ERPs in schizophrenic patients during word recognition task and reaction times

Electroencephalography and clinicalNeurophysiology, 92 (1994) 546-554 © 1994 Elsevier Science Ireland Ltd. 0168-5597/94/$07.00

546

EEP 93079

ERPs in schizophrenic patients during word recognition task and reaction times Sachiko Koyama a, Hiroto Hokama b, Makoto Miyatani b,,, Chikara Ogura b, Yasuhiro Nageishi a and Minoru Shimokochi a a Department of Behavioral Physiology, Faculty of Human Sciences, Osaka University, Osaka (Japan), and b Department of Neuropsychiatry, School of Medicine, University of the Ryukyus, Kyushu (Japan) (Accepted for publication: 20 June 1994)

Summary Event-related brain potentials (ERPs) were recorded in 28 schizophrenic patients and 26 healthy controls during a word recognition task. In each trial, stimuli consisting of S1 (word) and $2 (word or non-word) were presented. The subjects were required to indicate whether $2 was a word or a non-word by pressing buttons. For both groups, a clear N370 was elicited by $2 which were non-word or semantically unrelated to its S1. The N370 amplitude did not differ between the groups. The schizophrenics responded more slowlythan the controls, and the latencies of P200 and N370 were longer for patients than for controls. However, these latencies did not differ between the groups when their reaction times were matched. Key wards: Event-related potentials; Schizophrenics; Lexical decision; N400; Reaction time

Cognitive dysfunction in schizophrenia has been proposed to cause impaired performance. Many psychological tests have revealed that the performance of schizophrenic patients is poor c o m p a r e d with that of normal subjects. In general, schizophrenics respond more slowly, and show lower levels of accuracy than healthy controls. However, patients usually respond to experimental conditions in the same m a n n e r as normal subjects (Pritchard 1986). Event-related brain potentials (ERPs) can be a powerful tool in the study of cognition (e.g., Galambos and Hillyard 1981). Recording of E R P provides data concerning the nature, timing and duration of specific stages of information processing (Rugg et al. 1986; Rugg 1987). Several E R P components have been found to be abnormal in schizophrenics (see Pritchard 1986 for review). For example, the P300 amplitude in patients was reduced in a variety of tasks. The contingent

Correspondence to: Sachiko Koyama, Department of Integrative Physiology, National Institute for Physiological Sciences, Myoudaiji, Okazaki 444 (Japan). Tel.: +81 564 557769; Fax: +81 564 527913; E-mail: koyama @nips.ac.jp. * Present address: Department of Psychology,Faculty of Education, Hiroshima University, Hiroshima (Japan).

SSDI 0013-4694(94)00188-Q

negative variation (CNV) amplitude is also reduced in such patients. Such E R P abnormalities are linked with cognitive dysfunction in schizophrenics (Roth et al. 1986). Thus the m e a s u r e m e n t of E R P s is expected to be useful in clarifying deficits in information processing in schizophrenia. The N400 component of the E R P is associated with word recognition processes, and is elicited clearly when the presented word cannot be predicted. For example, N400 follows the first content word in a sentence (Van Petten and Kutas 1990) or follows an incongruent ending to a sentence (e.g., " H e spread the warm bread with socks"; Kutas and Hillyard 1980). Halgren and colleagues examined the generator of N400, and Smith et al. (1986) recorded the potential correlated to the scalp-recorded N400 from the human medial temporal lobe. Smith and Halgren (1989) recorded E R P s from patients who had undergone unilateral anterior temporal lobectomy using a word recognition task, and observed that the negative deflection peaking about 300 msec after the presentation of words was reduced for the patients compared with healthy controls. On the other hand, temporo-limbic system abnormalities in schizophrenia have been suggested (Flor-Henry 1969; Stevens 1973; Reynolds 1983; Bogerts et al. 1985). Flor-Henry (1969) pointed out that epilepsy of the left temporal lobe shows schizophreniclike psychotic reactions. Reynolds (1983) found a spe-

ERPs IN SCHIZOPHRENICS cific increase in dopamine levels in the left amygdala of schizophrenics compared with healthy controls. Thus, if abnormalities in the N400 component of the E R P are found, this abnormality can be interpreted as a further indicator of temporal lobe deficit. We have previously recorded the N400 component of the ERP in schizophrenics in order to investigate their language faculty (Koyama et al. 1991). A pair of stimuli consisting of S1 (word) and $2 ( w o r d / n o n - w o r d ) was presented in each trial. Subjects were asked to determine whether $2 was a word or non-word (lexical decision task). When S1 and $2 were semantically unrelated or $2 was a non-word, a distinct N400 followed $2, whereas when the two stimuli were semantically related, only a small negative-trending notch followed $2. The N400 amplitude in schizophrenics was shown not to differ from that in healthy controls. Thus, schizophrenics were suggested to utilize the context during word recognition. However, the N400 latency was delayed in the schizophrenic patients. The reaction times were also longer in the patients than in the controls regardless of $2 type, although contextual effects were found in both groups. In the present study, a comparison was made between the ERPs from patients and those from healthy controls whose reaction times did not differ from each other. If the N400 latency differs between the groups with equivalent reaction times, some process that N400 depends upon but that reaction time is independent of in schizophrenics is delayed. However, if the N400 latency does not differ between the reaction timematched groups, some process on which both N400 and reaction time depend is delayed in schizophrenic patients.

Methods

Subjects Twenty-eight patients (9 females and 19 males) were tested, all of whom had been diagnosed independently as schizophrenic by at least 2 psychiatrists based on DSM-III-R (American Psychiatric Association 1987) criteria. Their ages ranged from 16 to 40 years, with a mean age of 27.9. All were free from acute illness, neurological illness, and alcohol or drug abuse. Their mean BPRS score (Overall and Gorham 1962) was 38.0 (13-62) with a mean SANS score (Andreasen 1982) of 30.7 (0-63). Fourteen were medicated with a median daily dose equivalent to 561.3 mg chlorpromazine (100-1500 rag). All were chronic patients and in stable condition. The patient subtypes were: paranoid, 16; disorganized, 4; catatonic, 2; residual, 2; undifferentiated, 4. The mean educational attainment of these patients was 12.7 school years (9-16 years). The con-

547 trol group comprised 19 males and 7 females whose ages ranged from 22 to 43 years, with a mean age of 28.7. All the subjects were right-handed and had normal or corrected to normal vision. The experimental material and procedure were identical to those used in our previous study (Koyama et al. 1991). Data from 13 patients and all the controls were used in this previous study. Of the initial subjects, 2 patients who had difficulty in understanding the task were not tested further, and 6 others were eliminated because of excessive E O G artifacts (4), body movements (1), and poor performance (1). Of the controls, 3 were excluded because of excessive E O G artifacts.

Experimental design and material In each trial, $1 (word) and $2 (word or non-word) were presented, and subjects were required to determine whether the $2 was a word or a non-word. Three types of S1-$2 pairs were presented with equal probability: (1) $2 as the antonym or antithesis of S1 (related $2, e.g., "brother-sister"); (2) $2 as semantically unrelated to S1 (unrelated $2, e.g., "brother-drive"); and (3) $2 as a non-word (non-word $2, e.g., "brothergrofe"). The two response categories of w o r d / n o n word thus had respective probabilities of 0.67 and 0.33. All the word stimuli used were common Japanese nouns consisting of 2 kanji characters. For non-word $2, 30 non-words were made comprising pairs of kanji characters arbitrarily chosen by the experimenters. All were pronounceable (2 or 3 pronunciations being possible as most kanji characters have several readings, see Koyama et al. 1991 for more details). The S1 words selected for the related (R) stimuli were also used for the unrelated (U) and non-word (N) stimulus conditions. All the S1-$2 pairs were presented twice. Six blocks of 30 trials were performed for each subject. Within each block, the 3 types of $2 were presented in random sequence. Each S1-$2 pair appeared only once within a block.

Procedure Subjects were instructed to press the "yes" key if they considered $2 to be a word, or the " n o " key if they considered it a non-word. The subjects were also requested to minimize eye blinks. The sequence of events for each trial was: (1) presentation of a 2.3 cm horizontal bar (a warning stimulus: WS) for 500 msec in the center of the video display (NEC, PC-KD854); (2) S1 was presented above this bar for 500 msec; (3) only the bar was presented again for 1000 msec; and (4) $2 was presented above the bar until a response was made. The maximal duration of each $2 presentation was 1500 msec. Stimuli were presented at a visual

548

s. KOYAMA ET AL.

angle delimited to about 0.7 ° vertically and about 1.7 ° horizontally. Stimulus presentation was controlled by an N E C PC-9801VX21 computer.

Recording and analysis E E G s recorded from Fz, Cz and Pz (10/20 system) are reported in the present study. All the E E G s were recorded using A g / A g C 1 electrodes. Eye movements were monitored from an electrode placed at the left supra-orbital ridge. All electrodes were referred to linked earlobes (impedances of less than 5 kO). The E E G s were digitized on-line at 100 s a m p l e s / s e c in each channel then stored for later analysis with a microcomputer (NEC San-ei 7T18). The E E G s were digitized during an analysis period beginning 200 msec prior to the WS and ending 1000 msec after the presentation of $2. The bandpass of each amplifier was set at 0.1-30 Hz (3 dB points of 6 d B / o c t a v e roll-off curves, NEC, 1A98A). Trials in which the E O G variation exceeded 8 0 / z V or the E O G deflection exceeded + 100 tzV and trials in which there was an error response or a response omission (including responses longer than 3000 msec) were excluded from the E R P averaging. For both groups, approximately 30% of the trials had to be excluded from the averaging, mainly because of the existence of E O G artifacts. All the subjects had at least 15 good trials for each condition. Comparisons of the E R P s between patients and controls were made in 2 ways. Firstly, comparisons were made including all subjects, and secondly, comparisons were made between patients and controls who had about the same reaction time. These latter subjects were selected from the original pool of subjects according to the sum of the reaction times to the 3 types of $2. As a result, the 11 patients with faster reaction times than the remaining 17 patients, and the 11 controls with slower reaction times than the remaining 15 controls were selected and compared. These patients comprised 7 males and 4 females ranging in age from 16 to 39 years, with a m e a n age of 26.3, 3 of whom were medicated with a daily dose equivalent to 100, 600 and 650 mg chlorpromazine. Their mean BPRS score (Overall and G o r h a m 1962) was 34.0 (13-61) and their m e a n SANS score (Andreasen 1982) was 22.5

(0-51), not significantly different from those of the remaining patients with slower reaction times (BPRS, t (26) --- 1.39, P < 0.2; SANS, t (26) = 1.72, P < 0.1). The patient subtypes were: paranoid, 6; disorganized, 1; catatonic, 1; undifferentiated, 3. The m e a n educational attainment of the patients was 12.5 school years (9-16 years). The control group comprised 7 males and 4 females whose ages ranged from 22 to 43 years, with a mean age of 30.3. Peak amplitudes and latencies of P200, N370 and the late positive component (LPC) were derived from the E R P s for each subject by visual inspection. P200 was defined as the maximum positive peak in the latency range of 140-320 msec after the presentation of $2. N370 was defined as the maximum negativetrending p e a k in the latency range of P200-620 msec. LPC was defined as the maximum positive peak in the latency range of N370-900 msec. The N370 and the P200 peaks were measured with respect to a 400 msec pre-S2 baseline, and LPC peaks were measured with respect to a 200 msec pre-WS baseline. The CNV amplitude was measured as mean amplitude of pre-S2 400 msec latency range with respect to a 200 msec pre-WS baseline. The reaction time and error rate data were subjected to diagnosis (patients, c o n t r o l s ) x condition (R, U, N) analyses of variance (ANOVA), with repeated measures on the condition factor in each group. A N O V A s with 1 between-subject factor (diagnosis) and 2 within-subject factors (condition, site) were performed for all E R P data, with the exception of the CNV data for which A N O V A s with 1 between-subject factor (diagnosis) and 1 within-subject factor (site) were performed. Significant effects as determined by the A N O V A s were followed by post hoc tests with the Newman-Keuls procedure (Winer 1971, pp. 528-529). When an interaction was present in an A N O V A , internal ANOV/i,s were performed to localize its source. The significance level of P < 0.05 was adopted. Degrees of freedom were corrected with epsilon (e) estimates (Jennings and Wood 1976) when the F values were below the level of 5% defined by the most conservative test ( F (1, 52) = 4.05; F (1, 20) = 4.35). In these cases, we report the original degrees of freedom and the epsilon correction factor.

TABLE I Comparisons of group mean latency (msec) and reaction time (msec) in each stimulus condition. Standard deviation in parentheses. Stimulus condition Related Unrelated Non-word

P200 latency (Fz) Schiz. Cont. (n = 28) (n = 26) 241 (32) 225 (27) 243 (26) 223 (32) 238 (30) 217 (33)

N370 latency (Cz) Schiz. Cont. (n = 28) (n = 26) 364 (80) 319 (47) 435 (90) 365 (48) 447 (75) 374 (49)

LPC latency (Pz) Schiz. Cont. (n = 28) (n = 26) 576 (91) 537 (52) 660 (87) 636 (73) 746 (85) 701 (92)

Reaction time Schiz. (n = 28) 904 (194) 1000 (191) 1386 (281)

Cont. (n = 26) 657 (121) 762 (122) 923 (221)

E R P s IN S C H I Z O P H R E N I C S

549 normal (n=26)

schizophrenics (n=28)

Post hoc tests indicated that the reaction time for related $2 was faster than those for unrelated and non-word S2s. The reaction time for unrelated $2 was also shown to be faster than that for non-word $2. Analysis of error rate revealed a significant effect of diagnosis (F (1, 52)= 9.02, P < 0.01); patients: R, 3.3 + 6.7%; U, 7.5 + 11.2%; N, 12.7 + 15.0%; controls: R, 0.5 + 1.2%; U, 3.7 + 3.3%; N, 3.3 + 3.7%. The effects of condition (F (2, 104)= 10.44, P < 0.001) and the interaction between diagnosis and condition (F (2, 104) = 3.21, P < 0.05, e = 0.81) were also significant. Post hoc tests indicated that the error rate for non-word $2 was higher than for any other condition in the patients, and that for related $2 was lower than any other condition in the controls. There was a total of 94 omissions made by 15 patients and 3 omissions by 3 controls.

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Fig. 1. Group m e a n E R P s for related and non-word S2s and their differences (non-word $ 2 - related $2).

Results All subjects Performance Analysis of reaction times revealed significant effects of diagnosis (F (1, 52) = 42.95, P < 0.001; see Table I) and condition (F (2, 104) = 145.08, P < 0.001).

Fig. 1 shows the ERPs elicited by related and nonword S2s and their differences. As in our previous study, S2s elicited a P200-N370-LPC wave complex in both groups. The N370 component was clearly elicited by unrelated and non-word S2s, and appeared to be prolonged in the patients compared to the controls. Latency. Table I shows the peak latencies of P200, N370 and LPC. Analysis of P200 latency revealed a significant effect of diagnosis (F (1, 52)= 5.72, P < 0.05), while analysis of N370 latency revealed significant effects of both diagnosis (F (1, 52)= 20.82, P < 0.001) and condition (F (2, 104)= 30.73, P < 0.001). Post hoc tests indicated that the N370 latency for related $2 was shorter than those for unrelated and non-word S2s. Analysis of the P200-N370 peak-to-peak latency also revealed significant effects of diagnosis (F (1, 52) = 13.47, P < 0.001) and condition (F (2, 104) = 28.00, P < 0.001). Post hoc tests indicated that the latency for related $2 was shorter than those for unrelated and non-word S2s. Analysis of LPC latency revealed significant effects of diagnosis (F (1, 52) = 4.39, P < 0.05) and condition (F (2, 104) = 93.53, P < 0.001).

T A B L E II Peak amplitudes (/xV) of N370 and LPC. A 400 msec pre-S2 baseline was used for N370. A 200 msec pre-warning baseline was used for LPC. Standard deviation in parentheses. Stimulus condition

Schizophrenics (n = 28)

Controls (n = 26)

Fz

Cz

Pz

Fz

Cz

Pz

N370 Related Unrelated Non-word

0.8 (4.2) - 0 . 3 (3.2) - 0.9 (3.7)

0.7 (4.2) - 1 . 1 (3.8) - 1.9 (4.3)

1.4 (4.0) - 0 . 1 (3.7) - 0.8 (4.1)

2.0 (4.6) - 0 . 1 (4.4) - 1.0 (5.3)

1.3 (3.9) - 1 . 0 (4.4) - 1.9 (4.6)

1.6 (3.1) - 0 . 1 (3.7) - 0.4 (3.5)

LPC Related Unrelated Non-word

4.9 (4.8) 5.4 (5.2) 4.4 (4.7)

6.9 (6.1) 7.8 (6.5) 6.8 (5.0)

8.8 (6.7) 9.7 (6.9) 8.8 (4.8)

8.3 (5.9) 7.6 (4.3) 7.4 (3.9)

7.7 (4.4) 7.2 (4.2) 6.1 (4.0)

9.7 (4.6) 9.1 (3.7) 7.4 (4.1)

550

S. KOYAMA ET AL.

TABLE III Comparisons of group mean latency (msec) and reaction time (msec) in each stimulus condition in reaction time-matched subjects. Standard deviation in parentheses. Stimulus

P200 latency (Fz)

N370 latency (Cz)

LPC latency (Pz)

Reaction time

condition

Schiz. (n =11)

Cont. (n = 11)

Schiz. (n = 11)

Cont. (n=ll)

Schiz. (n =11)

Cont. (n=ll)

Schiz. (n=ll)

Cont. ( n = 11)

Related Unrelated Non-word

234 (32) 237 (29) 232 (31)

228 (26) 216 (28) 212 (30)

343 (51) 396 (65) 390 (58)

340 (39) 383 (57) 396 (59)

579 (84) 630 (70) 721 (95)

545 (59) 661 (60) 701 (94)

752 (96) 864 (128) 1 134 (176)

758 (105) 865 (90) 1 108 (188)

Post hoc tests showed the longest latency for non-word $2 and the shortest latency for related $2. Analysis of the N370-LPC peak-to-peak latency revealed a significant effect of condition ( F (2, 104) = 25.44, P < 0.001). Post hoc tests showed the longest latency for non-word $2 and the shortest latency for related $2. The effect of diagnosis was not significant ( F (1, 52) = 1.56). Amplitude. Analysis of P200 amplitude revealed a significant effect of site ( F (2, 104)= 9.62, P < 0.001; patients: Fz, 7.0 + 2.7/zV; Cz, 7.0 + 3.1 /zV; Pz, 6.2 + 3.2 /~V; controls: Fz, 6.3 + 3.1 /zV; Cz, 5.5 + 2.9 /zV; Pz, 4.9 + 2.7 /zV). Post hoc tests indicated that the value from Fz was larger than that from Pz. Analysis of N370 amplitude revealed a significant effect of condition ( F (2, 104) = 35.57, P < 0.001; Table II). Post hoc tests indicated that the amplitudes for both unrelated and non-word S2s were larger than that for related $2. The effect of diagnosis was not significant ( F < 1). Analysis of P200-N370 peak-to-peak amplitude showed no effect of diagnosis ( F (1, 52) = 2.78, P < 0.1). Analysis of LPC amplitude revealed significant effects of site ( F (2, 104)= 19.63, P < 0.001; Table II) and an interaction between diagnosis and site ( F (2, 104)= 9.12, P < 0.001). The effect of diagnosis was not significant ( F < 1). Subsequent diagnosis x type ANOVAs performed on separate data for each site showed that the LPC amplitude was larger for the controls than for the patients at Fz ( F (1, 52) = 6.12, P < 0.05). Analysis of CNV revealed significant effects of diagnosis ( F (1, 52) = 14.98, P < 0.001) and site ( F (2, 104)= 32.45, P < 0.001). Post hoc tests indicated that values from Fz were smaller than those from Cz and Pz: patients: Fz, 0.1 + 2.5 /.tV; Cz, - 1.6 + 2.4 /zV; Pz, - 1.2 + 2.5 /zV; controls: Fz, - 1 . 6 + 1.4 /~V; Cz, - 3 . 9 + 1.9 /zV; Pz, - 3 . 4 + 2.0/.tV.

unrelated $2 was faster than that for non-word $2. The effect of diagnosis was not significant ( F < 1). Analysis of error rate showed a significant effect of diagnosis ( F (1, 20) = 6.85, P < 0.05; patients: R, 3.8 + 9.0%; U, 9 . 2 + 9 . 8 % ; N, 10.8+ 11.3%; controls: R, 0.7 + 1.3%; U, 2.3 + 2.8%; N, 3.3 + 4.3%). There was a total of 20 omissions made by 4 patients and 3 omissions by 3 controls.

ERPs The group mean ERPs throughout the recording period at Pz are shown in Fig. 2. The amplitude of LPC appeared to be reduced in the subjects with slower responses in both groups. The CNV developing prior to $2 was reduced in the schizophrenic patients

normal FAST (n=15)

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Reaction time-matched subjects Performance Analysis of reaction times revealed a significant effect of condition ( F (2, 4 0 ) = 61.52, P < 0.001; see Table III). Post hoc tests indicated that the reaction time for related $2 was faster than those for unrelated and non-word S2s, and that the reaction time for

WS

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related unrelated

. . . . . . . . nonword

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Fig. 2. Group mean ERPs at Pz throughout the recording period.

ERPs IN S C H I Z O P H R E N I C S

551

nonword

unrelated

related normalFAST (n=l5)~,~ normalSLOW (n=11)r,.~J~

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schizophrenicsFAST (n=11),,.,~~ schizophrenicsSLOW (n=l7 )

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with slower responses compared with the other subject groups. Fig. 3 shows the ERPs elicited by S2s. The N370 for the patients with faster responses was similar to that for controls with slower responses in both latency and wave shape. Latency. Table III shows the peak latencies of P200, N370 and LPC. Analysis of P200 latency revealed no significant effect, while analysis of N370 latency showed a significant effect of condition ( F (2,

40) = 16.32, P < 0.001). Post hoc tests indicated that the N370 latency for related $2 was shorter than those for unrelated and non-word S2s. The effect of diagnosis was not significant ( F < 1). Analysis of LPC latency indicated a significant effect of condition ( F (2, 40) = 36.64, P < 0.001). Post hoc tests indicated that the LPC latency for non-word $2 was the longest and that LPC for related $2 was the shortest. The effect of diagnosis was not significant ( F < 1).

TABLE IV P200-N370 peak-to-peak amplitude (#V) and LPC peak amplitude (/xV). A 200 msec pre-warning baseline was used for LPC. Standard deviation in parentheses. Stimulus condition P200-N370 Fast Related Unrelated Non-word Slow Related Unrelated Non-word LPC Fast Related Unrelated Non-word Slow Related Unrelated Non-word

Schizophrenics (n = 11) Fz Cz

Pz

Controls (n = 11) Fz

Cz

Pz

5.6 (3.0) 8.2 (3.7) 7.2 (3.3)

6.0 (3.2) 9.1 (3.5) 8.4 (4.1)

4.3 (3.2) 7.4 (3.1) 6.9 (3.4)

3.1 (1.8) 5.3 (2.3) 7.0 (3.4)

2.9 (2.3) 5.7 (2.3) 6.7 (2.8)

2.3 (1.6) 4.2 (2.3) 4.2 (2.1)

6.4 (3.0) 7.5 (3.2) 7.7 (3.6)

6.4 (3.4) 8.4 (3.9) 8.4 (4.1)

5.0 (3.3) 6.5 (3.9) 6.5 (3.9)

5.8 (4.8) 8.4 (5.1) 7.4 (4.4)

5.6 (4.2) 8.2 (5.4) 8.0 (4.7)

4.1 (2.7) 6.8 (4.9) 6.4 (4.0)

6.0 (6.1) 9.1 (4.1) 6.2 (3.7)

10.3 (6.1) 13.3 (4.3) 9.6 (4.2)

12.7 (6.2) 15.5 (5.7) 11.9 (4.5)

9.8 (4.2) 8.6 (3.6) 8.4 (4.0)

8.7 (4.6) 8.2 (4.4) 7.2 (3.9)

11.1 (4.8) 10.5 (4.1) 9.3 (3.4)

4.3 (3.6) 3.1 (4.4) 3.3 (4.9)

4.7 (5.0) 4.3 (5.2) 5.0 (4.6)

6.3 (5.8) 6.0 (4.7) 6.9 (3.8)

6.2 (7.1) 6.2 (4.8) 6.0 (3.3)

6.4 (3.7) 5.8 (3.5) 4.6 (3.6)

7.8 (3.5) 7.3 (2.0) 4.7 (3.4)

552

Amplitude.

Analysis of P200 amplitude revealed no significant effect, while that of N370 amplitude showed a significant effect of condition ( F (2, 4 0 ) = 14.40, P < 0.001). Post hoc tests indicated that the amplitudes for unrelated and non-word S2s were larger than that for related $2. The effect of diagnosis was not significant ( F < 1). Analysis of P200-N370 peak-to-peak amplitude showed no effect of diagnosis ( F < 1; Table IV). Analysis of LPC revealed significant effects of diagnosis ( F (1, 20) = 7.82, P < 0.05), condition ( F (2, 40) = 4.66, P < 0.05) and site ( F (2, 40) = 9.72, P < 0.001; Table IV). Post hoc tests indicated that the amplitude for unrelated $2 was larger than that for non-word $2. The values recorded from Pz were larger than those from Fz and Cz. The interaction between diagnosis and site was also significant ( F (1, 40) = 8.02, P < 0.01). Subsequent diagnosis x condition ANOVAs performed on separate data for each site showed that the LPC amplitude was larger for the patients than for the controls at Cz ( F (1, 2 0 ) = 9.90, P < 0.01) and Pz ( F (1, 20) = 15.41, P < 0.01). Analysis of CNV revealed a significant site effect ( F (2, 40) = 17.37, P < 0.001). Post hoc tests indicated that the value from Fz was smaller than those from Cz and Pz; patients: Fz, - 0 . 2 + 2.3 /xV; Cz, - 3 . 2 + 1.9 tzV; Pz, - 2 . 9 + 1.9 /xV; controls: Fz, - 1 . 7 + 1.3 /zV; Cz, - 3 . 4 + 1.8 tzV; Pz, - 3 . 3 + 1.8/xV. In an additional analysis, A N O V A s with 2 between-subject factors (diagnosis, reaction time) and 2 within-subject factors (condition, site) were performed for all the E R P data with the exception of CNV. A significant effect of reaction time was found in the N370 latency ( F (1, 50) = 12.92, P < 0.01) and the LPC amplitude ( F (1, 50) = 18.75, P < 001). No interaction between reaction time and the other factors was found in any data set. ANOVAs with 2 between-subject factors (diagnosis, reaction times) and 1 withinsubject factor (site) were performed for the CNV data, and the effect of reaction time was found to be significant ( F (1, 50) = 5.09, P < 0.05).

Correlation As an additional analysis, product-moment correlations between the reaction time and the N370 latency at Cz, between the reaction time and LPC amplitude and latency at Pz, and between the reaction time and the CNV amplitude at Cz were computed separately for each condition and each group. The N370 latency in non-word $2 showed a significant positive correlation with reaction times for both groups (patients: r = 0.54, P < 0.01; controls: r = 0.67, P < 0.001). For the patients, the positive correlation between reaction time and latency in related $2 was also significant (r = 0.39, P < 0.05), whereas for the controls a positive correlation was observed between the reaction time

S. KOYAMA ET AL. and the N370 latency in unrelated $2 (r = 0.49, P < 0.05). Analysis of the LPC amplitude in non-word $2 showed a significant negative correlation with the reaction times in both groups (patients: r = - 0 . 4 5 , P < 0.05; controls: r = 0.63, P < 0.001). In the patients, the CNV amplitude in the N stimulus condition showed a significant negative correlation with the reaction time (r = - 0.50, P < 0.05).

Discussion

N400 In the present study, the N400 latency determined for schizophrenic patients did not differ from that of controls when the reaction times of the groups were quite similar. The variation observed in N370 latency was also similar between the groups in unrelated and non-word S2s. In both the patient and control groups, the N370 latency was correlated positively with reaction times. On the other hand, the LPC latency did not correlate with reaction time in any stimulus condition tested. In product-moment analysis, only the reaction times for non-word $2 showed a significant correlation between the N370 latency and the LPC amplitude in both groups and this might be because the reaction time for non-word $2 was longer than those for related and unrelated S2s. In addition, in related and unrelated S2s, the contextual effect might make the correlation indistinct. These results indicate that the information processing stage up to the point reflected by the N370 primarily determines the lexical decision time. Grillon et al. (1991) recorded the N400 latency in schizophrenic subjects. They reported that a difference was still observed when comparisons were made between reaction timematched patients and healthy controls using subtracted wave forms. However, their subjects were asked to refrain from responding quickly and this instruction might make the changes in ERPs associated with the reaction times unclear. We previously discussed the likelihood that schizophrenics have a deficit in selecting the appropriate responses rather than in processing the stimulus (Koyama et al. 1991) because the differences in reaction times are relatively larger than that in N370 latency. However, the present results indicate that the difference between patient and control groups in the processing stage reflected by N370 was amplified in the later stage of processing. Such an interpretation is compatible with the view of Meyer et al. (1988) who questioned the inference rule commonly applied to the E R P data which infers that if an experimental factor has a greater effect on mean reaction time than on the component's mean peak latency, then this factor influ-

ERPs IN SCHIZOPHRENICS ences some additional process whose operation mediates overt responses to presented stimuli. Instead, they proposed that a particular stage of processing entails a continuous activation mechanism with 2 thresholds, one set at an intermediate level triggering the onset of a corresponding E R P component, and the other at a higher level transmitting its output to later response-related processes. In this case, the factor effect found in the peak latency would not necessarily exhibit the same magnitude of effect as overt effects (see their Fig. 13). The latency of P200 was also delayed in the patients in the present study. Based upon the view of Meyer et al. (1988), the delayed N400 might be secondary to differences in P200, although the P200-N370 latency was significantly prolonged in the patients relative to the controls. The experimental factor modulating the P200 component should be investigated to clarify the nature of the process which is delayed in schizophrenia. The N200 component obtained by subtracting the E R P for frequent non-target stimuli from the E R P for rare target stimuli was reported previously to be delayed in schizophrenic subjects (Brecher et al. 1987). In addition reaction times in schizophrenics were shown to be delayed in a simple reaction time task (Neuchterlein 1977 for review). Thus, it appears that the process(es) regulating reaction time rather than those specific to linguistic process(es) are generally slow in schizophrenia. As in our previous study, no reduction of N370 amplitude was found in schizophrenics as compared with healthy controls. Adams et al. (1993) recorded ERPs from schizophrenics during a sentence reading task and reported that their patient group showed a reduced N400. They assessed the N400 amplitude by the waves formed by subtracting the ERPs for the best fit ending of each sentence from the ERPs to an anomalous ending. The magnitude of the group difference in the subtracted wave forms were parallel to the magnitude of the group difference in the LPC following the N400 (see their Fig. 5). Thus, their group difference in the N400 latency range was suggested to be mainly attributable to differences in LPC amplitude, and it is t h e r e f o r e difficult to conclude that schizophrenics have a reduced N400 based on their data. Grillon et al. (1991) also concluded that N400 was reduced in schizophrenics using subtracted wave forms. There is other evidence indicating that the LPC influences the ERPs in the N400 latency range. Firstly, in the present study (Fig. 1), the subtracted waves seem to be smaller for the schizophrenic patients than for the controls at Fz. The LPC amplitude with respect to 400 msec pre-S2 baseline showed a significant diagnosis x site interaction ( F (2, 104) = 4.22, P < 0.05) in addition to that with respect to the 200 msec pre-warn-

553 ing baseline. Post hoc tests indicated that the values from the patients were smaller than those from the controls at Fz; patients: Fz = 4.8 /~V, Cz = 8.8 /~V, Pz = 10.4 /~V; controls: Fz = 9.5 tzV, Cz = 10.8 /.~V, Pz = 12.0 gV. Secondly, our previous data also suggested that the LPC amplitude has an influence on the subtracted wave. We examined the subtracted wave and it appeared to be smaller at Fz in the patients than in the controls, but it was quite similar between the groups at the left and right temporal sites where the LPC amplitudes were also quite similar between the groups (see Fig. 2 in Koyama et al. 1991). Thirdly, Mitchell et al. (1991) recorded ERPs from schizophrenic subjects during a sentence reading task. The mean amplitude of the N400 latency range (300-500 msec) was more negative in the schizophrenic subjects than in the controls when an overt response was required, whereas the mean amplitude did not differ between the groups when no response was required. When overt responses were required, clear LPCs developed in the controls but not in the patients. Thus, the subtracted wave of the N400 latency range was shown to be affected by the LPC amplitude. In all the above data, under conditions where the N400 is most enhanced (anomalous endings or nonwords), the N400 amplitude was quite similar between schizophrenics and healthy controls. Thus, if the difference in the subtracted wave form between schizophrenics and healthy controls is found to occur after the influence of the LPC difference is eliminated, the smaller subtracted wave form would indicate the reduced contextual effect on N400 in patients but not a reduction in N400 itself. LPC

In both groups, LPC for the fast responders was larger than that for the slow responders. McCallum et al. (1989) also reported such LPC difference between fast and slow responders during a tone detection task using healthy subjects and they suggested that the LPC amplitude reflects the confidence with judgment. CNF CNV prior to imperative stimuli was reduced in the patients compared with the controls when data from all subjects were used. When a comparison was made, however, between reaction time-matched subjects, this difference was eliminated. Since the correlation between reaction time and CNV amplitude in the N stimulus condition was significant in the patient group, it can be concluded that the greater the CNV amplitude, the faster the response. In the control group, the difference in CNV amplitude did not produce a difference in reaction time.

554

Other investigators have also reported that correlations between CNV amplitude and reaction times were commonly modest when comparisons were made between healthy subjects (Loveless 1979), although the amplitude of CNV has been shown to be larger in fast responses when comparisons were made within subjects (e.g., Grunewald et al. 1979; Brunia and Vingerhoets 1980). This is probably due to the ceiling effect in CNV magnitude. We are grateful to Prof. Toshio Yamauchi and Dr. Ryoichi Toyoshima for the use of their facilities, and two anonymous reviewers and Prof. Ryusuke Kakigi for their constructive comments.

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