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N400 and semantic categorization in schizophrenia
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N400 and Semantic Categorization in Schizophrenia Christian Grillon, Rezvan Ameli, and William M. Glazer
The N400 component of event-related potentials (ERPs) was investigated in medicated schizophrenic patients and normal controls in a semantic categorization task. The subjects" task was to indicate whether pairs of words were semantically related or unrelated. The ERPs to the unrelated second words of the pairs contained a negative component, N400, which was reduced and delayed in the patients. However, inspection of individual subjects' data indicated that N400 was abnormal only in a subgroup of schizophrenics. Abnormalities in the amplitude of N400 suggest impairments in semantic expectancies, whereas abnormalities in the latency, of N400 suggest a delay in information processing.
Introduction Abnormalities in the semantic aspects of language in schizophrenic individuals are one of the hallmarks of the disorder. Schizophrenics" speech often contains incoherence and inappropriate associations that are referred to as "loosening of associations." A number of techniques such as verbal conditioning (Salzinger et al 1970), word associations (Horton et al 1963; Johnson et al 1964; Lisman and Cohen 1972), and computer-assisted grammatical analysis (Thomas et al 1990; King et al 1990) have been utilized to investigate the language of these patients. Schizophrenics' language is characterized by syntactic errors (Chaika 1974; Morice and Ingram I982), low complexity, low integrity and dysfluency (Thomas et al 1990), deviant word associations (Chapman and Chapman 1973), and insensitivity to verbal contexts (Mednick 1958). The importance of verbal context and prior experience has also been emphasized by Patterson (1987) who suggested that schizophrenics' language disturbance might be related to their failure to generate appropriate linguistic expectancies. Whether these abnormalities reflect a specific language competence deficit or an impairment in language performance is not clear. Schwartz (1982) argued that schizophrenics were only deficient in language performance and that this impairment was caused by a general information processing deficit (Nuechterlein and Dawson 1984). Indeed, schizophrenics have been shown to be slow in processing information (Yates 1966), to possess a defective filter mechanism (Venables 1964), and to be vulnerable to distraction (Oltmanns and Neale 1975; Grillon et al 1990). Any one of these deficits could potenti2!ly affect .~chizophrenics' language performance. Recently, the utilizatioh of event-related potentials (ERPs) has proven to be a powerful tool to investigate information and linguistic processing. ERPs provide information about
From the Yale University School of Medicine Department of Psychiatry Genetic Epidemiology Research Unit, New Haven, CT (CG, RA). and the Yale University School of Medicine, Connecticut Mental Health Center, New Haven, CT (WMG). Address reprint requests to Christian Grillon, Yale University School of Medicine, Depamnent of Psychiatry, GERU. 40 Temple Street (Lower Level), New Haven, CT 06510-3223. Received Febma,-y 9, 1990; revised August 22, 1990.
© 1991 Society of Biological Psychiatry
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the nature and timing of neuronal events independent of behavioral data such as reaction time. They also provide information about the topographical distribution of these neuronal events. This is particularly important ~ a u s e language functions are believed to be largely lateralized. An ERP negative component peaking at about 400 msec has been shown to associated with linguistic processes (Kurus and Hillyard 1980, 1984). This component, labeled N400, has been obtained in various linguistic tasks involving sentence processing (Kutas and Hillyard 1980, 1984; Polich et al 1980), lexical decision making (Rugg 1985; Bentin et al 1985; Boddy 1986; Bentin 1987), and semantic categorization (Polich et al 1980; Holcomb 1986). N 4 ~ is elicited by words that deviate from an established semantic context (Kutas and Hillyard 1984; Neville et al 1986). Its magnitude is positively related to word unexpectedness or unpredictability within a given context (Harbin et al 1984; Kutas and Hillyard 1984). It has been proposed that N400 is an inverse function of the amount of semantic priming that a word has received from a preceding context (Kutas and Hillyard 1984; Bentin et al 1985). Although the view of N400 as a specific index of language processing is still a matter of debate (Polich 1985; Barrett et al 1988), it is clear that the elicitation of a large N400 in response to unpredictable words reflects the ability to appreciate the semantic relationship between a word and the context in which it is presented. It is likely that failure to appreciate such a relationship (i.e., failure to elicit N400) and/or delay in this process (i.e., delay in eliciting N400) could have dramatic effects on language functions. At the present time, the study of language in schizophrenics with ERPs, and more particularly N400, is in its infancy. Patterson (1987) has hypothesized that N400 should be reduced in schizophrenics because of their inability to generate appropriate expectancies. However, recent studies have provided conflicting results. Adams et al (1989) have reported that N400 was reduced in 2 of 4 schizophrenics in a study utilizing sentences. Using a similar task, Andrews et al (1989) did not find any N400 amplitude abnormality in schizophrenics. However, Andrews et al found that the schizophrenics' N400 was reduced in a task requiring semantic decision making. None of these studies reported N400 latency measures. In the present experiment, N400 amplitude and latency were investigated in schizophrenics in a semantic categorization experiment.
Method
Subjects Subjects consisted of 17 male chronic schizophrenic patients recruited from the outpatient clinic of the Connecticut Mental Health Center. Their diagnosis was based on chart review and individual interviews. All patients were diagnosed as chronic schizophrenic according to the Research Diagnostic Criteria (RDC) (Spitzer et al 1978) and the DSM-III. The data of three patients were excluded from analysis because of excessive artifacts in the ERPs. The remaining 14 patients were matched with 14 normal controls for age (patients 36.4 _ 7. l years, range 26-54 years; controls 37.5 _ 5.9 years, range 30-49 years) and length of education (patients 12.6 ± 2.6 years, range 9-20 years; controls 13.5 ± 2.9 years, range 8-18 years). One subject from each group was left handed. All the patients were takin neuroleptic medication at the time of the recording. The average daily neuroleptic intake was 967 ( ± 499) mg chlorpromazine equivalent. The Brief Psychiatric Rating Scale score (BPRS) for 13 of the 14 patients (1 subject had not been assessed with the BPRS) was 35.4 ± 5.2.
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Stimuli The stimuli were single words (duration 289 msec) presented one at a time on a computer screen in a 5 x 4 cm rectangle. These words were presented in pairs and were or were. not semantically related (e.g., cat/dog versus cat/vase). All the words were easy to understand (Carroi and White 1973) and were chosen because of their high frequeacy of occurrence in spoken English language (Thorndike and Lorge 1944).
Procedure Subjects were comfortably seated in a reclining chair approximately 55 inches from the screen. They looked at the center of the computer monitor and were instructed that pairs of words would be sequentially presented on the screen, and that they s.~cJuld indicate their response by pressing either of two buttons with their dominan~ hand after presentation of the second word of each pair. They were also instructed to avoid blinking or moving their eyes whenever a word appeared on the screen. The task was to press the "yes" button when the word pairs were related and the "no" button when they were unrelated. The stimulus onset asynchrony between the first and the second word of each pair was 1020 msec. The subjects were told that accuracy was very important for the study and that speed was not taken into consideration. They were asked to refrain from quick responding. These instructions were given in order to delay the late positive component which can overlap with N400. There were a total of 45 related and 45 vP~related werd pairs thai were randomly intermixed.
ERP Recording The electroencephalogram (EEG) was recorded from 13 electrodes attached to an elastic cap. The electrodes were placed over midline frontal, central, and parietal (Fz, Cz, Pz); homologous central (C3, C4); occipital (01, 02); anterior temporal [BL, BR: half of the distance between F7(8) and T3(4)]; temporal (L41, R41: 33% of the interaural distance lateral to Cz); and temporo-parietal (WL, WR: 30% of the interaural distance lateral to a point 13% of the nasion-inion distance posterior to Cz) sites. Over the left hemisphere, BL and WL were approximately over Broca's area and Wernicke's area, respectively. All these electrodes were referred to linked mastoids. Eye movements were monitored via a horizontal derivation (bipolar recording: external canthus of each eye) and a vertical derivation (lower orbital ridge of the left eye referred to linked mastoids). Electrode impedance did not exceed 5 Kohm. Electrical activity was amplified with a ban@ass of 0.03 and 70 Hz.
Data Collection The EEG and electrooculogram (EOG) signals were digitized at a rate of 200 Hz for 100 msec before and 1180 msec a,,er stimulus onset. TriMs contaminated by eye movements, muscle artifacts, or lead sway were excluded during averaging by computer algorithms. The artifact rejection level was set at 100 IxV for most of the subjects; however, this criterion was lowered when eye artifacts were present in the UpE or LoE electrodes. The artifact-free EEG recordings were separately averaged according to Related or Unrelated word pair trials that were followed by a correct response. There was no difference between the control and patient group in the number of artifacts deleted.
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Data Analysis Peak amplitude (relative to 100 msec prestimulus baseline) and peak latency of the ERP components were computed using the following windows after visual inspection of the ERPs: NI00, 75-150 msec; P200, 150-250 m ~ ; N400, 300-550 msec; and SP, 500800 msec. In addition, the mean amplitudes for N400 over the 300-550 msec range and SP over the 500-800 msec range were calculated. We also attempted to determine N400 onset latency using three different measurement methods. In the first method, N400 onset latency w ~ determined by visu~ inspection, extrapolating the best fit of the descending edge of the wave to the baseline (Ritter et al 1983). Two other estimates were obtained by automatic computer measurements (Hansen and Hillyard 1984): "'baseline onset latency" (BOL), and "extrapolated onset latency" (EOL). The BOL method corresponds to Hansen and Hillyard's (1984) "baseline are~." In the BOL method, the negative deflection of the longest duration is searched in the prestimulus baseline period. The first continuous area in the 100-600 msec window, which exceeds twice this measure, is calculated and the latency of the first point of this area is reported. In the EOL method, two points of the waveform in the 100-600 msec range corresponding to 0.25 and 0.75 of the peak are calculate. A line passing through these two points is extrapolated and the point of intersection of this line with the baseline is reported. This last method was conceptually very close to the visual inspection method. All measurements were made at Pz when possible. When a measurement could not be determined at Pz, computations were performed at the electrode with the highest negativity. The data were submitted to a series of an~,iyses of variance (ANOVAs). For the midline electrodes, two-way ANOVAS were used with word type (related, unrelated) and electrode (Fz,Cz,Pz) as the two factors. For the lateral electrodes, the design was a three-way ANOVA with word type (related, unrelated); electrode [anterior temporal (BL,BR), temporal (L41 ,R41), central (C3,C4), temporo-parietal (WL,WR), occipital (01,02)]; and hemisphere (left, right) as the three factors. Similarly, group comparisons were performed with three-way ANOVAs with group (2), word type (2), and electrode (2) as the three factors, and four-way ANOVAs with group (2), word type (2), electrode (5), and hemisphere (2) as the four factors. In order to minimize type I errors, reduced degrees of freedom (Huyhn-Feldt) were used.
Results Behaviorol Data All the subjects performed above chance level. Both the controls and the patients had a high rate of response accuracy. The controls correctly identified 95.7% ( _+4.4%) related and 98.2% ( _ 2.8%) unrelated word pairs. The schizophrenics correctly identified 91.1% ( _+9.8%) related and 94.4% ( _ 6.7%) unrelated word pairs. These results were analyzed in an ANOVA with repeated measures with group (controls, patients) and word type (related, unrelated) as the two factors. The group main effect was significant [F(1,26) = 4.3, p ~< 0.051 andicating that the patients were less accurate than the controls. The group X word type interaction effect was not significant [F(1,26) = 1,1, p ~< 0.8]. In the present experiment, the reaction time (RT) was not a relevant index for evaluating the speed of information processing as the subjects were asked to refrain from quick responding. However, because the speed of responding might have affected the ERPs,
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Figure 1. Topographical distribution of the ERPs to related (continuous line) and unrelated (dashed line) words in the control group. Note that the representation of electrode locations is approximate.
the RT data were analyzed. The controls were faster to respond than the patients. The mean RT for the controls was 982 msec ( +__240 msec) for related and 1000 msec ( +__167 msec) for unrelated words. The mean RT for the patients was 1308 msec (+_ 475 msec) for related and 1472 msec ( ___462 msec) for unrelated words. Statistical analysis showed significant main effects for group [F(1,26) = 9.02, p ~ 0.006] and for word type [F(1,26) = 7.4, p <~ 0.001] and a group X word type interaction effect [F(1,26) = 4.7, p <~ 0.041.
Event-Related Potentials Measures The grand average ERPs to related and unrelated words at all electrode sites for the control and the patient groups are presented in Figures 1 and 2, respectively. Both the related and the unrelated words elicited a negative component (NI00:75-150 msec range) followed by a positive component (P200:150-250 msec range). P200 was followed by a sustained positivity (SP) which started 250 msec poststimulus and lasted throughout the duration of the recording epoch. There was a negative deflection in the 300-550 msec range in the ERPs to unrelated words. This deflection (N400) was more readily identifiable in the subtraction waveforms obtained by subtracting the voltage of the ERPs to related words from the corresponding points of the ERPs to unrelated words (Figure 3).
NIO0 and P200. There were no significant group differences in amplitude, latency, or topographical distribution for NI00 and P200. N400. The 300-550 msec range was the area of the largest difference between ERPs to related and unrelated words in both the controls and the schizophrenics [peak amplitude:
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BIOL PSYCHIATRY 1991;29:4b7--480
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Table I. N400 Measures in the Diffecence Waveforms Controls Amplitude
Patients
Mean ampl.
Latency
Amplitude
Mean ampl.
Fz
4.7 (2.2)
!.9 11.8)
406 t82)
3~2 (2.5)
0.6 (2.3)
487 (48~
Cz
5.9 (2.0)
2.7 (2.2)
418 (79)
3,6 t~2.6)
I,I (2.2~
482 (54)
Pz C3 C4
6.0 (!.9) 3.1 (2.0) 4.8 (i.7)
2.5 (I.7) 0.7 (1.7) 2.4 (i.5)
408 (71) 404 (73) 446 (81)
4.7 (2.7) 2.5 (2.5) 2.5 (2.1)
1.6 (1.8) 0.2 (2.3) 0.2 (2.1)
451 (66) 421 (79) 483 (74)
BL
3.6 (2.1)
0.9 (1.6)
411 (74)
3.2 (1.6)
0.4 (1.7)
458 (73)
BR !.41 R41 WL WR Ol 02
4.8 (!.8) 4.2 (2.1) 5.8 (2.0) 4.5 (2.6) 5.8 (2.0) 4.9 (2.3) 4.9 (2.3)
2.3 (1.7) 1.4 t!.9) 2.7 (i.9) 1.5 (1.9) 2.8 (1.7) ! .7 (1.7) 1.9 (1.4)
439 (82) 423 (74) 437 (80) 427 (74) 433 (77) 434 (59) 436 (75)
3.5 (2.6) 3.1 (2.3) 3.8 (2.6) 3.8 (2.0) 3.7 (2.3) 4.4 (1.4) 4.2 (2.8)
1.0 (2.7) 0.6 (2.0) 0.9 (2.4) !. 1 (! .9) 1.0 (2.3) ! .7 (! .0) 1.4 (1.0)
479 (64) 444 (65) 495 (48) 437 (76) 463 (64) 462 (53) 438 (59)
midline electrodes, F ( 1 , 2 6 ) = 10.0, p ~< 0.004; lateral electrodes, F ( 1 , 2 6 ) = 10.4, p ~< 0.003; m e a n amplitude: midline electrodes, F ( 1 , 2 6 ) = 10.1, p ~< 0.004; l a t e ~ electrodes, F ( 1 , 2 6 ) = 10.4, p ~< 0.003]. This difference appeared as a negative component (N400) in the difference waveforms (Figure 3). In the controls' difference waveforms, N400 was largest at Pz (6.03 IxV) where it peaked at 408 msec and was larger over the right than the left hemisphere [peak amplitude, F ( 1 , 1 3 ) = 13.0, p ~< 0.003; mean amplitude, F ( l , 1 3 ) = 10.9, p ~< 0,005]. Tables I and 2 show that N400 was smaller and later in the patients, compared with the controls. In addition, N400 was not asymmetrically distributed [ F ( 1 , 1 3 ) = 0.1, p <~ 0.7]. Group comparisons o f N400 were performed on the difference waveform measures. The reduced N 4 0 0 in the schizophrenics was significant only at midline electrodes for the peak amplitude measures [ F ( 1 , 2 6 ) = 4.1, p <~ 0.05] but was not significant at midline electrodes for the mean amplitude measures [F(1,26) = 2.9, p <~ 0.1] or at lateral electrodes for both the peak amplitude and the mean amplitude measures [ F ( 1 , 2 6 ) = 3.2, p ~< 0.08 and F ( ! , 2 6 ) = 3.5, p ~< 0.07, r e s ~ c t i v e l y ] . I n s ~ c t i o n of the individual N400 data indicated that there was a large intersubject variability in the schizophrenic group. N400 was in the normal range in some patients, whereas it was small or absent
Table 2. N400 Peak, Onset Latency, and Duration (msec) Difference Waveforms Methods
Controls (N = [3)
Patients (N = 13)
Peak latency Visual inspection (N400 duration) Baseline onset iat. (BOL) (N400 duration) Extrapolated onset lat. (EOL) (N400 duration)
406 +_ 78 294 ± 68 (112) 251 -- 89
486 ~ 84 394 ± 93 (91) 352 _ 104
df = 24; NS = nonsignificant;T = t-test ~p ~ 0.05: bp ~ 0.01.
(155)
(I 33)
295 +- 72 (111)
394 +_ 113 (91)
T 2.48"
3.12b 0.46 N5 2.65~' 0.55 NS 2.67b 0.65 NS
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in others. N400 peak amplitude was within 1 SD from the control's mean in 7 patients and l SD smaller than the controls' mean in 6 patients (Figure 4). The distribution of N400 over the two hemispheres was significantly different in the two groups [group x hemisphere interaction: peak amplitude, F(1,26) = 3.8, p <~ 0.06; mean amplitude, F(1,26) = 4.2, p ~< 0.05]; N400 was larger in the controls compared with the patients over the right hemisphere [peak amplitude, F(1,26) = 5.7, p ~< 0.02; mean amplitude, F(1,26) = 6. l, p <~ 0.02] but not over the left hemisphere. N400 was significantly delayed in the schizophrenic group, compared with the contr{. group [F(1,26) = 7.7, p ~< 0.01]. N400 latency was l SD later than the controls' mean in 7 patients (Figure 4). The patients with N400 amplitude reduction were not necessarily the same as the patients with N400 latency delay. Furthermore, in neither group was the correlation between N400 amplitude and N400 latency measures significant. SP. The ERP activity in the 500-800 msec range was larger (more positive) for related than for unrelated words in both groups [peak amplitude: midline electrodes, F(1,26) =
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Table 3. Subgroups" Performance
n Age (yr) Education {yr) RT to related words (msec) RT to unrelated words (msec) Accuracy to related words (%) Accuracy to unrelated words (%~
Fast RT patients
Slow RT patients
7 34.5 13. I 989 ! 160 95 97
7 38.2 14.0 1627 1785 87 92
Matc~ c~s 7 37.6 |4°0 I042 1042 96 97
RT = reaction time; n = number of patients,
6.1, p ~< 0.02; lateral electrodes, F(1,26) = 3.4, p <~ 0.07: :ateral electrodes, F(1,26) = 4.6, p ~< 0.04]. SP was larger in the control than in the p~,tiem i-roup [peak amplitude: midline electrodes, F(1,26) = 10.1, p <~ 0.003; lateral electrode~, ~'( 1,26) = 9.6, p <~ 0.004; mean amplitude: midline electrodes, F(1,26) = 8.2, p ~< 0.f~8; lateral electrodes, F(1,26) = 9.0, p <~ 0.0051. In addition, SP was larger over the right than over the left hemisphere for unrelated words but not for related words in the controls [word type x hemisphere interaction: peak amplitude, F(1,26) = 9.6, p <~ 0.008; mean amplitude, F(1,26) = 11.7, p ~< 0.004]. Such asymmetry was not present in the patient group [word type x hemisphere interaction: peak amplitude, F( i ,26) = 1.3, p ~< 0.3; mean amplitude, F(1,26) = 0.5, p ~< 0.5]. SP latency did not significantly differ in the two groups.
N400 Onset Latency. Because the peak latency of N490 differed in the two groups, we attempted to further characterize this effect by measuring N400 onset latency and duration in the difference waveforms. Latency measure3 could not be obtained in I control and 1 patient because N400 was too small. Table 2 shows the results of the peak and onset latency analyses. N400 onset latency was earlier in the control than in the patient group. In the control group, the estimate of N400 onset latency varied from 251 to 295 msec, whereas in the patient group it varied from 352 to 394 msec. In both groups, the visual inspection and the extrapolated onset latency methods provided similar results. These methods indicated that N400 started about i00 msec later in the patient than in the control group. An estimation of N400 duration was calculated by subtracting N400 onset latency from N400 peak latency (Table 2). N400 duration did not significantly differ in the two groups.
Influence of the Speed of Responding. There was a large RT difference between the controls and the patients. In order to assess whether this RT difference contributed to the N400 delay in the patients, we used the RT data as an independent variable and divided the subjects into two subgroups. First, the patients were divided into a slow RT and a fast RT group. Then, 7 controls were matched for RT with the 7 patients with fast RTs. The description of the subjects of each group and their perform,ance is provided in Table 3. The main results of this analysis were that (1) the ERPs of the fast patient group did not differ from the ERPs of the slow patient group, and (2) the ERP differences between the fast patient group and the RT matched control group were the same as the ones reported for the entire control and patient groups. Thus, there was no difference between
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the fast and slow RT patient groups in terms of their N400 latency and SP amplitude. Compared with their RT matched controls, however, the fast patients had delayed N400 peak latency [lateral electrode, F(I,12) = 9.42, p <~ 0.0091 and smaller SP amplitude [midline electrode, F(1,12) = 5.57, p <~ 0.03; lateral electrode, F(I,12) = 6.02, p ~<
0.031. Effects of drug treatment and clinical symptoms. All of the patients were taking medication at the time of testing. Pearson correlations between N400 latency, N400 peak amplitude, SP peak amplitude (at Pz), and the daily dosage of drug treatment expressed in chlorpromazine equivalent were performed to assess the effect of neuroleptic treatment on the results. None of the correlations reached significance. Similarly, there was no correlation between N400 latency, N400 peak amplitude, and SP amplitude, and the BPRS scores.
Discussion The elicitation of a N400 component to unrelated words in the present experiment is consistent with the general findings in the literature using either sentences (Kutas and Hillyard 1980, 1984) or pairs of words (Polich et al 1980; Harvey and Marsh 1983; Harbin et al 1984; Bentin 1987) and in which behavioral responses are or are not required (Kutas and Hillyard 1980, 1984; Rugg 1985; Benfin et al 1985). In this study, N400 was reduced and delayed in the schizophrenics compared with the controls. These abnormalities, however, did not characterize the entire schizophrenic group as a number of patients had a normal N400. The inspection of the individual data indicates that subgroups of schizophrenics had either a reduced or a delayed N400 and that patients with reduced N400 amplitude did not necessarily have a delayed N400 latency and vice and versa. This result is in agreement with Adams et al's (1989) findings in which N400 to unexpected last words of sentences was abnormal in 2 of 4 schizophrenics. It is possible that N400 variability is yet another aspect of the heterogeneity of the schizophrenic disorders. This view is consistent with studies indicating that subgroups of schizophrenics differ in their linguistic performance 0Vlanschreck et al 1988; Thomas et al 1990). For example, semantic facilitation has been found to be faster in schizophrenics with a thought disordex~ compared with schizophrenics without a thought disorder (Manschreck et al 1988). Similarly, measures of complexity, integrity, and fluency of speech are more impaired in chronic than in acute schizophrenics (Thomas et al 1990). In the present study, there were no correlations between N400 measures and the BPRS scores in the patients. However, it is possible that the utilization of scales assessing more specific symptoms, such as negative and positive symptoms (Andreasen 1982), might have helped to better characterize the schizophrenics with abnormal N400. Thomas et al (1990) have suggested that poor linguistic performance was more associated with negative than with positive symptoms. Assuming that N400 reduction characterizes a subgroup of schizophrenics, what does this tell us about language functioning in these individuals? N400 has been obtained in a number of protocols in which the semantic content of phrases or single words was investigated (Kutas and Hillyard 1980; Bentin et al 1985; Polich 1985; Bentin 1987). However, N400-like components have also been recorded in nonlinguistic experiments involving the detection of rare tones (N~iiitiinen ~id Mitchie 1979), the identification of human faces (Barrett et al 1988; Barrett and Rugg 1989), and the mental rotation of faces
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(Stuss et al 1983). In these studies, N400 w a interpreted as a sign of mismatch detection (N~t~nen and Mitchie 1979), stimulus classification (Ritter et al 1983), and furuher processing of complex nature (Stuss et al 1983). Thus, N400 could be considered as a response to the violation of semantic expectation ~Kutas and Hillya~ 1984) or to a general index of mismatch which is triggered by events that do r~t conform to expectation created by the previous context (Rugg 1984; Polich 1985). As Duncan-Jol~-~on et al (1984) have reported normal expectancy to nonlinguistic stimuli in schlzopn~ni~ by measuring the sensitivity of P300 amplitude to the sequential effects of stimulus presentation, it is possible that the N400 reduction in a subgroup of schizophremcs in the current study reflects language processing abnormalities in that subgroup. A study in which N400 to linguistic and nonlinguistic stimuli would be assessed in schizophrenics would clarify this issue. The delay in N400 latency seems to characterize another subgroup of ~chizophreuics. It was independent of the patients' reaction time and did not correlate with the amount of neuroleptic medication. Such a delayed N400 is compatible with the view that some schizophrenics are slower to process information than controls (Yates 1966). The impact of reduced speed of information processing could be extremely disrupting. Slowness of information processing could lead to a disruption in the normal flow of information by interference caused by stimuli that have not been fully processed (Braff and Saccuzzo 1981, 1982). As the speed and accuracy with which words are processed and recognized are dependent upon the timing of semantic processing, any delay in information processing could have detrimental effects on language-related fucctions. Both N400 and SP have been found to be asymmetrically distributed in normal individuals (Kutas and Hillyard 1982; Rugg 1984; Boddy 1986; Kutas et al 1988). In the present study, this was true in the controls but not in the schizophrenics. Although, the functional significance of this finding is unclear because of our fimited understanding about ERi' generation, it provides additional evidence of laterality impairment in schizophrenics (Flor-Henry 1969; Gruzelier and Venables 1974). Questions could be raised regarding the effects of antipsychotic medication on the results. It is unlikely that antipsychotic medication was responsible for N400 abnormalitiet'. Fh'st, the N400 measures did not correlate with the amount of neuroleptic medication. Second, it is difficult to explain how neuroleptic drugs would be responsible for N400 abnormality in some patients and not in others. In addition, assuming that the delay in mclu are data sugges~g N400 indicates a reduction in information processing st~cu, . . . . -' "l---that this impairment is not caused by antipsychotic medication. Braff and Saccuzzo (1982) have studied the speed of information processing in medicated and unmedicated schizophrenics using backward masking tasks and have argued that ~mtipsychotic medications do not contribute, but in fact may reverse, the schizophrenics' slowness of information processing. In summary, two types of abnormalities were identified in the N400 response of schizophrenics in the present study, each of which might be specific to a subgroup of schizophrenics. The first one consisted of a reduction in N400 amplitude. Whether this abnormality reflects a specific linguistic impairment or a general deficit in expectancy is not known. The second abnormality consisted of a delay in N400 latency and could reflect an information processing delay. Further studies should attempt to (1) characterize the specific symptoms associated with the reduction and delay in N400, and (2) assess N400 in linguistic and nonlinguistic tasks in on- and off-neuroleptic treatment schizophrenics.
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Research supported by Scottish Rite Grant to C. Grilion and by NIDA DA05348 and NIAAA AA07080 grits.
References Adams J, Faux S, McCarley RW, Marcy B, Shenton M (1989): The N400 and language processing in schizophrenia. Proc 9th lnt C,-,nf on Event-Related Potentials of the Brain (EPIC IX), pp 12-13. 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 (1989): ERP indices of semantic processing in schizophrenia. Proc 9th Int Conf Event-Related Potentials of the Brain (EPIC IX) pp 8-9. Barrett SE, Rugg MD (1989): Event-related potentials and the semantic matching of faces. Neuropsychologia, 27:913-922. Barrett SE, Rugg MD, Perrett DI (1988): Event-related potentials and the matching of familiar and unfamiliar faces. Neuropsychologia, 26:105-117. Bentin S (1987): Event-related potentials, semantic processes, and expectancy factors in word recognition. Brain Lang 30:308-327. Bentin S, McCarthy G, Wood C (1985): Event-related potentials, lexical decision and semantic priming. Electroencephalogr C:~inNeurophysiol 60:343-355. Boddy J (1986): Event-related potentials in chronometric analysis of prhned word recognition with different stimulus onset asynchronies. Psychophysiology 23:232-244. Braff DL, Saccuzzo P (1981): Information processing dysfunction in paranoid schizophrenia: A two-factor deficit. Am J Psychiatry 138:1051-1056. Braff DL, Saccuzzo P (1982): Effects of antipsychotic medication on speed of information processing in schizophrenic patients. Am J Psychiatry 142:170-174. Carrol JB, White MN (1973): Age-of-acquisition norms for 220 picturable nouns. J Verb Learn Verb Behav 12:563-576. Chaika E (1974): A linguistic look at schizophrenics' language. Brain Lang 1:257-276. Chapman l.J, Chapman JP (1973): Disordered Thought in Schizophrenia. Englewood Cliffs, NJ: Prentice Hall. Duncan-Johnson CC, Roth WT, Kopeil BS (1984): Effects of stimulus sequence on P300 and reaction time in schizophrenics. In Karrer R, Cohen J, Tueting P (eds), Brain and Information: Event-Related Potentials. Ann NY Acad Sci 425:570-577. Flor-Henry P (1969): Schizophrenic-like reactions and affective psychoses associated with temporal lobe epilepsy: Etiological factors. Am J Psychiatry 126:400--404. Grillon C, Courchesne E, Ameli R, Gever MA, Braff DL (1990): Increased distractibility in schizophrenic patients: Electrophysiological and behavioral evidence. Arch Gen Psychiatry 47:171-179. Gruzelier J, Venables P (1974): Bimodality and lateral asymmetry of skin conductance orienting activity in schizophrenics: Replication and evidence of lateral asymmetry in patients with depression and disorders of personality. Biol Psychiatry 8:55-73. Hansen JC, Hillyard SA (1984): Effects of stimulation rate and attribute cuing on event-related t~otentia!s during selective attention. Psychophysiology 21:394-405. 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. Harvey MT, Marsh GR (1983): Effect of semantic category typicality on amplitude and latency of N400. Po, chophysiology 20:444--445. Holcomb PJ (1986): ERP correlates of semantic facilitation. In McCaUum WC, Zappoli R, Denoth
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F (eds), Cerebral Psychophysiology. Studies in Event-Related Potentials (EEG suppl 38). Amsterdam: Elsevier, pp 320-322. Horton DL, Marlow D, Crowne DP (1963): The effect of instructional set and need for social approval on community of word-association responses. J Abnorm Soc Psychot 66:67-72. Johnson RC, Weiss RL, Zelhart PF (1964): Similarities and differences between ~rmal psychotic subjects in response to verbal stimuli. J Abnorm Soc Psychol 58:22i-228. King K, Fraser WI, Thomas P, Kendeil RE (1990): Reexamination of the language of psychotic subjects. Br J Psychiatry 156:211-215. Kutas M, Hillyard SA (1980): Reading senseless sentences: Brain potentials reflect semantic incongruity. Science 207:203-205. Kutas M, Hillyard SA ~i982): The lateral distribution of event-related potentials d ~ n g sentence processing. Neuropsychologia 20:579-590. Kutas M, Hillyard SA (1984): Brain pomntials durirtg reading reflect word expectancy and s e p t i c association. Nature 307:161-163. Kutas M, Van Peuen C, Besson M (19~8): Event-relatea potentials asymmetries during the reading of sentences. Electroencephalogr CTin Neurophysiol 69:218-233. Lisman SA, Cohen BD (1972): Self-editing deficits in schizophrema: A word-association analogue, J Abnorm Psychol 79:181-188. Manschreck TC, Maher BA, Milavetz H, Ames D, Weisstein CC, Schneyer ML ( 1988): Semantic priming in thought-disordered schiz~Dphrenic patients. Schizophr Res 1:61-66. Mednick SA (1958): A learning theory ~pproach to research in schizophrenia. Psychol Bull 55:316327. Morice RD, Ingrain JCL (1982): Language analysis in schizophrenia: Diagnostic implications. Aust NZ J Psychiatry 16:11-21. N~i~it[inenR, Mitchie PT (1979): Early selective attention effects on the evoked potentials: A critical review and interpretation. Biol Psychol 8:81-136. Neville HJ, Kutas M, Chesney G, Schmidt AL (1986): Event-related brain potentials during initial encoding and recognition memory of congruous and incongruous words. J Mem Lang 25:7592. Nuechtedein KH, Dawson ME (1984): Information processing and attentional fimctionmg ia~ the developmental course of schizophrenic disorders. Schizophr Bull 10:160--203. Oltmanns TF, Neale JM (1975): Schizophrenics' performance when distractors are present: Attentional deficit or differential task difficulty? J Abnorm Psychoi 84:205-209. Patterson T (1987): Studies toward the subcortical pathogenesis of schizophrenia. Schizophr Bull i 3:555-5 to. Polich J (1985): Semantic categorization and event-related potentials. Brain Lang 26:304-321. Polich J, Vanasse L, Donchin E (1980): Category expectancy and N200. Psychophysiology 18:2. Ritter W, Simson R, Vaughan HG Jr (1983): Event-related potentials correlates of two stages of information processing in physical and semantic discrimination tasks. Psychophysiology 20:168179. Rugg MD (1934): Event-related potentials and the phonological processing of words and nonwords. Neuropsychologia 22:435--443. Rugg MD (1985): The effects of semantic priming and word repetition on event-related potentials. Psychophysiology 22:642-647. Salzinger K, Portnoy S, Pisoni DB, Feldman RS (1970~: The immediacy hypothesis and responseproduced stimuli in schizophrenic speech. J Abnorm Psychol 76:258-264. Schwartz S (1982): Is there a schizephrenic language? Behav Brain Sci 5:579-626. Spitzer RL, Endicott J, Robin E (1978): Research diagnostic criteria: Rational and reliability. Arch Gen Psychiatry 35:773-782.
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Stuss DT, Sarazin FF, Leech EE, Picton TW (1983): Event-related potentials during naming and mental rotation. Electroencephalogr Clin Neurophysiol 56:133-146. Thomas P, King K, Fraser WI, Kendell RE (1990): Linguistic performance in schizophrenia: A comparison of acute and chronic patients. Br 3 Psychiatry 156:204-210. Thomdike EL, Lorge 1 (1944): The Teacher's Word Book of 30,O00 Words. New York: Teacher College, Columbia University. Venables PH (1964): Input dysfunction in schizophrenia. In Mawr BA (ed), Progress in Experimental Personality Research. New York: Acaden~ic Press, pp 1-47. Yates AJ (1966): Data processing levels and thought disorder in schizophrenia. Aust J Psyckol 18:103-107.
467
N400 and Semantic Categorization in Schizophrenia Christian Grillon, Rezvan Ameli, and William M. Glazer
The N400 component of event-related potentials (ERPs) was investigated in medicated schizophrenic patients and normal controls in a semantic categorization task. The subjects" task was to indicate whether pairs of words were semantically related or unrelated. The ERPs to the unrelated second words of the pairs contained a negative component, N400, which was reduced and delayed in the patients. However, inspection of individual subjects' data indicated that N400 was abnormal only in a subgroup of schizophrenics. Abnormalities in the amplitude of N400 suggest impairments in semantic expectancies, whereas abnormalities in the latency, of N400 suggest a delay in information processing.
Introduction Abnormalities in the semantic aspects of language in schizophrenic individuals are one of the hallmarks of the disorder. Schizophrenics" speech often contains incoherence and inappropriate associations that are referred to as "loosening of associations." A number of techniques such as verbal conditioning (Salzinger et al 1970), word associations (Horton et al 1963; Johnson et al 1964; Lisman and Cohen 1972), and computer-assisted grammatical analysis (Thomas et al 1990; King et al 1990) have been utilized to investigate the language of these patients. Schizophrenics' language is characterized by syntactic errors (Chaika 1974; Morice and Ingram I982), low complexity, low integrity and dysfluency (Thomas et al 1990), deviant word associations (Chapman and Chapman 1973), and insensitivity to verbal contexts (Mednick 1958). The importance of verbal context and prior experience has also been emphasized by Patterson (1987) who suggested that schizophrenics' language disturbance might be related to their failure to generate appropriate linguistic expectancies. Whether these abnormalities reflect a specific language competence deficit or an impairment in language performance is not clear. Schwartz (1982) argued that schizophrenics were only deficient in language performance and that this impairment was caused by a general information processing deficit (Nuechterlein and Dawson 1984). Indeed, schizophrenics have been shown to be slow in processing information (Yates 1966), to possess a defective filter mechanism (Venables 1964), and to be vulnerable to distraction (Oltmanns and Neale 1975; Grillon et al 1990). Any one of these deficits could potenti2!ly affect .~chizophrenics' language performance. Recently, the utilizatioh of event-related potentials (ERPs) has proven to be a powerful tool to investigate information and linguistic processing. ERPs provide information about
From the Yale University School of Medicine Department of Psychiatry Genetic Epidemiology Research Unit, New Haven, CT (CG, RA). and the Yale University School of Medicine, Connecticut Mental Health Center, New Haven, CT (WMG). Address reprint requests to Christian Grillon, Yale University School of Medicine, Depamnent of Psychiatry, GERU. 40 Temple Street (Lower Level), New Haven, CT 06510-3223. Received Febma,-y 9, 1990; revised August 22, 1990.
© 1991 Society of Biological Psychiatry
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the nature and timing of neuronal events independent of behavioral data such as reaction time. They also provide information about the topographical distribution of these neuronal events. This is particularly important ~ a u s e language functions are believed to be largely lateralized. An ERP negative component peaking at about 400 msec has been shown to associated with linguistic processes (Kurus and Hillyard 1980, 1984). This component, labeled N400, has been obtained in various linguistic tasks involving sentence processing (Kutas and Hillyard 1980, 1984; Polich et al 1980), lexical decision making (Rugg 1985; Bentin et al 1985; Boddy 1986; Bentin 1987), and semantic categorization (Polich et al 1980; Holcomb 1986). N 4 ~ is elicited by words that deviate from an established semantic context (Kutas and Hillyard 1984; Neville et al 1986). Its magnitude is positively related to word unexpectedness or unpredictability within a given context (Harbin et al 1984; Kutas and Hillyard 1984). It has been proposed that N400 is an inverse function of the amount of semantic priming that a word has received from a preceding context (Kutas and Hillyard 1984; Bentin et al 1985). Although the view of N400 as a specific index of language processing is still a matter of debate (Polich 1985; Barrett et al 1988), it is clear that the elicitation of a large N400 in response to unpredictable words reflects the ability to appreciate the semantic relationship between a word and the context in which it is presented. It is likely that failure to appreciate such a relationship (i.e., failure to elicit N400) and/or delay in this process (i.e., delay in eliciting N400) could have dramatic effects on language functions. At the present time, the study of language in schizophrenics with ERPs, and more particularly N400, is in its infancy. Patterson (1987) has hypothesized that N400 should be reduced in schizophrenics because of their inability to generate appropriate expectancies. However, recent studies have provided conflicting results. Adams et al (1989) have reported that N400 was reduced in 2 of 4 schizophrenics in a study utilizing sentences. Using a similar task, Andrews et al (1989) did not find any N400 amplitude abnormality in schizophrenics. However, Andrews et al found that the schizophrenics' N400 was reduced in a task requiring semantic decision making. None of these studies reported N400 latency measures. In the present experiment, N400 amplitude and latency were investigated in schizophrenics in a semantic categorization experiment.
Method
Subjects Subjects consisted of 17 male chronic schizophrenic patients recruited from the outpatient clinic of the Connecticut Mental Health Center. Their diagnosis was based on chart review and individual interviews. All patients were diagnosed as chronic schizophrenic according to the Research Diagnostic Criteria (RDC) (Spitzer et al 1978) and the DSM-III. The data of three patients were excluded from analysis because of excessive artifacts in the ERPs. The remaining 14 patients were matched with 14 normal controls for age (patients 36.4 _ 7. l years, range 26-54 years; controls 37.5 _ 5.9 years, range 30-49 years) and length of education (patients 12.6 ± 2.6 years, range 9-20 years; controls 13.5 ± 2.9 years, range 8-18 years). One subject from each group was left handed. All the patients were takin neuroleptic medication at the time of the recording. The average daily neuroleptic intake was 967 ( ± 499) mg chlorpromazine equivalent. The Brief Psychiatric Rating Scale score (BPRS) for 13 of the 14 patients (1 subject had not been assessed with the BPRS) was 35.4 ± 5.2.
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Stimuli The stimuli were single words (duration 289 msec) presented one at a time on a computer screen in a 5 x 4 cm rectangle. These words were presented in pairs and were or were. not semantically related (e.g., cat/dog versus cat/vase). All the words were easy to understand (Carroi and White 1973) and were chosen because of their high frequeacy of occurrence in spoken English language (Thorndike and Lorge 1944).
Procedure Subjects were comfortably seated in a reclining chair approximately 55 inches from the screen. They looked at the center of the computer monitor and were instructed that pairs of words would be sequentially presented on the screen, and that they s.~cJuld indicate their response by pressing either of two buttons with their dominan~ hand after presentation of the second word of each pair. They were also instructed to avoid blinking or moving their eyes whenever a word appeared on the screen. The task was to press the "yes" button when the word pairs were related and the "no" button when they were unrelated. The stimulus onset asynchrony between the first and the second word of each pair was 1020 msec. The subjects were told that accuracy was very important for the study and that speed was not taken into consideration. They were asked to refrain from quick responding. These instructions were given in order to delay the late positive component which can overlap with N400. There were a total of 45 related and 45 vP~related werd pairs thai were randomly intermixed.
ERP Recording The electroencephalogram (EEG) was recorded from 13 electrodes attached to an elastic cap. The electrodes were placed over midline frontal, central, and parietal (Fz, Cz, Pz); homologous central (C3, C4); occipital (01, 02); anterior temporal [BL, BR: half of the distance between F7(8) and T3(4)]; temporal (L41, R41: 33% of the interaural distance lateral to Cz); and temporo-parietal (WL, WR: 30% of the interaural distance lateral to a point 13% of the nasion-inion distance posterior to Cz) sites. Over the left hemisphere, BL and WL were approximately over Broca's area and Wernicke's area, respectively. All these electrodes were referred to linked mastoids. Eye movements were monitored via a horizontal derivation (bipolar recording: external canthus of each eye) and a vertical derivation (lower orbital ridge of the left eye referred to linked mastoids). Electrode impedance did not exceed 5 Kohm. Electrical activity was amplified with a ban@ass of 0.03 and 70 Hz.
Data Collection The EEG and electrooculogram (EOG) signals were digitized at a rate of 200 Hz for 100 msec before and 1180 msec a,,er stimulus onset. TriMs contaminated by eye movements, muscle artifacts, or lead sway were excluded during averaging by computer algorithms. The artifact rejection level was set at 100 IxV for most of the subjects; however, this criterion was lowered when eye artifacts were present in the UpE or LoE electrodes. The artifact-free EEG recordings were separately averaged according to Related or Unrelated word pair trials that were followed by a correct response. There was no difference between the control and patient group in the number of artifacts deleted.
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Data Analysis Peak amplitude (relative to 100 msec prestimulus baseline) and peak latency of the ERP components were computed using the following windows after visual inspection of the ERPs: NI00, 75-150 msec; P200, 150-250 m ~ ; N400, 300-550 msec; and SP, 500800 msec. In addition, the mean amplitudes for N400 over the 300-550 msec range and SP over the 500-800 msec range were calculated. We also attempted to determine N400 onset latency using three different measurement methods. In the first method, N400 onset latency w ~ determined by visu~ inspection, extrapolating the best fit of the descending edge of the wave to the baseline (Ritter et al 1983). Two other estimates were obtained by automatic computer measurements (Hansen and Hillyard 1984): "'baseline onset latency" (BOL), and "extrapolated onset latency" (EOL). The BOL method corresponds to Hansen and Hillyard's (1984) "baseline are~." In the BOL method, the negative deflection of the longest duration is searched in the prestimulus baseline period. The first continuous area in the 100-600 msec window, which exceeds twice this measure, is calculated and the latency of the first point of this area is reported. In the EOL method, two points of the waveform in the 100-600 msec range corresponding to 0.25 and 0.75 of the peak are calculate. A line passing through these two points is extrapolated and the point of intersection of this line with the baseline is reported. This last method was conceptually very close to the visual inspection method. All measurements were made at Pz when possible. When a measurement could not be determined at Pz, computations were performed at the electrode with the highest negativity. The data were submitted to a series of an~,iyses of variance (ANOVAs). For the midline electrodes, two-way ANOVAS were used with word type (related, unrelated) and electrode (Fz,Cz,Pz) as the two factors. For the lateral electrodes, the design was a three-way ANOVA with word type (related, unrelated); electrode [anterior temporal (BL,BR), temporal (L41 ,R41), central (C3,C4), temporo-parietal (WL,WR), occipital (01,02)]; and hemisphere (left, right) as the three factors. Similarly, group comparisons were performed with three-way ANOVAs with group (2), word type (2), and electrode (2) as the three factors, and four-way ANOVAs with group (2), word type (2), electrode (5), and hemisphere (2) as the four factors. In order to minimize type I errors, reduced degrees of freedom (Huyhn-Feldt) were used.
Results Behaviorol Data All the subjects performed above chance level. Both the controls and the patients had a high rate of response accuracy. The controls correctly identified 95.7% ( _+4.4%) related and 98.2% ( _ 2.8%) unrelated word pairs. The schizophrenics correctly identified 91.1% ( _+9.8%) related and 94.4% ( _ 6.7%) unrelated word pairs. These results were analyzed in an ANOVA with repeated measures with group (controls, patients) and word type (related, unrelated) as the two factors. The group main effect was significant [F(1,26) = 4.3, p ~< 0.051 andicating that the patients were less accurate than the controls. The group X word type interaction effect was not significant [F(1,26) = 1,1, p ~< 0.8]. In the present experiment, the reaction time (RT) was not a relevant index for evaluating the speed of information processing as the subjects were asked to refrain from quick responding. However, because the speed of responding might have affected the ERPs,
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L0iI
*
~
~
s~7. l . . . . . . . . . . . 300 600 900
Figure 1. Topographical distribution of the ERPs to related (continuous line) and unrelated (dashed line) words in the control group. Note that the representation of electrode locations is approximate.
the RT data were analyzed. The controls were faster to respond than the patients. The mean RT for the controls was 982 msec ( +__240 msec) for related and 1000 msec ( +__167 msec) for unrelated words. The mean RT for the patients was 1308 msec (+_ 475 msec) for related and 1472 msec ( ___462 msec) for unrelated words. Statistical analysis showed significant main effects for group [F(1,26) = 9.02, p ~ 0.006] and for word type [F(1,26) = 7.4, p <~ 0.001] and a group X word type interaction effect [F(1,26) = 4.7, p <~ 0.041.
Event-Related Potentials Measures The grand average ERPs to related and unrelated words at all electrode sites for the control and the patient groups are presented in Figures 1 and 2, respectively. Both the related and the unrelated words elicited a negative component (NI00:75-150 msec range) followed by a positive component (P200:150-250 msec range). P200 was followed by a sustained positivity (SP) which started 250 msec poststimulus and lasted throughout the duration of the recording epoch. There was a negative deflection in the 300-550 msec range in the ERPs to unrelated words. This deflection (N400) was more readily identifiable in the subtraction waveforms obtained by subtracting the voltage of the ERPs to related words from the corresponding points of the ERPs to unrelated words (Figure 3).
NIO0 and P200. There were no significant group differences in amplitude, latency, or topographical distribution for NI00 and P200. N400. The 300-550 msec range was the area of the largest difference between ERPs to related and unrelated words in both the controls and the schizophrenics [peak amplitude:
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Figure 3. Grand average difference waveforms in the control group (continuous line) and the patient (dashed line) group. The difference wavefom~s were const~a~cted by subtracting point by point the ERPs to related words from ERPs to unrelated words. N4tY3,is the negative potential resulting from this subtraction procedure. Note the N400 delay in the patients, compared with the controls.
niOL PSYCmATRY 199l;29:467-4~
N 4 0 0 in Schizophrenia
4"/3
Table I. N400 Measures in the Diffecence Waveforms Controls Amplitude
Patients
Mean ampl.
Latency
Amplitude
Mean ampl.
Fz
4.7 (2.2)
!.9 11.8)
406 t82)
3~2 (2.5)
0.6 (2.3)
487 (48~
Cz
5.9 (2.0)
2.7 (2.2)
418 (79)
3,6 t~2.6)
I,I (2.2~
482 (54)
Pz C3 C4
6.0 (!.9) 3.1 (2.0) 4.8 (i.7)
2.5 (I.7) 0.7 (1.7) 2.4 (i.5)
408 (71) 404 (73) 446 (81)
4.7 (2.7) 2.5 (2.5) 2.5 (2.1)
1.6 (1.8) 0.2 (2.3) 0.2 (2.1)
451 (66) 421 (79) 483 (74)
BL
3.6 (2.1)
0.9 (1.6)
411 (74)
3.2 (1.6)
0.4 (1.7)
458 (73)
BR !.41 R41 WL WR Ol 02
4.8 (!.8) 4.2 (2.1) 5.8 (2.0) 4.5 (2.6) 5.8 (2.0) 4.9 (2.3) 4.9 (2.3)
2.3 (1.7) 1.4 t!.9) 2.7 (i.9) 1.5 (1.9) 2.8 (1.7) ! .7 (1.7) 1.9 (1.4)
439 (82) 423 (74) 437 (80) 427 (74) 433 (77) 434 (59) 436 (75)
3.5 (2.6) 3.1 (2.3) 3.8 (2.6) 3.8 (2.0) 3.7 (2.3) 4.4 (1.4) 4.2 (2.8)
1.0 (2.7) 0.6 (2.0) 0.9 (2.4) !. 1 (! .9) 1.0 (2.3) ! .7 (! .0) 1.4 (1.0)
479 (64) 444 (65) 495 (48) 437 (76) 463 (64) 462 (53) 438 (59)
midline electrodes, F ( 1 , 2 6 ) = 10.0, p ~< 0.004; lateral electrodes, F ( 1 , 2 6 ) = 10.4, p ~< 0.003; m e a n amplitude: midline electrodes, F ( 1 , 2 6 ) = 10.1, p ~< 0.004; l a t e ~ electrodes, F ( 1 , 2 6 ) = 10.4, p ~< 0.003]. This difference appeared as a negative component (N400) in the difference waveforms (Figure 3). In the controls' difference waveforms, N400 was largest at Pz (6.03 IxV) where it peaked at 408 msec and was larger over the right than the left hemisphere [peak amplitude, F ( 1 , 1 3 ) = 13.0, p ~< 0.003; mean amplitude, F ( l , 1 3 ) = 10.9, p ~< 0,005]. Tables I and 2 show that N400 was smaller and later in the patients, compared with the controls. In addition, N400 was not asymmetrically distributed [ F ( 1 , 1 3 ) = 0.1, p <~ 0.7]. Group comparisons o f N400 were performed on the difference waveform measures. The reduced N 4 0 0 in the schizophrenics was significant only at midline electrodes for the peak amplitude measures [ F ( 1 , 2 6 ) = 4.1, p <~ 0.05] but was not significant at midline electrodes for the mean amplitude measures [F(1,26) = 2.9, p <~ 0.1] or at lateral electrodes for both the peak amplitude and the mean amplitude measures [ F ( 1 , 2 6 ) = 3.2, p ~< 0.08 and F ( ! , 2 6 ) = 3.5, p ~< 0.07, r e s ~ c t i v e l y ] . I n s ~ c t i o n of the individual N400 data indicated that there was a large intersubject variability in the schizophrenic group. N400 was in the normal range in some patients, whereas it was small or absent
Table 2. N400 Peak, Onset Latency, and Duration (msec) Difference Waveforms Methods
Controls (N = [3)
Patients (N = 13)
Peak latency Visual inspection (N400 duration) Baseline onset iat. (BOL) (N400 duration) Extrapolated onset lat. (EOL) (N400 duration)
406 +_ 78 294 ± 68 (112) 251 -- 89
486 ~ 84 394 ± 93 (91) 352 _ 104
df = 24; NS = nonsignificant;T = t-test ~p ~ 0.05: bp ~ 0.01.
(155)
(I 33)
295 +- 72 (111)
394 +_ 113 (91)
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in others. N400 peak amplitude was within 1 SD from the control's mean in 7 patients and l SD smaller than the controls' mean in 6 patients (Figure 4). The distribution of N400 over the two hemispheres was significantly different in the two groups [group x hemisphere interaction: peak amplitude, F(1,26) = 3.8, p <~ 0.06; mean amplitude, F(1,26) = 4.2, p ~< 0.05]; N400 was larger in the controls compared with the patients over the right hemisphere [peak amplitude, F(1,26) = 5.7, p ~< 0.02; mean amplitude, F(1,26) = 6. l, p <~ 0.02] but not over the left hemisphere. N400 was significantly delayed in the schizophrenic group, compared with the contr{. group [F(1,26) = 7.7, p ~< 0.01]. N400 latency was l SD later than the controls' mean in 7 patients (Figure 4). The patients with N400 amplitude reduction were not necessarily the same as the patients with N400 latency delay. Furthermore, in neither group was the correlation between N400 amplitude and N400 latency measures significant. SP. The ERP activity in the 500-800 msec range was larger (more positive) for related than for unrelated words in both groups [peak amplitude: midline electrodes, F(1,26) =
N400 in Schizophrenia
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Table 3. Subgroups" Performance
n Age (yr) Education {yr) RT to related words (msec) RT to unrelated words (msec) Accuracy to related words (%) Accuracy to unrelated words (%~
Fast RT patients
Slow RT patients
7 34.5 13. I 989 ! 160 95 97
7 38.2 14.0 1627 1785 87 92
Matc~ c~s 7 37.6 |4°0 I042 1042 96 97
RT = reaction time; n = number of patients,
6.1, p ~< 0.02; lateral electrodes, F(1,26) = 3.4, p <~ 0.07: :ateral electrodes, F(1,26) = 4.6, p ~< 0.04]. SP was larger in the control than in the p~,tiem i-roup [peak amplitude: midline electrodes, F(1,26) = 10.1, p <~ 0.003; lateral electrode~, ~'( 1,26) = 9.6, p <~ 0.004; mean amplitude: midline electrodes, F(1,26) = 8.2, p ~< 0.f~8; lateral electrodes, F(1,26) = 9.0, p <~ 0.0051. In addition, SP was larger over the right than over the left hemisphere for unrelated words but not for related words in the controls [word type x hemisphere interaction: peak amplitude, F(1,26) = 9.6, p <~ 0.008; mean amplitude, F(1,26) = 11.7, p ~< 0.004]. Such asymmetry was not present in the patient group [word type x hemisphere interaction: peak amplitude, F( i ,26) = 1.3, p ~< 0.3; mean amplitude, F(1,26) = 0.5, p ~< 0.5]. SP latency did not significantly differ in the two groups.
N400 Onset Latency. Because the peak latency of N490 differed in the two groups, we attempted to further characterize this effect by measuring N400 onset latency and duration in the difference waveforms. Latency measure3 could not be obtained in I control and 1 patient because N400 was too small. Table 2 shows the results of the peak and onset latency analyses. N400 onset latency was earlier in the control than in the patient group. In the control group, the estimate of N400 onset latency varied from 251 to 295 msec, whereas in the patient group it varied from 352 to 394 msec. In both groups, the visual inspection and the extrapolated onset latency methods provided similar results. These methods indicated that N400 started about i00 msec later in the patient than in the control group. An estimation of N400 duration was calculated by subtracting N400 onset latency from N400 peak latency (Table 2). N400 duration did not significantly differ in the two groups.
Influence of the Speed of Responding. There was a large RT difference between the controls and the patients. In order to assess whether this RT difference contributed to the N400 delay in the patients, we used the RT data as an independent variable and divided the subjects into two subgroups. First, the patients were divided into a slow RT and a fast RT group. Then, 7 controls were matched for RT with the 7 patients with fast RTs. The description of the subjects of each group and their perform,ance is provided in Table 3. The main results of this analysis were that (1) the ERPs of the fast patient group did not differ from the ERPs of the slow patient group, and (2) the ERP differences between the fast patient group and the RT matched control group were the same as the ones reported for the entire control and patient groups. Thus, there was no difference between
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the fast and slow RT patient groups in terms of their N400 latency and SP amplitude. Compared with their RT matched controls, however, the fast patients had delayed N400 peak latency [lateral electrode, F(I,12) = 9.42, p <~ 0.0091 and smaller SP amplitude [midline electrode, F(1,12) = 5.57, p <~ 0.03; lateral electrode, F(I,12) = 6.02, p ~<
0.031. Effects of drug treatment and clinical symptoms. All of the patients were taking medication at the time of testing. Pearson correlations between N400 latency, N400 peak amplitude, SP peak amplitude (at Pz), and the daily dosage of drug treatment expressed in chlorpromazine equivalent were performed to assess the effect of neuroleptic treatment on the results. None of the correlations reached significance. Similarly, there was no correlation between N400 latency, N400 peak amplitude, and SP amplitude, and the BPRS scores.
Discussion The elicitation of a N400 component to unrelated words in the present experiment is consistent with the general findings in the literature using either sentences (Kutas and Hillyard 1980, 1984) or pairs of words (Polich et al 1980; Harvey and Marsh 1983; Harbin et al 1984; Bentin 1987) and in which behavioral responses are or are not required (Kutas and Hillyard 1980, 1984; Rugg 1985; Benfin et al 1985). In this study, N400 was reduced and delayed in the schizophrenics compared with the controls. These abnormalities, however, did not characterize the entire schizophrenic group as a number of patients had a normal N400. The inspection of the individual data indicates that subgroups of schizophrenics had either a reduced or a delayed N400 and that patients with reduced N400 amplitude did not necessarily have a delayed N400 latency and vice and versa. This result is in agreement with Adams et al's (1989) findings in which N400 to unexpected last words of sentences was abnormal in 2 of 4 schizophrenics. It is possible that N400 variability is yet another aspect of the heterogeneity of the schizophrenic disorders. This view is consistent with studies indicating that subgroups of schizophrenics differ in their linguistic performance 0Vlanschreck et al 1988; Thomas et al 1990). For example, semantic facilitation has been found to be faster in schizophrenics with a thought disordex~ compared with schizophrenics without a thought disorder (Manschreck et al 1988). Similarly, measures of complexity, integrity, and fluency of speech are more impaired in chronic than in acute schizophrenics (Thomas et al 1990). In the present study, there were no correlations between N400 measures and the BPRS scores in the patients. However, it is possible that the utilization of scales assessing more specific symptoms, such as negative and positive symptoms (Andreasen 1982), might have helped to better characterize the schizophrenics with abnormal N400. Thomas et al (1990) have suggested that poor linguistic performance was more associated with negative than with positive symptoms. Assuming that N400 reduction characterizes a subgroup of schizophrenics, what does this tell us about language functioning in these individuals? N400 has been obtained in a number of protocols in which the semantic content of phrases or single words was investigated (Kutas and Hillyard 1980; Bentin et al 1985; Polich 1985; Bentin 1987). However, N400-like components have also been recorded in nonlinguistic experiments involving the detection of rare tones (N~iiitiinen ~id Mitchie 1979), the identification of human faces (Barrett et al 1988; Barrett and Rugg 1989), and the mental rotation of faces
N400 in Schizophrenia
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(Stuss et al 1983). In these studies, N400 w a interpreted as a sign of mismatch detection (N~t~nen and Mitchie 1979), stimulus classification (Ritter et al 1983), and furuher processing of complex nature (Stuss et al 1983). Thus, N400 could be considered as a response to the violation of semantic expectation ~Kutas and Hillya~ 1984) or to a general index of mismatch which is triggered by events that do r~t conform to expectation created by the previous context (Rugg 1984; Polich 1985). As Duncan-Jol~-~on et al (1984) have reported normal expectancy to nonlinguistic stimuli in schlzopn~ni~ by measuring the sensitivity of P300 amplitude to the sequential effects of stimulus presentation, it is possible that the N400 reduction in a subgroup of schizophremcs in the current study reflects language processing abnormalities in that subgroup. A study in which N400 to linguistic and nonlinguistic stimuli would be assessed in schizophrenics would clarify this issue. The delay in N400 latency seems to characterize another subgroup of ~chizophreuics. It was independent of the patients' reaction time and did not correlate with the amount of neuroleptic medication. Such a delayed N400 is compatible with the view that some schizophrenics are slower to process information than controls (Yates 1966). The impact of reduced speed of information processing could be extremely disrupting. Slowness of information processing could lead to a disruption in the normal flow of information by interference caused by stimuli that have not been fully processed (Braff and Saccuzzo 1981, 1982). As the speed and accuracy with which words are processed and recognized are dependent upon the timing of semantic processing, any delay in information processing could have detrimental effects on language-related fucctions. Both N400 and SP have been found to be asymmetrically distributed in normal individuals (Kutas and Hillyard 1982; Rugg 1984; Boddy 1986; Kutas et al 1988). In the present study, this was true in the controls but not in the schizophrenics. Although, the functional significance of this finding is unclear because of our fimited understanding about ERi' generation, it provides additional evidence of laterality impairment in schizophrenics (Flor-Henry 1969; Gruzelier and Venables 1974). Questions could be raised regarding the effects of antipsychotic medication on the results. It is unlikely that antipsychotic medication was responsible for N400 abnormalitiet'. Fh'st, the N400 measures did not correlate with the amount of neuroleptic medication. Second, it is difficult to explain how neuroleptic drugs would be responsible for N400 abnormality in some patients and not in others. In addition, assuming that the delay in mclu are data sugges~g N400 indicates a reduction in information processing st~cu, . . . . -' "l---that this impairment is not caused by antipsychotic medication. Braff and Saccuzzo (1982) have studied the speed of information processing in medicated and unmedicated schizophrenics using backward masking tasks and have argued that ~mtipsychotic medications do not contribute, but in fact may reverse, the schizophrenics' slowness of information processing. In summary, two types of abnormalities were identified in the N400 response of schizophrenics in the present study, each of which might be specific to a subgroup of schizophrenics. The first one consisted of a reduction in N400 amplitude. Whether this abnormality reflects a specific linguistic impairment or a general deficit in expectancy is not known. The second abnormality consisted of a delay in N400 latency and could reflect an information processing delay. Further studies should attempt to (1) characterize the specific symptoms associated with the reduction and delay in N400, and (2) assess N400 in linguistic and nonlinguistic tasks in on- and off-neuroleptic treatment schizophrenics.
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Research supported by Scottish Rite Grant to C. Grilion and by NIDA DA05348 and NIAAA AA07080 grits.
References Adams J, Faux S, McCarley RW, Marcy B, Shenton M (1989): The N400 and language processing in schizophrenia. Proc 9th lnt C,-,nf on Event-Related Potentials of the Brain (EPIC IX), pp 12-13. 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 (1989): ERP indices of semantic processing in schizophrenia. Proc 9th Int Conf Event-Related Potentials of the Brain (EPIC IX) pp 8-9. Barrett SE, Rugg MD (1989): Event-related potentials and the semantic matching of faces. Neuropsychologia, 27:913-922. Barrett SE, Rugg MD, Perrett DI (1988): Event-related potentials and the matching of familiar and unfamiliar faces. Neuropsychologia, 26:105-117. Bentin S (1987): Event-related potentials, semantic processes, and expectancy factors in word recognition. Brain Lang 30:308-327. Bentin S, McCarthy G, Wood C (1985): Event-related potentials, lexical decision and semantic priming. Electroencephalogr C:~inNeurophysiol 60:343-355. Boddy J (1986): Event-related potentials in chronometric analysis of prhned word recognition with different stimulus onset asynchronies. Psychophysiology 23:232-244. Braff DL, Saccuzzo P (1981): Information processing dysfunction in paranoid schizophrenia: A two-factor deficit. Am J Psychiatry 138:1051-1056. Braff DL, Saccuzzo P (1982): Effects of antipsychotic medication on speed of information processing in schizophrenic patients. Am J Psychiatry 142:170-174. Carrol JB, White MN (1973): Age-of-acquisition norms for 220 picturable nouns. J Verb Learn Verb Behav 12:563-576. Chaika E (1974): A linguistic look at schizophrenics' language. Brain Lang 1:257-276. Chapman l.J, Chapman JP (1973): Disordered Thought in Schizophrenia. Englewood Cliffs, NJ: Prentice Hall. Duncan-Johnson CC, Roth WT, Kopeil BS (1984): Effects of stimulus sequence on P300 and reaction time in schizophrenics. In Karrer R, Cohen J, Tueting P (eds), Brain and Information: Event-Related Potentials. Ann NY Acad Sci 425:570-577. Flor-Henry P (1969): Schizophrenic-like reactions and affective psychoses associated with temporal lobe epilepsy: Etiological factors. Am J Psychiatry 126:400--404. Grillon C, Courchesne E, Ameli R, Gever MA, Braff DL (1990): Increased distractibility in schizophrenic patients: Electrophysiological and behavioral evidence. Arch Gen Psychiatry 47:171-179. Gruzelier J, Venables P (1974): Bimodality and lateral asymmetry of skin conductance orienting activity in schizophrenics: Replication and evidence of lateral asymmetry in patients with depression and disorders of personality. Biol Psychiatry 8:55-73. Hansen JC, Hillyard SA (1984): Effects of stimulation rate and attribute cuing on event-related t~otentia!s during selective attention. Psychophysiology 21:394-405. 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. Harvey MT, Marsh GR (1983): Effect of semantic category typicality on amplitude and latency of N400. Po, chophysiology 20:444--445. Holcomb PJ (1986): ERP correlates of semantic facilitation. In McCaUum WC, Zappoli R, Denoth
N400 in Schizophrenia
elOL PSVCmA't~V
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1991 ;29:46%41~
F (eds), Cerebral Psychophysiology. Studies in Event-Related Potentials (EEG suppl 38). Amsterdam: Elsevier, pp 320-322. Horton DL, Marlow D, Crowne DP (1963): The effect of instructional set and need for social approval on community of word-association responses. J Abnorm Soc Psychot 66:67-72. Johnson RC, Weiss RL, Zelhart PF (1964): Similarities and differences between ~rmal psychotic subjects in response to verbal stimuli. J Abnorm Soc Psychol 58:22i-228. King K, Fraser WI, Thomas P, Kendeil RE (1990): Reexamination of the language of psychotic subjects. Br J Psychiatry 156:211-215. Kutas M, Hillyard SA (1980): Reading senseless sentences: Brain potentials reflect semantic incongruity. Science 207:203-205. Kutas M, Hillyard SA ~i982): The lateral distribution of event-related potentials d ~ n g sentence processing. Neuropsychologia 20:579-590. Kutas M, Hillyard SA (1984): Brain pomntials durirtg reading reflect word expectancy and s e p t i c association. Nature 307:161-163. Kutas M, Van Peuen C, Besson M (19~8): Event-relatea potentials asymmetries during the reading of sentences. Electroencephalogr CTin Neurophysiol 69:218-233. Lisman SA, Cohen BD (1972): Self-editing deficits in schizophrema: A word-association analogue, J Abnorm Psychol 79:181-188. Manschreck TC, Maher BA, Milavetz H, Ames D, Weisstein CC, Schneyer ML ( 1988): Semantic priming in thought-disordered schiz~Dphrenic patients. Schizophr Res 1:61-66. Mednick SA (1958): A learning theory ~pproach to research in schizophrenia. Psychol Bull 55:316327. Morice RD, Ingrain JCL (1982): Language analysis in schizophrenia: Diagnostic implications. Aust NZ J Psychiatry 16:11-21. N~i~it[inenR, Mitchie PT (1979): Early selective attention effects on the evoked potentials: A critical review and interpretation. Biol Psychol 8:81-136. Neville HJ, Kutas M, Chesney G, Schmidt AL (1986): Event-related brain potentials during initial encoding and recognition memory of congruous and incongruous words. J Mem Lang 25:7592. Nuechtedein KH, Dawson ME (1984): Information processing and attentional fimctionmg ia~ the developmental course of schizophrenic disorders. Schizophr Bull 10:160--203. Oltmanns TF, Neale JM (1975): Schizophrenics' performance when distractors are present: Attentional deficit or differential task difficulty? J Abnorm Psychoi 84:205-209. Patterson T (1987): Studies toward the subcortical pathogenesis of schizophrenia. Schizophr Bull i 3:555-5 to. Polich J (1985): Semantic categorization and event-related potentials. Brain Lang 26:304-321. Polich J, Vanasse L, Donchin E (1980): Category expectancy and N200. Psychophysiology 18:2. Ritter W, Simson R, Vaughan HG Jr (1983): Event-related potentials correlates of two stages of information processing in physical and semantic discrimination tasks. Psychophysiology 20:168179. Rugg MD (1934): Event-related potentials and the phonological processing of words and nonwords. Neuropsychologia 22:435--443. Rugg MD (1985): The effects of semantic priming and word repetition on event-related potentials. Psychophysiology 22:642-647. Salzinger K, Portnoy S, Pisoni DB, Feldman RS (1970~: The immediacy hypothesis and responseproduced stimuli in schizophrenic speech. J Abnorm Psychol 76:258-264. Schwartz S (1982): Is there a schizephrenic language? Behav Brain Sci 5:579-626. Spitzer RL, Endicott J, Robin E (1978): Research diagnostic criteria: Rational and reliability. Arch Gen Psychiatry 35:773-782.
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C. Grillon et al
Stuss DT, Sarazin FF, Leech EE, Picton TW (1983): Event-related potentials during naming and mental rotation. Electroencephalogr Clin Neurophysiol 56:133-146. Thomas P, King K, Fraser WI, Kendell RE (1990): Linguistic performance in schizophrenia: A comparison of acute and chronic patients. Br 3 Psychiatry 156:204-210. Thomdike EL, Lorge 1 (1944): The Teacher's Word Book of 30,O00 Words. New York: Teacher College, Columbia University. Venables PH (1964): Input dysfunction in schizophrenia. In Mawr BA (ed), Progress in Experimental Personality Research. New York: Acaden~ic Press, pp 1-47. Yates AJ (1966): Data processing levels and thought disorder in schizophrenia. Aust J Psyckol 18:103-107.