Auditory ERPs to non-target stimuli in schizophrenia: relationship to probability, task-demands, and target ERPs

INTERNATIONAL JOURNAL OF PSYCHOPHYSIOLOGY

ELSEVIER

International

Auditory relationship

Journal

of Psychophysiology

17 (1994) 219-231

ERPs to non-target stimuli in schizophrenia: to probability, task-demands, and target ERPs

*

Brian F. O’Donnell, Hiroto Hokama, Robert W. McCarley *, Robert S. Smith, Dean F. Salisbury, Erik Mondrow, Paul G. Nestor, Martha E. Shenton Department

ofPsychiatry

(116A), Brockton VA Medical Center, Harcard Medical School, 940 Belmont Street, Brockton, MA 02401, USA

Received

9 September

1993; revised 3 May 1994; accepted

3 May 1994

Abstract The effects of task demands and stimulus probability on the Nl and P2 components of the auditory event-related potential (ERP) to non-target stimuli were investigated in normal and medicated schizophrenic subjects. Subjects either read a book while tones were presented, or counted the rare (low probability) tones in an auditory oddball paradigm. The mismatch negativity to rare tones in the reading condition was present, and did not differ between groups. Nl amplitude was smaller in schizophrenic patients in all conditions. When subjects counted the rare tones, the amplitude and latency of P2 increased. This task-related effect on P2 was much greater in control than in schizophrenic subjects. Difference ERPs were used to better characterize the effect of task demands by subtracting the ERP in the reading condition from the ERP in the counting condition. The difference ERP consisted of a negative deflection at 182 ms, and a positive deflection at 276 ms, which were both reduced in schizophrenic subjects. N2 and P3 amplitude to target stimuli were reduced in patients as well, but these abnormalities were uncorrelated with Nl and P2 abnormalities to non-target stimuli. Despite automatic registration of stimulus mismatch, and normal processing speed, patients showed deficient task-related modulation of processing to both non-target and target stimuli. Reduction of Nl amplitude in schizophrenia occurs regardless of task demands, and may reflect a chronic, early-stage disturbance in information processing. Keywords:

Auditory

event-related

potentials;

Schizophrenia;

Nl, P2; MMN; Attention

1. Introduction

“Portions

of these

data

were

presented

at the American San Fran-

Psychiatric Association, 146th Annual Meeting, cisco. CA. Mav_ 22-27. 1993. * Corresponding

author.

0167-8760/94/$07.00 0 1994 Elsevier SSDI 0167-8760(94)00044-l

Science

Behavioral studies suggest that the performance of patients with schizophrenia is reduced on virtually all tasks requiring controlled or effortful processing of stimuli (Cohen and O’Donnell, 1993). Consistent with these behavioral find-

B.V. All rights reserved

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et al. /International

Journal

ings, event-related potential (ERP) studies suggest that ERP components elicited by target stimuli, such as the P3 component, are often abnormal in schizophrenic subjects (Blackwood et al., 1987; Faux et al., 1990; Grillon et al., 1991; McCarley et al., 1993a,b; O’Donnell et al., 1993; Pfefferbaum et al., 1984, 1989). Since the P3 appears to reflect processes involved in selective attention and working memory operations, such as generation of expectancies and context updating (Donchin and Coles, 19881, these findings are consistent with the hypothesis that schizophrenic patients have a severe disturbance of attentional processing, especially when stimulus encoding requires temporal integration of contextual information. ERPs also offer opportunities to study sensory and cognitive processes occurring prior to the emission of a response, or in the absence of a response, and thus can provide information complementary to behavioral measures of performance. These components are of interest because they might provide physiological information about the time-course of early attentional deficits, and the operation of working memory mechanisms involved in the comparison of sequential stimuli. Auditory stimuli typically elicit a negative deflection occurring about 100 ms after stimulus onset, the Nl or NlOO component, which is followed by a positive component at about 200 ms after stimulus onset, the P2 or P200 component. The Nl component to frequent, non-target stimuli has been reported to be depressed in schizophrenia in numerous studies using variants of the auditory oddball paradigm, while latency remains unchanged (Barrett et al., 1986; Ogura et al., 1991; O’Donnell et al., 1993; Pfefferbaum et al., 1984, 1989; Roth et al., 1980). When two different auditory stimuli are presented to a subject at different probabilities, the Nl component to the lower probability stimuli is enhanced. This enhancement occurs even when the subject is attending to stimuli in a different modality. Subtraction of frequent from rare stimuli in such a paradigm reveals that this effect consists of a broad negative component whose onset varies with stimulus discriminability, the “mismatch negativity” or MMN (N&&en, 1990;

qf Psychophysiology

I7 (3994) 219-231

Novak et al., 1990). The MMN appears to index an early, automatic comparison of the physical features of a stimulus with a representation of previous stimuli in working memory. Task-demands may also influence the amplitude of the Nl and P2 components. For example, Nl or P2 amplitude to frequent, non-target stimuli may be increased in the context of a discrimination task (Alho et al., 1987; Garcia-Larrea et al., 1992; Hackley, 1993; Hirata and Lehmann, 1990; McCallum et al., 1989; Picton and Hillyard, 1974; Picton et al., 1976). Reduction of the MMN have been reported by several investigators, but not for all stimulus conditions. Shelley et al. (1991) reported attenuated MMN in schizophrenia compared with age and gender matched controls. In their study, tones of two different durations were used in two conditions. In one condition, the long duration tone (100 ms) was the deviant stimulus ( p = 0.101, while the short duration tone (50 ms) was the standard, frequent stimulus. In the second condition, the probability of the two tones were reversed. Schizophrenic patients showed attenuation of MMN to long duration, but not to short duration, deviant tones. This laboratory (Catts et al., 1992) also found that long duration tones produced a more severe MMN decrement than short duration tones in patients off-medication. Javitt et al. (1993) have reported that MMN amplitude to pitch deviant tones was reduced in medicated schizophrenic patients. Since the MMN has been localized to primary auditory cortex and adjacent structures on the superior temporal plane, Javitt and colleagues suggested that these results were consistent with disturbances of early auditory information, possibly mediated by disturbed NMDA-receptor mediated neurotransmission. The auditory P2 component has also been reported to be of reduced amplitude in schizophrenia (Ogura et al., 1991; Pfefferbaum et al., 1989; Roth and Cannon, 1972; Roth et al., 1980; Shenton et al., 1989), although negative findings have sometimes been reported (Pffcfferbaum et al., 1984). While Nl latency is typically unaffected by schizophrenia, P2 latency has been reported to be earlier in schizophrenic patients

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Journal of Psychophysiology

relative to control patients when peak latency was measured from the ERP to frequent stimuli (Pfefferbaum et al., 1984, 1989; Roth et al., 1980). There are several possible explanations for this finding. The stimulus evaluation process represented by P2 may proceed more quickly in schizophrenia. Alternatively, the P2 deflection may include a late component which is attenuated in schizophrenia. If this were the case, then the peak latency in schizophrenia would be primarily determined by the early component, while the peak latency in control subjects would be determined by the superposition of both components. We studied how schizophrenic patients might differ from control subjects on ERP measures of early information processing of non-target stimuli, and how such early processing abnormalities related to the N2 and P3 components elicited by target stimuli. These effects were tested using an auditory oddball paradigm in which tones were presented while the subject read a book and ignored the tones, and then while the subject counted the rare, deviant tones.

2. Methods 2.1. Subjects Twenty chronic, right-handed male schizophrenic patients were recruited from the Brockton VA Medical Center. All the subjects were between the ages of 20 and 55 years. All were receiving neuroleptic medication. DSM-IIIR diagnosis (American Psychiatric Association, 1987) was ascertained on the basis of a structured psychiatric interview, the Schedule for Affective Disorders and Schizophrenia (Spitzer and Endicott, 197X), and medical chart reviews. None of the subjects had a history of electroconvulsive shock treatment, history of alcohol or drug abuse (DSM-IIIR criteria) within the past five years, or of neurologic illness affecting the CNS. The control group included twenty participants who were recruited from newspaper advertisements and were matched to the patient sample on the basis of age, gender, and handedness.

I7 (1994) 219-231

221

Subjects were excluded if they had a history of alcohol or drug abuse, psychiatric or neurologic illness, or psychiatric illness in a first degree relative. The age of the patient group (36.9 k 8.9 years) did not differ from the age of the control group (37.7 k 8.8 years; p = 0.94). Mental status scores (Folstein et al., 1975) were slightly lower in the schizophrenic (27.8 k 1.4) compared to the control subjects (29.1 + 1.4, p = 0.02). 2.2. ERP evaluation Recording procedures

Event-related potentials (ERPs) were recorded using an auditory oddball paradigm (Faux et al., 1990; O’Donnell et al., 1993). ERPs were elicited by tone pips of 40 ms duration (10 ms rise/fall time) with a 1.2-s inter-stimulus interval. Rare (p = 0.15) high pitched tones (1500 Hz, 97 dB SPL) were presented pseudorandomly interspersed among frequent low pitched tones (1000 Hz, 97 db SPL). Tones were delivered through Etymotic insert earphones against a background of continuous 70 dB binaural white noise. EEG was recorded from 28 tin plate scalp electrodes using an Electra-Cap International, Inc. electrode cap. Scalp electrode placements included all electrodes in the International lo-20 system (except Tl and T2) with eight additional interpolated electrodes (Faux et al., 1990). Fpl, Fp2, and Cz sites were located manually by International lo-20 measurements, and all other electrodes were positioned automatically at standard distances. A vertical electrooculogram (EOG) was recorded using right eye supra-and infra-orbital electrodes. Horizontal EOG was recorded form electrodes at the right and left external canthi. Electrode impedance was maintained at < 4 k0. Right and left ear impedence was matched within 1 kR. The EEG was filtered using a bandpass of 0.15-40 Hz, with 36 dB/octave rolloff for lowpass and 6 dB/octave for high pass. Single trial epochs were digitized and stored on hard disk for off-line processing. Each epoch consisted of 256 samples over 700 ms including a 100-ms prestimulus baseline interval. Two conditions were used which differed in task demands, but used the same oddball stimu-

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Journal of Psychophysiology I7 (1994) 219-231

lus paradigm. In the reading condition, subjects were instructed to read a novel and to ignore the tones. In the discrimination condition, the subjects silently counted the 1500 Hz tones while staring at a central fixation point to reduce eye movements. Six hundred tones were presented in both conditions. The reading condition always preceded the discrimination condition, as in the study of non-target ERPs in control subjects by Garcia-Larrea et al. (1992). In the discrimination condition, the sequence of tones was interrupted every 60-70 tones in order to assess whether the subject was keeping an accurate count. Accuracy was evaluated using the formula a=l-[lc-nl/n], where a equaled the proportion correct (overall accuracy) n equaled the number of target stimuli actually presented to the subject, and c was the number of high tones the subject reported. Patient accuracy (0.94 _+ 0.07) was poorer than control accuracy (0.98 & 0.04; t(38) = 2.5, p = 0.02).

Data processing All single-trial epochs were baseline corrected by subtracting the average baseline voltage from each point in the ERP prior to subsequent processing. Epochs were then digitally filtered with a low pass setting of 16 Hz in order to remove high frequency artifact. ERP epochs with vertical EOG artifact were corrected through individually computed weighting coefficients at each electrode site using the Semlitsch et al. (1986) procedure. After correction for vertical EOG artifact, all epochs with voltages in excess of k50 PV at any electrode site were rejected. Trials with residual HEOG artifact were rejected using single-trial visual inspection. ERPs to stimuli in each condition were averaged for each subject prior to component measurement. The presence of a mismatch negativity effect was tested by comparing the amplitude of the Nl deflection to frequent and rare stimuli in the reading condition, when the subject ignored the tones. A mismatch negativity would be indicated by a more negative Nl to rare compared to frequent tones.

The influence of task-demands on the Nl and P2 components was assessed by comparing ERPs to the frequent, non-target tones in the reading condition and the counting condition. The Nl and P2 components are most clearly visualized to frequent, non-target stimuli in an auditory oddball paradigm, since P2 overlaps with the N2 component elicited by target stimuli (Simson et al., 1976, 1977; see Fig. 31. Peak Nl latency and amplitude were measured at the most negative voltage at each electrode site in the latency range of 80-150 ms. Peak P2 amplitude and latency were measured at the most positive voltage at each electrode site in the latency range of 175-285 ms. Subtraction of the ERP to frequent stimuli in the reading condition from the ERP to frequent stimuli in the counting condition yielded a biphasic ERP consisting of a negative component most prominent at Fz with a peak latency at 180 ms, followed by a positive component with a maximal voltage at Cz and a peak latency at 280 ms. Subsequently, the negative component measured from the difference ERP will be referred to as “Nlb”, and the positive component as, “P2b”. Peak latency and amplitude of Nlb were measured between 140 and 250 ms. Peak latency and amplitude of the P2b component was measured from the subtraction ERP for each subject in the latency range of 240-330 ms. The N2 and P3 components were measured from the ERPs to target stimuli in the count condition. N2 latency and amplitude were measured at the most negative voltage between 180 and 290 ms. The P3 component was measured at the most positive voltage between 300 and 500 ms. 2.3. Statistical

analysis

For statistical analysis, component measures were obtained from Fz, Cz, and Pz, since all the components under consideration had maximum voltage values at midline electrode sites. Mixedmodel ANOVAs were used to assess group, electrode site, and condition effects. Diagnosis (conwas included as a trol vs. schizophrenic) between-groups factor, and electrode site as a

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Journal

of Psychophysiology I7 (1994) 219-231

223

Table 1 Non-target component amplitudes and latencies at Cz Mean and SD (in parentheses) are provided for each value Read (frequent Nl Amplitudes (pVcLv) Control Schizophrenic Latencies (ms) Control Schizophrenic

Read (rare tones)

tones) P2

- 4.4 (1.6) -2.6 (1.2)

2.6 (1.6) 2.8 (1.9)

126 (10) 125 (12)

- 5.1 (2.6) - 2.7 (1.6)

204 (20) 197 (19)

within-groups factor, for each ANOVA. The MMN effect was evaluated using the withingroups factor of stimulus probability (frequent or

-4.6 -2.2

205 (25) 199 (22)

RARE

(1.6) (1.3)

126 (8) 125 (10)

rare>. The influence and P2 components within-groups factor

4.6 (2.9) 2.9 (1.7) 247 (31) 215 (30)

of task-demands on the Nl was evaluated using the of task (read vs. count); and

RARE - FREQUENT

c 3 1 -1

.__.._ -...._.L-w ..

I

f+

P2

Nl

2.7 (2.7) 2.7 (2.6)

129 (11) 126 (8)

FREQUENT

Count P2

Nl

_’

MMN

;_b __yi_

-100

0

100200300400500500

-100

0

100200300400600500

MS

MS

-100

0

100200300400500600 MS

Control Schlrophrenlc

. .. ... . .. ..

Fig. 1. ERPs to frequent tones and rare (infrequent) tones in the reading condition, in which subjects ignored the tones while reading a book. Subtraction of the ERPs to frequent tones from the ERPs to the rare tones reveals the mismatch negativity (MMN), which is maximal at Fz. Control subjects are indicated by a solid line and schizophrenic subjects by a dotted line.

224

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Journal of Psychophysiology I7 (1994) 219-231

by ANOVAs on the Nlb and P2b components measured from the difference waveform (countminus-read). Group differences on N2 and P3 were compared using group x electrode site ANOVAs. Follow-up ANOVAs and t-tests were used to evaluate the locus of interactions. All p values reported here are two-tailed. The relationship of the amplitude and latency of early ERP components (Nl and P2) with later components associated with target detection (N2 and P3) was evaluated using Pearson correlation coefficients. For the correlational analyses, all components were measured at the Cz site.

READ

3. Results The of the uli are groups shown

mean values for the latency and amplitude Nl and P2 components to non-target stimlisted in Table 1. ERPs averaged within for each condition and stimulus type are in Figs. 1, 2 and 3.

3.1. Mismatch

negativity

(MMN)

Fig. 1 shows the ERPs averaged within groups to frequent and rare stimuli in the reading condition. Nl and P2 showed maximum values at the

COUNT

COUNT

- READ

P2b

_._p+& Nlb Nl

Control-_

-5

_

Schirophrenlc ..... ....

Fig. 2. ERPs to frequent, non-target tones in the reading and counting conditions, and the difference ERP (count-read) at midline electrode sites. Frequent tones elicit Nl and P2 components. The count-minus-read ERP shows a frontally maximal Nlb component followed by a P2b component largest at Cz and Pz. Control subjects are indicated by a solid line and schizophrenic subjects by a dotted line.

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Journal of Psychophysiology 17 (1994) 219-231

fronto-central electrode sites in both schizophrenic and control subjects. The MMN was visualized by subtracting the ERPs to frequent from the ERP to rare tones (third column, Fig. 1). The mismatch negativity was a broad negativity to rare stimuli extending from about 100-200 ms, and was most prominent at Fz. There was a main effect of group in the ANOVA on Nl amplitude, showing that Nl was significantly reduced in schizophrenia (F(1,38) = 14.01, p < 0.01). Nl amplitude was larger at Fz and at Cz than at Pz, as shown by a main effect of electrode site (F(2,76) = 38.5, p < 0.001). Nl amplitude to rare tones was greater than amplitude to frequent tones, as indicated by a main effect of probability, confirming the presence of the MMN (F(1,38) = 5.0, p = 0.03). The interaction terms involving group and probability were not significant, indicating that the MMN did not differ between groups. Nl latency was longer (3-5 ms) to the rare compared to the frequent stimuli (F(1,38) = 4.64, p = 0.04). P2 amplitude was significantly larger in Fz and Cz compared to Pz, as shown by a main effect of electrode site (F(2,76) = 14.2, p < 0.001). There was a mismatch negativity effect at Fz, but not at more posterior sites, as indicated by a probability x electrode interaction (E(2,76) = 5.2, p < 0.01). There were no latency differences between groups or conditions. 3.2. Effect components

of task-demands

on the Nl

and P2

Fig. 2 shows the ERPs to frequent stimuli in the reading condition, in the counting condition, and in the count-minus-read difference waveform along the midline electrode sites (Fz, Cz, and Pz). The count-minus-read difference ERP showed endogenous negative (Nlb) and positive (P2b) components. Nl component The schizophrenic group showed reduced Nl amplitude in both task conditions (F(1,38) = 23.0, p < 0.001). There was a main effect of electrode site, with larger voltage values at Fz and Cz than

225

at Pz (F(1,38) = 283.7, p < O.OOl), and an electrode site x group interaction (F(2,76) = 4.8, p = O.Ol), indicating that the difference between groups was larger at Fz than at more posterior sites. There was no effect of task-demands on Nl amplitude in either group. The ANOVA on Nl latency revealed no significant effects.

P2 component An ANOVA on P2 amplitude revealed that while there was no main effect of group on P2 amplitude, P2 amplitude was affected by task demands (F(1,38) = 10.3, p < O.Ol), and there was an interaction between task and group (F(1,38) = 10.2, p < 0.01). The interaction indicated that P2 amplitude was much larger in the counting compared to the reading condition in the control group, but showed little difference between conditions in the schizophrenic group. The P2 component was larger at Pz and Cz compared to Fz, indicated by a main effect of electrode site (F(2,76) = 15.4, p < 0.001). The task by electrode interaction was significant, with the largest task effect at Pz and Cz relative to Fz (F(2,76) = 18.9, p < 0.001). The group X electrode X task interaction was also significant (&X2,76) = 6.4, p = 0.003). Between group t-tests at each electrode site indicated that P2 did not differ between groups in the reading condition, but differed at Cz and Pz in the counting condition. ANOVAs on P2 latency showed a main effect of group on P2 latency (F(1,38) = 15.7, p < O.OOl), an effect of task (F(1,30) = 46.2, p = 0.002), and an interaction between group and task (F(1,38) = 10.8, p = 0.002). The main effect of task was due to an increase in P2 latency with in the counting compared to the reading condition. The interaction indicated that P2 latency did not differ between groups in the reading condition, but in the counting condition, P2 latency was much longer in the control group compared to the schizophrenic group. The increase in latency and amplitude of P2 with task-demands in the control group suggests the superimposition of a late positive component in the P2 latency range. This possibility was evaluated using count-minus-read difference waveforms.

226

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Count-minus-read difference components (Nlb and P2b) An ANOVA on Nlb showed a main effect of electrode, with a group X electrode interaction. Separate group ANOVAS indicated that Nlb showed a frontal to posterior gradient in the control group, with the largest value at Fz and the smallest value at Pz, while the patient group showed a minimum value at Cz. Between groups t-tests indicated that the groups differed at Fz, but not at Cz or Pz. The mean control group voltage at Fz was - 1.9 + 0.8 pV, and the schizophrenic voltage was - 1.3 * 1.0 pV. The ANOVA on Nlb latency revealed no significant effects. Nl latency at Fz was 185 + 29 ms. P2b was reduced in the schizophrenic group (F(1,38) = 5.5, p = 0.02). The voltage of the control group at Cz was 3.3 f 2.4 pV, and that of the schizophrenic group, 1.6 * 1.7 pV. There was a main effect of electrode site on amplitude, with a Cz maximum voltage in both groups. P2b latency was later at Pz (294 & 28 ms> than at Cz (277 f 30 ms> or Fz (277 + 30 ms) in both groups (F(2,76) = 8.0, p = 0.001).

FREQUENT

L------

-5.0 -100

3.3. N2 and P3 components to target stimuli

TARGET

0

I

-5.0 -100

100200300400500600

0

100200300400500600

MS

MS

Control

Fig. 3 shows the group averaged ERPs to frequent, non-target and rare, target stimuli in the count condition. A prominent P3 component was elicited in both groups to target stimuli, preceded by the N2 component. The ANOVA on N2 amplitude revealed a main effect of group (F(1,38) = 7.8, p < O.Ol), and a group by electrode interaction (F(2,76), indicating that N2 amplitude was reduced in schizophrenic patients, particularly at Fz. The mean value of N2 at Fz was - 2.9 _t 2.5 WV for the control subjects, and -0.4 + 2.2 PV for the schizophrenic subjects. There was a main effect of electrode site on N2 amplitude (F(2,76), indicating that N2 amplitude was larger at Fz than at more posterior sites. An ANOVA on N2 latency showed that N2 was prolonged in schizophrenic patients, with a main effect for group (F(2,76) = 5.8, p = 0.02). The mean latency for control subjects at Fz was 244 _t 35 ms, and for schizophrenic subjects, 270 + 25 ms.

Schizophrenic

_.___...__.

Fig. 3. ERPs to frequent and rare, target tones in the count condition. The target tones elicit the N2 and P3 components.

The ANOVA on P3 amplitude revealed a main effect of group (P(1,38) = 10.7, p < 0.011, indicating the schizophrenic patients had reduced amplitude across all sites. There was also a main effect of electrode site, with the largest P3 component at Pz, and the smallest at Fz, for both groups. The mean value of P3 at Pz was 12.3 PV for control subjects and 7.7 WV for schizophrenic subjects. An ANOVA on latency showed a main effect of electrode site, with P3 latency later at Pz (388 + 44 ms) then at Fz (363 I!I 37 ms> and Cz (367 + 42 ms). The two groups did not differ in latency.

B.F. O’Donnell et al. /International Table 2 Correlations

among

ERP component

amplitude

measures

Journal of Psychophysiology 17 (1994) 219-231

227

at Cz Count

Read Frequent

Frequent

Rare

Nl

P2

Nl

P2

-0.46 * 0.69 ** _ _

0.76 ** _ _

_ _

_

_

Rare

Nl

P2

N2

P3

Control

_

p2RF

0.79 ** _

N1~~ p2RR

0.89 ** -0.47 * _

N~CF p2CF

N2 P3

_

_

Schizophrenic

_

p2RF

0.65 ** _ _

N1~~ p2RR WF

_

p2CF

N2 P3

0.73 **

_

0.75 ** _

0.57 ** _ _

Subscript key to conditions: RF = read, frequent; * p < 0.05; **, p < 0.01; -, not significant.

Table 3 Correlations

among

ERP component

latency

RR = read,

measures

_ 0.62 **

rare;

CF = count,

frequent;

CR = count,

rare.

Significance

levels:

at Cz

Read

Count

Frequent Nl

_ _

0.49 *

Rare P2

Nl

Frequent P2

Nl

Rare P2

N2

_ _

0.53 *

_

0.60 **

P3

Control p2RF N1~~

0.50 * 0.85 **

_

0.91 **

0.61 * 0.46 *

p2RR %F p2CF

N2 P3

_ _

0.90 **

_

-

_ _

_ _

0.56 * 0.77 *

_

0.50 * _ _

_

Schizophrenic p2RF N1~~ p2RR %F p2CF

N2 P3

_

_

0.87 ** 0.51 * _

0.73 * -

0.59 ** 0.54 * 0.54 *

_

_

Subscript key to conditions: RF = read, frequent; * p < 0.05; ** p < 0.01; -, not significant.

RR = read,

_ _ _ _ rare;

0.66 ** _

CF = count,

frequent;

CR = count,

rare.

Significance

levels:

22x

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Journal of Psychophysiology

3.4. Correlations among ERP component measures The relationship of amplitude and latency measures of early, non-target ERP components (Nl, P2) to later, target ERP components (N2, P3) was evaluated using Pearson correlation coefficients. Table 2 shows the significant coefficients between amplitude measures at Cz for these components across conditions. The most consistent correlations were between Nl and P2 measures in different conditions. Similar findings were obtained when correlating component latencies (Table 3). There was little evidence for an association between the Nl and P2 components with the N2 and P3 components. The only predictor of P3 latency was N2 latency.

4. Conclusion Both schizophrenic and control subjects showed an effect of stimulus probability in the reading condition, with more negative Nl and P2 amplitudes to rare tones. The magnitude of this mismatch negativity effect did not differ between groups. Nl amplitude was depressed in schizophrenic patients whether or not stimuli were attended. In control subjects both P2 amplitude and latency were increased by task requirements, but these effects were small or absent in schizophrenic subjects. Consequently, there was no difference in P2 amplitude or latency between schizophrenic and control subjects in the reading condition, while in the counting condition, P2 latency was longer and amplitude larger in control subjects than in schizophrenic patients. Difference ERPs (read-minus-count) suggested that attention to frequent, non-target stimuli was associated with a biphasic ERP, with a frontal negative component (Nib) followed by a more central positive component (P2b). Both Nlb and P2b were reduced in schizophrenic patients, but did not differ in latency. The N2 and P3 components to target stimuli were reduced in schizophrenic subjects, but these reductions were not correlated with amplitude reductions in the non-target Nl and P2 components.

17 (1994) 219-231

5. Discussion

Non-target ERP components were reactive to probability and task demands. Moreover, these components were differentially sensitive to schizophrenia. In this discussion, ERP components will be discussed in temporal order of their appearance in the waveform. A variety of early ( < 200 ms> negative components were isolated in this study. The Nl component elicited by frequent stimuli was reduced in schizophrenic patients across different levels of probability and task demands. In control subjects, Nl amplitude decreases with decreased arousal or alertness; shorter interstimulus intervals; and .. .. longer periods of stimulation (Naatanen and Picton, 1987). The persistence of this reduction across conditions therefore suggests that the Nl abnormality indicates a chronic abnormality in schizophrenic patients, such as altered arousal or failure to show normal refractory effects, rather than a disturbance of task-related cognitive processing. The influence of medication on Nl amplitude in schizophrenia is unclear. Pfefferbaum et al. (1989) reported that schizophrenic patients off-medication showed no decrement in Nl amplitude in oddball paradigms, while Ogura et al. (1991) reported that patients off-medication did show a decrement in Nl amplitude. Infrequent stimuli in the reading condition were associated with a broad mismatch negativity in both groups, which affected both Nl and P2 amplitude. Mismatch negativity was not reduced in amplitude in the patients, indicating that subsequent ERP abnormalities could not be attributed to a failure in the automatic comparison of the physical features of the stimuli. These findings provide further support for the dissociation of the Nl and MMN components, since they can be differentially affected by schizophrenia. Other studies suggest that under some conditions (e.g. using long duration stimuli, or a much higher rate of stimulus presentation), schizophrenics may show a diminished MMN (Javitt et al., 1993; Shelley et al., 1991). Another difference between this protocol and that employed by Javitt et al. (1993) is the use of a demanding distractor task

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(reading) while tones were presented in the current study. Since selective attention can increase the amplitude of MMN in normal subjects (Woldorff et al., 19911, the use of a distractor task in the visual modality might prevent control subjects from allocating attention to tones and thereby result in a smaller MMN. Other investigators have reported prolongation of P2 latency to frequent auditory stimuli in control compared to schizophrenic subjects (Pfefferbaum et al., 1984; Pfefferbaum et al., 1989; Roth et al., 1980). The results from this study suggest that this prolongation in control subjects may be due to the enhancement of the P2 component when frequent stimuli must be discriminated from target stimuli, rather than more rapid stimulus processing in schizophrenic patients. The task modulated enhancement of P2 to frequent stimuli was severely reduced in schizophrenic subjects. Consequently, in the reading condition the P2 component did not differ in amplitude or latency between the control and schizophrenic groups. In the counting condition, the control subjects showed a larger P2 component with a later peak compared to schizophrenic Reduction of P2 amplitude in subjects. schizophrenic subjects was only present when the stimuli were task relevant, and therefore may index an attentional deficit, or failure to modulate task-related arousal, in the processing of non-target stimuli. Enhancement of late positive components to frequent stimuli in discrimination tasks has been described in normal subjects by other investigators. Picton and Hillyard (1974), using an auditory-oddball discrimination paradigm with clicks varying in intensity, reported enhancement of both the Nl and P2 components to non-target clicks, compared to the Nl and P2 components elicited while the subject read a book. The mechanism underlying enhancement of Nl or P2 in such studies has been attributed either to selective attention or task-related changes in arousal (Picton et al., 1976; Picton et al., 1978). Serial trial analysis by Hirata and Lehmann (1990) indicated that the Nl and P2 components to nontarget stimuli during a discrimination task differ as a function of the temporal relationship (before

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or after) a target stimuli. Their findings indicated that processing of a target stimulus activates additional, transient neural processes which operate on subsequent non-target stimuli. Garcia-Larrea et al. (1992) compared the Nl and P2 components elicited during presentation of a series of 1000 Hz tones, during an oddball sequence without task demands, and during an oddball sequence requiring counting of target tones. A P250 component appeared to frequent stimuli in the oddball paradigms which was essentially absent to the series of 1000 Hz tones, and which increased in absolute voltage to non-target stimuli during the discrimination task. Alho et al. (1987) reported that task-requirements were associated with an increased late positive component to non-target ERPs. In a systematic investigation of ERPs and task demands, McCallum et al. (1989) examined the ERPs to target and non-target stimuli, when four different, equiprobable stimuli were delivered sequentially to either the right or left ear. Of these eight stimuli, one was designated as a target. These ERPs were contrasted with ERPs collected to the stimuli without response requirements. They found that ERPs to frequent stimuli in the discrimination condition were associated with the presence of positive component which was comparable in amplitude to the target P300 component, with a similar peak latency. They suggested that the target P3 results in a facilitator-y updating of memory processes, while the non-target P3 results in an inhibitory updating. The lack of correlation between P2 to non-targets and P3 to targets in the counting condition suggests that these two components do reflect different processes. These components also differ in their relationship to underlying anatomic features in schizophrenia. Previous studies from this laboratory (McCarley et al., 1993; O’Donnell et al., 1993) indicated that the amplitude and topography of N2 and P3, but not of Nl and P2, were highly related to temporal lobe grey matter reduction in schizophrenia. Subtraction of the ERP in the reading condition from the ERP in the attend condition yielded a biphasic difference ERP. The negative component was termed “Nlb” in the results section. Nlb peaked much later than the classic Nl com-

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ponent, and like MMN, was largest at Fz in control subjects. It may represent the second component of the processing negativity, as discussed by Naatanen and Picton (1987). Nlb was significantly reduced in the schizophrenic subjects at Fz. The positive component with maximum amplitude at Cz resembled the topography of the auditory P3a component, usually elicited to deviant, unattended tones (Squires et al., 19751, and to non-target tones in a discrimination task (Garcia-Larrea et al., 1992). The P2b component in this study was earlier in latency and more anterior in distribution than that reported by McCallum and colleagues (280 ms vs. 310-315 ms>. The later component latency in the McCallum et al. (1989) study may have reflected the greater difficulty of categorizing multiple stimuli. Further parametric studies, varying stimulus discriminability and number of stimulus categories, would be useful in characterizing the conditions which elicit these non-target, endogenous components. Correlational analysis suggested that the latency and amplitude of Nl were highly correlated across probability and task-demands. P2 amplitude and latency were correlated within the reading condition, but did not reliably correlate with P2 measures obtained from the counting condition in control subjects, supporting the hypothesis that the P2 enhancement in the counting condition represents the superposition of a second, attentionally modulated component on the P2 elicited without task-demands. Finally, the amplitude and latency of early ERP components to non-target stimuli (Nl and P2), were poor predictors of the amplitude and latency of N2 and P3, suggesting that abnormalities of target processing in schizophrenia reflect different neural systems than those involved in processing of non-target stimuli. These findings document pervasive abnormalities in auditory information processing in schizophrenic patients, beginning as early as 100 ms after stimulus onset. The most consistent abnormality was a failure of task-related modulation of ERP components, despite automatic registration of stimulus mismatch, and normal processing speed as measured by ERP component latencies.

Since attentional mechanisms serve to either facilitate processing of task-relevant stimuli, or inhibit processing of irrelevant stimuli, on the basis of task demands, these findings suggest that serial auditory stimuli are poorly differentiated by schizophrenic subjects. These early-stage attentional deficits may partially account for subsequent late-stage abnormalities in response production and long-term memory encoding.

Acknowledgements This study was supported by NIMH 40,799 (R.W.M.), Department of Veterans Affairs (R.W.M.), NIMH Research Scientist Development Award KOl-MH00746-04 (M.E.S.), the Scottish Rite Foundation (M.E.S.), the Milton Foundation (M.E.S.), and the Stanley Foundation (M.E.S.).

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