Event-related potentials and thought disorder in schizophrenia

Schizophrenia Research 42 (2000) 187–191 www.elsevier.com/locate/schres

Event-related potentials and thought disorder in schizophrenia Akira Iwanami a, *, Yuka Okajima b, Dai Kuwakado b, Hiroshi Isono b, Kiyoto Kasai a, Akinobu Hata a, Kazuyuki Nakagome b, Masato Fukuda c, Kunitoshi Kamijima b a Department of Neuropsychiatry, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyoku, Tokyo 113-8655, Japan b Department of Psychiatry, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawaku, Tokyo 142-8666, Japan c Department of Neuropsychiatry, Faculty of Medicine, University of Gunma, 3-39-15 Showacho, Maebashi, Gunma 371-0034, Japan Received 30 October 1998; accepted 6 July 1999

Abstract We examined the relationship between event-related potentials and thought disorder in schizophrenia. The subjects were 29 chronic schizophrenic patients. Thought disorder was assessed using the Comprehensive Index of Positive Thought Disorder developed by Harrow and colleagues (Harrow, M., Quinlan, D., 1985. Disordered Thinking and Schizophrenic Psychopathology. Gardner Press, New York; Marengo, J.T., Harrow, M., Latin Kettering, L., Wilson, A., 1986. Evaluating bizarre–idiosyncratic thinking: a comprehensive index of positive thought disorder. Schzophr. Bull. 12, 497–511). Auditory event-related potentials were recorded during a standard oddball task. The P300 amplitude correlated negatively with the severity of the thought disorder. The P300 amplitude in the patients with thought disorder was significantly smaller than in the patients without thought disorder. These results suggest that a reduction in P300 amplitude is associated with a fundamental impairment of information processing in schizophrenic patients. © 2000 Elsevier Science B.V. All rights reserved. Keywords: Event-related potential; P300; Rating scale; Schizophrenia; Thought disorder

1. Introduction Since the description of Bleuler (1911/1956), thought disorder ( TD) has been recognized as a fundamental and primary dysfunction of schizophrenia. Although it is not easy to clinically evaluate the nature and the severity of TD, a number of rating scales that assess the severity of this disorder have recently been developed (Andreasen, 1986; Solovay et al., 1986; Harrow and Quinlan, 1985). The Comprehensive Index of Positive * Corresponding author. Tel.: +81-3-3815-5411; fax: +81-3-5800-6894. E-mail address: [email protected] (A. Iwanami)

Thought Disorder (CIPTD) (Marengo et al., 1986) is one such scale that has proved useful in quantitatively assessing the positive TD in schizophrenic patients. The CITPD is relatively short and easy to administer, and was found to be a satisfactory tool for evoking idiosyncratic and bizarre responses in those with a potential for disordered thought (Harrow and Quinlan, 1985). A reduced P300 amplitude of event-related potentials ( ERPs), particularly in the auditory task, is one of the most consistently replicated biological observations in schizophrenia, and has been assumed to be a vulnerability marker for this disease (Pritchard, 1986; Ford et al., 1992). This finding has also been regarded as an electrophysio-

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logical trait marker of schizophrenia, since it is observed in patients’ siblings (Saitoh et al., 1984) and in high-risk children (Friedman et al., 1982). Although several studies have reported a relationship between P300 and TD in schizophrenia, there have only been a few studies that used a comprehensive rating scale for TD. In the present study, we examined the relationship between ERP measures and TD assessed using the CIPTD in chronic schizophrenic patients.

2. Methods 2.1. Subjects Twenty-nine right-handed chronic schizophrenic patients (15 males and 14 females) in remission, who provided written informed consent, were included in this study (mean age, 34.7 years; SD 11.6). They had a mean age at onset of 23.7 years (SD, 7.4), and a mean duration of illness of 11.1 years (SD, 10.1). All of them met the DSM-IV criteria for schizophrenia (American Psychiatric Association, 1994). The subjects were receiving antipsychotic medication, and the mean daily dosage in chlorpromazine equivalents (Davis, 1976) was 1244 mg (SD, 1515). Symptoms present on the day of testing were rated with the Positive and Negative Syndrome Scale for Schizophrenia (PANSS ) ( Kay et al., 1987). The mean score was 16.0 (SD 5.7) for the positive subscale, 19.9 (6.3) for the negative subscale, and 35.7 (8.4) for the general psychopathology subscale. These values indicated that the symptoms of these patients were mild. 2.2. ERP recording The subjects performed a two-tone auditory discrimination task (oddball task) in a sound-proof room. They were presented with a series of 270 auditory stimuli with a fixed interstimulus interval of 1500 ms. Eighty-five percent of the stimuli were tones of 1000 Hz, and the other 15% were tones of 2000 Hz. Stimuli were presented in a Bernoulli sequence. The subjects were instructed to press a button as quickly as possible upon hearing the

infrequent high-pitch tones. The stimulus intensity was 75 dBSPL, and the tone duration was 50 ms, with a rise/fall time of 10 ms. The scalp electroencephalogram ( EEG) was recorded with Ag/AgMCl disc electrodes at Fz, Cz, and Pz monopolarly according to the international 10–20 electrode system, referred to linked earlobes. The bandpass was set at 0.15–120 Hz. Vertical and horizontal electro-oculograms ( EOG) were recorded from electrodes placed below and at the outer canthus of the right eye. EEG samples were acquired every 2.5 ms, beginning 40 ms before and ending 600 ms after the stimulus onset. Trials contaminated by peak to peak potentials of over 100 mV or accompanied by an EOG of over 75 V were eliminated from the averaging. The responses to frequent and rare tones with correct reactions were averaged separately. N100 was defined as the most negative peak between 50 and 150 ms poststimulus at Fz. P300 was defined as the most positive peak between 250 and 500 ms poststimulus at Pz. Amplitudes were measured with respect to an average voltage during the 40 ms prestimulus.

2.3. Assessment of TD The CIPTD evaluates positive disordered thoughts expressed through verbal and behavioral responses on Gorham’s Proverbs test (Gorham, 1956) and the comprehension subtest of the Wechsler Adult Intelligent Scale ( WAIS ) ( Wechsler, 1955). This rating scale includes five categories for disordered thoughts. Categories I– IV are assessments of verbal responses (category I, Linguistic form or structure; category II, Content of the statement, ideas expressed; category III, Intermixing; category IV, Relationship between response and question), and category V is an assessment of the behavior of the subjects during the test. Table 1 shows the categories and subcategories of the CIPTD. The Proverbs test and the WAIS comprehension subtest were administered to the patients. The subjects’ responses and the testers’ questions were tape-recorded so that they could be transcribed verbatim. As enough information was not available

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A. Iwanami et al. / Schizophrenia Research 42 (2000) 187–191 Table 1 Categories and subcategories of CIPTD Category I. Linguistic form or structure 1. Peculiar word form of use 2. Lack of shared communication Category II. Content of the statement, ideas expressed 3. Coherent but odd ideas 4. Deviant with respect to social convention 5. Illogical 6. Confused Category III. Intermixing 7. Overelaborated 8. Intermingled Category IV. Relationship between response and question 9. Attention to limited part of stimulus 10. Lack of relationship to stimulus material Category V. Behavior

to evaluate the behavior of the subjects, the category V assessment was not included in this study. Degrees of TD were evaluated by assigning scores of 0, 0.5, 1, or 3, representing absent to severe TD. After an ‘overall category score’ for each category was determined for each response of the subjects, an ‘overall score’ was evaluated for each response. The sum of the overall scores of the 12 responses was calculated for the Proverbs test and for the WAIS comprehension subtest, respectively. These values were defined as the ‘Proverbs test total score’ and the ‘Comprehension test total score’. The sum of the Proverbs test total score and the Comprehension test total score was defined as the ‘total overall score’. The sum of all of the overall category scores from both tests was defined as the ‘total category score’ (I–IV ). Ratings were completed by investigators trained to a certain reliability of 0.9.

According to the manual for CIPTD, patients with a Proverb test total score or Comprehension test score of more than 3 were defined as patients with TD. The relationship between the ERP indices and the three total score values and the four total category score values of TD were assessed using Pearson’s product moment correlation. Group differences were assessed using the Student’s t-test.

3. Results Pearson’s product–moment coefficients between the ERP measures and the TD scores were calculated. The N100 amplitude correlated negatively with the total Proverbs test score (r=−0.586, df= 27, p<0.01). The P300 amplitude correlated negatively with the total Comprehension test score (r= −0.499, df=27, p<0.01) and the total overall score (r=−0.378, df=27, p<0.05). The TD scores did not correlate significantly with current age, age at onset, duration of illness, or daily medication dosage. Table 2 shows Pearson’s product–moment coefficients between the ERP measures and the total category scores. The N100 amplitude correlated negatively with the total category scores II (r=−0.397, df=27, p<0.05), III (r=−0.506, df=27, p<0.01), and IV (r=−0.439, df=27, p<0.05). The P300 latency correlated positively with the total category score II (r=0.478, df=27, p<0.01). The P300 amplitude correlated negatively with the total category score I (r=−0.514, df=27, p<0.01). Eleven of the 29 patients had TD. Fig. 1 shows

Table 2 Pearson’s product–moment coefficients between ERP measures and total category scoresa

N100 latency N100 amplitude P300 latency P300 amplitude

Category I: Linguistic form or structure

Category II: Content of the statement, ideas expressed

Category III: Intermingling

Category IV: Relationship between response and question

0.246 −0.020 0.126 −0.514**

0.061 −0.397* 0.478** −0.229

0.260 −0.506** 0.285 −0.244

0.248 −0.437* 0.048 −0.243

a Probability: *p<0.05; **p<0.01.

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4. Discussion

Fig. 1. Grand mean ERP waveforms in patients with and without thought disorder. Negativity is upward.

the grand mean ERP waveforms for the target stimuli in the patients with and without TD. The mean values and standard deviations of clinical and ERP measures of the patients with and without TD were compared. The two groups did not differ significantly in current age or age at onset. The duration of illness for the patients with TD was significantly longer than it was in the patients without TD [t-test: t=−2.902, df=27, p<0.01; mean (SD) for the patients with TD, 17.4 (11.4) years, means for the patients without TD, 7.2 (7.5) years]. The two groups did not differ significantly in the three scales of PANSS. The P300 amplitude in the patients with TD was significantly smaller than it was those without TD [t=2.329, df=27, p<0.05; mean (SD) for the patients with TD, 5.5 (2.7) mV, means for the patients without TD, 10.0 (5.8) mV ].

In the present study, the P300 amplitude correlated negatively with the total Comprehension test score and the total overall score, and the P300 amplitude in the patients with TD was significantly smaller than in patients without TD. Considering that TD associated with schizophrenia is characterized by a persistent and stable nature (Marengo and Harrow, 1987, 1997) and is often observed in subjects with a high risk for schizophrenia (Parnas and Schulsinger, 1986), the findings of the present study suggest that a reduction in the P300 amplitude is associated with a genetic impairment of information processing in this disease. Several studies have discovered a relationship between ERPs and TD in schizophrenia, using a symptom rating scale. Juckel et al. (1996) investigated 88 stabilized schizophrenic patients and reported that patients with high scores on the BPRS TD factor exhibited smaller P300 amplitudes than did patients with low scores on this factor, a finding which seems consistent with the results of the present study. Moreover, Laurent and Baribeau (1992) reported that the P300 amplitude in patients with TD was significantly smaller than in patients without TD or in the controls, in a study involving a selective attention task. They also reported that schizophrenic patients with TD showed a worsening of ERP abnormalities in the clinical course. Higashima et al. (1998) recorded auditory P300 in 73 medicated schizophrenic patients and found that the TD factor score, which was extracted using a principal component analysis of the PANSS items, correlated negatively with P300 amplitude. In contrast, McConaghy et al. (1993), using a selective attention task to elicit ERP, found that P300 amplitude in schizophrenics did not correlate with values of the Object Sorting Test (OST ), which assesses loosening of thinking, but did correlate with positive and negative TDs assessed by symptom rating scales. This inconsistency may be due to differences in the paradigms applied to elicit P300, and in the different rating scales used to assess TD. Since OST, which assesses mainly loosening of thinking, is not a comprehensive measure of TD, a significant correlation between the P300 amplitude and the OST-assessed TD score may

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not be expected. The lack of a correlation between the P300 amplitude and overall category II, III, and IV scores in the present study may give evidence to support this explanation. The association between the total category scores of the CIPTD and the N100 and P300 values were different. Although N100 amplitude correlated negatively with the total category II (content of the statement, ideas expressed), III (intermixing), and IV (relationship between response and question) scores, P300 latency correlated positively with the total category II score, while its amplitude correlated negatively with the total category I score. Considering that N100 is hypothesized to be generated mainly in frontal and temporal regions and P300 in temporal and parietal regions, these results suggested that different regions of the brain are associated with different types of TD. Recently, asymmetry of the P300 with reduced left hemispheric amplitude has been repeatedly reported in schizophrenia (Turetsky et al., 1998; Salisbury et al., 1998). The absence of a topographic analysis was one of the limitations of this study. Therfore, in a future study, a topographic analysis of ERPs with larger sample size is necessary to confirm the results of this study.

Acknowledgements We would like to thank Professor Martin Harrow (Department of Psychiatry, University of Illinois) and Professor Shin-ichi Niwa (Department of Neuropsychiatry, Fukushima Medical College) for their assistance in developing the Japanese version of the Comprehensive Index of Positive Thought Disorder.

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