Semantic matching of pictures in schizophrenia: A cross-cultural ERP study

Semantic Matching of Pictures in Schizophrenia: A Cross-Cultural ERP Study Maria A. Bobes, Zhang Xiao Lei, Sergio Ib~ifiez, Hou Yi, and Mitchell Valdes-Sosa

In this study the N400 of schizophrenics was compared with that of control subjects in a picture semantic-matching task. The comparison of N400 difference waveforms (subtraction of event-related potentials of congruent from those of incongruent trials) between control and patients was supplemented by separate analysis for congruent and incongruent trials. The N400 latency was delayed in patients. Also, the amplitude of N400 in the difference waveform was reduced in schizophrenics; however only congruent trials were different for patients (more negative) with respect to controls. This result is consistent with the hypothesis that schizophrenics use context poorly, but inconsistent with simple versions of the idea that associations are generally disinhibited in schizophrenia. Since the amplitudes of N400 and an auditory P300 were not correlated, a general processing deficit does not explain the results. Finally, by using picture matching, a cross-cultural comparison of N400 in schizophrenics from Cuba and China was possible, which indicated that the 17400 abnormalities were similar in both groups.

Key Words: ERPs, N400, P300, schizophrenia, cross-cultural comparison B I O L PSYCHIATRY

1996;40:189-202

Introduction Semantic disturbances have been considered a hallmark of schizophrenia (Morice 1986). Loosening of associations, associative intrusions, bizarre reasoning, and thematic shifts have been described in this disease (Kaplan and Sadock 1991). Several attempts have been made to document experimentally the posited semantic disturbances, and to understand their specific nature. One line of research suggests that the spread of activation within semantic networks is enhanced, or disinhibited From the Cuban Center for Neuroscience, Havana, Cuba (MAB, MV-S), the Mental Health Institute, Beijing Medical University, Beijing, China (ZXL, HY), and Hnos. Ameijeiras Hospital, Havana, Cuba (SI). Address reprint requests to Dr. Maria A. Bobes, Center for Neuroscience, Ave 25 y 158, Cubanacan, Playa, Havana, Cuba Apdo. 6880. Received May 13, 1994; revised June 26, 1995.

© 1996 Society of Biological Psychiatry

in schizophrenia (Maher et al 1983). This claim has been substantiated by the demonstration of larger priming effects for schizophrenics in a lexical decision task (Maher et al 1987; Manschreck et al 1988; Kwapil et al 1990). Priming is said to occur when the recognition of one word is facilitated by the previous presentation of a semantic associate (e.g., from "doctor" to "nurse"). A recent study (Spitzer et al 1993) again found larger priming in schizophrenics and extended the results to indirect priming (from "death" to "wood" via "coffin"), effects that were larger in thought-disordered patients. This implies that semantic activation spreads faster and wider in schizophrenics than in control subjects. Another line of evidence suggests that the use of context is weak in schizophrenia (Cohen and Servan-Schreiber 1992). Chapman et al (1964) found that schizophrenics 0006-32231961515.00 SSDI 0006-3223(95)00352-H

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tended to interpret the dominant meaning of an ambiguous word, when a sentence context should have mediated the subordinate meaning. This result has been replicated in several studies (Benjamin and Watt 1969; Cohen et al 1988), and confirmed with other methods (Salzinger et al 1970; Schwartz 1982). This indicates that the semantic activation created by the context is not used efficiently in processing subsequent stimuli, although the results cannot pinpoint if the deficiency affects lexical access or postlexical processes.

N400 and Semantic Priming Additional information about semantic processing in schizophrenia can be obtained by the use of the eventrelated potential (ERP) component known as N400 (Kutas and Hillyard 1984; Kutas and VanPetten 1988). First described by Kutas and Hillyard (1980), this negative deflection is enhanced for written sentences endings with semantically incongruent words, relative to sentences with a congruent termination. This component has also been elicited using written word pairs, with a larger N400 elicited by semantically incongruent pairs than by semantically related pairs (Harbin et al 1984; Bentin et al 1985; Rugg 1985). The N400 has also been obtained using speech sounds (McCallum et al 1984; Neville 1985) and pictures as stimuli (Barrett and Rugg 1990; Friedman et al 1988; Friedman 1990). The negativities elicited by incongruent pairs of words and incongruent pairs of pictures may not be completely equivalent. Some authors have viewed N400 as an index of the ease of lexical access, with more negative responses when less contextual preactivation of the eliciting word is present (Kutas and Hillyard 1984). Another interpretation of N400 views this waveform as a reflection of postlexical processes, such as the integration of the products of lexical access with the context (Halgren 1990; Rugg 1990).

N400 in Schizophrenia Only a few studies have been published using N400 to assess semantic function in schizophrenics, all using printed stimuli. Some of these studies have used word pairs as stimuli (Grillon et al 1991; Koyama et al 1991, 1994), and the others have used sentences (Andrews et al 1990, 1993; Mitchell et al 1991, McCarley et al 1991). In these studies N400 peak latency appeared consistently delayed with respect to controls, whereas the amplitude data seem more contradictory. A delayed latency for N400 implies that either access to meaning in the mental lexicon, or its postlexical use (the view of N400 espoused here) is slower in schizophrenics. This conclusion is supported by the results of Koyama et al (1994), who found that N400

M.A. Bobes et al

latency is highly correlated with reaction time in a lexical decision task. Since all of the studies of N400 in schizophrenia were performed with printed words as stimuli, it is difficult to determine if the slower semantic processing is a consequence of disturbances within the semantic system itself, or if it is (at least partially) due to slower word decoding. Andrews et al (1993) suggest that task demands affect N400 amplitude in schizophrenia. If active semantic matching is required, then N400 amplitude would be reduced in schizophrenics as compared to controls (see Grillon et al 1991 and semantic matching condition in Mitchell et al 1991 and McCarley et al 1991). If active semantic matching is not required (passive reading in Mitchell et al 1991 and Andrews et al 1993; lexical decision in Koyama et al 1991, 1994) then no significant amplitude reduction would be present. N400 amplitude is usually assessed with difference waveforms obtained by subtracting ERPs associated with congruent and incongruent trials. It is important to differentiate if N400 amplitude reduction in schizophrenics (during semantic matching tasks) is the product of an enhanced positivity for incongruent trials or an enhanced negativity for congruent trials. In other words, is the N400 to deviant stimuli reduced, or do all stimuli elicit a larger N400? This is difficult to assess because in the published studies the basic issue was if the N400 difference waveform was reduced. If N400 reflects lexical access, then the hypothesis of facilitated or disinhibited semantic associations would predict enhanced positivity for incongruent trials. On the other hand, reduced use of context would be consistent with enhanced negativity for congruent trials, for both the prelexical and postlexical explanations of N400.

P300 and N400 in Schizophrenia Signal detection is abnormal in schizophrenics (Comblatt et al 1989), which has been explained by defective "attentional filtering" of stimuli (Garmezy 1977). Many studies report a reduced P300 amplitude (with a normal latency) in schizophrenics (McCarley et al 1991; Pritchard 1986), which has been interpreted as an index of the attentional deficit posited for these patients (BaribeauBraun et al 1983; Duncan et al 1987; Duncan 1988, Grillon et al 1990; Ward et al 1991). Alterations of other attention-related components like N100, N200, and early processing negativities support this concept (Laurent and Baribeau 1992; Strandburg et al 1994). It is necessary to establish of the N400 abnormalities, described above, are related to a specific deficit of the semantic system, or if they reflect a more general processing deficit (Chapman and Chapman 1973). In some

ERPs and Schizophrenia

models (see Cohen and Servan-Schreiber 1992) the impaired performance in signal detection is explained by the same mechanism as the impaired use of semantic context. If this were so, then perhaps the abnormalities of P300 amplitude would be correlated with the alterations of N400 across subjects.

Cross-Cultural Studies Recent cross-cultural research, sponsored by the WHO (Jablensky 1992), has shown that when a uniform design and methodology, and standardized research and diagnostic instruments are used, a similar symptom profile is found for schizophrenia in many different cultures. Although this basic similarity of form in the manifestations of schizophrenia is suggestive of a common pathophysiological mechanism, these studies can only demonstrate a resemblance at a symptom complex level. If pathophysiological markers, such as N400 abnormalities, are also similar in schizophrenics from different cultures, the case for a common disease entity would be strengthened. In this direction, no experimental cross-cultural study of semantic processing has been carried out. One obstacle in carrying out cross-cultural N400 studies, however, is the difficulty in equating stimulus material. This is particularly difficult for printed-word stimuli due to the large variations found in writing systems. An extreme contrast may be found in Chinese and Spanish speaking subjects. Chinese writing is based on a logographic script in which the relations between phonology and orthography are very "opaque" (Wang 1973). In Spanish, an alphabetic script is used, in which the relations between phonology and orthography are very regular. If concepts equally familiar in different cultures are depicted, then the use of paradigms based on picture matching is a good way to circumvent this difficulty.

The Present Study In the present study a group of schizophrenics was compared to control subjects in a semantic matching task that used pictures of common objects and animals as stimuli. The ERPs associated with picture presentation were examined to determine if the N400 component was altered in the patients. The study was designed to achieve several goals. First, by using pictures the linguistic process of decoding printed words was bypassed. If deficits within the semantic system of schizophrenics, above and beyond deficits in word recognition skills, contribute to the N400 amplitude reductions previously described, then these abnormalities should also be present in a picture-matching task.

BIOLPSYCHIATRY 1996;40:189-202

191

Second, special attention was directed to a possible N400 amplitude reduction. The comparison of N400 amplitude between schizophrenics and controls was carded out separately for congruent and incongruent trials. Specific contrasts were performed to establish if the N400 amplitude reduction found in schizophrenics during semantic matching tasks was due to an enhanced negativity for congruent trials, or an enhanced positivity for incongruent trials. Third, in addition to N400, the P300 in an auditory oddball paradigm was also measured in a subset of subjects to establish if there was any correlation between abnormalities of these components that could be attributable to a general processing deficit. A failure to find this correlation would suggest specific deficits, perhaps originating in different mechanisms for each component. And last, a cross-cultural comparison of N400 abnormalities in schizophrenia was performed, to determine if this component was similarly altered in patients from Cuba and China, when the same symptom profile (same diagnostic criteria) was used as inclusion criteria. An important advantage of using pictorial stimuli is that it allows comparisons between speakers/readers of very different languages, using exactly the same stimulus material.

Materials and Methods

Subjects Twenty schizophrenic patients were recruited at each of two sites: the Institute of Mental Health of Beijing Medical University, and the "Hermanos Ameijeiras" Hospital in Havana (Table 1). All patients met DSM-III (APA 1980) criteria, and were selected by chart review. A new psychiatric interview was made 1 day before the ERP recording to confirm the classification. All brief psychiatric rating scale (BPRS) scores were over 30. All of the patients were medicated with neuroleptics at the time of the ERP recording (see Table 1). The two control groups, one in each country, matched in sex, age, and educational level with the corresponding patient group (Table 1), were recruited. Only individuals with a negative history of neurological or psychiatric disease, and not taking psychoactive drugs, were included.

Semantical Matching Task STIMULI. Pictures were selected from a larger pool of stimuli previously rated on familiarity by three judges in each country (China and Cuba), who did not participate in the ERP experiment. An attempt was made to include objects and animals well known to people from both cultures. The 100 pictures, equal in size (black lines on

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Table 1. The Four Groups of Twenty Subjects Included in the Study Schizophrenics

A g e r a n g e (years) Mean age Sex Women Men Years of education > 10 years > 8 years M e a n daily dose o f neuroleptic a

Controls

Chinese

Cuban

Chinese

Cuban

20-35 28.1

18-36 31.1

21-36 28.2

22-37 26.3

10 10 20 -480 mg

13 7 17 3 600 m g

10 10

7 13

20 ---

20 ---

All subjects (patients and controls) were right-handed (handedness was taken by personal report) and all of them had normal or corrected to normal vision. "Converted to chlorpromazine equivalents.

white background), were presented on a VGA monitor and were approximately 8 cm high and 8 cm wide. The black line drawings occupied about one third of the background and were roughly equivalent in size. Since subjects sat at approximately 1 m from the screen, the pictures subtended a vertical and horizontal visual angle of about 4.6 degrees. The stimuli selected from the larger pool of drawings were organized into a sequence in which half of the items were followed by a semantical associate, and half of the items were followed by a nonrelated item. The degree of association between items was initially judged by the experimenters. The relationship between successive items was assessed by 10 judges who did not participate in the ERP experiments (only pairs considered to be semantically associated, or nonassociated, by eight or more judges were accepted as such). Any pair of pictures not corresponding to the experimenters' judgment were replaced until an agreement was reached.

with the picture onset. The following sequence of events comprised each trial: the letter string "XXXXXX" was presented as a warning until the subject pressed a key to initiate the trial; a picture was presented for 1 sec followed by a 200-msec blackout; finally, the subject verbally responded if the stimulus was related to the previous one (yes or no) as soon as the warning stimulus reappeared. The response was delayed until the EEG recording was finished to reduce artifacts, thus reaction time was not measured.

Oddball Task In addition to N400, an auditory P300 was recorded in the Cuban control and schizophrenic groups with free field stimuli (tone pips of 60-dB hearing level effective intensity, 50-msec duration, and 10-msec rise/fall time). The subjects had to count targets (2000 Hz) on 20% of the trials, which were randomly interspersed among standards (1000 Hz, 80%). The interstimulus interval was 1.5 sec. Both the P300 and the N400 paradigm were presented in the same recording session, and the order of presentation was counterbalanced across subjects.

Electrophysiological Recording Electrophysiological data acquisition and analysis were carried out on MEDICID 3M systems. Disk electrodes (Ag/AgC1) were placed with electrolytic paste on seven active derivations (F7, F8, Fz, Cz, Pz, O1, and 02) of the 10/20 international system in both Cuban groups. In Chinese subjects the 19 derivations of the 10/20 system were recorded. All active electrodes were referred to linked earlobes. Interelectrode impedance was always

SemanUcally Related

l

Procedure The pictures were presented sequentially in a pseudorandom order. The subjects had to look at each picture, respond to it, and then remember it until the comparison to the following stimulus. In 50% of the trials the picture was semantically related to the preceding stimulus, whereas in the other 50% they were not related (Figure 1). No picture was presented twice in the list. The subjects had to discriminate between semantically related and unrelated pairs. Thus each picture (except the first) was always used as context for one trial and as stimulus for the following one. During the experiment the subjects sat in a comfortable chair in front of the cathode ray tube monitor, and were instructed to minimize body and eye movements. The electroencephalogram (EEG) recording was synchronized

Semantically Unrelated

Figure 1. Examples of semantically congruent and incongruent picture pairs.

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below 5 kO. A bipolar derivation was used to record the electro-oculogram (EOG), with one electrode just above the upper orbital ridge and the other on the external canthus of the right eye. The signals were filtered between 0.5 and 30 Hz (3 dB down). Additionally, a notch filter with peak at the power line frequency was used. In each trial 256 points of digitized EEG (12-bit resolution) were recorded at a sampling rate of 4 msec, totaling 1.02 sec, and stored on magnetic disk for off-line analysis. A prestimulus baseline of 100 msec was obtained in each trial and data acquisition continued 920 msec after stimulus onset. Each EEG segment was visually inspected and those with artifacts or excessive activity in the EOG were eliminated. Trials with incorrect responses were also eliminated from further analysis. For every subject, averaged ERPs for each recording site were obtained for each stimulus condition, and were submitted to low-pass digital (zero phase distortion) filtering with upper cut of 5.5 Hz. The average amplitude of the ERP waveforms was measured for each individual in predefined time windows (defined below) for statistical tests. All data points were corrected (prior to plotting or measurement) by subtracting the average prestimulus amplitude value. In other words, all amplitude values were measured with respect to the average amplitude of the prestimulus window corresponding to each ERP. Discrimination behavior was analyzed using the Signal Detection Theory measures d' and the logarithm of 13 (Swets 1964). The use of d' permits an assessment of the accuracy of performance without contamination from variations in criterion (response bias), which could be important from one culture to another or between controls and patients.

Statistical Analysis Behavioral and ERP measures were submitted to analysis of variance (ANOVA) using two between-subject factors: Nationality (Cubans vs. Chinese) and mental Health condition (controls vs. schizophrenics). For the ERP measures two additional within-subject factors were employed: Congruity (congruent vs. incongruent) and recording Electrode (three levels, including only midline derivations) as repeated measures. For P300 measures, only one between factor, mental Health, and one within factor, Electrode (three levels, including only midline derivations) were included. The Greenhouse-Geisser procedure was used, when appropriate, to mitigate violations of the sphericity assumption in repeated-measures designs (Keselman and Rogan 1980). Additional ANOVAs and planned comparisons are described below, some including more recording sites. For tests comparing Chinese and Cuban recordings

only the seven derivations common to both montages were included in these analyses.

Results Semantical Matching Task BEHAVIOR. The mean d' for discriminating between congruent and incongruent pictures (Table 2) was very high and significantly different from zero for both Cuban and Chinese control subjects (t tests, p < .001). The mean percent of errors was also very low (Table 2). A slight d' difference between Chinese and Cuban control subjects was only marginally significant (t = 1.94, p < .059). Response bias (log 13) for Cubans and for Chinese control subjects (Table 2) were not statistically different from each other. Both schizophrenic groups (Cuban and Chinese) were able to discriminate well above chance level (Table 2); however, schizophrenic patients had a lower mean d' than controls. In the patient groups the Cuban subjects also performed slightly better than the Chinese. An ANOVA on the d' (Table 2) confirmed that schizophrenics performed significantly worse than controls, and that Cubans had a slight advantage. The interaction between Health and Nationality was not significant. An item analysis revealed that the difference in performance between Cuban and Chinese was concentrated in nine pictures. About 31% of the mistakes were generated by these pictures, which were only 9% of the total. These pictures corresponded to the concepts of pineapple, stapler, coffee cup, guitar, motorboat, hose, pail, pencil, and truck. If these items were excluded then the d' was equivalent in both groups. No effect was significant for response bias (Table 2).

Table 2. Behavioral Results (d', Log [3, and Percent of Errors) Obtained in the Semantic Matching Task Controls

d' L o g 13 Errors

Schizophrenics

Cuban

Chinese

Cuban

Chinese

5.27 -+ 2.03 0.91 --- 1.9 3.8%

4.1 -+ 1.74 0.94 + 2.11 5.6%

4.6 -+ 2.03 1.37 -+ 1.8 5.3%

2.84 --+ 1.49 0.88 -+ 1.73 8.1%

ANOVA d'

Condition Nationality Condition × Nationality

L o g 13

F(1,76)

p

F(1,76)p

5.9 15.8 --

0.017 0.001 ns

----

ns ns ns

In the upper panel mean and standard deviation. In the bottom panel, the results from a between-subjects factors ANOVA carried out upon d' and log 13.

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__congruous .... incongruous

CUBAN Control

CHINESE

/~Schizophrenic

Control

Schizophrenic

Fz

Cz

Pz

-100 0

460

"

920 ms-100 b

460

T

920' ms-100 0

T

460

920 ms-100 0

460

920'ms

Figure 2. Grand average ERPs elicited at midline sites in the four groups studied. On the left both Cuban control and schizophrenic groups are shown and on the right both Chinese control and schizophrenic groups are shown. The ERPs associated with congruent trials (solid line) are overlaid on ERPs elicited by incongruent trials (slashed lines). In this and other figures positive deflections point up. ated with the congruent ones, an effect present in both control groups (Figure 2). This negativity was seen clearly in the difference waveforms (Figure 3), where it was very similar in morphology, amplitude, and latency in both control groups. This negativity apparently corresponds to the N400 component. The negativity appears in the averaged difference waveform as a single peak, with onset at Cz about 350 msec, lasting until about 650 msec, and has its m a x i m u m at about 504 msec.

E R P s . The ERPs obtained at midline sites in the semantic paradigm in control and schizophrenic subjects are shown in Figure 2. No significant effects in the amplitude or latency of the ERPs were found before 300 msec for any factor. Thus attention will be directed to the late ERP components. Amplitude values for the other sites recorded are shown in Table 3. After 300 msec the recordings associated with incongruent pictures became more negative than those associ-

Table 3. Group Mean Amplitude of the Difference Waveform in the Time Window between 380 and 620 msec at All Sites for Each Group Group

Fpl

Cuban controls

. .

. .

. .

. .

. .

. .

. .

. .

Cuban . schizophrenics .

.

.

.

.

.

.

.

.

.

.

.

.

.

.

Chinese controls

0.69

Fp2

1.03

F3

0.86

F4

1.34

C3

1.41

C4

P3

0.95

P4

O1

O2

F7

F8

0.68 1.14 0.98 1.08 (1.36) (1.30) (1.96) (1.16) 0.45

0.51

0.09

0.55

(2.51) (2.81) (1.48) (2.16) 1.26

1.39

0.34

0.82

0.33

0.86

T3

T4

T5

T6 --

.

.

.

-.

.

.

.

.

.

.

.

.

0.43

0.67

0.95

Fz

Cz

Pz

1.18 1.86 1.76 (1.92) (2.02) (1.98) 0.64

0.48

0.84

(1.61) (2.03) (2.11) 1.29

1.35

1.36

1.18

(2.08) (2.10) (2.12) (1.83) (1.93) (1.52) (2.23) (2.09) (2.24) (2.02) (2.42) (1.76) (1.37) (1.26) (1.52) (1.96) (1.93) (1.39) (1.89) Chinese 0.99 1.26 0.97 0.99 0.74 0.62 0.62 0.62 0.51 0.52 0.48 0.64 0.33 0.42 0.62 0.83 0.66 0.47 0.08 schizophrenics (1.77) (1.03) (1.64) (1.42) (1.84) (1.27) (2.12) (2.23) (1.95) (1.76) (1.30) (1.57) (0.91) (1.11) (1.28) (1.37) (1.26) (1.84) (2.06) Standard derivations in parentheses.

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I

--

Table 4. Mean Peak Latency (and Standard Deviation) of N400 at Cz Derivation and P300 at Pz Derivation

Control

. . . . Sch zophrenic

CUBAN

Controls

CHINESE Cuban

Chinese

Cuban

Chinese

N400

4 8 8 ± 56.9

4 6 9 ± 92.4

537 -+ 63.6

5 0 4 + 92.8

P300

373 ± 38,8

--

3 8 0 ± 38.4

--

Fz

EOG "" . . . . .

". . . .

t

-100

0

460

920'ms

-100

0

460

920 m s

Figure 3. Grand average difference waveforms obtained by subtracting the ERPs associated with congruent trials from the ERPs associated with incongruent trials, in the four groups studied: Cuban controls and schizophrenics and Chinese controls and schizophrenics. The difference waveforms from controls (solid line) are overlaid on the waveforms forms schizophrenics (slashed lines).

An ANOVA, for the controls, was performed on a measure of N400, the mean amplitude for the time window from 380 to 620 msec, which includes the peak of the negative modulation of the ERPs. The main effects of Congruity [F(1,38) = 27.35, p < .0001] and Electrode [F(2.8,106.3) = 28.03, p < .0001] were significant, the first of which reflects the more negative values for incongruent recordings with respect to congruent ones. No interactions were significant. The fact that the interaction between Nationality and Congruity was not significant reflects that the amplitude of N400 was about the same for Cubans and Chinese control subjects. The maximum peak latency of N400 at Cz appeared slightly delayed in Cuban control subjects with respect to Chinese (Table 4), but this difference was not statistically significant. The scalp topography of the N400 in the Chinese group (where the complete 10/20 system was recorded) shows that its maximum amplitude is reached at central-frontal sites and in the left hemisphere (Table 3).

Schizophrenics

the N400 was different in morphology, amplitude, and latency from controls. In both groups of patients, the negativity appeared as a notched peak in frontal and central sites, and as a slow wave in occipital sites. Visual inspection indicated that the notched peak morphology appeared in 28 of the 40 individual recordings from both schizophrenic groups, which represents 70% of the total. The negative activity (including both peaks around the notch) is clearly diminished in amplitude at the midline derivations (Figure 3) in both schizophrenic groups with respect to controls. This was so in the grand averages at all sites for Cuban subjects and at 14 sites for the Chinese subjects, although for the latter the amplitudes were slightly larger for the patients group at five sites (Fpl, Fp2, F3, F7, O1). These effects on N400 amplitude were first tested by an ANOVA for midline site on the mean amplitude in the time window from 380 to 620 msec (Table 5), which Table 5. Summary of the Results Obtained from the N400 Repeated Measure ANOVA Factor

F

df

p

Congruity

27.0

1,76

0.0001

Electrode

20.0

1.46,110.6

0.0001

Nationality

--

--

ns

Health

--

--

ns

Nationality x Health

--

--

Congruity X Health

5.8

1,76

Congruity X

--

--

ns

--

--

ns

Electrode x Health

--

--

ns

Electrode x

--

--

ns

--

--

ns

Congruity × Electrode

--

--

ns

Congruity × Electrode

--

--

ns

ns 0.018

Nationality Congruity X Health x Nationality

Nationality Electrode x Health × Nationality

× Health Congruity × Electrode

3.6

1.46,105.3

0.05

× Nationality

N400 IN SCHIZOPHRENICPATIENTS. The ERPs associated with incongruent pictures in Cuban and Chinese patients also became more negative than those associated with congruent pictures after 300 msec (Figure 2); however, as can be seen in the difference waveform (Figure 3),

Congruity × Electrode

--

--

ns

X Health × Nationality Two within-subject factors (Congruity and Electrode), and two betweensubject factors (Nationality and Health) were included. Test was performed on mean amplitude in the time window between 380 and 620 msec.

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includes both peaks around the notch. Incongruent ERPs were more negative in this time window as reflected in a significant Congruity effect. The significant Electrode reflects a greater positivity toward the posterior region. The interaction between Congruity and Nationality was not significant, thus the amplitude of N400 was equivalent in the groups from the two countries. Also, the interaction between Congruity, Electrode, and Health was not significant, which indicates that the topography of N400 is not different between controls and schizophrenics.* The critical interaction between Congruity and Health was significant (Table 5), which indicates the smaller N400 difference waveform in schizophrenics. The triple interaction between Congruity, Electrode, and Nationality was significant, suggesting a possible topographic difference between Cubans and Chinese. No other interaction was significant. An additional ANOVA, with more electrodes, was performed on the difference waveform including all sites common to Chinese and Cuban subjects (Fz, Cz, Pz, F7, F8, O1, 02). The mean amplitude of the difference waveform at the N400 window defined above was used. Health and Nationality were between-subjects factors and Electrode was a within-subject factor. The critical Health effect was marginally significant [F(1,17) = 3.3, p < .066]. The lower significance level for this analysis could be due to the inclusion of sites F7 and O1, where the amplitude of N400 was somewhat larger for Chinese patients than Chinese controls. In planned comparisons examining each electrode separately, the only significant differences were found at Cz [F(1,76) = 7.6, p < .007] and Pz [F(1,76) = 5.1, p < .026] with smaller values for the patients. The difference at Cz was significant, even if corrected by the Bonferroni criterion. Thus, the results at Cz were examined in more detail. In Figure 4 the mean amplitude of N400 in Cz derivation for the same time window used in the ANOVAs is shown for both controls and schizophrenics. Values for congruent and incongruent trials are plotted separately. The amplitude of congruent recording is larger for controls than schizophrenics, whereas the amplitude for incongruent recordings in both groups are similar. This means that the N400 difference waveform reduction in schizophrenics (in comparison with controls) originates from an enhanced negativity in congruent ERPs, in the face of relatively invariant incongruent ERPs. To confirm the pattern of results just described for

* This result was corroborated in an special ANOVA carried out for the Chinese groups, which included the 19 derivations of the 10/20 system, and in which the normalization recommended by McCarthy and Wood (1985) for correcting amplitude differences in topographic comparisons was carried out (see Table 3).

,uV

0--0

CONTROLS

• ...... A

SCHIZOPHRENICS

87-

N400

15o

P$00

T

5-

Q

fi e~ tfl

32± .................. •

i

Congruent (Expected)

•

i

Incongruent (Unexpected)

i

Standard (Expected)

Target (Unexpected)

Figure 4. Mean ERP amplitude values (and standard errors) for N400 (left) and P300 (right) in control and schizophrenic groups as a function of stimulus expectancy. In controls P300 is more positive for unexpected (infrequent) stimuli, and N400 is more negative for unexpected (incongruent) stimuli. The slopes of the corresponding lines for the patients are smaller, reflecting the smaller P300 and N400 effects. Note that the patients' P300 deviates from controls for the unexpected stimulus condition, whereas the patients' N400 deviates from controls for the expected stimulus condition.

controls and schizophrenics (Figure 4), additional planned comparisons were performed for Cz. For controls incongruent ERPs are more negative than congruent ERPs [F(1,76) = 30.5, p < .0001]. For schizophrenics, however, this contrast is not significant, which reflects the smaller N400 difference waveform in these patients. Comparison of the ERP amplitudes with reference to congruity is perhaps more important. For incongruent trials the ERPs from controls and schizophrenics did not differ, whereas for congruent trials the ERPs from schizophrenics were significantly more negative than the controls [F(1,76) = 6.7, p < .01]. Mean N400 peak latency at Cz is shown in Table 4. An ANOVA demonstrates that N400 latency is significantly delayed for patients as compared with controls [F(1,76) = 6.3, p < .01]. Neither Nationality nor the interaction between Health and Nationality was significant. This indicates that the latency delay in patients with respect to controls is equivalent in both countries, a value of about 40 msec. The amplitude of the late positivity (LP) that follows N400 was measured in the time window from 710 to 870 msec. No significant effects were found in the ANOVAs on this measure.

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Figure 5. Grand average ERPs elicited in the oddball paradigm in both control and schizophrenic Cuban groups. The ERPs associated with frequent standard trials (solid line) are overlaid in ERPs elicited by infrequent target trials (slashed lines).

Oddball Task The ERPs obtained at midline sites in the oddball paradigm in control and schizophrenic Cuban subjects are shown in Figure 5. The earliest ERP peak was N l l 0 for both frequent and infrequent recordings. No effect of Health was significant in this time region. In the controls following N110, a P200 component was found. For the infrequent recording P200 is reduced in amplitude and a prominent positive peak follows P200. This represents the N 2 0 0 - P 3 0 0 complex. The P300 was largest at Pz. The mean peak latency of P300 (Table 4) was not statistically different from the values obtained for controls; however, the amplitude of the P300 is reduced in schizophrenics as compared to controls. An A N O V A was performed for P300 mean amplitude from 320 to 440 msec (Table 6) for infrequent target ERPs. The main effect of Health was significant, which reflects smaller P300 in schizophrenics with respect to controls. The Electrode effect also was significant, which reflects the more positive values associated with posterior sites. The P300 amplitude at Pz is plotted in Figure 4. The values for the standard and the target ERPs are plotted separately. The P300 reduction in schizophrenics arises from a reduction of the positivity in the target ERPs with respect to controls (Figure 4), with a relatively invariant standard ERP. This was confirmed by a t test performed

separately for standard and target ERPs. For the standards, P300 amplitude was not different between controls and patients (t = 1.3, df = 38, p > .2); however, target ERPs were less positive in patients than in controls (t = 5.23, df = 38, p < .001). The scatter plots of P300 amplitude as a function of N400 amplitude (both obtained from difference waveforms) are shown in Figure 6. The Pearson correlation coefficient between the N400 and P300 amplitudes for the pool of patients and controls (r = .15, n = 40) was not significant.

Discussion The study was carried out at two different sites, Havana and Beijing, in which the ethnic composition and cultural background of the subjects were very dissimilar. In spite of these dissimilarities the behavioral and ERP abnormalities associated with schizophrenia were very similar in the Cuban and Chinese data. Therefore the implications of the pooled data from both countries will be discussed first, before turning to cross-cultural comparisons.

Behavioral Data The results indicate that schizophrenics make more mistakes than control subjects in picture matching. Grillon et al (1991) also found that schizophrenics were less efficient 0 Controls • Pctients

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than controls in a semantic matching task with words. Picture matching is assumed to share with word matching the same mechanisms involving semantic memory and response organization. The fact that category decisions are faster with pictures than with words has led to the hypothesis that pictures are more directly connected to the semantic memory (Potter and Faulconer 1975; Paivio 1986). A parsimonious account of impaired semantic matching for both words and pictures is obtained by assuming that the underlying deficit is located either in the use of semantic memory or in response organization. Additional results from our group with another sample of subjects (Gutierrez 1994) suggest that the abnormal picture matching found in schizophrenics does not arise from difficulties in identifying the stimuli. Thus, the mistakes made by the patients probably arise from deficits subsequent to memory access, possibly in integrating the products of retrieval with the context. This conclusion is in line with the theory espoused by Cohen and ServanSchrieber (1992) based on studies on linguistic processing in schizophrenics (see Introduction).

N400 Abnormalities The present study replicates and extends previous reports of N400 abnormalities in schizophrenia. One result in which all studies (including this one) are in agreement is that N400 latency is prolonged in schizophrenic patients (Grillon et al 1991; Koyama et al 1991, 1994; Mitchell et al 1991; Andrews et al 1993). This fact is independent of the task imposed on the subjects. The delayed latency of N400 could be due to slower information processing as has been pointed out before (Grillon et al 1991). It is important to identify the locus of this putative deficit. Many authors believe that P300 is an index of stimulus evaluation time. Thus reports of normal P300 latencies in schizophrenia suggest that evaluation of the more elementary stimuli, typical of "oddball" paradigms, is not affected in this disease (Duncan 1988). Previous reports on N400 in schizophrenia used printed word as stimuli (Grillon et al 1991; Koyama et al 1991, 1994; McCarley et al 1991; Mitchell et al 1991; Andrews et al 1993), a fact that opens the question of whether the delayed latency could be due to difficulties in word recognition during reading; however, the fact that delayed N400 latencies were obtained when pictures were used as stimuli reinforces the idea that the deficit is not specific to word recognition. A deficit in the use of semantic memory would explain the results with both words and pictures. The abnormal notched peak morphology of the grand average N400 difference waveform was also described by Koyama et al (1991) as a double-peak morphology. These authors suggest that this split wave shape constitutes one

of the ERP abnormalities characteristic of schizophrenia. In 70% of the cases in this study such a notched-peak morphology was observed. One explanation of these results is that N400 is comprised of several components, a subgroup of which are more retarded than the others in schizophrenics. The idea that in the N400 time region several subcomponents are active has been suggested before (VanPetten et al 1991). More research is necessary to determine the precise nature of the two peaks. The amplitude of N400 (measured in the difference waveform) was clearly reduced at midline sites in schizophrenics, a result that agrees with previous N400 studies employing semantic matching tasks (Grillon et al 1991; Mitchell et al 1991; McCadey et al 1991). This was reflected by the fact that N400 amplitude differences between patients and controls were significant in all tests restricted to the midline. The ANOVA on N400, which included all sites common to Cuban and Chinese subjects, just missed significance. This was probably due to a few sites where the reduction was not significant, and to a small group of sites where the trend was reversed, although this last effect was not significant at any electrode. The lack of significantly larger N400 amplitudes for controls with respect to patients (or the reversal of this trend) at some sites could be explained either by the enhancement of a separate component in patients, or by smaller signal to noise ratio at these electrodes, alternatives that difficult to evaluate due to the lack of significant test outcomes. It is necessary to underline that the diminution of N400 for patients at Cz was significant with the test restricted to this site, even when the stringent Bonferroni criterion was applied. An aspect that was not sufficiently discussed in previous papers is the basis of this reduction, which could be due to either an increased positivity in incongruent trials (smaller N400 in incongruent trials), an increased negativity in congruent trials (larger N400 in congruent trials), or both. In this study the amplitude measurements in the N400 time window are similar in control and schizophrenics for incongruent trials; however, in congruent trials the amplitude in this time window is significantly more negative for schizophrenics relative to controls. The sample size of control and schizophrenic groups (each with 40 subjects when collapsed over nationality) was adequate to ensure the necessary statistical power of these tests. If the data from previous papers are examined, the same pattern can be found (more negative congruent trials in schizophrenics), both for studies that employ active semantic matching tasks (Mitchell et al 1991), and some employing other tasks (Koyama et al 1991, 1994; Andrews et al 1993). The interpretation of this pattern of results depends of course on which hypothesis about the functional meaning

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of N400 is accepted. If N400 is consider to reflect prelexical priming (Kutas and Hillyard 1984), then the results of this study suggest that in schizophrenics less priming is produced by congruent stimuli, since the amount of negativity should be inversely related to the amount of contextual preactivation. This is in direct contradiction with the proposal that associations are facilitated or disinhibited in schizophrenia (Maher et al 1983); however, it is necessary to point out that enhanced priming during lexical decision in schizophrenia is larger when the time between stimuli, or stimulus onset asynchrony (SOA), is very short (Spitzer et al 1993). The SOA used in this paper was much larger than those typically used in priming studies (more than 1 sec), and diminished priming for long SOAs is not necessarily incompatible with enhanced priming at short SOAs. A different interpretation of the results emerges if N400 is conceived as a reflection of the amount of postlexical processing (Halgren 1990). Under this hypothesis, the results described in this study suggest that in schizophrenia the congruent stimuli require equivalent amounts of postlexical processing as incongruent stimuli, since the amount of negativity in both cases is similar. In contrast, controls seem to require less processing for congruent stimuli since the N400 associated with congruent stimuli is smaller than that associated with incongruent stimuli. The idea that postlexical processing is deficient in schizophrenics is also concordant with the behavioral results obtained in our study. The last explanation is in line with the suggestion by Andrews et al (1993) that N400 amplitude is reduced in schizophrenia only if the subjects are involved in an active matching task. They also suggest that if the subjects read passively, or are involved in another task such as lexical decision, N400 is not reduced. If this is true, then only the mental operations not common to both groups of task could be responsible for the N400 amplitude abnormalities. Since lexical access is presumably necessary for passive reading and lexical decision, these operations should correspond to postlexical processes invoked by the active matching task. Whatever explanation of N400 is accepted, the results indicate that in schizophrenics the processing of congruent stimuli is not facilitated by context as it is in controls. This conclusion converges with the data obtained with ambiguous words, mentioned in the Introduction; however the results are inconsistent with any simple version of the enhanced (or disinhibited) associations hypothesis. The scalp topography of N400 of schizophrenics was not different from that of controls. This result is in contradiction with the report by McCarley et al (1991), who found that N400 was reduced with respect to controls in a sentence matching task, with the difference between

groups largest at left-side electrodes (see Figure 9 in McCarley et al 1991); however, the difference in stimulus modality has to be taken into account when discussing these topographic effects. As mentioned in the Introduction the N400 elicited by words may not be entirely equivalent to that elicited by pictures. If N400 is really a mixture of subcomponents the relative amplitude of these (and thus the overall topography) could vary when elicited by different types of stimuli.

N400, P300, Signal Detection, and Attention Some authors have identified N400 as a delayed N200 (Polich 1985; Deacon et al 1991), which is part of the late positive complex that includes P300. In a certain sense both N200 and N400 are elicited by deviant stimuli (Kutas and VanPetten 1988). This opens the possibility that the reduced N400 of schizophrenics arises through the same mechanisms as the P300 reduction also found in these subjects. In other words the amplitude reduction of both P300 and N400 could be due to defective attention. One recent model explicitly postulates that the defect in signal detection (related to P300 amplitude) and the deficit in semantical context utilization are due to the same mechanism (Cohen and Servan-Schreiber 1992). Several considerations, however, are contrary to such a unitary explanation. First, the effect of directing attention away from words is to reduce the negativity associated with incongruent stimuli (McCarthy and Nobre 1993), whereas the results from the present study indicate that in schizophrenics N400 is large for both congruent and incongruent stimuli. Second, smaller P300 amplitudes are associated with reduced N200 amplitudes, as typical for the frequent standard stimuli. If N400 were delayed N200 then it should be reduced for the deviant (incongruent stimuli); however this prediction is false: in schizophrenia, the N400 is enhanced for all stimuli. The last argument is that the amplitudes of N400 and P300 are not correlated across subjects, suggesting independent processes. All of these considerations argue against the explanation that N400 is reduced in schizophrenics due to a generalized attentional deficit. The absence of any congruity effects on the late positivity following N400, and its equivalence between controls and schizophrenics, were interesting findings. They support the idea that N400 and late positivities may reflect different processes. The smaller N400 is not a result of a generalized defect that afflicts all cognitive processes within the same task. In fact, the smaller oddball P300 in schizophrenics, in the presence of a normal amplitude of the LP following N400, leads to the conclusion that each component can index different processes, even within the family of late positivities.

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Patient Characteristics Two aspects of patient selection should be discussed, since they limit the scope of the conclusions. First, in common with previous studies of N400 in schizophrenia, all patients in this study were under neuroleptic medication. It is necessary to dissociate the effects of illness itself from effects due to medication. It would be useful to repeat this study with unmedicated schizophrenics, ideally in "first break" cases. In spite of this limitation, the present study could be useful because it draws attention to one ERP profile, among many possible that could be associated with schizophrenia. This could help optimize studies of unmedicated schizophrenics, subjects who are somewhat difficult to recruit. The second limitation that should be discussed is that patients could have differed in psychopathology. Perhaps additional tests on the patients should have been performed to assess the extent and severity of language, thought, and intellectual disorders. This idea has been advanced by GriUon et al (1991), who suggested that for ERP studies a more detailed exploration of symptoms, for example with the Scale for the Assessment of Positive Symptoms (SAPS) and Scale for the Assessment of Negative Symptoms (SANS) scales (Andreasen 1982), would be useful. One study has found significant correlation between ratings of positive thought disorder and of attention deficit with N400 amplitude (Andrews et al 1993). Moreover, in another study enhanced semantic priming in schizophrenics relative to control subjects was larger for thought-disordered patients (Spitzer et al 1993). These problems will have to be dealt with in future studies. Cross-Cultural E R P Comparison This study cuts across several psycholinguistic differences between Spanish and Chinese by using a semantic matching task based on pictures of concepts common to both

cultures. No previous cross-cultural studies have been carried out with schizophrenic patients using N400. Indeed, the use of pictures not only facilitates comparisons between cultures, but also helps comparisons across different educational levels in the same culture. In spite of the initial goals, Chinese subjects made somewhat more mistakes than Cubans in the semantic matching task; however, these errors were concentrated in a few items (such as a drawing of a pineapple). If these troublesome items are excluded the discrimination sensitivity score for the matching task does not differ between countries. Also the critical interaction between nationality and health condition was not significant for the discrimination sensitivity. Moreover, trials associated with mistakes were excluded from the ERP averages. Additionally the ERPs obtained, after excluding trials with mistakes, did not differ between controls from both countries. In summary, despite the arguments that support the utility of pictures for cross-cultural N400 studies, the need for adequate norms is underlined. No differences were found in behavior or in the ERPs between Cuban and Chinese schizophrenics. If the conclusions derived from the preceding discussion is accepted, this implies that schizophrenics in both countries have difficulty in using context for postlexical processing of complex stimuli such as pictures or words. This type of data buttresses the case for a common disease entity. Further cross-cultural ERP work is necessary to confirm these ideas and to extend our knowledge of the pathophysiology of schizophrenia. The research described in this paper was supported by the collaboration agreement between the Institute of Mental Health of Beijing Medical University and the Cuban Center for Neuroscience. The authors wish to acknowledge Dr. Milagros Marot for the selection and evaluation of the Cuban patients. The helpful comments of three anonymous reviewers are gratefully acknowledged.

References American Psychiatric Association (1980): Diagnostic and Statistical Manual of Disorders, 3rd ed. Washington, DC: American Psychiatric Press. Andreasen NC (1982): Negative symptoms in schizophrenia. Arch Gen Psychiatry 39:784-788. Andrews S, Mitchell P, Fox AM, Catts SV, Ward PB, McConaghy N (1990): ERP indices of semantic processing in schizophrenia. In Brunia CHM, Gaillard AWK, Kok A (eds), Psychophysiological Brain Research, vol 2. Tilburg, The Netherlands: Tilburg University Press, pp 221-225. Andrews S, Shelly AM, Ward PB, Fox AM, Catts SV, McConaghy N (1993): Event-related potential indices of semantic processing in schizophrenia. Biol Psychiatry 34:443-458. Baribeau-Braun J, Picton TW, Gosselin J (1983): Schizophrenia:

A neurophysiological evaluation of abnormal information processing. Science 219:874-876. Barrett S, Rugg M (1990): Event related potentials and the semantic matching of pictures. Brain Cogn 14:201-212. Benjamin TB, Watt NF (1969): Psychopathology and semantic interpretation of ambiguous words. J Abnorm Psychol 74: 706-714. Bentin S, McCarthy C, Wood CC (1985): Event related potentials associated with semantic priming. Electroencephalogr Clin Neurophysiol 60:343-355. Cohen JD, Servan-Schreiber D (1992): Context, cortex and dopamine: A connectionist approach to behavior and biology in schizophrenia. Psychol Rev 99:145-177. Cohen RM, Semple WE, Gross M, Nordahl TE, Holcomb HH,

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Dowling MS, Pickard D (1988): The effects of neuroleptics on dysfunction in a prefrontal substrate of sustained attention in schizophrenia. Life Sci 43:1141-1150. Cornblatt B, Lenzenweger MF, Erlenmeyer-Kimling L (1989): A continuous performance test, identical pairs version: II. Contrasting attentional profiles in schizophrenic and depressed patients. Psychiatry Res 29:65- 85. Chapman JL, Chapman JP (1973): Problems in the measurement of cognitive deficit. Psychol Bull 79:380-385. Chapman JL, Chapman JP, Miller GA (1964): A theory of verbal behavior in schizophrenia. In Maher BA (ed), Progress in Experimental Personality Research, vol 1. San Diego, CA: Academic Press, p 135. Deacon D, Breton F, Ritter W, Vaughan HG (1991): The relationship between N2 and N400: Scalp distribution, stimulus probability, and task relevance. Psychophysiology 28: 185-200. Duncan C (1988): Event-related brain potentials: A window on information processing in schizophrenia. Schizophr Bull 14: 199 -203. Duncan CC, Morisha JM, Fawcett RW, Kirsh DG (1987): P300 in schizophrenia: State or trait marker? Psychopharmacol Bull 23:497-501. Friedman D (1990): Cognitive event-related potential components during continuous recognition memory for pictures. Psychophysiology 27:136-148. Friedman D, Sutton S, Putnam L, Brown C, Erlenmeyer-Kimling L (1988): ERP components in picture matching in children and adults. Psychophysiology 25:570-589. Garmezy N (1977): The psychology and psychopathology of attention. Schizophr Bull 3:360-369. Grillon C, Courchesne E, Ameli R, Geyer MA, Braff DL (1990): Increased distractibility in schizophrenic patients. Electrophysiological and behavioral evidence. Arch Gen Psychiatry 47:171-179. Grillon C, Ameli R, Glozer WM (1991): N400 and semantic categorization in schizophrenia. Biol Psychiatry 29:467-480. Gutierrez J (1994): Esquizofrenia y preactivacion contextual: Un estudio de potenciales relacionados con eventos cognitivos. Unpublished thesis dissertation, Havana Higher Institute of Medical Sciences. Halgren E (1990): Insights from evoked potentials into the neuropsychological mechanisms of reading. In Schiebel AB, Wechsler AF (eds), Neurobiology of Higher Cognitive Function. New York: Guilford, pp 103-150. Harbin TJ, Marsh GR, Harvey MT (1984): Differences in the late components of the event related potentials due to age and to semantic and non-semantic tasks. Electroencephalogr Clin Neurophysiol 59:489-496. Jablensky A (1992): Cross-cultural aspects of schizophrenia. Triangle 31:163-174. Kaplan HI, Sadock BJ (1991): Synopsis of Psychiatry. Baltimore, MD: William & Wilkins. Keselman HJ, Rogan JC (1980): Repeated measure F test and psychophysiological research: Controlling the number of false positives. Psychophysiology 17:499-503. Koyama S, Nageishi Y, Simakochi M, Hokama H, Miyazato Y, Miyatomi M, Ogura C (1991): The N400 component of event

BIOL PSYCHIATRY 1996;40:189-202

201

related potentials in schizophrenic patients: A preliminary study. Electroencephalogr Clin Neurophysiol 78:124-132. Koyama S, Hokama H, Miyatani M, Ogura C, Nageishi Y, Shimakochi M, (1994): ERPs in schizophrenic patients during word recognition task and reaction time. Electroencephalogr Clin Neurophysiol 92:546-554. Kutas M, Hillyard SA (1980): Reading senseless sentences. Brain potentials reflect semantic incongruity. Science 207: 203-205. Kutas M, Hillyard SA (1984): Brain potentials during reading reflect word expectancy and semantic association. Nature 307:161-163. Kutas M, VanPetten C (1988): Event related potential studies of language. In AcHes PK, Jennings JR, Coles MGH (eds), Advances in Psychophysiology. Greenwich, CT: JAI Press. Kwapil TR, Hegley DC, Chapman LJ, Chapman JP (1990): Facilitation of word recognition by semantic priming in schizophrenia. J Abnorm Psychology 99:215-221. Laurent JP, Baribeau J (1992): AERPs and clinical evaluation of thought disorders over five years. Int J Psychophysiol 13: 271-282. Maher BA, Manschreck TC, Molino MA (1983): Redundancy, pause distribution and thought disorder in schizophrenia. Lang Speech 26:191-199. Maher BA, Manschreck TC, Hoover TM, Weisstein CC (1987): Thought disorder and measure features of language production in schizophrenia. In Harvey P, Walker E (eds), Positive

and Negative Symptoms in Psychosis: Description, Research and Future Directions. Hillsdale, NJ: Erlbaum, pp 195-215. Manschreck TC, Maher BA, Milavetz JJ, Ames D, Weisstein CC, Schneyer ML (1988): Semantic priming in thought disordered schizophrenic patients. Schizophr Res 1:61- 66. McCallum WC, Famer SF, Pocock PK (1984): The effect of physical and semantic incongruities on auditory event related potentials. Electroencephalogr Clin Neurophysiol 59:477488. McCarley R, Faux SF, Shenton ME, Nestor PG, Adams J (1991): Event-related potentials in schizophrenia: Their pathological correlates and a new model of schizophrenic pathophysiology. Schizophr Res 4:209-231. McCarthy G, Nobre A (1993): Modulation of semantic processing by spatial selective attention. Electroencephalogr Clin Neurophysiol 88:210-219. McCarthy G, Wood CC (1985): Scalp distributions of event related potentials: An ambiguity associated with analysis of variance models. Electroencephalogr Clin Neurophysiol 62: 203-208. Mitchell PF, Andrews S, Fox AM, Catts SV, Ward PB, McCounghy N (1991): Active and passive attention in schizophrenia: An ERPs study of information processing in a linguistic task. Biol Psychology 32:101-124. Morice R (1986): The structure, organization, and use of language in schizophrenia. In Burrows O, Norman P, Rubinstein T (eds), Handbook of Studies on Schizophrenia, Part I. Amsterdam: Elsevier Science Publishers, pp 131-144. Neville H (1985): Biological constraints on semantic processing: A comparison of spoken and signed languages. Psychophysiology 22:576.

202

BIOL PSYCHIATRY

M . A . Bobes et al

1996;40:189-202

Palvio A (1986): Mental Representations. New York: Oxford University Press. Polich J (1985): Semantic categorization and event related potentials. Brain Lang 26:304-321. Potter MC, Faulconer BA (1975): Time to understand pictures and words. Nature 253:437-438. Pritchard WS (1986): Cognitive event-related potential correlates of schizophrenia. Psychol Bull 100:43-66. Rugg M (1985): The effects of semantic priming and word repetition on event related potentials. Psychophysiology 22: 435-443. Rugg M (1990): Event related potentials dissociate repetition effects of high and low frequency words. Mem Cogn 18:367379. Salzinger K, Portnoy S, Pisoni DB, Feldman RS (1970): The immediacy hypothesis and response-produced stimuli in schizophrenic speech. Abnorm Psychology 76:258-264. Schwartz S (1982): Is there a schizophrenic language? Behav Brain Sci 5:579-626.

Spitzer M, Braun U, Hermle L, Maier S (1993): Associative semantic network dysfunction in thought-disordered schizophrenic patients: Direct evidence from indirect semantic priming. Biol Psychiatry 34:864-877. Strandburg RJ, Marsh JT, Brown WS, Asamow RF, Guthrie D, Higa J, Yee-Bradbury CM, Nuechterlein KH (1994): Reduced attention related negative potentials in schizophrenic adults. Psychophysiology 31:272-281. Swets JA (1964): Signal Detection and Recognition by Human Observers. New York: Wiley. VanPetten C, Kutas M, Kluender R, Mitchiner M, Melsaac H (1991): Fractionating the word repetition effect with event related potentials. J Cogn Neurosci 3:131-150. Wang WS (1973): The Chinese language. Scientific Am 173:5160. Ward PB, Catts SV, Fox AM, Michie PT, McConaghy N (1991): Auditory selective attention and event-related potentials in schizophrenia. Br J Psychiatry 158:534-539.