P300 subcomponents reflect different aspects of psychopathology in schizophrenia

P300 Subcomponents Reflect Different Aspects of Psychopathology in Schizophrenia Thomas Frodl-Bauch, Ju¨rgen Gallinat, Eva-Maria Meisenzahl, Hans-Ju¨rgen Mo¨ller, and Ulrich Hegerl Background: The aim of the study was to investigate abnormalities of P300 subcomponents in schizophrenic patients as well as relationships between these subcomponents and positive versus negative schizophrenic symptoms. Methods: Nineteen schizophrenic patients and 19 healthy controls were tested with an auditory event-related potential oddball paradigm designed to elicit the P300. The P300 data were analyzed by separating P300 subcomponents with a recently developed dipole source model. Results: Compared to healthy controls, schizophrenic patients showed reduced P300 amplitudes of the temporobasal dipoles, corresponding mainly to P3b. Positive symptoms of the Positive and Negative Syndrome Scale correlated positively with the temporo-basal but not with temporo-superior dipole P300 activities, whereas negative symptoms correlated positively with the temporo-superior but not with temporo-basal dipole activities. Conclusions: The P300 subcomponents separated with the dipole model are affected in a different manner by positive versus negative symptoms. Furthermore, the positive correlation between the severity of psychopathology and the P300 amplitudes of the different dipole activities appears to be a state-dependent effect, which has to be separated from the P300 amplitude reduction as a trait marker in schizophrenic patients. Biol Psychiatry 1999; 45:116 –126 © 1999 Society of Biological Psychiatry Key Words: Evoked potential, P3a, P3b, hemispheric differences, positive and negative symptoms, neurotransmitter

Introduction

T

he P300 component of the event-related potential (ERP) induced by auditory stimuli occurs with a latency of about 300 msec in normal young adults after a From the Department of Clinical Neurophysiology, EEG, Psychiatric Hospital Ludwig Maximilians Universita¨t, Munich, Germany. Address reprint requests to Dr. Thomas Frodl-Bauch, Ludwigs Maximilians University Munich, Psychiatric Hospital, Department of Clinical Neurophysiology, EEG, Nussbaumstrasse 7, 80336 Munich, Germany. Received April 1, 1997; revised August 11, 1997; revised October 31, 1997; revised March 2, 1998; accepted March 6, 1998.

© 1999 Society of Biological Psychiatry

target stimulus is discriminated from nontarget stimuli (Sutton et al 1965; Donchin et al 1986; Polich and Kok 1995). Reduction of the auditory P300 amplitude is one of the most robust biological findings in schizophrenia (e.g., Roth et al 1981; Pritchard 1986; Shenton et al 1989; McCarley et al 1989; Michie et al 1990; Ford et al 1994; Hegerl et al 1995; Bougerol et al 1996). Also of interest has been the observation of P300 topographic asymmetries showing smaller P300 over left temporal areas in schizophrenic patients (Morstyn et al 1983; McCarley et al 1989; Roemer and Shagass 1990; Holinger et al 1992). Left posterior superior temporal gyrus volume reductions have been related to reduced P300 (McCarley et al 1989, 1993). Therefore, activity over the left temporal area might be the best discriminator between schizophrenic patients and healthy controls; however, several studies have found no evidence for lateral asymmetry (Kemali et al 1988; Pfefferbaum et al 1989). P300 latency effects are not as pronounced as amplitude differences between schizophrenic and control subjects. Longer P300 latencies in schizophrenic patients have been observed in some studies (Pfefferbaum et al 1989; Blackwood et al 1987; Romani et al 1987; St Clair et al 1989; Souza et al 1995) but not in others (Pfefferbaum et al 1984; Ford et al 1994). The finding of a reduced P300 amplitude has stimulated the interest of psychiatrists and psychologists. Reduced P300 amplitudes in schizophrenics suggest that this ERP measure may reflect a trait marker (Pritchard 1986; Duncan 1988) and characterizes a subgroup of patients with higher risk of developing tardive dyskinesia, poorer outcome, and a more incomplete remission (Hegerl et al 1995; Strik et al 1993b). The auditory P300 amplitude has been found to be independent of antipsychotic medication or clinical improvement (Blackwood et al 1987; Duncan 1988; Ford et al 1994; Juckel et al 1996), and the P300 amplitude reduction fulfills some of the criteria for a trait marker. Other evidence, however, suggests that this component may also reflect state-dependent effects of the actual psychopathology and of fluctuations in arousal and attention. Significant relationships between the severity of schizophrenic symptoms and P300 amplitude have been reported; however, concerning this issue, the literature is 0006-3223/99/$19.00 PII S0006-3223(98)00108-5

Subcomponents of P300 in Schizophrenia

far from being consistent. Negative relationships between P300 amplitude and negative symptoms have been observed (Pfefferbaum et al 1989; Strik et al 1993a; Eikmeier and Lodemann 1993; Juckel et al 1996) as well as positive correlations between P300 amplitudes and positive symptoms (McCarley et al 1989; Shenton et al 1989; Bougerol et al 1996), which might indicate state-dependent effects of the actual psychopathology.

Dipole Model of P300 The clinical relevance and research implications of P300 findings in schizophrenia have been limited by methodological problems. P300 is composed of subcomponents that overlap when recorded at the scalp and which differ in function and generators (Ruchkin et al 1987; Johnson 1989; Halgren et al 1995a, 1995b; Falkenstein et al 1995; Knight et al 1997). These P300 subcomponents often have not been considered independently. Furthermore, the reliability of P300 measurements has been only moderate (Roth et al 1975; Sklare and Lynn 1984; Fabiani et al 1987; Segalowitz and Barnes 1993; Hegerl and FrodlBauch 1997). A methodological advance might be the dipole source analysis BESA (Brain Electrical Source Analysis) (Scherg and von Cramon 1985, 1986, 1990) with the recently developed dipole model of the auditory P300 (Hegerl and Frodl-Bauch 1997), which can be used to distinguish temporally overlapping activities recorded with the scalp electrodes. The scalp data are transformed into the dipole source activity of a temporo-basal and a temporo-superior dipole pair. The dipoles are thought to represent activity of circumscribed cortical areas. The recently developed dipole model of the auditory P300 (Hegerl and Frodl-Bauch 1997) could facilitate the clinical application. In healthy subjects it has been shown that two dipoles per hemisphere explain most of the variance of the scalp-recorded P300: a temporo-basal dipole pair, which mainly represents the classical P3b recorded at parietal electrode sites, and a temporo-superior dipole pair, which mainly represents the P300 recorded at frontal electrode sites. The frontal distribution and shorter latency of the P300 activity of the temporo-superior dipoles suggest that this subcomponent is related to P3a; however, P3a is typically evoked by “novel” stimuli. The P3a has a more frontocentral scalp distribution and an earlier peak latency than the P3b (Squires et al 1975; Courchesne et al 1975; Knight 1997). Such “novel” stimuli were not included in our paradigm. Therefore, it remains unclear to what degree the P300 activity of the temporo-superior dipoles corresponds to P3a. The two dipole pairs reflect two functionally different physiological processes, because they differ in latency, amplitude, and age dependence. Dipole source analysis

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not only separates these P300 subcomponents but also enhances the test–retest reliabilities of P300 subcomponent amplitudes. The significant increase of the test–retest reliability for P3b amplitudes from r 5 .78 (Pz referenced to linked mastoids) to r 5 .88 (temporo-basal dipoles) corresponds to an increase of the common variance of run 1 and run 2 from 61 to 77%. Furthermore, the reliability of the temporo-superior dipoles was significantly higher than that obtained with principle component analysis (PCA). In the present study P300 subcomponents were analyzed using conventional scalp data measurements and this P300 dipole model. Separating subcomponents could result in findings reconciling some of the contradictory findings about P300 in schizophrenia. The aim of the study was: • To test the hypothesis that schizophrenics have smaller P300 amplitudes of their parietal electrodes or temporo-basal dipoles than healthy controls (confirmatory analysis), • To test whether or not schizophrenic patients differ from healthy controls with regard to the P300 parameters of the temporo-superior dipoles (exploratory analysis), • To test whether or not schizophrenic patients differ from healthy controls with regard to hemispheric differences in the amplitude of either electrodes (confirmatory analysis) or P300 dipoles (exploratory analysis), and • To analyze the correlations between the different P300 dipole activities on the one hand and positive as well as negative symptoms on the other hand (exploratory analysis).

Methods and Materials Subjects Twenty-two schizophrenic inpatients from the psychiatric hospital of the Ludwigs Maximilians University in Munich were studied. Psychiatric diagnoses were determined by the consensus of at least two psychiatrists, who concurred on a diagnosis based on DSM-IV criteria. Two subjects had to be excluded because of artifacts in their ERPs. The Positive and Negative Syndrome Scale (PANSS) score was absent at 1 patient. Of the remaining 19 patients, 12 patients had the DSM-IV diagnosis of the paranoid type, 3 of the disorganized type, 3 of the residual type, and 1 of the undifferentiated type. Clinical information about the 19 patients is presented in Table 1. They all had received neuroleptic medications for at least 3 months. Two patients were treated with haloperidol, 2 with perphenazine, 3 with perazine, 1 with ziprasidone, 1 with pimozide, 1 with fluphenazine, 1 with flupentixol, 7 with clozapine, and 1 with risperidone. Three patients additionally received antidepressants. For comparison 19 unmedicated healthy controls from the hospital staff and Munich

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Table 1. Mean (6SD) Demographic and Clinical Data for Schizophrenic and Control Groups

Age (years 6 SD) Gender School education (years 6 SD) Handedness PANSS positive symptoms 6 SD PANSS negative symptoms 6 SD Illness durations (years 6 SD) Number of hospital stays 6 SD Chlorpromazine equivalents (mg 6 SD) Additional antidepressive medication

Schizophrenics (n 5 19)

Healthy controls (n 5 19)

Student’s t test

27.6 6 4.9 3 female, 16 male 11.1 6 1.8 16 right, 3 left 17.7 6 4.8 18.9 6 9.0 6.8 6 6.1 3.7 6 5.1 452 6 308 3

28.6 6 5.3 3 female, 16 male 11.2 6 1.8 16 right, 3 left

ns ns

population matched according to age, gender, and handedness underwent the same procedure. Neither the healthy controls nor their first-degree relatives had a history of neurologic or mental illness. Schizophrenics and healthy controls did not differ in education years. Each group consisted of 16 right- and 3 left-handed subjects according to the Edinburgh Handedness Scale. Healthy controls and schizophrenic patients were recorded during the afternoon in springtime.

msec poststimulus). After artifact rejection, 87 6 12.7 target trials for schizophrenic patients and 94 6 5.0 target trials for healthy controls were left for averaging. The potentials were averaged separately for the target stimuli. Amplitudes were measured with reference to a 200-msec prestimulus baseline. The average data were digitally filtered (0.5–20 Hz). To analyze the target P300 with BESA, the data were transformed from Cz reference to average reference. In BESA data reduction from 256 to 97 data points took place.

P300 Method

Dipole Source Analysis

An auditory “oddball” paradigm was used in which tones (80 dB SPL, 40 msec duration, 10 msec rise/fall time using a fixed 1.5-sec interstimulus interval) were presented binaurally via eartips in pseudorandomized order. Twenty percent of these tones were targets (100 sinusoidal tones, 1000 Hz), and 80% were standards (400 sinusoidal tones, 500 Hz). Subjects were seated with eyes closed in a reclining chair and were instructed to press a button with their dominant hand in response to target stimuli. Reaction time (t 5 1.63, p 5 .11; 423.8 6 84.1 vs. 371.1 6 111.6 msec) and error rates (t 5 1.0; p 5 .33; 88.8 6 22.3 vs. 97.8 6 8.4 msec) were not significantly different between schizophrenics and healthy controls.

Dipole source analysis was performed with BESA (Scherg and von Cramon 1985, 1986, 1990), which can be used to distinguish temporally overlapping activities recorded with the scalp electrodes. The scalp data were transformed into the dipole source activity of a given number of dipoles using a four-shell head model. The dipoles are thought to represent activity of circumscribed cortical areas. Therefore, they change dipole strength during time, but not location or orientation. The optimal location and orientation of the dipoles are determined numerically by an iterative process (simplex algorithm) optimizing the residual variance (variance of the measured scalp data unexplained by the dipole model), whereas the dipole source potentials are determined by the direct linear approach, as described by Scherg and Picton (1991). P300 dipole source analysis is carried out with the dipole model described in Hegerl and Frodl-Bauch (1997, Figure 1). In that study, two pairs of dipoles, a temporo-basal dipole pair and a temporo-superior dipole pair, were found using the data of 54 healthy subjects. The individual data were analyzed by starting first with the grand average dipole model and then determining the dipole parameters without fitting the dipole configurations. The P300 interval was started 40 msec after the individual P2 peak and had a duration of 166 msec. The P300 dipole amplitudes and latencies were defined as the most positive points of the dipole activity in the P300 interval. The magnitude of the dipole activity (source potential) was measured in units of nano-ampere-meters (nAm). The unit nAm is used for current 3 distance (Am) with respect to the dipole localization in the brain electrical source head model.

EEG Recording and Averaging Event-related potentials were recorded with 31 channels (29 tin electrodes of an electro cap and 3 additional tin electrodes at the nasion and the mastoids, all referenced to Cz). The electrodes were positioned precisely according to the International 10/20 system. A coronal line of four electrodes was added between frontal and central electrode locations, another coronal line of four electrodes was added between central and parietal electrode locations, and one electrode was added at the inion. Electrode impedance was maintained at less than 5kV. The electroencephalogram was amplified with band-pass filters of 0.16 –70 Hz (sampling rate of 256 Hz). Electro-oculogram was recorded with electrodes above and lateral to the eyes and at the nasion. For artifact suppression all trials were excluded if their voltage exceeded 650 mV in any one of the 31 channels at any moment during the averaging epoch (from 200 msec prestimulus to 800

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Statistical Analysis Analysis of variance was employed for the single channel P300 with group (patients vs. controls) as between-subject factor, and anterior–posterior (frontal, central, and parietal electrode sites) and coronal (five coronal electrode sites) as within-subject factors. The dipole data were calculated for amplitude and latency with group (patients vs. controls) as between-subject factor, and dipole pair (temporo-superior vs. temporo-basal) and hemisphere (left vs. right) as within-subject factors. Spearman’s Rho was used to assess the relationship between P300 parameters and PANSS factor scores. Analysis of covariance was employed to test the effect of age.

Results Scalp Data and Dipole Model Figure 1 illustrates the grand average waveforms of the scalp data at F3, F4, P3, and P4 and of the temporosuperior and temporo-basal dipoles for healthy controls and schizophrenic patients. Table 2 presents the mean amplitudes and latencies of scalp data measurements and dipole source analysis for healthy controls and schizophrenic patients.

Schizophrenics in Comparison to Healthy Controls

Figure 1. Grand mean event-related potentials averaged across subjects for healthy controls (n 5 19) and schizophrenic patients (n 5 19). Top: Grand average scalp data F3, F4 and P3, P4, referenced to linked mastoids. Bottom: Dipole model of the target P300 for the grand average data. This dipole solution was developed for the time interval 269 – 435 msec in healthy subjects (Hegerl and Frodl-Bauch 1997). Two dipoles per hemisphere, a temporo-basal dipole pair, and a temporo-superior dipole pair explain most of the variance of the scalp data. Residual variance was only 12%.

Single Channel P300 For the analysis of single channel P300 the data were calculated with reference to linked mastoids. The amplitudes and latencies of the P300 were defined as the most positive point in the P300 time interval (166-msec time window starting 40 msec after the P200 peak). Analysis of variance (ANOVA) was employed for 15 electrodes referenced to linked mastoids (F7, F3, Fz, F4, F8, T3, C3, Cz, C4, T4, T5, P3, Pz, P4, T6).

PANSS Scale All patients were rated for psychopathology by a psychiatrist using the PANSS. The PANSS was developed by Kay et al (1987) to provide an instrument for the evaluation of positive and negative schizophrenic symptoms and syndromes.

The visual impressions obtained from Figure 1 were confirmed by ANOVA. ANOVA was performed on the conventional scalp data measurements for 15 electrodes (F7, F3, Fz, F4, F8, T3, C3, Cz, C4, T4, T5, P3, Pz, P4, T6; mean values are presented in Table 3). No overall effect was found for P300 amplitudes [F(1/36) 5 1.1; p . .20]. Significant main effects were found for anterior–posterior [F(1/36) 5 30.9; p , .001] and coronal [F(1/36) 5 66.8; p , .001]. The amplitudes

Table 2. Mean (6SD) Dipole Measures for P300 from Frontal Electrode Fz, Parietal Electrode Pz, and Temporo-superior and Temporo-basal Dipoles for Healthy Controls and Schizophrenic Patients Healthy controls Frontal electrode Fz Amplitudes (mV) Latencies (msec) Parietal electrode Pz Amplitudes (mV) Latencies (msec) Temporo-superior dipoles Amplitudes (nAm) Latencies (msec) Temporo-basal dipoles Amplitudes (nAm) Latencies (msec)

Schizophrenic patients

6.7 (5.6) 314.3 (21.1)

6.4 (5.7) 325.9 (22.8)

11.9 (4.6) 318.0 (21.9)

9.4 (3.2) 331.2 (21.7)

2.8 (2.8) 311.3 (31.6)

2.9 (2.4) 323.7 (31.6)

7.4 (2.8) 311.8 (27.2)

5.6 (2.0) 326.3 (23.8)

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were higher over right frontal electrodes than over other recording sites. Separate analysis revealed significant group effects for the parietal scalp recording sites [F(1/36) 5 4.9; p 5 .033]. No significant main effect was seen for P300 latency [F(1/36) 5 3.0; p 5 .09]. The factor anterior– posterior did not reveal significant effects [F(1/36) 5 0.6; p . .5], whereas the factor coronal showed significant differences [F(1/36) 5 3.9; p , .01]. P300 latency recorded over the left recording sites was longer [F(1/36) 5 5.6, p 5 .023] than that recorded over the right hemisphere. Concerning P300 amplitudes comparable results were obtained for dipole source analysis (Table 3). Analysis of variance found no overall effect for P300 amplitude between the schizophrenic and control subject groups [F(1/36) 5 1.5; p . .20]. Significant main effects were observed for dipole pair [F(1/36) 5 60.37; p , .001] and for hemisphere [F(1/36) 5 18.9; p , .001]. Furthermore, the interaction group 3 dipole tended to become significant [F(1/36) 5 3.6; p 5 .068], and there was a significant effect for the interaction hemisphere 3 dipole [F(1/36) 5 10.1; p , .005]. Post hoc, separate variance analysis was conducted for each dipole pair. The amplitudes of temporo-basal dipoles according to parietal recording sites were significantly smaller for schizophrenic patients in comparison to healthy controls [group: F(1/36) 5 4.6; p 5 .039], whereas the amplitudes of temporo-superior dipoles were not different between patients and controls [F(1/36) 5 0.01; p . .90]. P300 amplitudes of the temporo-superior dipoles were larger over the right hemisphere [hemisphere: F(1/36) 5 26.6; p , .001], whereas the temporo-basal dipole P300 amplitudes were not significantly lateralized [F(1/36) 5 1.9; p 5 .18]; however, schizophrenic patients and healthy controls did not differ concerning

Table 3. Mean (6SD) P300 Amplitude from Each Electrode Position and Dipole Pair for Schizophrenic and Control Subject Groups

Group Hemisphere Group 3 hemisphere

Group Hemisphere Group 3 hemisphere p , .05. p , .005. c p , .01. a b

df

Temporosuperior dipoles

Temporobasal dipoles

1, 36 1, 36 1, 36

0.01 26.6b 0.1

4.6a 1.9 1.2

df

F3, F4

P3, P4

1, 36 1, 36 1, 36

0.1 8.9c 1.0

5.1a 3.35 0.5

Table 4. Spearman’s Correlation Coefficients between the P300 Dipole Parameters Referenced to Linked Mastoids [Amplitudes (nAm), Latencies (msec)] and P300 Scalp Electrode Data [Amplitudes (mV), latencies (msec)] and the PANSS Positive and Negative Symptom Scores PANSS positive symptoms Temporosuperior dipole amplitudes Temporosuperior dipole latencies Temporobasal dipole amplitudes Temporobasal dipole latencies Fz amplitudes Fz latencies Pz amplitudes Pz latencies

PANSS negative symptoms

r 5 .10

r 5 .47a

r 5 .14

r 5 2.61b

r 5 .59b

r 5 2.04

r 5 2.57b

r 5 2.18

r 5 .15 r 5 .09 r 5 .53a r 5 2.35

r 5 .41 r 5 2.60b r 5 2.06 r 5 2.27

p , .05. p , .01.

a b

hemispheric effects, obtained from the interaction between hemisphere and group for the temporo-superior dipole amplitudes [F(1/36) 5 0.07; p . .70] and for the temporo-basal dipole amplitudes [F(1/36) 5 1.2; p . .20]. P300 dipole latencies did not show significant main group effects [F(1/36) 5 2.7; p 5 .12]. No significant effects were seen for the factor dipole pair [F(1/36) 5 0.09; p . .70] and for the factor hemisphere [F(1/36) 5 0.4; p . .50].

Correlations with Psychopathology: Positive and Negative Syndromes of the PANSS Table 4 shows the correlations between dipole analysis of the temporo-superior and temporo-basal dipoles and positive and negative syndromes of the PANSS. Partial correspondence between Fz and temporo-superior dipoles and Pz and temporo-basal dipoles can be observed. Figure 2 illustrates the significant positive correlation between the P300 amplitudes of the temporo-basal (P3b) dipoles and the positive symptoms (r 5 .59; p 5 .008). Furthermore, latencies of the temporo-basal (P3b) dipoles correlated negatively with the positive symptoms (r 5 2.57; p 5 .01). Temporo-basal (P3b) dipole amplitudes (r 5 2.04; p 5 .875) and latencies (r 5 2.18; p 5 .474) were not correlated to the negative symptoms. In contrast to the temporo-basal dipole activity, the temporo-superior dipole amplitudes show a positive correlation to negative (r 5 .47; p 5 .043; Figure 3), but not to positive symptoms (r 5 .10; p 5 .672), and temporo-superior dipole latencies show a negative corre-

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Analysis of covariance did not show significant age effects.

Discussion

Figure 2. The relationship between positive symptoms of the PANSS and the amplitudes of the temporo-basal dipoles (mean value of right and left dipole) in 19 schizophrenic patients.

A temporo-superior dipole pair mainly representing P300 from frontal electrode sites and a temporo-basal dipole pair mainly representing P300 from parietal electrode sites (P3b) were used to analyze the scalp electrode data of 32 electrodes. Furthermore, frontal electrodes F3, F4 and parietal electrodes P3, P4 were presented. Considering the grand average waveforms suggests partial correspondence between temporo-superior dipole activity and frontal P300 and between temporo-basal dipole activity and parietal P3b.

Schizophrenics in Comparison to Healthy Controls lation to negative (r 5 2.61; p 5 .006), but not to positive symptoms (r 5 .14; p 5 .570). Scalp data measurements and dipole source analysis revealed comparable results (Table 4).

Medication and Age Influences No significant correlations were found between the neuroleptic chlorpromazine equivalent doses and P300 parameters. Furthermore, no significant group differences concerning dipole amplitudes were obtained between patients receiving atypical and patients receiving typical neuroleptics.

Figure 3. The relationship between negative symptoms of the PANSS and the amplitudes of the temporo-superior dipoles (mean value of right and left dipole) in 19 schizophrenic patients.

The present data replicate those from previous studies concerning amplitude reductions in schizophrenic patients. The P300 amplitude of the temporo-basal dipoles corresponding mainly to the classical P3b was reduced. Therefore, the hypothesis was confirmed. The amplitude of the temporo-superior dipoles, reflecting activity at more frontal electrodes, however, did not differ between schizophrenic patients and healthy controls. This finding is in line with the study of Michie et al (1990), who also found no P300 differences between schizophrenic patients and healthy controls when considering frontal recordings, whereas P300 over parietal sites (P3b) was reduced in schizophrenic patients. Reduced parietal P3b and unaffected frontal P300 amplitudes could explain the different midline anterior–posterior scalp distribution of P300 in schizophrenics, having a somewhat more frontal maximal amplitude than seen in controls (Pfefferbaum et al 1989; Miyazato et al 1989). There are some tentative physiological and psychological interpretations for the P3b reductions in schizophrenic patients: 1. The amplitude reductions could result from the structural cortical abnormalities found in a subgroup of schizophrenic patients (McNeil et al 1993; Weinberger et al 1987; Lewis and Murray 1987). P300 findings in patients with cortical lesions indicate that multiple brain regions (e.g., the temporal–parietal cortices) contribute to the parietal scalp P3b (Knight 1997, for review). Direct evidence for a relationship between cortical abnormalities and reduced P300 stems from McCarley et al (1989, 1993). This research group found that temporal lobe tissue loss in schizophrenics correlated significantly with P300 measurements. These arguments support a neuro-

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anatomical explanation of the P300 reduction in schizophrenic patients. 2. Neurochemical dysfunction could also result in P300 reduction. The glutamatergic system is the most important excitatory neurotransmitter system and plays an important role in the electrogenesis of P3b potentials (McCarley et al 1991). Of special importance are the N-methyl-D-aspartate (NMDA) receptors. As discussed, e.g., by Javitt et al (1995), these receptors have long excitatory postsynaptic potentials of 10 –100 msec, which could correspond to late components, such as P300. Evidence for a glutamatergic deficiency in schizophrenic patients has been reported (Kornhuber et al 1993; Kornhuber and Weller 1994) and could explain the reduced P3b amplitudes (McCarley et al 1991). A neurodevelopmental disturbance may be the cause of both the structural and glutamatergic abnormalities (Glenthøj and Hemmingsen 1997). These biological factors could be the basis of cognitive dysfunction found not only in acute psychotic but also in stabilized schizophrenic patients. Such cognitive dysfunction has also been related to P300 amplitude reductions (Pritchard 1986). Concerning P300 latencies, the scalp data measurements and the dipole source analysis did not reveal significantly longer P300 latencies for schizophrenic patients. Concerning other aspects, the findings obtained with the temporo-basal dipoles correspond to those obtained with parietal recordings, and the findings obtained with temporo-superior dipoles to those obtained with frontal recordings.

Hemispherical Asymmetries P300 amplitudes of temporo-basal dipoles did not show significant hemispheric asymmetries, whereas P300 amplitudes were larger for the right temporo-superior dipoles in both schizophrenic patients and healthy controls. Hemispheric asymmetry with higher amplitudes over right frontal recording sites and no hemispheric asymmetry over parietal recording sites have been seen in healthy controls (Alexander et al 1996). Differences between schizophrenic patients and healthy controls with respect to hemispheric asymmetries were not observed, however, in the literature several studies found such differences in hemispheric asymmetries (Morstyn et al 1983; Faux et al 1993; Strik et al 1993b; McCarley et al 1993; O’Donnell et al 1995), whereas others did not (Pfefferbaum et al 1989; Ford et al 1994). These inconsistencies were explained by methodological differences. P300 paradigms were performed with counting tasks as well as with button press tasks. Button press tasks require

motor responses with negative potentials contralaterally to the button press site at central electrodes (Coles et al 1988) that might affect the lateral distribution of the P300.

Correlations with Psychopathology Although P300 amplitudes of the temporo-basal dipoles are smaller in schizophrenic patients than in healthy controls, positive correlations have been found between the severity of psychopathology and P300 amplitudes. A clear pattern emerges when temporo-basal and temporosuperior dipoles, as well as positive and negative symptoms, are considered independently. Positive correlations were found between both positive symptoms and the P300 amplitudes of the temporo-basal dipoles, and between negative symptoms and the P300 amplitudes of the temporo-superior dipoles. The P300 latencies of the temporo-basal dipoles were correlated negatively with positive symptoms, and the P300 latencies of the temporo-superior dipoles were correlated negatively with negative symptoms. The positive correlation between the severity of psychopathology and P300 amplitudes appears to be contradictory to many studies reporting negative correlations between psychopathology and P300 amplitudes; however, the picture becomes clearer when studies on remitted and stabilized patients are considered separately from those of actively psychotic inpatients. When stabilized or remitted patients are investigated, negative correlations between P300 and negative symptoms are consistently reported (Pfefferbaum et al 1989; Strik et al 1993a; Eikmeier and Lodemann 1993; Juckel et al 1996; Table 5). These negative correlations, however, appear to be mediated by trait effects; schizophrenic patients with small P300 have a poorer outcome and a more incomplete remission (Hegerl et al 1995; Strik et al 1993b). This interpretation is supported by the finding that intraindividual changes in psychopathology are not correlated to corresponding changes in P300 (Blackwood et al 1987; Ford et al 1994; Juckel et al 1996). When acutely psychotic inpatients are investigated, positive correlations between the severity of positive symptoms and P300 amplitude have been found (McCarley 1989; Shenton et al 1989; Bougerol et al 1996; Figure 2, Table 5). Therefore, a trait factor relates a small P300 to more residual symptoms. In a state-dependent manner an increase in psychopathology is related with an increase in P300. These findings could be in agreement with an episodic subcortical hyperactivity superimposed on a basic dopaminergic and glutamatergic hypofunction that results in a changed neuroplastic response to environmental stimulation due to dopaminergic sensitization (Carlsson 1988; Glenthøj and Hemmingsen 1997). As a further implication, it has to be assumed that severely

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Table 5. Studies on the Relationship between P3b Amplitudes and Negative as Well as Positive Symptoms of Remitted Schizophrenic Patients and Acute Schizophrenic Inpatients Subjects Pfefferbaum et al 1989

n 5 18; unmedicated; outpatients

Eikmeier and Lodemann 1993

n 5 15; remitted patients

Strik et al 1993

n 5 18; remitted or stabilized patients n 5 88; stabilized patients

Juckel et al 1996

Bougerol et al 1996

n 5 50; mainly inpatients

Shenton et al 1989; McCarley et al 1989

n 5 11; actively symptomatic

Laurent et al 1993

n 5 19; inpatients

Egan et al 1994

n 5 16; only partially responding inpatients

P300 method

Negative symptoms

Positive symptoms

Choice reaction time task; 20% targets; Pz; sternovertebral reference Choice reaction time task; 15% targets; Cz; linked ears Counting task; 20% targets; reference independent Counting task; 20% targets; Cz; linked mastoids Counting task; 20% targets; Fz, Cz, Pz to linked mastoids Counting task; 15% targets; subtracting paradigm; T3 to linked ears Counting task; 20% targets; Cz–Pz; nose Choice reaction time task; 10%, 30% targets; Pz; linked earlobes

r 5 2.57; p , .05; BPRS

ns

r 5 2.54; p , .05; SANS

ns

r 5 2.58; p , .01; SANS

ns

r 5 2.22; p , .05; BPRS

ns

ns

r 5 .33; p , .05; PANSS

ns

r 5 .61; p , .05; SAPS

ns

r 5 2.67; p , .05; SAPS

ns

r 5 2.59; p , .05; PSAS

BPRS, Brief Psychiatric Rating Scale; SANS, Scale for the Assessment of Negative Symptoms; SAPS, Scale for the Assessment of Positive Symptoms. PSAS, Psychiatric Symptom Assessment Scale; PANSS, Positive and Negative Syndrome Scale.

psychotic patients with pronounced cognitive and hallucinatory symptoms will have P300 reductions because they are not able to perform adequately on the oddball paradigm. This may be an explanation for the fact that negative correlations have also been reported between P3b amplitudes and positive symptoms in schizophrenic inpatients in two studies (Laurent et al 1993; Egan et al 1994; Table 5). Of special interest is the finding of a positive correlation between the frontal P300 (temporo-superior dipoles) and negative symptoms. This result was obtained by separating P300 subcomponents with dipole source analysis. Comparable studies have not been published up to now. Correlations between P300 of temporo-basal dipoles and positive symptoms and between P300 of temporo-superior dipoles and negative symptoms suggest different underlying neurophysiological and neurochemical substrates. At present, knowledge about the neurobiological basis of both P300 and positive and negative symptoms is still rudimentary; however, adrenergic hyperactivity has been related to positive symptoms (Gelernter and van Kammen 1990) as well as to enhanced P3b amplitude (Pineda et al 1989;

Swick et al 1994). Therefore, positive correlations between P3b parameters and positive symptoms could be mediated by adrenergic influences. A transient NMDAreceptor hyperactivity during the psychotic state could also be an explanation for the positive correlation between P3b amplitudes and positive symptoms (McCarley et al 1991). Concerning the positive correlation between frontal dipole P300 amplitude and negative symptoms, it is of interest that cholinergic hyperactivity is related to both negative symptoms (Tandon and Greden 1991; Tandon et al 1992) and higher P300 amplitudes (Hammond et al 1987; Meador et al 1987; Meador 1995; Dierks et al 1994). Lacking sufficient empirical evidence, these ideas must be considered speculative at the present time. Recent findings have stressed the clinical value of P300 in schizophrenia. Reduced P300 amplitudes were found to predict a bad clinical outcome with antipsychotic treatment (Ford et al 1994) and a bad prognosis in comparison to core schizophrenics (Hegerl et al 1995; Strik et al 1993b). P300 parameters might become of clinical value for defining subgroups of schizophrenics that are more

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homogenous concerning pathogenetic aspects and outcome. Our findings show acute psychopathological statedependent effects on P300 subcomponents that might overlap with the trait-dependent effects related to structural deficits or possibly genetic predisposition. It appears to be important for clinical application to separate patients in acute psychotic states from patients in stabilized or residual states. Methodological advances, such as dipole source analysis, delivering more reliable (Hegerl and Frodl-Bauch 1997) and possibly more valid P300 parameters, will facilitate the clinical application of the P300 paradigm in psychiatry.

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