- Email: [email protected]
Novelty P3 and P3b in first-episode schizophrenia and chronic schizophrenia
Progress in Neuro-Psychopharmacology & Biological Psychiatry 30 (2006) 1426 – 1434 www.elsevier.com/locate/pnpbp
Novelty P3 and P3b in first-episode schizophrenia and chronic schizophrenia Müge Devrim-Üçok a,⁎, H. Yasemin Keskin-Ergen a , Alp Üçok b a b
Department of Physiology, University of Istanbul, Istanbul Medical Faculty, 34093 Çapa-Istanbul, Turkey Department of Psychiatry, University of Istanbul, Istanbul Medical Faculty, 34093 Çapa-Istanbul, Turkey Received 25 January 2006; received in revised form 28 May 2006; accepted 29 May 2006 Available online 7 July 2006
Abstract The objective of this study was to evaluate P3b and novelty P3 responses in patients with first-episode schizophrenia (FES) and chronic schizophrenia (CS). P3b is consistently reported to be reduced in CS. However, novelty P3 results in CS are controversial. Novelty P3 is not studied, and there are only a few P3b studies in patients with FES. Subject groups comprised 31 patients with FES and 36 younger control subjects, and 26 patients with CS and 35 older control subjects. Automatically elicited auditory novelty P3 and effortfully elicited auditory P3b potentials were assessed. P3b amplitudes were reduced in both patients with FES and CS relative to their controls. CS and FES patients did not differ in P3b amplitude. Novelty P3 amplitude was reduced in patients with CS. Novelty P3 amplitude in patients with FES did not differ from their controls. P3b amplitude reduction may be a trait marker of schizophrenia and may not progress over the course of illness, although this can only be definitively determined by longitudinal studies. Novelty P3 amplitude reduction present in patients with CS, is not found at the onset of illness. Novelty P3 seems unaffected early in the disease process. © 2006 Elsevier Inc. All rights reserved. Keywords: Chronic schizophrenia; Event-related potentials; First-episode; Novelty P3; P3b; Schizophrenia
1. Introduction P3 (P300) family of event-related potentials (ERPs) is studied in schizophrenia to investigate attention and information processing deficits that have been implicated as a core feature of this illness. P3b is elicited by attended, task-relevant stimuli and reflects the allocation of attentional resources when a target stimulus engages memory operations during task performance (Donchin and Coles, 1988; Polich and Kok, 1995). P3a is elicited by infrequent, task-irrelevant stimuli. When the infrequent, task-irrelevant stimuli were novel environmental sounds, the elicited component is often called the novelty P3. Abbreviations: BPRS, Brief Psychiatric Rating Scale-Expanded; CS, chronic schizophrenia; DSM-IV, Diagnostic and Statistical Manual of Mental Disorders Fourth Edition; DUP, duration of untreated psychosis; EOG, electrooculogram; ERPs, event-related potentials; FES, first-episode schizophrenia; SANS, Scale for the Assessment of Negative Symptoms; SAPS, Scale for the Assessment of Positive Symptoms; SCID, Structured Clinical Interview for DSM-IV. ⁎ Corresponding author. Tel./fax: +90 212 635 26 31. E-mail address: [email protected] (M. Devrim-Üçok). 0278-5846/$ - see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.pnpbp.2006.05.019
Although it is not yet known whether the P3a and novelty P3 are identical, it is assumed that they reflect involuntary orienting of attention towards the unexpected or novel events in the stimulus context (Friedman et al., 2001; Knight, 1984, 1996). We will use the terms P3a and novelty P3 to refer to the P3 components elicited by pure tones and novel environmental sounds, respectively. P3b is usually maximum over parietal scalp sites, and P3a and novelty P3 have a more frontally-oriented scalp distribution (Friedman et al., 2001). P3b amplitude reduction is a widely replicated finding in schizophrenia (see reviews Ford et al., 1992; McCarley et al., 1991). However, P3b latency prolongation is less consistently reported in schizophrenia (Blackwood et al., 1991; Coburn et al., 1998; Roxborough et al., 1993). Most of these studies have investigated P3b in chronic schizophrenia (CS). The ERP abnormalities in CS may be due to ongoing chronic process, antipsychotic medication and/or hospitalization. Therefore, it is of considerable interest whether the ERP abnormalities are trait markers of schizophrenia and present at onset or occur secondary to chronicity. Many studies (Blackwood et al., 1991; Kidogami et al., 1991; Roxborough et al., 1993) with
M. Devrim-Üçok et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 30 (2006) 1426–1434
some exceptions (Friedman et al., 1988) reported reduced P3b amplitude in unaffected first-degree relatives of patients suggesting that it is an endophenotype marker of vulnerability to schizophrenia. Investigating first-episode schizophrenia (FES) patients is another approach to understand whether P3b reduction is a trait feature. Although there are few studies, there is a consensus over P3b amplitude reduction in FES (Brown et al., 2002; Demiralp et al., 2002; Hirayasu et al., 1998; Salisbury et al., 1998; Valkonen-Korhonen et al., 2003; Wang et al., 2003). P3b prolongation was also observed in FES by our group (Demiralp et al., 2002) and Wang et al. (2003). Several studies have shown P3b amplitude to be inversely correlated with illness duration (Martin-Loeches et al., 2001; Mathalon et al., 2000b; Olichney et al., 1998). However, similarity in P3b amplitudes between FES and CS patients has also been reported (Brown et al., 2002; Hirayasu et al., 1998). Moreover, some reports relate the P3b reduction in CS to severity of psychopathology (Ford et al., 1999a; Mathalon et al., 2000a; Turetsky et al., 1998), whereas others indicate that P3b amplitude is unrelated to changes in clinical state (Blackwood et al., 1987; Ford et al., 1994). P3a and especially novelty P3 responses have been investigated less than P3b in schizophrenia. Reduction of P3a and novelty P3 amplitudes (Alain et al., 2002; Grillon et al., 1990b; Merrin and Floyd, 1994) were reported in some studies, however, normal (Frodl et al., 2001; Michie et al., 2002) or even increased amplitudes (Schall et al., 1999) were also reported in schizophrenia. P3a latency prolongation was also reported (Frodl et al., 2001). Startling (high sound pressure level) noises that elicit P3 automatically has also been evaluated, and both normal (Ford et al., 1999b), and reduced P3 amplitudes (Mathalon et al., 2000a; Pfefferbaum et al., 1989) were demonstrated. P3a responses of unaffected, first-degree relatives of patients were not different from the controls (Michie et al., 2002). Valkonen-Korhonen et al. (2003) reported P3a reduction in a group of acutely psychotic first-episode patients. To our knowledge, novelty P3 responses in FES have not been reported before. The aim of this study was to investigate auditory P3b and novelty P3 components and their relations with clinical features in FES and CS. It is more informative to study different ERPs
1427
reflecting distinct processes in the same patient group and to evaluate FES and CS patients with the same experimental settings. This study was undertaken to determine the contribution of trait features and/or chronicity to possible disturbances in automatic and selective attention processes in schizophrenia. If abnormalities in processing target and/or novel stimuli in FES are present, this will indicate that these disturbances are the core features of the illness, rather than being related with chronicity. 2. Methods 2.1. Subjects Thirty-one inpatients with FES (26 paranoid, 3 catatonic, 1 undifferentiated, and 1 disorganized) were compared with 36 younger control subjects. Also, 26 inpatients with CS (24 paranoid, and 2 catatonic) were compared with 35 older control subjects. Subject demographic characteristics and clinical scales of the patients are presented in Table 1. Each patient group did not differ from its respective control group in gender (χ2-test), age and education level (unpaired t-test). All the patients met DSM-IV diagnostic criteria for schizophrenia and were in the acute phase of illness. Patients were diagnosed for schizophrenia at a consensus meeting incorporating clinical, and Structured Clinical Interview for DSM-IV (SCID) data (First et al., 1997). All SCID interviews were made by a trained senior interviewer (AU). Controls were screened by using the Structured Clinical Interview for DSM-III-R-Non-Patient Edition. Exclusion criteria for patients included any organic disorder known to cause psychosis or cognitive impairment and alcohol/drug abuse. In first-episode group one patient had major depressive disorder. In chronic group two patients had major depressive disorder and one had obsessive–compulsive disorder. A patient was accepted in his/her first psychotic episode, if all following conditions were fulfilled: no past diagnosis of nonaffective possible psychosis; no previous antipsychotic treatment and an inpatient care. The date of onset of the first identifiable positive symptoms was timed by the senior psychiatrist in research team on the basis of a best-estimate approach using data gathered from multiple sources including medical records, and direct patient,
Table 1 Subject demographic characteristics and clinical scales of the patients Paradigm
Gender (F/M) Age (years) Education (years) BPRS SANS SAPS Target detection accuracy (%)
First-episode schizophrenia
Younger controls
Chronic schizophrenia
Older controls
P3b (n = 26)
Novelty P3 (n = 30)
P3b (n = 35)
Novelty P3 (n = 36)
P3b (n = 22)
Novelty P3 (n = 26)
P3b (n = 32)
Novelty P3 (n = 35)
12/14 22.3 (5.9) 11.3 (2.9) 66.6 (18.4) 46.4 (22.0) 38.5 (17.8) 97.8 (3.3)
15/15 22.1 (5.7) 10.9 (2.9) 66.4 (17.3) 52.0 (24.2) 37.4 (18.5)
16/19 23.7 (6.2) 12.0 (3.7)
16/20 23.6 (6.1) 12.0 (3.6)
3/19 35.3 (11.6) 12.5 (3.2) 60.7 (8.6) 51.7 (13.7) 37.1 (14.1) 98.3 (1.9)
5/21 35.6 (11.5) 12.5 (3.2) 60.6 (9.0) 50.9 (14.2) 37.4 (13.4)
7/25 32.9 (10.8) 11.1 (5.6)
8/27 33.5 (11.2) 11.2 (5.7)
98.7 (2.1)
98.1 (2.5)
Data are given as mean (S.D.). Abbreviations: BPRS, Brief Psychiatric Rating Scale-Expanded; SANS, Scale for the Assessment of Negative Symptoms; SAPS, Scale for the Assessment of Positive Symptoms.
1428
M. Devrim-Üçok et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 30 (2006) 1426–1434
and family interviews. We defined duration of untreated psychosis (DUP) from the time of onset of first positive symptoms to the first hospitalisation. First-episode and DUP were also defined in detail in our previous study (Ucok et al., 2004). In first-episode patients diagnosis of schizophrenia was confirmed, at the sixth month after discharge, with a reinterview using SCID. Mean ± S.D. DUP was 11.2 ± 10.2 months. Chronic illness was defined as at least 3 years of illness duration after the diagnosis of schizophrenia (mean ± S.D., 9.6 ± 6.7 years, mean ± S.D. number of hospitalisations, 4.4 ± 3.9). There was one lefthanded subject in each group, except the older controls. Psychopathology was evaluated with Brief Psychiatric Rating Scale-Expanded (BPRS) (Lukoff et al., 1986), Scale for the Assessment of Positive Symptoms (SAPS) (Andreasen, 1984), and Scale for the Assessment of Negative Symptoms (SANS) (Andreasen, 1983). All measures were collected by 2 trained raters. Inter-rater reliabilities for BPRS, SANS and SAPS total scores were acceptable (κ = .78, κ = .76, and κ = .83 respectively). Antipsychotic medications were given to control the acute excitation to the majority of patients before recording (mean ± S.D. duration of medication, 8.6 ± 4 days). Therefore, although all first-episode patients were neuroleptic-naive when admitted to the hospital, only 11 of them were still neuroleptic-naive, whereas 5 patients were taking typical (mean haloperidol equivalent dose = 11.4 mg) and 15 patients were taking atypical antipsychotics either risperidone (n = 7, mean ± S.D. dose, 4.1 ± 0.7 mg/day) or olanzapine (n = 6, mean ± S.D. dose, 16.7 ± 3.9 mg/day) or quetiapine (n = 2, mean dose = 600 mg/day) during the study. In the CS group 3 patients were neurolepticfree for at least 30 days, 9 patients were taking typical (mean ± S.D. haloperidol equivalent dose, 12.2 ± 3.2mg/day) and 14 patients were taking atypical antipsychotics either olanzapine (n = 8, mean ± S.D. dose, 14.6 ± 3.5 mg/day) or risperidone (n = 4, mean ± S.D. dose, 4.6 ± 1.5 mg/day) or quetiapine (n = 1, 600 mg/ day) or clozapine (n = 1, 300 mg/day). The study was approved by the Ethical Committee at the Istanbul Medical Faculty, Istanbul, Turkey. All subjects gave written informed consent after procedures had been fully described.
involve a task, always preceded the oddball paradigm. Target detection accuracies of the subjects were determined by the following formula = [(60 − |60 − number of detected targets|) × 100/60], 60 being the number of target stimuli in the oddball paradigm. 2.3. ERP recording ERPs were recorded from 11 Ag–AgCl bridge electrodes placed at F3, Fz, F4, T3, C3, Cz, C4, T4, P3, Pz, P4 according to the 10–20 system in reference to linked earlobes. Electrooculogram (EOG) was recorded by two electrodes, placed just below the infraorbital ridge and above the eyebrow of the right eye. Electrode impedances were below 10 kΩ. The EEG was recorded with a band-pass filter of 0.5–70 Hz and digitised at 256 Hz. 2.4. Data analysis Trials on which the EEG or EOG voltages exceeded ± 90 μV were rejected automatically. Remaining trials were inspected visually for additional artifacts such as smaller EOG excursions and muscle activity. The average for both target and novel stimuli was based on at least 25 trials. Averaged data for target and novel stimuli were digitally low-pass filtered at 15 Hz and 30 Hz respectively and baseline corrected to a prestimulus 250 ms. P3b was identified as the most positive peak in the averaged response to target stimuli between 250 and 450 ms. Novelty P3 was defined as the most positive peak in the averaged response to novel stimuli between 250 and 400 ms. Peak amplitudes and latencies were measured. P3b data of 5 FES (3 paranoid, 2 catatonic; 3 neurolepticnaïve, 2 on atypical antipsychotics), 4 CS patients (all paranoid; 1 on atypical, 3 on typical antipsychotics), 1 younger and 3 older control subjects and novelty P3 data of 1 FES patient (paranoid, neuroleptic-naïve) were excluded due to low artefactfree target/novel trials and/or to target detection accuracy of less than 90%. 2.5. Statistical analysis
2.2. ERP testing Auditory ERPs were obtained during an oddball paradigm and a novelty paradigm. Oddball paradigm consisted of standard (1000 Hz) and target (1500 Hz) stimuli with respective probabilities of 0.8 and 0.2. Subjects were instructed to keep a mental count of the target tones. Novelty paradigm consisted of standard (1000 Hz), deviant (1500 Hz) and novel stimuli with probabilities of 0.6, 0.2, and 0.2, respectively. Subjects were not required to respond actively to any stimuli. Novel stimuli were a collection of environmental sampled sounds. There were 18 different novel sounds which were presented three or four times throughout the recording. Subjects were not informed of the occurrence of the novel stimuli. All stimuli were 80 dB and 1000 ms in duration. In each paradigm, 300 stimuli were binaurally presented in a random series with an interstimulus interval (ISI) of 2 s. The novelty paradigm, which did not
P3b and novelty P3 amplitudes and latencies were assessed separately with two main analyses of variance (ANOVA) repeated measures design. Group was the between-subjects factor in all the analyses. In the first analysis, there were two within-subjects factors which were 3 anteroposterior regions (frontal: F3, Fz, F4; central: C3, Cz, C4; and parietal: P3, Pz, P4) and 3 lateral regions (left: F3, C3, P3; midline: Fz, Cz, Pz; and right: F4, C4, P4). In the second analysis, 2 midtemporal sites (T3, T4) were the within-subjects factor. These analyses were done separately for the FES vs. younger controls and CS vs. older controls. If ERP components differed in both FES and CS compared to controls, they were also submitted to repeated measures ANOVA to determine the effects of chronicity free from the effects of age difference between the two groups. There were two between-subjects factors. One was the diagnosis [patients (FES and CS) vs. controls (younger and
M. Devrim-Üçok et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 30 (2006) 1426–1434
1429
Fig. 1. Event-related potential responses to target stimuli during oddball paradigm in first-episode schizophrenia patients (n = 26) and younger control subjects (n = 35).
older)] and the other one was the age [younger subjects (FES and younger controls) vs. older subjects (CS and older controls)]. The within-subjects factors were the same as above and gender was used as covariate. By this analysis both the effects of age and the effects of being chronically affected by schizophrenia on ERPs were investigated. If there was an interaction between the diagnosis and age, showing that younger and older controls did not differ in the concerned ERP, but FES and CS patients did, this was attributed to the effects of chronicity rather than age. Greenhouse–Geisser correction was applied when factors had more than two levels, with only the corrected probability values reported. Difference contrasts were used to analyze the significant main and/or interaction effects. Spearman correlation analysis was used to assess the relationships between P3b and novelty P3 parameters and clinical variables. Two-tailed p-values ≤ .05 were considered significant for correlation coefficients.
3.1.1. FES vs. younger controls FES patients showed a reduction in P3b amplitude compared to controls [F(1,59) = 4.50, p = .038] (Fig. 1, Table 2). Groups showed the expected parietocentral distribution of P3b [F (2,118) = 89.17, p = .001]. P3b amplitude was larger along the midline compared to the lateral sites [F(2,118) = 5.85, p = .007]. At temporal sites P3b amplitude was also reduced in FES [F (1,59) = 7.11, p = .01)]. Group × temporal site interaction was not significant. P3b latency did not differ between groups. P3b latency was longer in parietal region compared to central and frontal regions [F(2,118) = 7.77, p = .003], and along the lateral sites compared to midline [F(2,118) = 4.38, p = .019]. A significant group × anteroposterior site interaction [F(2,118) = 3.54, p = .049] was observed. Difference contrasts demonstrated a tendency for the P3b latency to be shorter in frontal region, whereas longer in parietal region in FES [Parietal vs. central and frontal: F(1,59) = 3.53, p = .06; central vs. frontal: F(1,59) = 3.54, p = .06].
3. Results
3.1.2. CS vs. older controls CS patients showed a reduced P3b amplitude compared to controls [F(1,52) = 27.55, p = .001] (Fig. 2, Table 2). Parietocentral distribution of the P3b [F(2,104) = 65.84, p = .001] did not differ between groups. P3b amplitude was larger along the midline compared to the lateral sites [F(2,104) = 5.53,
3.1. P3b For target detection accuracy, FES and CS patients did not differ from their controls (Table 1). Table 2 P3b and novelty P3 amplitudes and latencies
P3b Fz Cz Pz Novelty P3 Fz Cz Pz
First-episode schizophrenia
Younger controls
Amplitude
Amplitude
(n = 26) 4.9 (5.4) 7.4 (5.4) 9.3 (6.5) (n = 30) 8.4 (4.6) 10.5 (6.1) 10.7 (5.1)
Latency 306 (27) 309 (29) 322 (31) 313 (31) 310 (34) 314 (32)
(n = 35) 7.1 (4.0) 11.0 (4.8) 11.9 (5.0) (n = 36) 9.6 (4.6) 11.6 (6.0) 11.8 (5.6)
Data are given as mean (S.D.). Amplitudes in μV, latencies in ms.
Latency 315 (31) 313 (34) 315 (35) 307 (29) 308 (30) 316 (33)
Chronic schizophrenia
Older controls
Amplitude
Amplitude
(n = 22) 2.4 (3.0) 4.2 (3.0) 5.5 (3.0) (n = 26) 5.9 (4.3) 6.8 (4.1) 6.5 (3.1)
Latency 318 (33) 319 (31) 323 (43) 317 (30) 319 (28) 323 (33)
(n = 32) 7.2 (3.6) 10.1 (4.6) 10.4 (4.4) (n = 35) 10.0 (4.5) 11.6 (5.1) 10.9 (4.4)
Latency 308 (33) 309 (31) 314 (34) 312 (30) 311 (30) 317 (33)
1430
M. Devrim-Üçok et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 30 (2006) 1426–1434
Fig. 2. Event-related potential responses to target stimuli during oddball paradigm in chronic schizophrenia patients (n = 22) and older control subjects (n = 32).
p = .007]. There was a significant group × lateral site interaction [F(2,104) = 4.02, p = .025]. Difference contrasts demonstrated that P3b amplitudes reduced more at midline than lateral sites in CS [midline vs. left and right: F(1,52) = 10.10, p = .002; left vs. right: p = .3]. To eliminate amplitude differences between groups, scalp distributions were statistically reanalyzed after normalizing the P3b amplitudes using the root mean square method (McCarthy and Wood, 1985). A significant group × lateral site interaction was again found [F(2,104) = 4.40, p = .021] and contrasts demonstrated that this effect was originated primarily from the midline sites [midline vs. left and right: F(1,52) = 7.78, p = .007; left vs. right: F(1,52) = 3.11, p = .084]. P3b amplitudes at temporal sites were also reduced in CS [F(1,52) = 23.90, p = .001]. No group × temporal site effect was found. P3b latency did not differ between groups. Groups showed a longer P3b latency at parietal region compared to frontal and central regions [F(2,104) = 8.16, p = .003]. 3.1.3. FES vs. CS Schizophrenia subtypes (χ2-test), clinical scores (unpaired t-test) and medication status (neuoroleptic-naïve/free, on atypical antipsychotic, on typical antipsychotic; χ2-test) did not differ between the FES and CS patients. These analyses were done on the patients whose P3b responses were evaluated. Patients showed a reduction in P3b amplitude compared to controls [F(1,110) = 22.35, p = .001]. Older subjects showed a smaller P3b than the younger subjects [F (1,110) = 4.69, p = .037]. Most importantly, although the P3b reduction in CS compared to FES patients was larger than the reduction in older compared to younger controls, the interaction between diagnosis and age was not significant [F(1,110) = 2.06, p = .15] (Fig. 3). This finding indicated that CS and FES patients did not differ in P3b amplitude. Similar results were obtained for the temporal sites. Patients [F(1,110) = 26.84, p = .001] and older subjects [F(1,110) = 5.41, p = .022] showed a reduced P3b amplitude, and the interaction between diagnosis and age was not significant [F(1,110) = 1.70, p = .19].
3.2. Novelty P3 3.2.1. FES vs. younger controls Novelty P3 amplitudes of FES patients were not different from controls [F(1,64) = 0.88, p = .35] (Fig. 4, Table 2). Novelty P3 had a centroparietal distribution [F(2,128) = 24.28, p = .001] and this topography did not differ between groups. Novelty P3 was larger along the midline compared to lateral sites [F(2,128) = 39.73, p = .001]. Novelty P3 latencies did not differ between groups. Novelty P3 latency was longer in parietal region compared to frontal and central regions [F(2,128) = 8.43, p = .001].
Fig. 3. Event-related potential responses to target stimuli during oddball paradigm in first-episode (n = 26) and chronic schizophrenia patients (n = 22) (left), and younger (n = 35) and older control subjects (n = 32) (right).
M. Devrim-Üçok et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 30 (2006) 1426–1434
1431
Fig. 4. Event-related potential responses to novel stimuli during novelty paradigm in first-episode schizophrenia patients (n = 30) and younger control subjects (n = 36) (left), and chronic schizophrenia patients (n = 26) and older control subjects (n = 35) (right).
3.2.2. CS vs. older controls A reduction in novelty P3 amplitude was observed in CS compared to controls [F(1,59) = 14.80, p = .001] (Fig. 4, Table 2). Centroparietal distribution of novelty P3 [F(2,118) = 7.53, p = .003] did not differ between groups. Novelty P3 was larger along the midline compared to lateral sites [F(2,118) = 20.49, p = .001]. There was a significant group × lateral site interaction [F(2,118) = 7.27, p = .001]. Difference contrasts demonstrated that novelty P3 amplitudes reduced more at midline than the lateral sites in CS [midline vs. left and right: F(1,59) = 17.42, p = .001; left vs. right: p = .76]. Analysis on the normalized novelty P3 amplitudes again yielded a significant group × lateral site interaction [F(2,118) = 3.35, p = .041], reflecting a greater reduction at midline than the lateral sites [midline vs. left and right: F(1,59) = 7.71, p = .007; left vs. right: p = 1]. Novelty P3 amplitude at temporal sites was also reduced in CS [F(1,59) = 8.33, p = .005]. Novelty P3 latencies did not differ between groups. Novelty P3 latency was longer in parietal region compared to frontal and central regions [F(2,118) = 10.49, p = .001]. 3.3. Correlations with psychopathology 3.3.1. FES No correlations were found between ERP parameters and clinical severity measures, age at onset and DUP in FES. 3.3.2. CS In CS patients P3b amplitudes at Fz (r = 0.471, p = .042), F3 (r = 0.458, p = .049), and F4 (r = 0.556, p = .013) were associated with SAPS scores; the greater the positive symptoms, the greater the P3b. P3b amplitudes at F3 (r = 0.495, p = .023), and F4 (r = 0.494, p = .023) were also associated with the total BPRS scores. P3b latencies at F4 (r = 0.556, p = .013), C4 (r = 0.540,
p = .017), T4 (r = 0.563, p = .012), Pz (r = 0.669, p = .002), P3 (r = 0.535, p = .018), and P4 (r = 0.516, p = .024) were associated with the SANS scores; the greater the negative symptoms, the longer the P3b latency. Novelty P3 amplitudes at Fz (r = 0.544, p = .011), F3 (r = 0.458, p = .037), F4 (r = 0.589, p = .005), C3 (r = 0.441, p = .045), and T3 (r = 0.554, p = .009) were correlated with SAPS scores; the greater the positive symptoms the greater the novelty P3. Novelty P3 amplitudes at F3 (r = 0.460, p = .021), F4 (r = 0.484, p = .014), T3 (r = 0.506, p = .010), and T4 (r = 0.488, p = .013) were also correlated with BPRS scores. There were no significant associations between the ERP parameters and the duration of illness in CS. 4. Discussion To our knowledge the present study is the first to report on the novelty P3 in FES and to evaluate novelty P3 and P3b responses in both FES and CS. P3b amplitude reduction, which was evident not only in CS but also in FES, suggests that it is a trait marker for the illness. Our findings are consistent with previous P3b studies in FES (Brown et al., 2002; Demiralp et al., 2002; Hirayasu et al., 1998; Salisbury et al., 1998; Valkonen-Korhonen et al., 2003; Wang et al., 2003) and support the suggestion that P3b reduction is a trait-like feature of schizophrenia. Novelty P3 amplitude reduction was only found in CS which is in line with some of the previous studies (Grillon et al., 1990b; Merrin and Floyd, 1994). FES patients who were relatively free of confounds such as the long-term effects of antipsychotics and chronicity did not demonstrate novelty P3 abnormality. The neural network for target detection is distinct from that for novelty processing, although some areas are commonly activated by target and novel stimuli. Prefrontal lesions reduce
1432
M. Devrim-Üçok et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 30 (2006) 1426–1434
the novelty P3 component and the automatic response to novel stimuli, whereas they do not affect the P3b to target stimuli (Knight, 1984). Hippocampal lesions result in widespread reductions of novelty P3, with decrements being most pronounced over prefrontal regions, whereas only the frontal aspect of P3b which is considered as an instance of P3a is disrupted (Knight, 1996). Lesions involving the temporal– parietal junction reduce both novelty P3 and P3b during the novelty oddball task (Knight et al., 1989). However, a recent event-related functional magnetic resonance imaging study have shown that when novel events occurred outside of attentional focus, as it was in the present study, the activated regions were confined to the prefrontal cortex and hippocampus (Yamaguchi et al., 2004). When subjects ignored the incoming stimuli, novel events would not be actively processed aside from the initial automatic orienting (Friedman et al., 1998). In this study novelty P3 was elicited during passive ignore condition. Since the attention of the subjects was not controlled, we can not be sure that they did not attend to the stimuli. However, we supposed that by using a passive novelty paradigm, we had the chance to eliminate more or less the activities related to discrimination or classification of the stimuli. In the present study novelty P3 reduction was observed only in CS. Therefore, we suggest that the prefrontal– hippocampal system that is thought to be involved in generating automatic orienting response to novel events is disrupted in chronic stages of schizophrenia, whereas at the onset of illness it is preserved. Our suggestion is consistent with some of the imaging studies reporting normal prefrontal and hippocampal structure in FES, but lower volumes of gray matter in these regions in CS (Molina et al., 2004; Razi et al., 1999). However, there are also studies demonstrating smaller hippocampal and prefrontal gray matter volumes in FES (Hirayasu et al., 2001; Velakoulis et al., 1999). The absence of novelty P3 abnormality in patients with FES suggests a degenerative process that occurs after the onset of schizophrenia. It remains to be determined whether the novelty P3 reduction in chronic schizophrenia is related to the disease process itself or to a secondary effect, as long-term antipsychotic treatment. In contrast to our finding of normal novelty P3 in FES, Valkonen-Korhonen et al. (2003) reported a P3a reduction in psychotic first-episode patients. This could be explained firstly by the differences in patient groups. Valkonen-Korhonen et al. (2003) studied a heterogeneous group of psychotic first-episode patients in which only approximately half of them were diagnosed as schizophreniform disorder or schizophrenia. However, in our study all the first-episode patients were diagnosed as schizophrenia. Secondly, the deviant stimuli that were utilized were different. Our deviant stimuli were novel environmental sounds, whereas pure tones were applied in the mentioned study. Novel sounds were shown to be more distracting and to elicit a larger P3 than the deviant pure tones in normal subjects (Grillon et al., 1990a). Therefore, it is possible that, even though FES patients have some problems in automatic orienting of attention, more distracting deviant stimuli somehow compensate this defect and elicit a normal response.
P3b amplitudes in CS patients were not different from FES patients. This observation suggests that there is no further deterioration after illness onset. Additionally, we could not find a correlation between the P3b amplitude and illness duration in CS patients. Our findings are in line with the studies reporting similar P3b amplitudes in FES and CS patients (Brown et al., 2002; Hirayasu et al., 1998). However, there were several studies which have reported P3b amplitude to be inversely correlated with illness duration (MartinLoeches et al., 2001; Mathalon et al., 2000b; Olichney et al., 1998). The present and the mentioned studies are crosssectional, and therefore only suggestive of longitudinal processes. Longitudinal data are needed to disentangle the effects of chronicity on P3b. We observed symmetrical temporal site reduction in P3b in both FES and CS. Some studies reported a greater left than right temporal P3b amplitude reduction (McCarley et al., 1993, 2002; Salisbury et al., 1998) in contrast to others reporting symmetric reduction (Ford et al., 1994; Pfefferbaum et al., 1989). It is suggested that neuroanatomical differences between patients studied by different laboratories might explain the difference in P3b asymmetry (Ford et al., 2000). Since we did not have the imaging data of our patients we can not comment on this suggestion. Several limitations about the present study should be noted. First, although the duration was very short, majority of the patients were taking antipsychotic medication which made it difficult to eliminate their possible effects on ERPs. Some studies suggest that medication may increase P3b amplitude in schizophrenia (Coburn et al., 1998; Gonul et al., 2003; Umbricht et al., 1998), whereas others suggest that medication has no effect on P3b amplitude (Ford et al., 1994; Pfefferbaum et al., 1989). Pfefferbaum et al. (1989) also reported that medication has no effect on automatically elicited P3. Therefore, it seems that medication can be discarded as a distorting factor for P3 responses. Second, the duration of stimuli we used was longer than the other studies. Long duration stimuli lead to stimulus-off potentials that can affect the response to subsequent stimuli if the ISI is short. However, our ISI of 2 s likely fell outside the latency range of any off potentials (Bullock et al., 1994; Picton et al., 1978). It was shown that long stimuli elicited sustained negative potentials (Keidel, 1971; Picton et al., 1978). Since in this study the EEG was recorded with a high-pass filter of 0.5 Hz, the attenuation of the scalp recorded P3 potentials through algebraic summation with the sustained negativity would be minimal. These sustained negative potentials could have an effect on the generation of novelty P3 and P3b by increasing the cortical excitability (Birbaumer et al., 1990; Ergenoglu et al., 1998). However, it is not known whether their effect on cortical excitability is different in schizophrenia patients and controls. In a previous study we also used these relatively long-duration stimuli and observed P3b reduction in FES (Demiralp et al., 2002). Third, our novel stimuli were not unique and each was repeated three or four times which could make our findings difficult to compare with the previous studies. However, with recurrence of novel events a reduction in novelty P3 amplitude and a shift from a frontally
M. Devrim-Üçok et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 30 (2006) 1426–1434
to a parietally oriented topography were reported, whether the eliciting novel events were a sequence of unique novel stimuli (Friedman and Simpson, 1994), repetitions of a single novel event (Knight, 1984), or repetitions of identical novel sounds (Cycowicz et al., 1996). More importantly, Friedman et al. (1998) showed that the novelty P3 amplitude decrements to repetition of identical and recurrence of unique novel events were similar. 5. Conclusion Based on our results, P3b amplitude reduction can be considered as a trait marker of schizophrenia. Novelty P3 amplitude reductions present in patients with CS, are not found at the onset of illness. Automatic orienting of attention processes indexed by novelty P3 seems to be unaffected at the early stage of schizophrenia. Assessment of P3b and novelty P3 potentials in these FES patients longitudinally will elucidate how these potentials are affected over time from schizophrenia onset. Acknowledgments This work was supported by the Research Fund of The University of Istanbul. Project numbers: 173/15012004 and B-971/10052001. References Alain C, Bernstein LJ, Cortese F, Yu H, Zipursky RB. Deficits in automatically detecting changes in conjunction of auditory features in patients with schizophrenia. Psychophysiology 2002;39:599–606. Andreasen NC. The Scale for the Assessment of Negative Symptoms (SANS). Iowa City, IA: University of Iowa; 1983. Andreasen NC. The Scale for the Assessment of Positive Symptoms (SAPS). Iowa City, IA: University of Iowa; 1984. Birbaumer N, Elbert T, Canavan AGM, Rockstroh B. Slow potentials of the cerebral cortex and behavior. Physiol Rev 1990;70:1–41. Blackwood DH, Whalley LJ, Christie JE, Blackburn IM, St Clair DM, McInnes A. Changes in auditory P3 event-related potential in schizophrenia and depression. Br J Psychiatry 1987;150:154–60. Blackwood DH, St Clair DM, Muir WJ, Duffy JC. Auditory P300 and eye tracking dysfunction in schizophrenic pedigrees. Arch Gen Psychiatry 1991; 48:899–909. Brown KJ, Gonsalvez CJ, Harris AWF, Williams LM, Gordon E. Target and non-target ERP disturbances in first episode vs. chronic schizophrenia. Clin Neurophysiol 2002;113:1754–63. Bullock TH, Karamursel S, Achimowicz JZ, McClune MC, Basar-Eroglu C. Dynamic properties of human visual evoked and omitted stimulus potentials. Electroencephalogr Clin Neurophysiol 1994;91:42–53. Coburn KL, Shillcutt SD, Tucker KA, Estes KM, Brin FB, Merai P, et al. P300 delay and attenuation in schizophrenia: reversal by neuroleptic medication. Biol Psychiatry 1998;44:466–74. Cycowicz YM, Friedman D, Rothstein M. An ERP developmental study of repetition priming by auditory novel stimuli. Psychophysiology 1996;3: 680–90. Demiralp T, Ucok A, Devrim M, Isoglu-Alkac U, Tecer A, Polich J. N2 and P3 components of event-related potential in first-episode schizophrenic patients: scalp topography, medication, and latency effects. Psychiatry Res 2002;111:167–79. Donchin E, Coles MG. Is the P300 component a manifestation of context updating? Behav Brain Sci 1988;11:357–74.
1433
Ergenoglu T, Demiralp T, Beydagi H, Karamursel S, Devrim M, Ermutlu N. Slow cortical potential shifts modulate P300 amplitude and topography in humans. Neurosci Lett 1998;251:61–4. First MB, Spitzer RL, Gibbon M, Williams JBW. Structured Clinical Interview for DSM-IV Axis I disorders (SCID-I), Clinical Version. Washington, DC: American Psychiatric Press; 1997. Ford JM, Pfefferbaum A, Roth WT. P3 and schizophrenia. Ann N Y Acad Sci 1992;658:146–62. Ford JM, White PM, Csernansky JG, Faustman WO, Roth WT, Pfefferbaum A. ERPs in schizophrenia: effects of antipsychotic medication. Biol Psychiatry 1994;36:153–70. Ford JM, Mathalon DH, Marsh L, Faustman WO, Harris D, Hoff AL, et al. P300 amplitude is related to clinical state in severely and moderately ill patients with schizophrenia. Biol Psychiatry 1999a;46:94–101. Ford JM, Roth WT, Menon V, Pfefferbaum A. Failures of automatic and strategic processing in schizophrenia: comparisons of event-related brain potential and startle blink modification. Schizophr Res 1999b;37:149–63. Ford JM, Mathalon DH, White PM, Pfefferbaum A. Left temporal deficit of P300 in patients with schizophrenia: effects of task. Int J Psychophysiol 2000;38:71–9. Friedman D, Simpson GV. ERP amplitude and scalp distribution to target and novel events: effects of temporal order in young, middle-aged and older adults. Cogn Brain Res 1994;2:49–63. Friedman D, Cornblatt B, Vaughan Jr H, Erlenmeyer-Kimling L. Auditory event-related potentials in children at risk for schizophrenia: the complete initial sample. Psychiatry Res 1988;26:203–21. Friedman D, Kazmerski VA, Cycowicz YM. Effects of aging on the novelty P3 during attend and ignore oddball tasks. Psychophysiology 1998;35: 508–20. Friedman D, Cycowicz YM, Gaeta H. The novelty P3: an event-related brain potential (ERP) sign of the brain's evaluation of novelty. Neurosci Biobehav Rev 2001;25:355–73. Frodl T, Meisenzahl EM, Muller D, Greiner J, Juckel G, Leinsinger G, et al. Corpus callosum and P300 in schizophrenia. Schizophr Res 2001;49: 107–19. Gonul AS, Suer C, Coburn K, Ozesmi C, Oguz A, Yilmaz A. Effects of olanzapine on auditory P300 in schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 2003;27:173–7. Grillon C, Courchesne E, Ameli R, Elmasian R, Braff DL. Effects of rare nontarget stimuli on brain electrophysiological activity and performance. Int J Psychophysiol 1990a;3:257–67. Grillon C, Courchesne E, Ameli R, Geyer MA, Braff DL. Increased distractibility in schizophrenic patients. Electrophysiologic and behavioral evidence. Arch Gen Psychiatry 1990b;47:171–9. Hirayasu Y, Asato N, Ohta H, Hokama H, Arakaki H, Ogura. Abnormalities of auditory event-related potentials in schizophrenia prior to treatment. Biol Psychiatry 1998;43:244–53. Hirayasu Y, Tanaka S, Shenton ME, Salisbury DF, DeSantis MA, Levitt JJ, et al. Prefrontal gray matter volume reduction in first episode schizophrenia. Cereb Cortex 2001;11:374–81. Keidel WD. D.C.-potentials in the auditory evoked response in man. Acta Otolaryngol 1971;71:242–8. Kidogami Y, Yoneda H, Asaba H, Sakai T. P300 in first degree relatives of schizophrenics. Schizophr Res 1991;6:9–13. Knight RT. Decreased response to novel stimuli after prefrontal lesions in man. Electroencephalogr. Clin Neurophysiol 1984;59:9–20. Knight RT. Contribution of human hippocampal region to novelty detection. Nature 1996;38:256–9. Knight RT, Scabini D, Woods DL, Clayworth CC. Contributions of temporal– parietal junction to the human auditory P3. Brain Res 1989;502:109–16. Lukoff D, Nuechterlein KH, Ventura J. Manual for the Expanded Brief Psychiatric Rating Scale. Schizophr Bull 1986;12:594–602. Martin-Loeches M, Molina V, Munoz F, Hinojosa JA, Reig S, Desco M, et al. P300 amplitude as a possible correlate of frontal degeneration in schizophrenia. Schizophr Res 2001;49:121–8. Mathalon DH, Ford JM, Pfefferbaum A. Trait and state aspects of P300 amplitude reduction in schizophrenia: a retrospective longitudinal study. Biol Psychiatry 2000a;47:434–49.
1434
M. Devrim-Üçok et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 30 (2006) 1426–1434
Mathalon DH, Ford JM, Rosenbloom M, Pfefferbaum A. P300 reduction and prolongation with illness duration in schizophrenia. Biol Psychiatry 2000b; 47:413–27. McCarthy G, Wood CC. Scalp distributions of event-related potentials: an ambiguity associated with analysis of variance models. Electroencephalogr Clin Neurophysiol 1985;62:203–8. McCarley RW, Faux SF, Shenton ME, Nestor PG, Adams J. Event-related potentials in schizophrenia: their biological and clinical correlates and a new model of schizophrenic pathophysiology. Schizophr Res 1991;4:209–31. McCarley RW, Shenton ME, O'Donnell BF, Faux SF, Kikinis R, Nestor PG, et al. Auditory P300 abnormalities and left posterior superior temporal gyrus volume reduction in schizophrenia. Arch Gen Psychiatry 1993;50:190–7. McCarley RW, Salisbury DF, Hirayasu Y, Yurgelun-Todd DA, Tohen M, Zarate C, et al. Association between smaller left posterior superior temporal gyrus volume on magnetic resonance imaging and smaller left temporal P300 amplitude in first-episode schizophrenia. Arch Gen Psychiatry 2002;59: 321–31. Merrin EL, Floyd TC. P300 responses to novel auditory stimuli in hospitalized schizophrenic patients. Biol Psychiatry 1994;36:527–42. Michie PT, Innes-Brown H, Todd J, Jablensky AV. Duration mismatch negativity in biological relatives of patients with schizophrenia spectrum disorders. Biol Psychiatry 2002;52:749–58. Molina V, Sanz J, Sarramea F, Benito C, Palomo T. Lower prefrontal gray matter volume in schizophrenia in chronic but not in first episode schizophrenia patients. Psychiatry Res 2004;131:45–56. Olichney JM, Iragui VJ, Kutas M, Nowacki R, Morris S, Jeste DV. Relationship between auditory P300 amplitude and age of onset of schizophrenia in older patients. Psychiatry Res 1998;79:241–54. Pfefferbaum A, Ford JM, White PM, Roth WT. P3 in schizophrenia is affected by stimulus modality, response requirements, medication status, and negative symptoms. Arch Gen Psychiatry 1989;46:1035–44. Picton TW, Woods DL, Proulx GB. Human auditory sustained potentials: I. The nature of the response. Electroencephalogr Clin Neurophysiol 1978;45: 186–97. Polich J, Kok A. Cognitive and biological determinants of P300: an integrative review. Biol Psychol 1995;41:103–46.
Razi K, Greene KP, Sakuma M, Ge S, Kushner M, DeLisi LE. Reduction of the parahippocampal gyrus and the hippocampus in patients with chronic schizophrenia. Br J Psychiatry 1999;174:512–9. Roxborough H, Muir WJ, Blackwood DH, Walker MT, Blackburn IM. Neuropsychological and P300 abnormalities in schizophrenics and their relatives. Psychol Med 1993;23:305–14. Salisbury DF, Shenton ME, Sherwood AR, Fischer IA, Yurgelun-Todd DA, Tohen M, et al. First-episode schizophrenic psychosis differs from firstepisode affective psychosis and controls in P300 amplitude over left temporal lobe. Arch Gen Psychiatry 1998;55:173–80. Schall U, Catts SV, Karayanidis F, Ward PB. Auditory event-related potential indices of fronto-temporal information processing in schizophrenia syndromes: valid outcome prediction of clozapine therapy in a three-year follow-up. Int J Neuropsychopharmacol 1999;2:83–93. Turetsky B, Colbath EA, Gur RE. P300 subcomponent abnormalities in schizophrenia: II. Longitudinal stability and relationship to symptom change. Biol Psychiatry 1998;43:31–9. Ucok A, Polat A, Cakir S, Genc A, Turan N. Duration of untreated psychosis may predict acute treatment response in first-episode schizophrenia. J Psychiatr Res 2004;38:163–8. Umbricht D, Javitt D, Novak G, Bates J, Pollack S, Lieberman J, et al. Effects of clozapine on auditory event-related potentials in schizophrenia. Biol Psychiatry 1998;44:716–25. Valkonen-Korhonen M, Purhonen M, Tarkka IM, Sipila P, Partanen J, Karhu J, et al. Altered auditory processing in acutely psychotic never-medicated firstepisode patients. Brain Res Cogn Brain Res 2003;17:747–58. Velakoulis D, Pantelis C, McGorry PD, Dudgeon P, Brewer W, Cook M, et al. Hippocampal volume in first-episode psychoses and chronic schizophrenia: a high-resolution magnetic resonance imaging study. Arch Gen Psychiatry 1999;56:133–41. Wang J, Hirayasu Y, Hiramatsu K, Hokama H, Miyazato H, Ogura C. Increased rate of P300 latency prolongation with age in drug-naive and first-episode schizophrenia. Clin Neurophysiol 2003;114:2029–35. Yamaguchi S, Hale LA, D'Esposito M, Knight RT. Rapid prefrontal– hippocampal habituation to novel events. J Neurosci 2004;24:5356–63.
Novelty P3 and P3b in first-episode schizophrenia and chronic schizophrenia Müge Devrim-Üçok a,⁎, H. Yasemin Keskin-Ergen a , Alp Üçok b a b
Department of Physiology, University of Istanbul, Istanbul Medical Faculty, 34093 Çapa-Istanbul, Turkey Department of Psychiatry, University of Istanbul, Istanbul Medical Faculty, 34093 Çapa-Istanbul, Turkey Received 25 January 2006; received in revised form 28 May 2006; accepted 29 May 2006 Available online 7 July 2006
Abstract The objective of this study was to evaluate P3b and novelty P3 responses in patients with first-episode schizophrenia (FES) and chronic schizophrenia (CS). P3b is consistently reported to be reduced in CS. However, novelty P3 results in CS are controversial. Novelty P3 is not studied, and there are only a few P3b studies in patients with FES. Subject groups comprised 31 patients with FES and 36 younger control subjects, and 26 patients with CS and 35 older control subjects. Automatically elicited auditory novelty P3 and effortfully elicited auditory P3b potentials were assessed. P3b amplitudes were reduced in both patients with FES and CS relative to their controls. CS and FES patients did not differ in P3b amplitude. Novelty P3 amplitude was reduced in patients with CS. Novelty P3 amplitude in patients with FES did not differ from their controls. P3b amplitude reduction may be a trait marker of schizophrenia and may not progress over the course of illness, although this can only be definitively determined by longitudinal studies. Novelty P3 amplitude reduction present in patients with CS, is not found at the onset of illness. Novelty P3 seems unaffected early in the disease process. © 2006 Elsevier Inc. All rights reserved. Keywords: Chronic schizophrenia; Event-related potentials; First-episode; Novelty P3; P3b; Schizophrenia
1. Introduction P3 (P300) family of event-related potentials (ERPs) is studied in schizophrenia to investigate attention and information processing deficits that have been implicated as a core feature of this illness. P3b is elicited by attended, task-relevant stimuli and reflects the allocation of attentional resources when a target stimulus engages memory operations during task performance (Donchin and Coles, 1988; Polich and Kok, 1995). P3a is elicited by infrequent, task-irrelevant stimuli. When the infrequent, task-irrelevant stimuli were novel environmental sounds, the elicited component is often called the novelty P3. Abbreviations: BPRS, Brief Psychiatric Rating Scale-Expanded; CS, chronic schizophrenia; DSM-IV, Diagnostic and Statistical Manual of Mental Disorders Fourth Edition; DUP, duration of untreated psychosis; EOG, electrooculogram; ERPs, event-related potentials; FES, first-episode schizophrenia; SANS, Scale for the Assessment of Negative Symptoms; SAPS, Scale for the Assessment of Positive Symptoms; SCID, Structured Clinical Interview for DSM-IV. ⁎ Corresponding author. Tel./fax: +90 212 635 26 31. E-mail address: [email protected] (M. Devrim-Üçok). 0278-5846/$ - see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.pnpbp.2006.05.019
Although it is not yet known whether the P3a and novelty P3 are identical, it is assumed that they reflect involuntary orienting of attention towards the unexpected or novel events in the stimulus context (Friedman et al., 2001; Knight, 1984, 1996). We will use the terms P3a and novelty P3 to refer to the P3 components elicited by pure tones and novel environmental sounds, respectively. P3b is usually maximum over parietal scalp sites, and P3a and novelty P3 have a more frontally-oriented scalp distribution (Friedman et al., 2001). P3b amplitude reduction is a widely replicated finding in schizophrenia (see reviews Ford et al., 1992; McCarley et al., 1991). However, P3b latency prolongation is less consistently reported in schizophrenia (Blackwood et al., 1991; Coburn et al., 1998; Roxborough et al., 1993). Most of these studies have investigated P3b in chronic schizophrenia (CS). The ERP abnormalities in CS may be due to ongoing chronic process, antipsychotic medication and/or hospitalization. Therefore, it is of considerable interest whether the ERP abnormalities are trait markers of schizophrenia and present at onset or occur secondary to chronicity. Many studies (Blackwood et al., 1991; Kidogami et al., 1991; Roxborough et al., 1993) with
M. Devrim-Üçok et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 30 (2006) 1426–1434
some exceptions (Friedman et al., 1988) reported reduced P3b amplitude in unaffected first-degree relatives of patients suggesting that it is an endophenotype marker of vulnerability to schizophrenia. Investigating first-episode schizophrenia (FES) patients is another approach to understand whether P3b reduction is a trait feature. Although there are few studies, there is a consensus over P3b amplitude reduction in FES (Brown et al., 2002; Demiralp et al., 2002; Hirayasu et al., 1998; Salisbury et al., 1998; Valkonen-Korhonen et al., 2003; Wang et al., 2003). P3b prolongation was also observed in FES by our group (Demiralp et al., 2002) and Wang et al. (2003). Several studies have shown P3b amplitude to be inversely correlated with illness duration (Martin-Loeches et al., 2001; Mathalon et al., 2000b; Olichney et al., 1998). However, similarity in P3b amplitudes between FES and CS patients has also been reported (Brown et al., 2002; Hirayasu et al., 1998). Moreover, some reports relate the P3b reduction in CS to severity of psychopathology (Ford et al., 1999a; Mathalon et al., 2000a; Turetsky et al., 1998), whereas others indicate that P3b amplitude is unrelated to changes in clinical state (Blackwood et al., 1987; Ford et al., 1994). P3a and especially novelty P3 responses have been investigated less than P3b in schizophrenia. Reduction of P3a and novelty P3 amplitudes (Alain et al., 2002; Grillon et al., 1990b; Merrin and Floyd, 1994) were reported in some studies, however, normal (Frodl et al., 2001; Michie et al., 2002) or even increased amplitudes (Schall et al., 1999) were also reported in schizophrenia. P3a latency prolongation was also reported (Frodl et al., 2001). Startling (high sound pressure level) noises that elicit P3 automatically has also been evaluated, and both normal (Ford et al., 1999b), and reduced P3 amplitudes (Mathalon et al., 2000a; Pfefferbaum et al., 1989) were demonstrated. P3a responses of unaffected, first-degree relatives of patients were not different from the controls (Michie et al., 2002). Valkonen-Korhonen et al. (2003) reported P3a reduction in a group of acutely psychotic first-episode patients. To our knowledge, novelty P3 responses in FES have not been reported before. The aim of this study was to investigate auditory P3b and novelty P3 components and their relations with clinical features in FES and CS. It is more informative to study different ERPs
1427
reflecting distinct processes in the same patient group and to evaluate FES and CS patients with the same experimental settings. This study was undertaken to determine the contribution of trait features and/or chronicity to possible disturbances in automatic and selective attention processes in schizophrenia. If abnormalities in processing target and/or novel stimuli in FES are present, this will indicate that these disturbances are the core features of the illness, rather than being related with chronicity. 2. Methods 2.1. Subjects Thirty-one inpatients with FES (26 paranoid, 3 catatonic, 1 undifferentiated, and 1 disorganized) were compared with 36 younger control subjects. Also, 26 inpatients with CS (24 paranoid, and 2 catatonic) were compared with 35 older control subjects. Subject demographic characteristics and clinical scales of the patients are presented in Table 1. Each patient group did not differ from its respective control group in gender (χ2-test), age and education level (unpaired t-test). All the patients met DSM-IV diagnostic criteria for schizophrenia and were in the acute phase of illness. Patients were diagnosed for schizophrenia at a consensus meeting incorporating clinical, and Structured Clinical Interview for DSM-IV (SCID) data (First et al., 1997). All SCID interviews were made by a trained senior interviewer (AU). Controls were screened by using the Structured Clinical Interview for DSM-III-R-Non-Patient Edition. Exclusion criteria for patients included any organic disorder known to cause psychosis or cognitive impairment and alcohol/drug abuse. In first-episode group one patient had major depressive disorder. In chronic group two patients had major depressive disorder and one had obsessive–compulsive disorder. A patient was accepted in his/her first psychotic episode, if all following conditions were fulfilled: no past diagnosis of nonaffective possible psychosis; no previous antipsychotic treatment and an inpatient care. The date of onset of the first identifiable positive symptoms was timed by the senior psychiatrist in research team on the basis of a best-estimate approach using data gathered from multiple sources including medical records, and direct patient,
Table 1 Subject demographic characteristics and clinical scales of the patients Paradigm
Gender (F/M) Age (years) Education (years) BPRS SANS SAPS Target detection accuracy (%)
First-episode schizophrenia
Younger controls
Chronic schizophrenia
Older controls
P3b (n = 26)
Novelty P3 (n = 30)
P3b (n = 35)
Novelty P3 (n = 36)
P3b (n = 22)
Novelty P3 (n = 26)
P3b (n = 32)
Novelty P3 (n = 35)
12/14 22.3 (5.9) 11.3 (2.9) 66.6 (18.4) 46.4 (22.0) 38.5 (17.8) 97.8 (3.3)
15/15 22.1 (5.7) 10.9 (2.9) 66.4 (17.3) 52.0 (24.2) 37.4 (18.5)
16/19 23.7 (6.2) 12.0 (3.7)
16/20 23.6 (6.1) 12.0 (3.6)
3/19 35.3 (11.6) 12.5 (3.2) 60.7 (8.6) 51.7 (13.7) 37.1 (14.1) 98.3 (1.9)
5/21 35.6 (11.5) 12.5 (3.2) 60.6 (9.0) 50.9 (14.2) 37.4 (13.4)
7/25 32.9 (10.8) 11.1 (5.6)
8/27 33.5 (11.2) 11.2 (5.7)
98.7 (2.1)
98.1 (2.5)
Data are given as mean (S.D.). Abbreviations: BPRS, Brief Psychiatric Rating Scale-Expanded; SANS, Scale for the Assessment of Negative Symptoms; SAPS, Scale for the Assessment of Positive Symptoms.
1428
M. Devrim-Üçok et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 30 (2006) 1426–1434
and family interviews. We defined duration of untreated psychosis (DUP) from the time of onset of first positive symptoms to the first hospitalisation. First-episode and DUP were also defined in detail in our previous study (Ucok et al., 2004). In first-episode patients diagnosis of schizophrenia was confirmed, at the sixth month after discharge, with a reinterview using SCID. Mean ± S.D. DUP was 11.2 ± 10.2 months. Chronic illness was defined as at least 3 years of illness duration after the diagnosis of schizophrenia (mean ± S.D., 9.6 ± 6.7 years, mean ± S.D. number of hospitalisations, 4.4 ± 3.9). There was one lefthanded subject in each group, except the older controls. Psychopathology was evaluated with Brief Psychiatric Rating Scale-Expanded (BPRS) (Lukoff et al., 1986), Scale for the Assessment of Positive Symptoms (SAPS) (Andreasen, 1984), and Scale for the Assessment of Negative Symptoms (SANS) (Andreasen, 1983). All measures were collected by 2 trained raters. Inter-rater reliabilities for BPRS, SANS and SAPS total scores were acceptable (κ = .78, κ = .76, and κ = .83 respectively). Antipsychotic medications were given to control the acute excitation to the majority of patients before recording (mean ± S.D. duration of medication, 8.6 ± 4 days). Therefore, although all first-episode patients were neuroleptic-naive when admitted to the hospital, only 11 of them were still neuroleptic-naive, whereas 5 patients were taking typical (mean haloperidol equivalent dose = 11.4 mg) and 15 patients were taking atypical antipsychotics either risperidone (n = 7, mean ± S.D. dose, 4.1 ± 0.7 mg/day) or olanzapine (n = 6, mean ± S.D. dose, 16.7 ± 3.9 mg/day) or quetiapine (n = 2, mean dose = 600 mg/day) during the study. In the CS group 3 patients were neurolepticfree for at least 30 days, 9 patients were taking typical (mean ± S.D. haloperidol equivalent dose, 12.2 ± 3.2mg/day) and 14 patients were taking atypical antipsychotics either olanzapine (n = 8, mean ± S.D. dose, 14.6 ± 3.5 mg/day) or risperidone (n = 4, mean ± S.D. dose, 4.6 ± 1.5 mg/day) or quetiapine (n = 1, 600 mg/ day) or clozapine (n = 1, 300 mg/day). The study was approved by the Ethical Committee at the Istanbul Medical Faculty, Istanbul, Turkey. All subjects gave written informed consent after procedures had been fully described.
involve a task, always preceded the oddball paradigm. Target detection accuracies of the subjects were determined by the following formula = [(60 − |60 − number of detected targets|) × 100/60], 60 being the number of target stimuli in the oddball paradigm. 2.3. ERP recording ERPs were recorded from 11 Ag–AgCl bridge electrodes placed at F3, Fz, F4, T3, C3, Cz, C4, T4, P3, Pz, P4 according to the 10–20 system in reference to linked earlobes. Electrooculogram (EOG) was recorded by two electrodes, placed just below the infraorbital ridge and above the eyebrow of the right eye. Electrode impedances were below 10 kΩ. The EEG was recorded with a band-pass filter of 0.5–70 Hz and digitised at 256 Hz. 2.4. Data analysis Trials on which the EEG or EOG voltages exceeded ± 90 μV were rejected automatically. Remaining trials were inspected visually for additional artifacts such as smaller EOG excursions and muscle activity. The average for both target and novel stimuli was based on at least 25 trials. Averaged data for target and novel stimuli were digitally low-pass filtered at 15 Hz and 30 Hz respectively and baseline corrected to a prestimulus 250 ms. P3b was identified as the most positive peak in the averaged response to target stimuli between 250 and 450 ms. Novelty P3 was defined as the most positive peak in the averaged response to novel stimuli between 250 and 400 ms. Peak amplitudes and latencies were measured. P3b data of 5 FES (3 paranoid, 2 catatonic; 3 neurolepticnaïve, 2 on atypical antipsychotics), 4 CS patients (all paranoid; 1 on atypical, 3 on typical antipsychotics), 1 younger and 3 older control subjects and novelty P3 data of 1 FES patient (paranoid, neuroleptic-naïve) were excluded due to low artefactfree target/novel trials and/or to target detection accuracy of less than 90%. 2.5. Statistical analysis
2.2. ERP testing Auditory ERPs were obtained during an oddball paradigm and a novelty paradigm. Oddball paradigm consisted of standard (1000 Hz) and target (1500 Hz) stimuli with respective probabilities of 0.8 and 0.2. Subjects were instructed to keep a mental count of the target tones. Novelty paradigm consisted of standard (1000 Hz), deviant (1500 Hz) and novel stimuli with probabilities of 0.6, 0.2, and 0.2, respectively. Subjects were not required to respond actively to any stimuli. Novel stimuli were a collection of environmental sampled sounds. There were 18 different novel sounds which were presented three or four times throughout the recording. Subjects were not informed of the occurrence of the novel stimuli. All stimuli were 80 dB and 1000 ms in duration. In each paradigm, 300 stimuli were binaurally presented in a random series with an interstimulus interval (ISI) of 2 s. The novelty paradigm, which did not
P3b and novelty P3 amplitudes and latencies were assessed separately with two main analyses of variance (ANOVA) repeated measures design. Group was the between-subjects factor in all the analyses. In the first analysis, there were two within-subjects factors which were 3 anteroposterior regions (frontal: F3, Fz, F4; central: C3, Cz, C4; and parietal: P3, Pz, P4) and 3 lateral regions (left: F3, C3, P3; midline: Fz, Cz, Pz; and right: F4, C4, P4). In the second analysis, 2 midtemporal sites (T3, T4) were the within-subjects factor. These analyses were done separately for the FES vs. younger controls and CS vs. older controls. If ERP components differed in both FES and CS compared to controls, they were also submitted to repeated measures ANOVA to determine the effects of chronicity free from the effects of age difference between the two groups. There were two between-subjects factors. One was the diagnosis [patients (FES and CS) vs. controls (younger and
M. Devrim-Üçok et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 30 (2006) 1426–1434
1429
Fig. 1. Event-related potential responses to target stimuli during oddball paradigm in first-episode schizophrenia patients (n = 26) and younger control subjects (n = 35).
older)] and the other one was the age [younger subjects (FES and younger controls) vs. older subjects (CS and older controls)]. The within-subjects factors were the same as above and gender was used as covariate. By this analysis both the effects of age and the effects of being chronically affected by schizophrenia on ERPs were investigated. If there was an interaction between the diagnosis and age, showing that younger and older controls did not differ in the concerned ERP, but FES and CS patients did, this was attributed to the effects of chronicity rather than age. Greenhouse–Geisser correction was applied when factors had more than two levels, with only the corrected probability values reported. Difference contrasts were used to analyze the significant main and/or interaction effects. Spearman correlation analysis was used to assess the relationships between P3b and novelty P3 parameters and clinical variables. Two-tailed p-values ≤ .05 were considered significant for correlation coefficients.
3.1.1. FES vs. younger controls FES patients showed a reduction in P3b amplitude compared to controls [F(1,59) = 4.50, p = .038] (Fig. 1, Table 2). Groups showed the expected parietocentral distribution of P3b [F (2,118) = 89.17, p = .001]. P3b amplitude was larger along the midline compared to the lateral sites [F(2,118) = 5.85, p = .007]. At temporal sites P3b amplitude was also reduced in FES [F (1,59) = 7.11, p = .01)]. Group × temporal site interaction was not significant. P3b latency did not differ between groups. P3b latency was longer in parietal region compared to central and frontal regions [F(2,118) = 7.77, p = .003], and along the lateral sites compared to midline [F(2,118) = 4.38, p = .019]. A significant group × anteroposterior site interaction [F(2,118) = 3.54, p = .049] was observed. Difference contrasts demonstrated a tendency for the P3b latency to be shorter in frontal region, whereas longer in parietal region in FES [Parietal vs. central and frontal: F(1,59) = 3.53, p = .06; central vs. frontal: F(1,59) = 3.54, p = .06].
3. Results
3.1.2. CS vs. older controls CS patients showed a reduced P3b amplitude compared to controls [F(1,52) = 27.55, p = .001] (Fig. 2, Table 2). Parietocentral distribution of the P3b [F(2,104) = 65.84, p = .001] did not differ between groups. P3b amplitude was larger along the midline compared to the lateral sites [F(2,104) = 5.53,
3.1. P3b For target detection accuracy, FES and CS patients did not differ from their controls (Table 1). Table 2 P3b and novelty P3 amplitudes and latencies
P3b Fz Cz Pz Novelty P3 Fz Cz Pz
First-episode schizophrenia
Younger controls
Amplitude
Amplitude
(n = 26) 4.9 (5.4) 7.4 (5.4) 9.3 (6.5) (n = 30) 8.4 (4.6) 10.5 (6.1) 10.7 (5.1)
Latency 306 (27) 309 (29) 322 (31) 313 (31) 310 (34) 314 (32)
(n = 35) 7.1 (4.0) 11.0 (4.8) 11.9 (5.0) (n = 36) 9.6 (4.6) 11.6 (6.0) 11.8 (5.6)
Data are given as mean (S.D.). Amplitudes in μV, latencies in ms.
Latency 315 (31) 313 (34) 315 (35) 307 (29) 308 (30) 316 (33)
Chronic schizophrenia
Older controls
Amplitude
Amplitude
(n = 22) 2.4 (3.0) 4.2 (3.0) 5.5 (3.0) (n = 26) 5.9 (4.3) 6.8 (4.1) 6.5 (3.1)
Latency 318 (33) 319 (31) 323 (43) 317 (30) 319 (28) 323 (33)
(n = 32) 7.2 (3.6) 10.1 (4.6) 10.4 (4.4) (n = 35) 10.0 (4.5) 11.6 (5.1) 10.9 (4.4)
Latency 308 (33) 309 (31) 314 (34) 312 (30) 311 (30) 317 (33)
1430
M. Devrim-Üçok et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 30 (2006) 1426–1434
Fig. 2. Event-related potential responses to target stimuli during oddball paradigm in chronic schizophrenia patients (n = 22) and older control subjects (n = 32).
p = .007]. There was a significant group × lateral site interaction [F(2,104) = 4.02, p = .025]. Difference contrasts demonstrated that P3b amplitudes reduced more at midline than lateral sites in CS [midline vs. left and right: F(1,52) = 10.10, p = .002; left vs. right: p = .3]. To eliminate amplitude differences between groups, scalp distributions were statistically reanalyzed after normalizing the P3b amplitudes using the root mean square method (McCarthy and Wood, 1985). A significant group × lateral site interaction was again found [F(2,104) = 4.40, p = .021] and contrasts demonstrated that this effect was originated primarily from the midline sites [midline vs. left and right: F(1,52) = 7.78, p = .007; left vs. right: F(1,52) = 3.11, p = .084]. P3b amplitudes at temporal sites were also reduced in CS [F(1,52) = 23.90, p = .001]. No group × temporal site effect was found. P3b latency did not differ between groups. Groups showed a longer P3b latency at parietal region compared to frontal and central regions [F(2,104) = 8.16, p = .003]. 3.1.3. FES vs. CS Schizophrenia subtypes (χ2-test), clinical scores (unpaired t-test) and medication status (neuoroleptic-naïve/free, on atypical antipsychotic, on typical antipsychotic; χ2-test) did not differ between the FES and CS patients. These analyses were done on the patients whose P3b responses were evaluated. Patients showed a reduction in P3b amplitude compared to controls [F(1,110) = 22.35, p = .001]. Older subjects showed a smaller P3b than the younger subjects [F (1,110) = 4.69, p = .037]. Most importantly, although the P3b reduction in CS compared to FES patients was larger than the reduction in older compared to younger controls, the interaction between diagnosis and age was not significant [F(1,110) = 2.06, p = .15] (Fig. 3). This finding indicated that CS and FES patients did not differ in P3b amplitude. Similar results were obtained for the temporal sites. Patients [F(1,110) = 26.84, p = .001] and older subjects [F(1,110) = 5.41, p = .022] showed a reduced P3b amplitude, and the interaction between diagnosis and age was not significant [F(1,110) = 1.70, p = .19].
3.2. Novelty P3 3.2.1. FES vs. younger controls Novelty P3 amplitudes of FES patients were not different from controls [F(1,64) = 0.88, p = .35] (Fig. 4, Table 2). Novelty P3 had a centroparietal distribution [F(2,128) = 24.28, p = .001] and this topography did not differ between groups. Novelty P3 was larger along the midline compared to lateral sites [F(2,128) = 39.73, p = .001]. Novelty P3 latencies did not differ between groups. Novelty P3 latency was longer in parietal region compared to frontal and central regions [F(2,128) = 8.43, p = .001].
Fig. 3. Event-related potential responses to target stimuli during oddball paradigm in first-episode (n = 26) and chronic schizophrenia patients (n = 22) (left), and younger (n = 35) and older control subjects (n = 32) (right).
M. Devrim-Üçok et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 30 (2006) 1426–1434
1431
Fig. 4. Event-related potential responses to novel stimuli during novelty paradigm in first-episode schizophrenia patients (n = 30) and younger control subjects (n = 36) (left), and chronic schizophrenia patients (n = 26) and older control subjects (n = 35) (right).
3.2.2. CS vs. older controls A reduction in novelty P3 amplitude was observed in CS compared to controls [F(1,59) = 14.80, p = .001] (Fig. 4, Table 2). Centroparietal distribution of novelty P3 [F(2,118) = 7.53, p = .003] did not differ between groups. Novelty P3 was larger along the midline compared to lateral sites [F(2,118) = 20.49, p = .001]. There was a significant group × lateral site interaction [F(2,118) = 7.27, p = .001]. Difference contrasts demonstrated that novelty P3 amplitudes reduced more at midline than the lateral sites in CS [midline vs. left and right: F(1,59) = 17.42, p = .001; left vs. right: p = .76]. Analysis on the normalized novelty P3 amplitudes again yielded a significant group × lateral site interaction [F(2,118) = 3.35, p = .041], reflecting a greater reduction at midline than the lateral sites [midline vs. left and right: F(1,59) = 7.71, p = .007; left vs. right: p = 1]. Novelty P3 amplitude at temporal sites was also reduced in CS [F(1,59) = 8.33, p = .005]. Novelty P3 latencies did not differ between groups. Novelty P3 latency was longer in parietal region compared to frontal and central regions [F(2,118) = 10.49, p = .001]. 3.3. Correlations with psychopathology 3.3.1. FES No correlations were found between ERP parameters and clinical severity measures, age at onset and DUP in FES. 3.3.2. CS In CS patients P3b amplitudes at Fz (r = 0.471, p = .042), F3 (r = 0.458, p = .049), and F4 (r = 0.556, p = .013) were associated with SAPS scores; the greater the positive symptoms, the greater the P3b. P3b amplitudes at F3 (r = 0.495, p = .023), and F4 (r = 0.494, p = .023) were also associated with the total BPRS scores. P3b latencies at F4 (r = 0.556, p = .013), C4 (r = 0.540,
p = .017), T4 (r = 0.563, p = .012), Pz (r = 0.669, p = .002), P3 (r = 0.535, p = .018), and P4 (r = 0.516, p = .024) were associated with the SANS scores; the greater the negative symptoms, the longer the P3b latency. Novelty P3 amplitudes at Fz (r = 0.544, p = .011), F3 (r = 0.458, p = .037), F4 (r = 0.589, p = .005), C3 (r = 0.441, p = .045), and T3 (r = 0.554, p = .009) were correlated with SAPS scores; the greater the positive symptoms the greater the novelty P3. Novelty P3 amplitudes at F3 (r = 0.460, p = .021), F4 (r = 0.484, p = .014), T3 (r = 0.506, p = .010), and T4 (r = 0.488, p = .013) were also correlated with BPRS scores. There were no significant associations between the ERP parameters and the duration of illness in CS. 4. Discussion To our knowledge the present study is the first to report on the novelty P3 in FES and to evaluate novelty P3 and P3b responses in both FES and CS. P3b amplitude reduction, which was evident not only in CS but also in FES, suggests that it is a trait marker for the illness. Our findings are consistent with previous P3b studies in FES (Brown et al., 2002; Demiralp et al., 2002; Hirayasu et al., 1998; Salisbury et al., 1998; Valkonen-Korhonen et al., 2003; Wang et al., 2003) and support the suggestion that P3b reduction is a trait-like feature of schizophrenia. Novelty P3 amplitude reduction was only found in CS which is in line with some of the previous studies (Grillon et al., 1990b; Merrin and Floyd, 1994). FES patients who were relatively free of confounds such as the long-term effects of antipsychotics and chronicity did not demonstrate novelty P3 abnormality. The neural network for target detection is distinct from that for novelty processing, although some areas are commonly activated by target and novel stimuli. Prefrontal lesions reduce
1432
M. Devrim-Üçok et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 30 (2006) 1426–1434
the novelty P3 component and the automatic response to novel stimuli, whereas they do not affect the P3b to target stimuli (Knight, 1984). Hippocampal lesions result in widespread reductions of novelty P3, with decrements being most pronounced over prefrontal regions, whereas only the frontal aspect of P3b which is considered as an instance of P3a is disrupted (Knight, 1996). Lesions involving the temporal– parietal junction reduce both novelty P3 and P3b during the novelty oddball task (Knight et al., 1989). However, a recent event-related functional magnetic resonance imaging study have shown that when novel events occurred outside of attentional focus, as it was in the present study, the activated regions were confined to the prefrontal cortex and hippocampus (Yamaguchi et al., 2004). When subjects ignored the incoming stimuli, novel events would not be actively processed aside from the initial automatic orienting (Friedman et al., 1998). In this study novelty P3 was elicited during passive ignore condition. Since the attention of the subjects was not controlled, we can not be sure that they did not attend to the stimuli. However, we supposed that by using a passive novelty paradigm, we had the chance to eliminate more or less the activities related to discrimination or classification of the stimuli. In the present study novelty P3 reduction was observed only in CS. Therefore, we suggest that the prefrontal– hippocampal system that is thought to be involved in generating automatic orienting response to novel events is disrupted in chronic stages of schizophrenia, whereas at the onset of illness it is preserved. Our suggestion is consistent with some of the imaging studies reporting normal prefrontal and hippocampal structure in FES, but lower volumes of gray matter in these regions in CS (Molina et al., 2004; Razi et al., 1999). However, there are also studies demonstrating smaller hippocampal and prefrontal gray matter volumes in FES (Hirayasu et al., 2001; Velakoulis et al., 1999). The absence of novelty P3 abnormality in patients with FES suggests a degenerative process that occurs after the onset of schizophrenia. It remains to be determined whether the novelty P3 reduction in chronic schizophrenia is related to the disease process itself or to a secondary effect, as long-term antipsychotic treatment. In contrast to our finding of normal novelty P3 in FES, Valkonen-Korhonen et al. (2003) reported a P3a reduction in psychotic first-episode patients. This could be explained firstly by the differences in patient groups. Valkonen-Korhonen et al. (2003) studied a heterogeneous group of psychotic first-episode patients in which only approximately half of them were diagnosed as schizophreniform disorder or schizophrenia. However, in our study all the first-episode patients were diagnosed as schizophrenia. Secondly, the deviant stimuli that were utilized were different. Our deviant stimuli were novel environmental sounds, whereas pure tones were applied in the mentioned study. Novel sounds were shown to be more distracting and to elicit a larger P3 than the deviant pure tones in normal subjects (Grillon et al., 1990a). Therefore, it is possible that, even though FES patients have some problems in automatic orienting of attention, more distracting deviant stimuli somehow compensate this defect and elicit a normal response.
P3b amplitudes in CS patients were not different from FES patients. This observation suggests that there is no further deterioration after illness onset. Additionally, we could not find a correlation between the P3b amplitude and illness duration in CS patients. Our findings are in line with the studies reporting similar P3b amplitudes in FES and CS patients (Brown et al., 2002; Hirayasu et al., 1998). However, there were several studies which have reported P3b amplitude to be inversely correlated with illness duration (MartinLoeches et al., 2001; Mathalon et al., 2000b; Olichney et al., 1998). The present and the mentioned studies are crosssectional, and therefore only suggestive of longitudinal processes. Longitudinal data are needed to disentangle the effects of chronicity on P3b. We observed symmetrical temporal site reduction in P3b in both FES and CS. Some studies reported a greater left than right temporal P3b amplitude reduction (McCarley et al., 1993, 2002; Salisbury et al., 1998) in contrast to others reporting symmetric reduction (Ford et al., 1994; Pfefferbaum et al., 1989). It is suggested that neuroanatomical differences between patients studied by different laboratories might explain the difference in P3b asymmetry (Ford et al., 2000). Since we did not have the imaging data of our patients we can not comment on this suggestion. Several limitations about the present study should be noted. First, although the duration was very short, majority of the patients were taking antipsychotic medication which made it difficult to eliminate their possible effects on ERPs. Some studies suggest that medication may increase P3b amplitude in schizophrenia (Coburn et al., 1998; Gonul et al., 2003; Umbricht et al., 1998), whereas others suggest that medication has no effect on P3b amplitude (Ford et al., 1994; Pfefferbaum et al., 1989). Pfefferbaum et al. (1989) also reported that medication has no effect on automatically elicited P3. Therefore, it seems that medication can be discarded as a distorting factor for P3 responses. Second, the duration of stimuli we used was longer than the other studies. Long duration stimuli lead to stimulus-off potentials that can affect the response to subsequent stimuli if the ISI is short. However, our ISI of 2 s likely fell outside the latency range of any off potentials (Bullock et al., 1994; Picton et al., 1978). It was shown that long stimuli elicited sustained negative potentials (Keidel, 1971; Picton et al., 1978). Since in this study the EEG was recorded with a high-pass filter of 0.5 Hz, the attenuation of the scalp recorded P3 potentials through algebraic summation with the sustained negativity would be minimal. These sustained negative potentials could have an effect on the generation of novelty P3 and P3b by increasing the cortical excitability (Birbaumer et al., 1990; Ergenoglu et al., 1998). However, it is not known whether their effect on cortical excitability is different in schizophrenia patients and controls. In a previous study we also used these relatively long-duration stimuli and observed P3b reduction in FES (Demiralp et al., 2002). Third, our novel stimuli were not unique and each was repeated three or four times which could make our findings difficult to compare with the previous studies. However, with recurrence of novel events a reduction in novelty P3 amplitude and a shift from a frontally
M. Devrim-Üçok et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 30 (2006) 1426–1434
to a parietally oriented topography were reported, whether the eliciting novel events were a sequence of unique novel stimuli (Friedman and Simpson, 1994), repetitions of a single novel event (Knight, 1984), or repetitions of identical novel sounds (Cycowicz et al., 1996). More importantly, Friedman et al. (1998) showed that the novelty P3 amplitude decrements to repetition of identical and recurrence of unique novel events were similar. 5. Conclusion Based on our results, P3b amplitude reduction can be considered as a trait marker of schizophrenia. Novelty P3 amplitude reductions present in patients with CS, are not found at the onset of illness. Automatic orienting of attention processes indexed by novelty P3 seems to be unaffected at the early stage of schizophrenia. Assessment of P3b and novelty P3 potentials in these FES patients longitudinally will elucidate how these potentials are affected over time from schizophrenia onset. Acknowledgments This work was supported by the Research Fund of The University of Istanbul. Project numbers: 173/15012004 and B-971/10052001. References Alain C, Bernstein LJ, Cortese F, Yu H, Zipursky RB. Deficits in automatically detecting changes in conjunction of auditory features in patients with schizophrenia. Psychophysiology 2002;39:599–606. Andreasen NC. The Scale for the Assessment of Negative Symptoms (SANS). Iowa City, IA: University of Iowa; 1983. Andreasen NC. The Scale for the Assessment of Positive Symptoms (SAPS). Iowa City, IA: University of Iowa; 1984. Birbaumer N, Elbert T, Canavan AGM, Rockstroh B. Slow potentials of the cerebral cortex and behavior. Physiol Rev 1990;70:1–41. Blackwood DH, Whalley LJ, Christie JE, Blackburn IM, St Clair DM, McInnes A. Changes in auditory P3 event-related potential in schizophrenia and depression. Br J Psychiatry 1987;150:154–60. Blackwood DH, St Clair DM, Muir WJ, Duffy JC. Auditory P300 and eye tracking dysfunction in schizophrenic pedigrees. Arch Gen Psychiatry 1991; 48:899–909. Brown KJ, Gonsalvez CJ, Harris AWF, Williams LM, Gordon E. Target and non-target ERP disturbances in first episode vs. chronic schizophrenia. Clin Neurophysiol 2002;113:1754–63. Bullock TH, Karamursel S, Achimowicz JZ, McClune MC, Basar-Eroglu C. Dynamic properties of human visual evoked and omitted stimulus potentials. Electroencephalogr Clin Neurophysiol 1994;91:42–53. Coburn KL, Shillcutt SD, Tucker KA, Estes KM, Brin FB, Merai P, et al. P300 delay and attenuation in schizophrenia: reversal by neuroleptic medication. Biol Psychiatry 1998;44:466–74. Cycowicz YM, Friedman D, Rothstein M. An ERP developmental study of repetition priming by auditory novel stimuli. Psychophysiology 1996;3: 680–90. Demiralp T, Ucok A, Devrim M, Isoglu-Alkac U, Tecer A, Polich J. N2 and P3 components of event-related potential in first-episode schizophrenic patients: scalp topography, medication, and latency effects. Psychiatry Res 2002;111:167–79. Donchin E, Coles MG. Is the P300 component a manifestation of context updating? Behav Brain Sci 1988;11:357–74.
1433
Ergenoglu T, Demiralp T, Beydagi H, Karamursel S, Devrim M, Ermutlu N. Slow cortical potential shifts modulate P300 amplitude and topography in humans. Neurosci Lett 1998;251:61–4. First MB, Spitzer RL, Gibbon M, Williams JBW. Structured Clinical Interview for DSM-IV Axis I disorders (SCID-I), Clinical Version. Washington, DC: American Psychiatric Press; 1997. Ford JM, Pfefferbaum A, Roth WT. P3 and schizophrenia. Ann N Y Acad Sci 1992;658:146–62. Ford JM, White PM, Csernansky JG, Faustman WO, Roth WT, Pfefferbaum A. ERPs in schizophrenia: effects of antipsychotic medication. Biol Psychiatry 1994;36:153–70. Ford JM, Mathalon DH, Marsh L, Faustman WO, Harris D, Hoff AL, et al. P300 amplitude is related to clinical state in severely and moderately ill patients with schizophrenia. Biol Psychiatry 1999a;46:94–101. Ford JM, Roth WT, Menon V, Pfefferbaum A. Failures of automatic and strategic processing in schizophrenia: comparisons of event-related brain potential and startle blink modification. Schizophr Res 1999b;37:149–63. Ford JM, Mathalon DH, White PM, Pfefferbaum A. Left temporal deficit of P300 in patients with schizophrenia: effects of task. Int J Psychophysiol 2000;38:71–9. Friedman D, Simpson GV. ERP amplitude and scalp distribution to target and novel events: effects of temporal order in young, middle-aged and older adults. Cogn Brain Res 1994;2:49–63. Friedman D, Cornblatt B, Vaughan Jr H, Erlenmeyer-Kimling L. Auditory event-related potentials in children at risk for schizophrenia: the complete initial sample. Psychiatry Res 1988;26:203–21. Friedman D, Kazmerski VA, Cycowicz YM. Effects of aging on the novelty P3 during attend and ignore oddball tasks. Psychophysiology 1998;35: 508–20. Friedman D, Cycowicz YM, Gaeta H. The novelty P3: an event-related brain potential (ERP) sign of the brain's evaluation of novelty. Neurosci Biobehav Rev 2001;25:355–73. Frodl T, Meisenzahl EM, Muller D, Greiner J, Juckel G, Leinsinger G, et al. Corpus callosum and P300 in schizophrenia. Schizophr Res 2001;49: 107–19. Gonul AS, Suer C, Coburn K, Ozesmi C, Oguz A, Yilmaz A. Effects of olanzapine on auditory P300 in schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 2003;27:173–7. Grillon C, Courchesne E, Ameli R, Elmasian R, Braff DL. Effects of rare nontarget stimuli on brain electrophysiological activity and performance. Int J Psychophysiol 1990a;3:257–67. Grillon C, Courchesne E, Ameli R, Geyer MA, Braff DL. Increased distractibility in schizophrenic patients. Electrophysiologic and behavioral evidence. Arch Gen Psychiatry 1990b;47:171–9. Hirayasu Y, Asato N, Ohta H, Hokama H, Arakaki H, Ogura. Abnormalities of auditory event-related potentials in schizophrenia prior to treatment. Biol Psychiatry 1998;43:244–53. Hirayasu Y, Tanaka S, Shenton ME, Salisbury DF, DeSantis MA, Levitt JJ, et al. Prefrontal gray matter volume reduction in first episode schizophrenia. Cereb Cortex 2001;11:374–81. Keidel WD. D.C.-potentials in the auditory evoked response in man. Acta Otolaryngol 1971;71:242–8. Kidogami Y, Yoneda H, Asaba H, Sakai T. P300 in first degree relatives of schizophrenics. Schizophr Res 1991;6:9–13. Knight RT. Decreased response to novel stimuli after prefrontal lesions in man. Electroencephalogr. Clin Neurophysiol 1984;59:9–20. Knight RT. Contribution of human hippocampal region to novelty detection. Nature 1996;38:256–9. Knight RT, Scabini D, Woods DL, Clayworth CC. Contributions of temporal– parietal junction to the human auditory P3. Brain Res 1989;502:109–16. Lukoff D, Nuechterlein KH, Ventura J. Manual for the Expanded Brief Psychiatric Rating Scale. Schizophr Bull 1986;12:594–602. Martin-Loeches M, Molina V, Munoz F, Hinojosa JA, Reig S, Desco M, et al. P300 amplitude as a possible correlate of frontal degeneration in schizophrenia. Schizophr Res 2001;49:121–8. Mathalon DH, Ford JM, Pfefferbaum A. Trait and state aspects of P300 amplitude reduction in schizophrenia: a retrospective longitudinal study. Biol Psychiatry 2000a;47:434–49.
1434
M. Devrim-Üçok et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 30 (2006) 1426–1434
Mathalon DH, Ford JM, Rosenbloom M, Pfefferbaum A. P300 reduction and prolongation with illness duration in schizophrenia. Biol Psychiatry 2000b; 47:413–27. McCarthy G, Wood CC. Scalp distributions of event-related potentials: an ambiguity associated with analysis of variance models. Electroencephalogr Clin Neurophysiol 1985;62:203–8. McCarley RW, Faux SF, Shenton ME, Nestor PG, Adams J. Event-related potentials in schizophrenia: their biological and clinical correlates and a new model of schizophrenic pathophysiology. Schizophr Res 1991;4:209–31. McCarley RW, Shenton ME, O'Donnell BF, Faux SF, Kikinis R, Nestor PG, et al. Auditory P300 abnormalities and left posterior superior temporal gyrus volume reduction in schizophrenia. Arch Gen Psychiatry 1993;50:190–7. McCarley RW, Salisbury DF, Hirayasu Y, Yurgelun-Todd DA, Tohen M, Zarate C, et al. Association between smaller left posterior superior temporal gyrus volume on magnetic resonance imaging and smaller left temporal P300 amplitude in first-episode schizophrenia. Arch Gen Psychiatry 2002;59: 321–31. Merrin EL, Floyd TC. P300 responses to novel auditory stimuli in hospitalized schizophrenic patients. Biol Psychiatry 1994;36:527–42. Michie PT, Innes-Brown H, Todd J, Jablensky AV. Duration mismatch negativity in biological relatives of patients with schizophrenia spectrum disorders. Biol Psychiatry 2002;52:749–58. Molina V, Sanz J, Sarramea F, Benito C, Palomo T. Lower prefrontal gray matter volume in schizophrenia in chronic but not in first episode schizophrenia patients. Psychiatry Res 2004;131:45–56. Olichney JM, Iragui VJ, Kutas M, Nowacki R, Morris S, Jeste DV. Relationship between auditory P300 amplitude and age of onset of schizophrenia in older patients. Psychiatry Res 1998;79:241–54. Pfefferbaum A, Ford JM, White PM, Roth WT. P3 in schizophrenia is affected by stimulus modality, response requirements, medication status, and negative symptoms. Arch Gen Psychiatry 1989;46:1035–44. Picton TW, Woods DL, Proulx GB. Human auditory sustained potentials: I. The nature of the response. Electroencephalogr Clin Neurophysiol 1978;45: 186–97. Polich J, Kok A. Cognitive and biological determinants of P300: an integrative review. Biol Psychol 1995;41:103–46.
Razi K, Greene KP, Sakuma M, Ge S, Kushner M, DeLisi LE. Reduction of the parahippocampal gyrus and the hippocampus in patients with chronic schizophrenia. Br J Psychiatry 1999;174:512–9. Roxborough H, Muir WJ, Blackwood DH, Walker MT, Blackburn IM. Neuropsychological and P300 abnormalities in schizophrenics and their relatives. Psychol Med 1993;23:305–14. Salisbury DF, Shenton ME, Sherwood AR, Fischer IA, Yurgelun-Todd DA, Tohen M, et al. First-episode schizophrenic psychosis differs from firstepisode affective psychosis and controls in P300 amplitude over left temporal lobe. Arch Gen Psychiatry 1998;55:173–80. Schall U, Catts SV, Karayanidis F, Ward PB. Auditory event-related potential indices of fronto-temporal information processing in schizophrenia syndromes: valid outcome prediction of clozapine therapy in a three-year follow-up. Int J Neuropsychopharmacol 1999;2:83–93. Turetsky B, Colbath EA, Gur RE. P300 subcomponent abnormalities in schizophrenia: II. Longitudinal stability and relationship to symptom change. Biol Psychiatry 1998;43:31–9. Ucok A, Polat A, Cakir S, Genc A, Turan N. Duration of untreated psychosis may predict acute treatment response in first-episode schizophrenia. J Psychiatr Res 2004;38:163–8. Umbricht D, Javitt D, Novak G, Bates J, Pollack S, Lieberman J, et al. Effects of clozapine on auditory event-related potentials in schizophrenia. Biol Psychiatry 1998;44:716–25. Valkonen-Korhonen M, Purhonen M, Tarkka IM, Sipila P, Partanen J, Karhu J, et al. Altered auditory processing in acutely psychotic never-medicated firstepisode patients. Brain Res Cogn Brain Res 2003;17:747–58. Velakoulis D, Pantelis C, McGorry PD, Dudgeon P, Brewer W, Cook M, et al. Hippocampal volume in first-episode psychoses and chronic schizophrenia: a high-resolution magnetic resonance imaging study. Arch Gen Psychiatry 1999;56:133–41. Wang J, Hirayasu Y, Hiramatsu K, Hokama H, Miyazato H, Ogura C. Increased rate of P300 latency prolongation with age in drug-naive and first-episode schizophrenia. Clin Neurophysiol 2003;114:2029–35. Yamaguchi S, Hale LA, D'Esposito M, Knight RT. Rapid prefrontal– hippocampal habituation to novel events. J Neurosci 2004;24:5356–63.