thought disorder,” Schizophrenia Research, vol. 50, no. 1-2, pp. 27–40, 2001.
[30]
T. T. J. Kircher, P. F. Liddle, M. J. Brammer, S. C. R. Williams, R. M. Murray, and P. K. McGuire, “Neural correlates of formal thought disorder in schizophrenia: preliminary findings from a functional magnetic resonance imaging study,” Archives of General Psychiatry, vol. 58, no. 8, pp. 769–774, 2001.
[31]
A. W. MacDonald III, C. S. Carter, J. G. Kerns et al., “Specificity of prefrontal dysfunction and context processing deficits to schizophrenia in never-medicated patients with first-episode psychosis,” American Journal of Psychiatry, vol. 162, no. 3, pp. 475–484, 2005.
[32]
I. H. Park, H. J. Park, J. W. Chun, E. Y. Kim, and J. J. Kim, “Prefrontal functional dissociation in the semantic network of patients with schizophrenia,” NeuroReport, vol. 19, no. 14, pp. 1391–1395, 2008.
[33]
M. Nakamura, P. G. Nestor, J. J. Levitt et al., “Orbitofrontal volume deficit in schizophrenia and thought disorder,” Brain, vol. 131, no. 1, pp. 180–195, 2008.
[34]
J. Sun, J. J. Maller, L. Guo, and P. B. Fitzgerald, “Superior temporal gyrus volume change in schizophrenia: a review on Region of Interest volumetric studies,” Brain Research Reviews, vol. 61, no. 1, pp. 14–32, 2009.
[35]
H. Horn, A. Federspiel, M. Wirth et al., “Structural and metabolic changes in language areas linked to formal thought disorder,” British Journal of Psychiatry, vol. 194, no. 2, pp. 130–138, 2009.
[36]
N. C. Andreasen, Scale for the Assessment of Positive Symptoms (SAPS), The University of Iowa, Iowa City, Iowa, USA, 1984.
[37]
C. Van Petten, “Words and sentences: event-related brain potential measures,” Psychophysiology, vol. 32, no. 6, pp. 511–525, 1995.
[38]
D. A. Nathaniel-James, P. Fletcher, and C. D. Frith, “The functional anatomy of verbal initiation and suppression using the Hayling Test,” Neuropsychologia, vol. 35, no. 4, pp. 559–566, 1997.
[39]
P. Allen, A. Mechelli, K. E. Stephan et al., “Fronto-temporal interactions during overt verbal initiation and suppression,” Journal of Cognitive Neuroscience, vol. 20, no. 9, pp. 1656–1669, 2008.
[40]
American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, American Psychiatric Association, Washington, DC, USA, 4th edition, 1994.
[41]
M. Annett, “A classification of hand preference by association analysis,” The British journal of psychology, vol. 61, no. 3, pp. 303–321, 1970.
[42]
H. E. Nelson and J. R. Willison, National Adult Reading Test (NART): Test Manual, NFER-Nelson, Windsor, UK, 2nd edition, 1991.
[43]
N. C. Andreasen, Scale for the Assessment of Negative Symptoms (SANS), The University of Iowa, Iowa City, Iowa, USA, 1984.
[44]
S. M. Arcuri, S. Rabe-Hesketh, R. G. Morris, and P. K. McGuire, “Regional variation of cloze probabilities for sentence contexts,” Behavior Research Methods, Instruments, and Computers, vol. 33, no. 1, pp. 80–90, 2001.
[45]
D. Norris, J. M. McQueen, and A. Cutler, “Bias effects in facilitatory phonological priming,” Memory and Cognition, vol. 30, no. 3, pp. 399–411, 2002.
[46]
S. M. Arcuri, Neural and cognitive studies of thought disorder in schizophrenia, Ph.D. thesis, King’s College, University of London, London, UK, 2003.
[47]
E. Bullmore, C. Long, J. Suckling et al., “Colored noise and computational inference in neurophysiological (fMRI) time series analysis: resampling methods in time and wavelet domains,” Human Brain Mapping, vol. 12, no. 2, pp. 61–78, 2001.
[48]
K. J. Friston, S. Williams, R. Howard, R. S. J. Frackowiak, and R. Turner, “Movement-related effects in fMRI time-series,” Magnetic Resonance in Medicine, vol. 35, no. 3, pp. 346–355, 1996.
[49]
E. Bullmore, M. Brammer, S. C. R. Williams et al., “Statistical methods of estimation and inference for functional MR image analysis,” Magnetic Resonance in Medicine, vol. 35, no. 2, pp. 261–277, 1996.
[50]
J. Talairach and P. Tournoux, Co-Planar Stereotaxic Atlas of the Human Brain, Thieme, New York, NY, USA, 1993.
[51]
E. T. Bullmore, M. J. Brammer, S. Rabe-Hesketh et al., “Methods for diagnosis and treatment of stimulus-correlated motion in generic brain activation studies using fMRI,” Human Brain Mapping, vol. 7, no. 1, pp. 38–48, 1999.
[52]
H. Kadota, H. Sekiguchi, S. Takeuchi, M. Miyazaki, Y. Kohno, and Y. Nakajima, “The role of the dorsolateral prefrontal cortex in the inhibition of stereotyped responses,” Experimental Brain Research, vol. 203, no. 3, pp. 593–600, 2010.
[53]
J. M. Novick, I. P. Kan, J. C. Trueswell, and S. L. Thompson-Schill, “A case for conflict across multiple domains: memory and language impairments following damage to ventrolateral prefrontal cortex,” Cognitive Neuropsychology, vol. 26, no. 6, pp. 527–567, 2009.
[54]
F. Homae, R. Hashimoto, K. Nakajima, Y. Miyashita, and K. L. Sakai, “From perception to sentence comprehension: the convergence of auditory and visual information of language in the left inferior frontal cortex,” NeuroImage, vol. 16, no. 4, pp. 883–900, 2002.
[55]
J. R. Binder, R. H. Desai, W. W. Graves, and L. L. Conant, “Where is the semantic system? A critical review and meta-analysis of 120 functional neuroimaging studies,” Cerebral Cortex, vol. 19, no. 12, pp. 2767–2796, 2009.
[56]
M. Vigneau, V. Beaucousin, P. Y. Hervé et al., “Meta-analyzing left hemisphere language areas: phonology, semantics, and sentence processing,” NeuroImage, vol. 30, no. 4, pp. 1414–1432, 2006.
[57]
W. W. Graves, R. Desai, C. Humphries, M. S. Seidenberg, and J. R. Binder, “Neural systems for reading aloud: a multiparametric approach,” Cerebral Cortex, vol. 20, no. 8, pp. 1799–1815, 2010.
[58]
M. D'Esposito, B. R. Postle, and B. Rypma, “Prefrontal cortical contributions to working memory: evidence from event-related fMRI studies,” Experimental Brain Research, vol. 133, no. 1, pp. 3–11, 2000.
[59]
D. M. Barch, T. S. Braver, F. W. Sabb, and D. C. Noll, “Anterior cingulate and the monitoring of response conflict: evidence from an fMRI study of overt verb generation,” Journal of Cognitive Neuroscience, vol. 12, no. 2, pp. 298–309, 2000.
[60]
J. G. Kerns, J. D. Cohen, A. W. MacDonald III, R. Y. Cho, V. A. Stenger, and C. S. Carter, “Anterior cingulate conflict monitoring and adjustments in control,” Science, vol. 303, no. 5660, pp. 1023–1026, 2004.
[61]
P. H. Ghatan, J. C. Hsieh, K. M. Petersson, S. Stone-Elander, and M. Ingvar, “Coexistence of attention-based facilitation and inhibition in the human cortex,” NeuroImage, vol. 7, no. 1, pp. 23–29, 1998.
[62]
B. A. Kuhl, N. M. Dudukovic, I. Kahn, and A. D. Wagner, “Decreased demands on cognitive control reveal the neural processing benefits of forgetting,” Nature Neuroscience, vol. 10, no. 7, pp. 908–914, 2007.
[63]
T. T. J. Kircher, M. Brammer, N. T. Andreu, S. C. R. Williams, and P. K. McGuire, “Engagement of right temporal cortex during processing of linguistic context,” Neuropsychologia, vol. 39, no. 8, pp. 798–809, 2001.
[64]
G. I. de Zubicaray, F. O. Zelaya, C. Andrew, S. C. R. Williams, and E. T. Bullmore, “Cerebral regions associated with verbal response initiation, suppression and strategy use,” Neuropsychologia, vol. 38, no. 9, pp. 1292–1304, 2000.
[65]
A. E. Cavanna and M. R. Trimble, “The precuneus: a review of its functional anatomy and behavioural correlates,” Brain, vol. 129, no. 3, pp. 564–583, 2006.
[66]
M. Wimber, K. H. B？uml, Z. Bergstr？m, G. Markopoulos, H. J. Heinze, and A. Richardson-Klavehn, “Neural markers of inhibition in human memory retrieval,” The Journal of Neuroscience, vol. 28, no. 50, pp. 13419–13427, 2008.
[67]
P. Fusar-Poli, O. D. Howes, P. Allen et al., “Abnormal frontostriatal interactions in people with prodromal signs of psychosis: a multimodal imaging study,” Archives of General Psychiatry, vol. 67, no. 7, pp. 683–691, 2010.
[68]
B. A. Kuhl, I. Kahn, N. M. Dudukovic, and A. D. Wagner, “Overcoming suppression in order to remember: contributions from anterior cingulate and ventrolateral prefrontal cortex,” Cognitive, Affective and Behavioral Neuroscience, vol. 8, no. 2, pp. 211–221, 2008.
[69]
C. Metzler, “Effects of left frontal lesions on the selection of context-appropriate meanings,” Neuropsychology, vol. 15, no. 3, pp. 315–328, 2001.
[70]
P. W. Burgess and T. Shallice, “Response suppression, Initiation and strategy use following frontal lobe lesions,” Neuropsychologia, vol. 34, no. 4, pp. 263–272, 1996.
