- Email: [email protected]
Visual P3 amplitude modulation deficit in schizophrenia is independent of duration of illness
Schizophrenia Research 130 (2011) 210–215
Contents lists available at ScienceDirect
Schizophrenia Research j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / s c h r e s
Visual P3 amplitude modulation deficit in schizophrenia is independent of duration of illness Andres H. Neuhaus a,⁎, Eric Hahn a, Constanze Hahn b, Thi Minh Tam Ta a, Carolin Opgen-Rhein a, Carsten Urbanek a, Michael Dettling a a b
Department of Psychiatry and Psychotherapy, Charité University Medicine, Campus Benjamin Franklin, Berlin, Germany Department of Biopsychology, Ruhr University Bochum, Germany
a r t i c l e
i n f o
Article history: Received 13 September 2010 Received in revised form 8 February 2011 Accepted 8 February 2011 Available online 5 March 2011 Keywords: P3 P300 Event-related potentials Visual attention Attention Network Test Schizophrenia Trait marker
a b s t r a c t Background: In the search for markers of schizophrenia, functional deficits during inhibition have been a major focus. In previous studies, we found a reduced amplitude modulation of the visual P3 component of the event-related potential (ERP) in schizophrenic patients during inhibition in the Attention Network Test (ANT). The objective of the present study was to explore whether this deficit exhibits properties of a trait or state marker of schizophrenia. Methods: Eighteen recent onset inpatients and eighteen chronic schizophrenic outpatients as well as 36 healthy controls, including a young adult and an old adult group to match recent onset and chronic illness groups for age and sex, were included. Participants were tested with ANT while 32-channel electroencephalogram was recorded and visual P3 amplitudes were analyzed. Amplitude modulation was defined as the variation of P3 amplitude at Pz as a function of ANT flanker conditions. Results: There were no significant behavioral between-group differences in terms of alerting, orienting, and inhibition. Mean visual P3 was significantly lower in schizophrenic patients than in healthy controls. Parietal P3 amplitude was significantly less modulated in both recent onset (− 0.035) and chronic schizophrenic patients (− 0.081) compared with young (− 0.588; p b 0.05) and older healthy controls, respectively (− 0.556; p b 0.05). No correlations were obtained between P3 modulation and clinical or demographic variables. Conclusion: The results provide evidence that the observed deficit of visual P3 amplitude modulation is independent of duration of illness and age and may contain properties of a trait marker of schizophrenia. © 2011 Elsevier B.V. All rights reserved.
1. Introduction The identification of neurocognitive markers of schizophrenic illness has attracted extensive research in the past years. Among other neurocognitive deficits in schizophrenia, those related to behavioral inhibition have received considerable attention. Inhibitory deficits were reported in a wide range of tasks including the Stroop task (e.g. Carter et al., 1997; Hepp et al., 1996) or the Go/NoGo paradigm (e.g. Ehlis et al., 2007; Ford et al., 2004). In line with that research, our group has recently identified and replicated a functional deficit in schizophrenic patients during inhibition in the Attention Network Test (ANT; Neuhaus et al., 2007, 2010a). ANT has been introduced to allow for behavioral assessment of alerting, orienting, and inhibition via specific reaction time patterns (Fan et al., 2002). Alerting in the context of ANT refers to the ability to phasically increase response preparation in reaction to an external ⁎ Corresponding author at: Department of Psychiatry and Psychotherapy, Charité University Medicine Berlin, Campus Benjamin Franklin, Eschenallee 3, 14050 Berlin, Germany. Tel.: +49 30 8445 8412; fax: +49 30 8445 8393. E-mail address: [email protected] (A.H. Neuhaus). 0920-9964/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.schres.2011.02.009
warning stimulus. Orienting refers to the beneficial effect of spatial cueing for behavioral performance. Inhibition as measured with ANT refers to the resolution of a flanker compatibility conflict and has been associated with anterior cingulate activation in functional imaging and electrophysiological source localization studies (Fan et al., 2005; Neuhaus et al., 2007). Given that anterior cingulate has been consistently identified as hypoactive in schizophrenia (Minzenberg et al., 2009), this disorder has been associated with significantly altered surrogate parameters of inhibition during ANT at the behavioral level (Urbanek et al., 2009; Wang et al., 2005), using event-related potentials (ERP; Neuhaus et al., 2010a), and in genetic studies (Opgen-Rhein et al., 2008). The electrophysiological characterization of inhibition in the ANT revealed a parietal modulation of the P3 component as a function of target class in a normative study (Neuhaus et al., 2010b). In another study, the same ERP pattern was obtained in healthy controls as well as in depressive patients, but not in schizophrenic patients (Neuhaus et al., 2010a), suggesting an illness-specific deficit. Our results are consistent with previous studies that employed variants of a Go/NoGo paradigm and identified diminished parietal P3 amplitude modulations, i.e. Go/NoGo differences, in acute (Pass et al., 1980) and in
A.H. Neuhaus et al. / Schizophrenia Research 130 (2011) 210–215
atypical antipsychotic medication and were free from benzodiazepine co-medication for at least two weeks. Schizophrenic patients consisted of a group of 18 post-acute inpatients with recent onset schizophrenia (DOI less than 5 years; duration of post-acute state, i.e. time interval between admission and testing, between 6 and 12 weeks) and a group of 18 stable outpatients with chronic schizophrenia (DOI at least 10 years). Ratings of the Positive and Negative Syndrome Scale (PANSS) were conducted on the day of testing. Thirty-six age-matched healthy subjects (15 f, 21 m) served as controls. None of these participants had a history of substance abuse other than tobacco smoking, nor a history of psychiatric disorder according to DSM-IV as determined by a semi-structured clinical interview (SKID I/II), or a history of severe medical or neurological disorder. All control subjects were free from pharmacological treatment. All participants were right-handed and reported normal or corrected-to-normal vision. Table 1 summarizes demographic and clinical data. All subjects gave written, informed consent before participating in this study. The study protocol was approved by the local ethics committee and the study was conducted in accordance with the Declaration of Helsinki.
Table 1 Summary of demographic and clinical data (mean ± standard deviation). Schizophrenia
N (f/m) Age [years] DOI [years] N episodes PANSS P PANSS N PANSS G CPZ eq. [mg/day]
Controls
p
Recent onset
Chronic
Recent onset Chronic matched matched
18 (7/11) 28.44 ± 5.6 2.91 ± 2.3 1.53 ± 0.9 12.44 ± 3.9 17.33 ± 5.1 36.43 ± 8.6 503.67 ± 357.0
18 (8/10) 43.17 ± 6.3 15.06 ± 5.1 4.63 ± 3.2 11.94 ± 3.1 15.35 ± 4.8 31.19 ± 8.4 537.88 ± 381.4
18 (7/11) 27.39 ± 2.7 – – – – – –
18 (8/10) 40.94 ± 7.3 – – – – – –
– n.s.a b0.001b 0.001b n.s.b n.s.b n.s.b n.s.b
DOI, duration of illness; PANSS, Positive and Negative Syndrome Scale (P, positive; N, negative; G, general); CPZ eq., chlorpromazine equivalents. a For both t-tests between recent onset schizophrenia and matched controls and between chronic schizophrenia and matched controls. b t-tests between recent onset and chronic schizophrenia.
chronic schizophrenic patients (Knott et al., 1999). Taken together, these studies suggest that the parietal P3 modulation deficit may be a trait marker of schizophrenia; however, this preliminary conclusion is derived from only two studies that used different designs including different patient selection criteria and different paradigms. In the present study, we sought to investigate the parietal P3 modulation as a potential trait marker by asking whether the P3 modulation deficit depends on the duration of illness (DOI). For this purpose, in- and outpatient samples were assessed at different stages of schizophrenic illness within the same study design.
2.2. Task design An exhaustive description of the task is given elsewhere (Fan et al., 2002; Neuhaus et al., 2010b). Briefly, ANT combines cued detection with a flanker-type paradigm. Target stimuli consisted of five horizontally arranged arrows or lines presented above or below fixation. By left or right button press, subjects had to indicate the direction of the central arrow irrespective of flanking conditions. Flankers were either lines (neutral target) or arrows pointing to the same (compatible) or to the opposite direction (incompatible); a behavioral estimate of inhibition is obtained when subtracting mean reaction times (RTs) of compatible from incompatible trials. Cue stimuli preceded target presentation by 500 ms to direct attention in time only (alerting) or in space and time (orienting); behavioral estimates of alerting and orienting are obtained when subtracting mean RTs of trials following double cues (above and below fixation) from the no cue condition and when subtracting mean RTs of trials following spatial cues (above or below fixation) from the center cue condition, respectively. Target presentation had a maximum
2. Methods 2.1. Subjects Thirty-six patients (15 f, 21 m) meeting DSM-IV criteria for schizophrenia participated in this study. None of the included patients had a history of any severe medical or neurological disorder and never underwent electroconvulsive therapy. All patients received oral
+ T1=400-1600 ms
Cue
*
211
+
No cue
*
Center cue
*+ *
Double cue
*+
+
Spatial cue
*
+ 100 ms +
+
+
Neutral
+
+
Compatible
+
+
Incompatible
400 ms
Target + ≤ 1700 ms RT≤ + 3500 ms- RT- T1 Σ 4000 ms Fig. 1. Attention Network Test schematic.
212
A.H. Neuhaus et al. / Schizophrenia Research 130 (2011) 210–215
Table 2 Summary of behavioral and parietal P3 results (mean ± standard deviation). Schizophrenia
RT [ms] Accuracy [%] Alerting [ms] Orienting [ms] Inhibition [ms] P3neutral [μV] P3compatible [μV] P3incompatible [μV] P3 slope a b
Controls
p
Recent onset
Chronic
Recent onset matched
Chronic matched
612.58 ± 118.4 95.58 ± 6.7 53.57 ± 35.1 57.12 ± 32.7 109.26 ± 43.8 3.88 ± 2.6 3.89 ± 2.1 3.82 ± 2.1 − 0.035 ± 0.91
653.95 ± 119.7 98.17 ± 1.4 35.11 ± 48.5 70.53 ± 27.7 112.47 ± 58.3 3.97 ± 2.1 3.69 ± 1.7 3.81 ± 1.8 − 0.081 ± 0.62
538.95 ± 58.6 98.98 ± 1.0 43.73 ± 26.6 51.05 ± 16.5 93.62 ± 34.8 4.68 ± 1.7 4.68 ± 2.1 3.51 ± 1.6 − 0.588 ± 0.60
583.61 ± 78.9 98.90 ± 1.2 49.41 ± 29.9 57.42 ± 31.8 111.67 ± 27.9 4.56 ± 1.9 3.91 ± 1.9 3.44 ± 1.9 − 0.556 ± 0.69
n.s.a b0.05b n.s.a n.s.a n.s.a n.s.a n.s.a n.s.a b0.05a
For both t-tests between recent onset schizophrenia and controls and between chronic schizophrenia and controls. Only for t-test between recent onset schizophrenia and their controls.
duration of 1700 ms and was followed by a variable fixation period immediately after response. The duration of each trial added up to 4000 ms. A total of 288 pseudo-randomized trials (4 cues × 3 targets× 8 repetitions per block× 3 blocks) without feedback was presented. Subjects were instructed to respond as fast and as accurately as possible. The task is illustrated in Fig. 1.
accuracy was significantly different between recent onset schizophrenia and young controls. Accuracy and mean RT showed a trendlevel negative correlation in recent onset schizophrenia patients only (r = −0.410; p = 0.091). Table 2 summarizes mean behavioral data. Fig. 2 illustrates mean RTs by cue and target conditions. 3.2. Parietal P3 modulation
2.3. ERP acquisition EEG was recorded with 32 Ag/AgCl electrodes positioned according to the extended International 10/20 system. Electrode impedances were kept below 5 kΩ. EEG was assessed with a Neuroscan SynAmps (El Paso, TX, US) with a sampling rate of 250 Hz and an analog high-pass filter set at 0.1 Hz. EEG analysis included ocular artifact correction using independent component analysis (Jung et al., 2000), re-referencing to average reference, artifact tagging (≥80 μV at any electrode), data segmentation for different target conditions (800 ms pre-stimulus to 800 ms post-stimulus), artifact rejection, baseline correction (−800 to −500 ms prior to target onset), and averaging a minimum of 30 artifactfree and correctly responded trials (within 1000 ms) for each analyzed experimental condition. P3 was then identified at Pz as the most positive deflection 300 to 600 ms after target onset and consecutively determined at Fz, Cz, and Pz as peak amplitude measure between 300 and 600 ms post target stimulus. Regression slopes were calculated to determine P3 amplitude modulation as a function of target class that were factorized as 0 (neutral), 1 (compatible), and 2 (incompatible). 2.4. Statistical analysis Statistical analyses were conducted with PASW Statistics 18 (Chicago, IL, US). Demographic data and behavioral data were analyzed with t-tests as appropriate. Examination of ERP data was performed with repeated measures analysis of variance. Target conditions (neutral, compatible, and incompatible) and midline electrodes (Fz, Cz, and Pz) were entered as within-subject factors and diagnostic groups (schizophrenia vs. controls) as well as stage of illness (recent onset vs. chronic schizophrenia and their respective control groups) were entered as between-subject factors resulting in a 3 × 3 × 2 × 2 design for P3 analysis. Post hoc analyses including comparison of individual regression slopes were computed as t-tests for paired or independent samples, as required. Correlations were computed as Pearson correlations. All tests were performed as twotailed tests with an alpha level set at p b 0.05. 3. Results 3.1. Behavioral performance There were no significant differences between groups regarding behavioral ANT effects of alerting, orienting, and inhibition. Mean
Repeated measures ANOVA revealed a significant main effect of ‘electrode’ (F2, 136 = 37.991; p b 0.001) and significant interactions of ‘electrode × diagnostic group’ (F2, 136 = 4.473; p = 0.013), ‘target condition × electrode’ (F4, 272 = 3.717; p = 0.006), and ‘target condition × electrode × diagnostic group’ (F4, 272 = 2.410; p = 0.049). Furthermore, a significant main effect of group on mean P3 was found (p = 0.019) indicating significantly lower mean P3 amplitude in schizophrenia. Of note, no interaction was obtained that involved the factor ‘stage of illness’ (recent onset vs. chronic schizophrenia and their respective control groups). Grand average curves stratified by diagnostic and age groups are illustrated in Fig. 3. Regarding the effect of ‘electrode’, P3 amplitudes across the whole sample were highest at Pz (3.99 ± 1.8 μV), intermediate at Cz (3.26 ± 2.1 μV), and lowest at Fz (2.07 ± 1.4 μV; all T71 N 3.172; all p b 0.005). When stratified for diagnostic groups (‘electrode × diagnostic group’), P3 amplitudes of both healthy controls and schizophrenic patients showed a similar pattern, however, there was no significant difference between P3 amplitude at Cz (4.03 ± 2.2 μV) and Pz (4.13 ± 1.7 μV; T35 = 0.314; p = 0.756) in healthy controls. The interaction of ‘target condition × electrode’ was further pursued by comparing P3 amplitudes following different target conditions at each midline electrode across the whole sample. Here, significant differences emerged only at electrode Pz between neutral and incompatible targets (T71 = 3.570; p = 0.001) and between compatible and incompatible targets (T71 = 2.561; p = 0.013), indicating a significant P3 modulation in inhibition trials only. To further characterize this parietal P3 amplitude modulation, P3 regression slopes were calculated as a function of target class separately for each group (‘target condition × electrode × diagnostic group’). Here, schizophrenic patients as a group exhibited a significantly less modulated parietal P3 amplitude (−0.05 ± 0.8) than healthy controls (−0.57 ± 0.6; T70 = −3.087; p = 0.003). Interestingly, both recent onset schizophrenic patients (−0.03 ± 0.9) and chronic schizophrenic patients (− 0.08 ± 0.6) showed a significantly shallower parietal P3 slope compared to their respective control groups, i.e. young (−0.59 ± 0.6; T34 = −2.142; p = 0.039) and old controls (−0.56 ± 0.7; T34 = −2.180; p = 0.036). Parietal P3 amplitudes and regression slopes are summarized in Table 2. There were no correlations of P3 slope with age (r =0.003; p=0.987) in healthy controls or with age (r=0.222; p= 0.194), duration of illness (r= −0.057; p =0.740), number of episodes (r= −0.230; p =0.213), PANSS scores (positive: r = 0.144; p = 0.544; negative: r = 0.298;
A.H. Neuhaus et al. / Schizophrenia Research 130 (2011) 210–215
213
Schizophrenia
Controls
Recent onset
Reaction time [ms]
800 700 600 500 400
Chronic
Reaction time [ms]
800 700 600 500 400 Neutral
Compatible
Incompatible
Neutral
Compatible
Targets No cue
Incompatible
Targets Center cue
Double cue
Spatial cue
Fig. 2. Mean RTs stratified by cue and target conditions for schizophrenia patients (left column) and healthy controls (right column). Recent onset patients and young controls are shown in the top row, chronic patients and old controls are shown in the bottom row.
p= 0.139; general: r =0.291; p =0.178), or chlorpromazine equivalents (r =0.323; p =0.116) in schizophrenia patients. 4. Discussion We conducted a study on ERP correlates of inhibition as measured with the ANT in two independent samples of schizophrenic patients. Post-acute inpatients with recent onset schizophrenia and outpatients
Recent onset Schizophrenia
[µV] 4
with chronic schizophrenia were compared with age-matched healthy control groups in order to explore the potential influence of duration of illness. Whereas P3 amplitude was clearly modulated in both healthy control groups, both recent onset and chronic schizophrenic patient groups lacked parietal P3 amplitude modulation during neutral, compatible, and incompatible trials. No significant behavioral differences of ANT effects were found between schizophrenic patients and both control groups which
Recent onset matched Controls
[µV] 4 2
2
-600 -400 -200
Chronic Schizophrenia
200 400 600 [ms]
-2
-2
-4
-4
[µV] 4
Chronic matched Controls
[µV] 4
2
2
-2
-2
-4
-4
Neutral targets
Compatible targets
Incompatible targets
Fig. 3. Grand average ERP at parietal midline electrode Pz stratified by condition for each experimental group. Target onset is at 0 ms. During inhibition trials, there is no modulation of parietal P3 amplitude in both recent onset schizophrenia and chronic schizophrenia (left) whereas a P3 amplitude modulation is clearly present in both recent onset matched controls and chronic matched controls (right).
214
A.H. Neuhaus et al. / Schizophrenia Research 130 (2011) 210–215
confirms findings from the majority of previous studies (AhnAllen et al., 2008; Neuhaus et al., 2007, 2010a; Opgen-Rhein et al., 2008; Urbanek et al., 2009). The relatively low accuracy of recent onset schizophrenia patients could be attributable to a speed-accuracy-tradeoff given the negative correlation between those measures, although the latter finding only reached borderline significance. At the neurophysiological level, our study showed that parietal P3 amplitude was significantly modulated as a function of target class in both healthy control groups, but not in recent onset or chronic schizophrenia patients. The pattern of parietal modulation of P3 amplitude in healthy controls and the failure to modulate P3 in schizophrenia replicate findings from our previous studies (Neuhaus et al., 2007, 2010a). These findings are extended in that we found comparable patterns of P3 modulation in young and older controls, thus arguing against an influence of age on P3 modulation with target class, which is also supported by correlation analysis. Moreover, the failure of both patient groups to modulate P3 amplitude provides evidence that this deficit is independent of duration of illness. Likewise, deficient P3 modulation could not be accounted for by age, antipsychotic medication, or clinical disparities such as number of episodes or duration of illness. The fact that duration of illness does not seem to affect the deficient P3 modulation in our patient sample is well in line with other findings. Although it has been found that a longer DOI is associated with decreased performance of frontal lobe functions (Liddle and Morris, 1991), the majority of studies arrive at the conclusion that neurocognitive deficits, once present at the onset of schizophrenia, do not further deteriorate in the course of illness (DeLisi et al., 1995; Goldberg et al., 1993; Heaton et al., 2001). A wealth of studies has investigated absolute P3 amplitudes in schizophrenia that are usually obtained using an auditory oddball paradigm. The P3 amplitude deficit in schizophrenia is a longstanding and most consistent finding (e.g. Braff, 1993; Ford et al., 2004; Roth and Cannon, 1972; van der Stelt et al., 2005). However, despite the reliability of P3 abnormalities in schizophrenia, this deficit is not specific to this disorder. Among other disorders, P3 deficits have been found in depression (e.g. Gangadhar et al., 1993; Urretavizcaya et al., 2003) and bipolar disorder (O'Donnell et al., 2004; Salisbury et al., 1999). On the other hand, the amplitude modulation of the visual P3 was absent in schizophrenia, but comparable between healthy controls and depressive patients, suggesting a more specific deficit than absolute P3 amplitude (Neuhaus et al., 2010a). Our results are well in line with previous research on P3 amplitude modulation in normative samples as well as in schizophrenia. In healthy controls, an amplitude modulation of parietal P3 as a function of Go/NoGo conditions has been described in other studies that employed variants of a Go/NoGo paradigm (Ford et al., 2004; Jonkman et al., 2003; Knott et al., 1999; Pass et al., 1980). Interestingly, earlier studies already identified diminished parietal P3 amplitude modulations, i.e. Go/NoGo differences, in different samples of schizophrenic patients, i.e. acute (Pass et al., 1980), chronic (Knott et al., 1999), and mixed in- and outpatients (Ford et al., 2004). By testing recent onset and chronic schizophrenic patients within the same study design, the present study is able to confirm trait marker properties of parietal P3 modulation. The comparability of P3 data obtained from recent onset and chronic schizophrenic patients also argues against state or residual marker properties. Different explanations have been brought forward to enhance our understanding of underlying cognitive mechanisms of P3 modulation and its deficits in schizophrenia. Knott et al. (1999) have argued that schizophrenic patients may insufficiently allocate attentional resources, which may be reflected in minimal target/non-target differences. Jonkman et al. (2003) hypothesized that parietal Go/ NoGo differences might reflect an investment of effort in updating task-relevant information as a protection against interference effects. However, as schizophrenic patients and controls exhibit similar
behavioral performances in terms of ANT effects, especially inhibition, in our study, both explanations imply less expenditure of effort (allocation of attention or context updating, respectively) and thus superior performance of schizophrenic patients relative to healthy controls. Ford et al. (2004) have also argued in favor of a context updating model postulating that repetitive presentations of the same target lead to a P3 decrease, because context updating is not necessary, whereas the presentation of a different target leads to a P3 increase via context updating. This notion, however, cannot explain our data, given that all targets occurred at the same frequency and were presented in a pseudo-randomized order. A potential explanation for P3 amplitude modulation may arise from the very general finding that P3 amplitude is attenuated when task difficulty increases (Hagen et al., 2006; Polich, 1987). Considering that rationale, P3 modulation in controls may reflect graded target detection processes owing to different degrees of difficulty depending on the flankers presented together with the target. In our data, inhibition, i.e. overcoming of conflict induced by incompatible flankers, is associated with the highest P3 attenuation, consistent with the idea of P3 modulation by demanding cognitive operations. The lack of P3 modulation in schizophrenia may indicate a failure to detect or to differentially process varying degrees of task difficulty, i.e. the flanking condition. This hypothesis is consistent with recent research on visual processing deficits in schizophrenia. Specifically, schizophrenia has been theoretically linked with an impaired ability to utilize contextual information for stimulus interpretation (Hemsley, 2005; Phillips and Silverstein, 2003). Impaired visual context processing has also been shown in experiments with schizotypal subjects (Uhlhaas et al., 2004) and with schizophrenic patients (Dakin et al., 2005; Must et al., 2004; Yoon et al., 2009). Interestingly and consistent with our paradigm, in the latter study schizophrenic patients exhibited altered suppression of contextual information that was horizontally oriented while vertically arranged context information yielded no difference to healthy controls. Our data thus support the assumption that schizophrenia is associated with a relative failure to combine stimulus features into coherent object presentations, as outlined earlier by Uhlhaas and Mishara (2007). Coherent object presentations, however, are a necessary prerequisite to generate distinct down-stream neural activity, such as P3 modulation. In summary, incompatible flanking conditions necessitating inhibition may underlie parietal P3 modulation in controls while the relative inability to fully process flanking conditions may cause deficient parietal P3 modulation in schizophrenic patients. In spite of providing a first step in answering the question whether P3 modulation may serve as a trait marker of schizophrenia, this study is limited by the lack of longitudinal data. Several assessments of the same sample over time would be of particular importance. Nevertheless, the present study is in good accordance with previous research and may therefore serve as an approximation. As another limitation, medication status was not systematically controlled for, limiting the ability to address the role of antipsychotic agents within our study design; however, no correlation was found between CPZ equivalents and our crucial P3 measures. Furthermore, it cannot be excluded that the lack of parietal P3 modulation in schizophrenia patients is, at least partially, due to a general P3 amplitude decrease that may lead to a floor effect. Here, the application of simpler target arrays could prove helpful in determining whether the P3 modulation deficit is specific to the study design or the illness. Last, when investigating potential trait markers of schizophrenia, the inclusion of unmedicated first-episode or even prodromal subjects is desirable. In this regard, the current study can only serve as an approximation and cannot strictly prove, but only suggest trait marker properties of P3 modulation. In sum, conclusive evidence is presented that modulation of parietal P3 amplitude as a function of target class is reduced in schizophrenia, independent of duration of illness. Against the background of recent
A.H. Neuhaus et al. / Schizophrenia Research 130 (2011) 210–215
data on the specificity of the P3 amplitude modulation deficit, this ERP measure merits further investigation as a potential trait marker of schizophrenia. Role of funding source None. Contributors Authors AHN, EH, and MD designed the study. Author CU wrote the experimental protocol. Authors CH, TMT, and AHN analyzed the data. Author COR managed the literature searches and analyses. Author AHN wrote the first draft of the manuscript. All authors contributed to and have approved the final manuscript. Conflict of interest All authors declare that they have no conflicts of interest. Acknowledgement The authors thank all participants who contributed their time and effort to this study.
References AhnAllen, C.G., Nestor, P.G., Shenton, M.E., McCarley, R.W., Niznikiewicz, M.A., 2008. Early nicotine withdrawal and transdermal nicotine effects on neurocognitive performance in schizophrenia. Schizophr. Res. 100 (1–3), 261–269. Braff, D.L., 1993. Information processing and attention dysfunctions in schizophrenia. Schizophr. Bull. 19 (2), 233–259. Carter, C.S., Mintun, M., Nichols, T., Cohen, J.D., 1997. Anterior cingulate dysfunction and selective attention deficits in schizophrenia: [15O]H2O PET study during single-trial Stroop task performance. Am. J. Psychiatry 154 (12), 1670–1675. Dakin, S., Carlin, P., Hemsley, D., 2005. Weak suppression of context in chronic schizophrenia. Curr. Biol. 15 (20), R822–R824. DeLisi, L.E., Tew, W., Xie, S., Hoff, A.L., Sakuma, M., Kushner, M., Lee, G., Shedlack, K., Smith, A.M., Grimson, R., 1995. A prospective follow-up study of brain morphology and cognition in first episode schizophrenia patients: preliminary findings. Biol. Psychiatry 38 (6), 349–360. Ehlis, A.C., Reif, A., Herrmann, M.J., Lesch, K.P., Fallgatter, A.J., 2007. Impact of catechol-Omethyltransferase on prefrontal brain functioning in schizophrenia spectrum disorders. Neuropsychopharmacology 32 (1), 162–170. Fan, J., McCandliss, B.D., Sommer, T., Raz, A., Posner, M.I., 2002. Testing the efficiency and independence of attentional networks. J. Cogn. Neurosci. 14 (3), 340–347. Fan, J., McCandliss, B.D., Fossella, J., Flombaum, J.I., Posner, M.I., 2005. The activation of attentional networks. Neuroimage 26 (2), 471–479. Ford, J.M., Gray, M., Whitfield, S.L., Turken, A.U., Glover, G., Faustman, W.O., Mathalon, D.H., 2004. Acquiring and inhibiting prepotent responses in schizophrenia: event-related brain potentials and functional magnetic resonance imaging. Arch. Gen. Psychiatry 61 (2), 119–129. Gangadhar, B.N., Ancy, J., Janakiramaiah, N., Umapathy, C., 1993. P300 amplitude in non-bipolar, melancholic depression. J. Affect. Disord. 28 (1), 57–60. Goldberg, T.E., Hyde, T.M., Kleinman, J.E., Weinberger, D.R., 1993. Course of schizophrenia: neuropsychological evidence for a static encephalopathy. Schizophr. Bull. 19 (4), 797–804. Hagen, G.F., Gatherwright, J.R., Lopez, B.A., Polich, J., 2006. P3a from visual stimuli: task difficulty effects. Int. J. Psychophysiol. 59 (1), 8–14. Heaton, R.K., Gladsjo, J.A., Palmer, B.W., Kuck, J., Marcotte, T.D., Jeste, D.V., 2001. Stability and course of neuropsychological deficits in schizophrenia. Arch. Gen. Psychiatry 58 (1), 24–32. Hemsley, D.R., 2005. The schizophrenic experience: out of context? Schizophr. Bull. 31 (1), 43–53. Hepp, H.H., Maier, S., Hermle, L., Spitzer, M., 1996. The Stroop effect in schizophrenic patients. Schizophr. Res. 22 (3), 187–195. Jonkman, L.M., Lansbergen, M., Stauder, J.E.A., 2003. Developmental differences in behavioral and event-related brain responses associated with response preparation and inhibition in a go/nogo task. Psychophysiology 40 (5), 752–761.
215
Jung, T.P., Makeig, S., Westerfield, M., Townsend, J., Courchesne, E., Sejnowski, T.J., 2000. Removal of eye activity artifacts from visual event-related potentials in normal and clinical subjects. Clin. Neurophysiol. 111 (10), 1745–1758. Knott, V., Mahoney, C., Labelle, A., Ripley, C., Cavazzoni, P., Jones, B., 1999. Event-related potentials in schizophrenic patients during a degraded stimulus version of the continuous performance task. Schizophr. Res. 35 (3), 263–278. Liddle, P.F., Morris, D.L., 1991. Schizophrenic syndromes and frontal lobe performance. Br. J. Psychiatry 158 (3), 340–345. Minzenberg, M.J., Laird, A.R., Thelen, S., Carter, C.S., Glahn, D.C., 2009. Meta-analysis of 41 functional neuroimaging studies of executive dysfunction in schizophrenia. Arch. Gen. Psychiatry 66 (8), 811–822. Must, A., Janka, Z., Benedek, G., Keri, S., 2004. Reduced facilitation effect of collinear flankers on contrast detection reveals impaired lateral connectivity in the visual cortex of schizophrenia patients. Neurosic. Lett. 357 (2), 131–134. Neuhaus, A.H., Koehler, S., Opgen-Rhein, C., Urbanek, C., Hahn, E., Dettling, M., 2007. Selective anterior cingulate cortex deficit during conflict solution in schizophrenia: an event-related potential study. J. Psychiatr. Res. 41 (8), 635–644. Neuhaus, A.H., Trempler, N.R., Hahn, E., Luborzewski, A., Karl, C., Hahn, C., Opgen-Rhein, C., Urbanek, C., Schaub, R., Dettling, M., 2010a. Evidence of specificity of a visual P3 amplitude modulation deficit in schizophrenia. Schizophr. Res. 124 (1–3), 119–126. Neuhaus, A.H., Urbanek, C., Opgen-Rhein, C., Hahn, E., Ta, T.M.T., Koehler, S., Gross, M., Dettling, M., 2010b. Event-related potentials associated with Attention Network Test. Int. J. Psychophysiol. 76 (2), 72–79. O'Donnell, B.F., Vohs, J.L., Hetrick, W.P., Carroll, C.A., Shekhar, A., 2004. Auditory eventrelated potential abnormalities in bipolar disorder and schizophrenia. Int. J. Psychophysiol. 53 (1), 45–55. Opgen-Rhein, C., Neuhaus, A.H., Urbanek, C., Hahn, E., Sander, T., Dettling, M., 2008. Executive attention in schizophrenic males and the impact of COMT val108/ 158met genotype on performance on the attention network test. Schizophr. Bull. 34 (6), 1231–1239. Pass, H.L., Klorman, R., Salzman, L.F., Klein, R.H., Kaskey, G.B., 1980. The late positive component of the evoked response in acute schizophrenics during a test of sustained attention. Biol. Psychiatry 115 (1), 9–20. Phillips, W.A., Silverstein, S.M., 2003. Convergence of biological and psychological perspectives on cognitive coordination in schizophrenia. Behav. Brain Sci. 26 (1), 65–82. Polich, J., 1987. Task difficulty, probability, and inter-stimulus interval as determinants of P300 from auditory stimuli. Electroencephal. Clin. Neurophysiol. 68 (4), 311–320. Roth, W.T., Cannon, F.H., 1972. Some features of the auditory event-related response in schizophrenia. Arch. Gen. Psychiatry 27 (4), 466–471. Salisbury, D.F., Shenton, M.E., McCarley, R.W., 1999. P300 topography differs in schizophrenia and manic psychosis. Biol. Psychiatry 45 (1), 98–106. Uhlhaas, P.J., Mishara, A.L., 2007. Perceptual anomalies in schizophrenia: integrating phenomenology and cognitive neuroscience. Schizophr. Bull. 33 (1), 142–156. Uhlhaas, P.J., Silverstein, S.M., Phillips, W.A., Lovell, P.G., 2004. Evidence for impaired visual context processing in schizotypy with thought disorder. Psychiatry Res. 68 (2–3), 249–260. Urbanek, C., Neuhaus, A.H., Opgen-Rhein, C., Strathmann, S., Wieseke, N., Schaub, R., Hahn, E., Dettling, M., 2009. Attention network test (ANT) reveals gender-specific alterations of executive function in schizophrenia. Psychiatry Res. 168 (2), 102–109. Urretavizcaya, M., Moreno, I., Benlloch, L., Cardoner, N., Serrallonga, J., Menchon, J.M., Vallejo, J., 2003. Auditory event-related potentials in 50 melancholic patients: increased N100, N200 and P300 latencies and diminished P300 amplitude. J. Affect. Disord. 74 (3), 293–297. Van der Stelt, O., Lieberman, J.A., Belger, A., 2005. Auditory P300 in high-risk, recent onset and chronic schizophrenia. Schizophr. Res. 77 (2–3), 309–320. Wang, K., Fan, J., Dong, Y., Wang, C.Q., Lee, T.M., Posner, M.I., 2005. Selective impairment of attentional networks of orienting and executive control in schizophrenia. Schizophr. Res. 78 (2–3), 235–241. Yoon, J.H., Rokem, A.S., Silver, M.A., Minzenberg, M.J., Ursu, S., Ragland, J.D., Carter, C.S., 2009. Diminished orientation-specific surround suppression of visual processing in schizophrenia. Schizophr. Bull. 35 (6), 1078–1084.
Contents lists available at ScienceDirect
Schizophrenia Research j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / s c h r e s
Visual P3 amplitude modulation deficit in schizophrenia is independent of duration of illness Andres H. Neuhaus a,⁎, Eric Hahn a, Constanze Hahn b, Thi Minh Tam Ta a, Carolin Opgen-Rhein a, Carsten Urbanek a, Michael Dettling a a b
Department of Psychiatry and Psychotherapy, Charité University Medicine, Campus Benjamin Franklin, Berlin, Germany Department of Biopsychology, Ruhr University Bochum, Germany
a r t i c l e
i n f o
Article history: Received 13 September 2010 Received in revised form 8 February 2011 Accepted 8 February 2011 Available online 5 March 2011 Keywords: P3 P300 Event-related potentials Visual attention Attention Network Test Schizophrenia Trait marker
a b s t r a c t Background: In the search for markers of schizophrenia, functional deficits during inhibition have been a major focus. In previous studies, we found a reduced amplitude modulation of the visual P3 component of the event-related potential (ERP) in schizophrenic patients during inhibition in the Attention Network Test (ANT). The objective of the present study was to explore whether this deficit exhibits properties of a trait or state marker of schizophrenia. Methods: Eighteen recent onset inpatients and eighteen chronic schizophrenic outpatients as well as 36 healthy controls, including a young adult and an old adult group to match recent onset and chronic illness groups for age and sex, were included. Participants were tested with ANT while 32-channel electroencephalogram was recorded and visual P3 amplitudes were analyzed. Amplitude modulation was defined as the variation of P3 amplitude at Pz as a function of ANT flanker conditions. Results: There were no significant behavioral between-group differences in terms of alerting, orienting, and inhibition. Mean visual P3 was significantly lower in schizophrenic patients than in healthy controls. Parietal P3 amplitude was significantly less modulated in both recent onset (− 0.035) and chronic schizophrenic patients (− 0.081) compared with young (− 0.588; p b 0.05) and older healthy controls, respectively (− 0.556; p b 0.05). No correlations were obtained between P3 modulation and clinical or demographic variables. Conclusion: The results provide evidence that the observed deficit of visual P3 amplitude modulation is independent of duration of illness and age and may contain properties of a trait marker of schizophrenia. © 2011 Elsevier B.V. All rights reserved.
1. Introduction The identification of neurocognitive markers of schizophrenic illness has attracted extensive research in the past years. Among other neurocognitive deficits in schizophrenia, those related to behavioral inhibition have received considerable attention. Inhibitory deficits were reported in a wide range of tasks including the Stroop task (e.g. Carter et al., 1997; Hepp et al., 1996) or the Go/NoGo paradigm (e.g. Ehlis et al., 2007; Ford et al., 2004). In line with that research, our group has recently identified and replicated a functional deficit in schizophrenic patients during inhibition in the Attention Network Test (ANT; Neuhaus et al., 2007, 2010a). ANT has been introduced to allow for behavioral assessment of alerting, orienting, and inhibition via specific reaction time patterns (Fan et al., 2002). Alerting in the context of ANT refers to the ability to phasically increase response preparation in reaction to an external ⁎ Corresponding author at: Department of Psychiatry and Psychotherapy, Charité University Medicine Berlin, Campus Benjamin Franklin, Eschenallee 3, 14050 Berlin, Germany. Tel.: +49 30 8445 8412; fax: +49 30 8445 8393. E-mail address: [email protected] (A.H. Neuhaus). 0920-9964/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.schres.2011.02.009
warning stimulus. Orienting refers to the beneficial effect of spatial cueing for behavioral performance. Inhibition as measured with ANT refers to the resolution of a flanker compatibility conflict and has been associated with anterior cingulate activation in functional imaging and electrophysiological source localization studies (Fan et al., 2005; Neuhaus et al., 2007). Given that anterior cingulate has been consistently identified as hypoactive in schizophrenia (Minzenberg et al., 2009), this disorder has been associated with significantly altered surrogate parameters of inhibition during ANT at the behavioral level (Urbanek et al., 2009; Wang et al., 2005), using event-related potentials (ERP; Neuhaus et al., 2010a), and in genetic studies (Opgen-Rhein et al., 2008). The electrophysiological characterization of inhibition in the ANT revealed a parietal modulation of the P3 component as a function of target class in a normative study (Neuhaus et al., 2010b). In another study, the same ERP pattern was obtained in healthy controls as well as in depressive patients, but not in schizophrenic patients (Neuhaus et al., 2010a), suggesting an illness-specific deficit. Our results are consistent with previous studies that employed variants of a Go/NoGo paradigm and identified diminished parietal P3 amplitude modulations, i.e. Go/NoGo differences, in acute (Pass et al., 1980) and in
A.H. Neuhaus et al. / Schizophrenia Research 130 (2011) 210–215
atypical antipsychotic medication and were free from benzodiazepine co-medication for at least two weeks. Schizophrenic patients consisted of a group of 18 post-acute inpatients with recent onset schizophrenia (DOI less than 5 years; duration of post-acute state, i.e. time interval between admission and testing, between 6 and 12 weeks) and a group of 18 stable outpatients with chronic schizophrenia (DOI at least 10 years). Ratings of the Positive and Negative Syndrome Scale (PANSS) were conducted on the day of testing. Thirty-six age-matched healthy subjects (15 f, 21 m) served as controls. None of these participants had a history of substance abuse other than tobacco smoking, nor a history of psychiatric disorder according to DSM-IV as determined by a semi-structured clinical interview (SKID I/II), or a history of severe medical or neurological disorder. All control subjects were free from pharmacological treatment. All participants were right-handed and reported normal or corrected-to-normal vision. Table 1 summarizes demographic and clinical data. All subjects gave written, informed consent before participating in this study. The study protocol was approved by the local ethics committee and the study was conducted in accordance with the Declaration of Helsinki.
Table 1 Summary of demographic and clinical data (mean ± standard deviation). Schizophrenia
N (f/m) Age [years] DOI [years] N episodes PANSS P PANSS N PANSS G CPZ eq. [mg/day]
Controls
p
Recent onset
Chronic
Recent onset Chronic matched matched
18 (7/11) 28.44 ± 5.6 2.91 ± 2.3 1.53 ± 0.9 12.44 ± 3.9 17.33 ± 5.1 36.43 ± 8.6 503.67 ± 357.0
18 (8/10) 43.17 ± 6.3 15.06 ± 5.1 4.63 ± 3.2 11.94 ± 3.1 15.35 ± 4.8 31.19 ± 8.4 537.88 ± 381.4
18 (7/11) 27.39 ± 2.7 – – – – – –
18 (8/10) 40.94 ± 7.3 – – – – – –
– n.s.a b0.001b 0.001b n.s.b n.s.b n.s.b n.s.b
DOI, duration of illness; PANSS, Positive and Negative Syndrome Scale (P, positive; N, negative; G, general); CPZ eq., chlorpromazine equivalents. a For both t-tests between recent onset schizophrenia and matched controls and between chronic schizophrenia and matched controls. b t-tests between recent onset and chronic schizophrenia.
chronic schizophrenic patients (Knott et al., 1999). Taken together, these studies suggest that the parietal P3 modulation deficit may be a trait marker of schizophrenia; however, this preliminary conclusion is derived from only two studies that used different designs including different patient selection criteria and different paradigms. In the present study, we sought to investigate the parietal P3 modulation as a potential trait marker by asking whether the P3 modulation deficit depends on the duration of illness (DOI). For this purpose, in- and outpatient samples were assessed at different stages of schizophrenic illness within the same study design.
2.2. Task design An exhaustive description of the task is given elsewhere (Fan et al., 2002; Neuhaus et al., 2010b). Briefly, ANT combines cued detection with a flanker-type paradigm. Target stimuli consisted of five horizontally arranged arrows or lines presented above or below fixation. By left or right button press, subjects had to indicate the direction of the central arrow irrespective of flanking conditions. Flankers were either lines (neutral target) or arrows pointing to the same (compatible) or to the opposite direction (incompatible); a behavioral estimate of inhibition is obtained when subtracting mean reaction times (RTs) of compatible from incompatible trials. Cue stimuli preceded target presentation by 500 ms to direct attention in time only (alerting) or in space and time (orienting); behavioral estimates of alerting and orienting are obtained when subtracting mean RTs of trials following double cues (above and below fixation) from the no cue condition and when subtracting mean RTs of trials following spatial cues (above or below fixation) from the center cue condition, respectively. Target presentation had a maximum
2. Methods 2.1. Subjects Thirty-six patients (15 f, 21 m) meeting DSM-IV criteria for schizophrenia participated in this study. None of the included patients had a history of any severe medical or neurological disorder and never underwent electroconvulsive therapy. All patients received oral
+ T1=400-1600 ms
Cue
*
211
+
No cue
*
Center cue
*+ *
Double cue
*+
+
Spatial cue
*
+ 100 ms +
+
+
Neutral
+
+
Compatible
+
+
Incompatible
400 ms
Target + ≤ 1700 ms RT≤ + 3500 ms- RT- T1 Σ 4000 ms Fig. 1. Attention Network Test schematic.
212
A.H. Neuhaus et al. / Schizophrenia Research 130 (2011) 210–215
Table 2 Summary of behavioral and parietal P3 results (mean ± standard deviation). Schizophrenia
RT [ms] Accuracy [%] Alerting [ms] Orienting [ms] Inhibition [ms] P3neutral [μV] P3compatible [μV] P3incompatible [μV] P3 slope a b
Controls
p
Recent onset
Chronic
Recent onset matched
Chronic matched
612.58 ± 118.4 95.58 ± 6.7 53.57 ± 35.1 57.12 ± 32.7 109.26 ± 43.8 3.88 ± 2.6 3.89 ± 2.1 3.82 ± 2.1 − 0.035 ± 0.91
653.95 ± 119.7 98.17 ± 1.4 35.11 ± 48.5 70.53 ± 27.7 112.47 ± 58.3 3.97 ± 2.1 3.69 ± 1.7 3.81 ± 1.8 − 0.081 ± 0.62
538.95 ± 58.6 98.98 ± 1.0 43.73 ± 26.6 51.05 ± 16.5 93.62 ± 34.8 4.68 ± 1.7 4.68 ± 2.1 3.51 ± 1.6 − 0.588 ± 0.60
583.61 ± 78.9 98.90 ± 1.2 49.41 ± 29.9 57.42 ± 31.8 111.67 ± 27.9 4.56 ± 1.9 3.91 ± 1.9 3.44 ± 1.9 − 0.556 ± 0.69
n.s.a b0.05b n.s.a n.s.a n.s.a n.s.a n.s.a n.s.a b0.05a
For both t-tests between recent onset schizophrenia and controls and between chronic schizophrenia and controls. Only for t-test between recent onset schizophrenia and their controls.
duration of 1700 ms and was followed by a variable fixation period immediately after response. The duration of each trial added up to 4000 ms. A total of 288 pseudo-randomized trials (4 cues × 3 targets× 8 repetitions per block× 3 blocks) without feedback was presented. Subjects were instructed to respond as fast and as accurately as possible. The task is illustrated in Fig. 1.
accuracy was significantly different between recent onset schizophrenia and young controls. Accuracy and mean RT showed a trendlevel negative correlation in recent onset schizophrenia patients only (r = −0.410; p = 0.091). Table 2 summarizes mean behavioral data. Fig. 2 illustrates mean RTs by cue and target conditions. 3.2. Parietal P3 modulation
2.3. ERP acquisition EEG was recorded with 32 Ag/AgCl electrodes positioned according to the extended International 10/20 system. Electrode impedances were kept below 5 kΩ. EEG was assessed with a Neuroscan SynAmps (El Paso, TX, US) with a sampling rate of 250 Hz and an analog high-pass filter set at 0.1 Hz. EEG analysis included ocular artifact correction using independent component analysis (Jung et al., 2000), re-referencing to average reference, artifact tagging (≥80 μV at any electrode), data segmentation for different target conditions (800 ms pre-stimulus to 800 ms post-stimulus), artifact rejection, baseline correction (−800 to −500 ms prior to target onset), and averaging a minimum of 30 artifactfree and correctly responded trials (within 1000 ms) for each analyzed experimental condition. P3 was then identified at Pz as the most positive deflection 300 to 600 ms after target onset and consecutively determined at Fz, Cz, and Pz as peak amplitude measure between 300 and 600 ms post target stimulus. Regression slopes were calculated to determine P3 amplitude modulation as a function of target class that were factorized as 0 (neutral), 1 (compatible), and 2 (incompatible). 2.4. Statistical analysis Statistical analyses were conducted with PASW Statistics 18 (Chicago, IL, US). Demographic data and behavioral data were analyzed with t-tests as appropriate. Examination of ERP data was performed with repeated measures analysis of variance. Target conditions (neutral, compatible, and incompatible) and midline electrodes (Fz, Cz, and Pz) were entered as within-subject factors and diagnostic groups (schizophrenia vs. controls) as well as stage of illness (recent onset vs. chronic schizophrenia and their respective control groups) were entered as between-subject factors resulting in a 3 × 3 × 2 × 2 design for P3 analysis. Post hoc analyses including comparison of individual regression slopes were computed as t-tests for paired or independent samples, as required. Correlations were computed as Pearson correlations. All tests were performed as twotailed tests with an alpha level set at p b 0.05. 3. Results 3.1. Behavioral performance There were no significant differences between groups regarding behavioral ANT effects of alerting, orienting, and inhibition. Mean
Repeated measures ANOVA revealed a significant main effect of ‘electrode’ (F2, 136 = 37.991; p b 0.001) and significant interactions of ‘electrode × diagnostic group’ (F2, 136 = 4.473; p = 0.013), ‘target condition × electrode’ (F4, 272 = 3.717; p = 0.006), and ‘target condition × electrode × diagnostic group’ (F4, 272 = 2.410; p = 0.049). Furthermore, a significant main effect of group on mean P3 was found (p = 0.019) indicating significantly lower mean P3 amplitude in schizophrenia. Of note, no interaction was obtained that involved the factor ‘stage of illness’ (recent onset vs. chronic schizophrenia and their respective control groups). Grand average curves stratified by diagnostic and age groups are illustrated in Fig. 3. Regarding the effect of ‘electrode’, P3 amplitudes across the whole sample were highest at Pz (3.99 ± 1.8 μV), intermediate at Cz (3.26 ± 2.1 μV), and lowest at Fz (2.07 ± 1.4 μV; all T71 N 3.172; all p b 0.005). When stratified for diagnostic groups (‘electrode × diagnostic group’), P3 amplitudes of both healthy controls and schizophrenic patients showed a similar pattern, however, there was no significant difference between P3 amplitude at Cz (4.03 ± 2.2 μV) and Pz (4.13 ± 1.7 μV; T35 = 0.314; p = 0.756) in healthy controls. The interaction of ‘target condition × electrode’ was further pursued by comparing P3 amplitudes following different target conditions at each midline electrode across the whole sample. Here, significant differences emerged only at electrode Pz between neutral and incompatible targets (T71 = 3.570; p = 0.001) and between compatible and incompatible targets (T71 = 2.561; p = 0.013), indicating a significant P3 modulation in inhibition trials only. To further characterize this parietal P3 amplitude modulation, P3 regression slopes were calculated as a function of target class separately for each group (‘target condition × electrode × diagnostic group’). Here, schizophrenic patients as a group exhibited a significantly less modulated parietal P3 amplitude (−0.05 ± 0.8) than healthy controls (−0.57 ± 0.6; T70 = −3.087; p = 0.003). Interestingly, both recent onset schizophrenic patients (−0.03 ± 0.9) and chronic schizophrenic patients (− 0.08 ± 0.6) showed a significantly shallower parietal P3 slope compared to their respective control groups, i.e. young (−0.59 ± 0.6; T34 = −2.142; p = 0.039) and old controls (−0.56 ± 0.7; T34 = −2.180; p = 0.036). Parietal P3 amplitudes and regression slopes are summarized in Table 2. There were no correlations of P3 slope with age (r =0.003; p=0.987) in healthy controls or with age (r=0.222; p= 0.194), duration of illness (r= −0.057; p =0.740), number of episodes (r= −0.230; p =0.213), PANSS scores (positive: r = 0.144; p = 0.544; negative: r = 0.298;
A.H. Neuhaus et al. / Schizophrenia Research 130 (2011) 210–215
213
Schizophrenia
Controls
Recent onset
Reaction time [ms]
800 700 600 500 400
Chronic
Reaction time [ms]
800 700 600 500 400 Neutral
Compatible
Incompatible
Neutral
Compatible
Targets No cue
Incompatible
Targets Center cue
Double cue
Spatial cue
Fig. 2. Mean RTs stratified by cue and target conditions for schizophrenia patients (left column) and healthy controls (right column). Recent onset patients and young controls are shown in the top row, chronic patients and old controls are shown in the bottom row.
p= 0.139; general: r =0.291; p =0.178), or chlorpromazine equivalents (r =0.323; p =0.116) in schizophrenia patients. 4. Discussion We conducted a study on ERP correlates of inhibition as measured with the ANT in two independent samples of schizophrenic patients. Post-acute inpatients with recent onset schizophrenia and outpatients
Recent onset Schizophrenia
[µV] 4
with chronic schizophrenia were compared with age-matched healthy control groups in order to explore the potential influence of duration of illness. Whereas P3 amplitude was clearly modulated in both healthy control groups, both recent onset and chronic schizophrenic patient groups lacked parietal P3 amplitude modulation during neutral, compatible, and incompatible trials. No significant behavioral differences of ANT effects were found between schizophrenic patients and both control groups which
Recent onset matched Controls
[µV] 4 2
2
-600 -400 -200
Chronic Schizophrenia
200 400 600 [ms]
-2
-2
-4
-4
[µV] 4
Chronic matched Controls
[µV] 4
2
2
-2
-2
-4
-4
Neutral targets
Compatible targets
Incompatible targets
Fig. 3. Grand average ERP at parietal midline electrode Pz stratified by condition for each experimental group. Target onset is at 0 ms. During inhibition trials, there is no modulation of parietal P3 amplitude in both recent onset schizophrenia and chronic schizophrenia (left) whereas a P3 amplitude modulation is clearly present in both recent onset matched controls and chronic matched controls (right).
214
A.H. Neuhaus et al. / Schizophrenia Research 130 (2011) 210–215
confirms findings from the majority of previous studies (AhnAllen et al., 2008; Neuhaus et al., 2007, 2010a; Opgen-Rhein et al., 2008; Urbanek et al., 2009). The relatively low accuracy of recent onset schizophrenia patients could be attributable to a speed-accuracy-tradeoff given the negative correlation between those measures, although the latter finding only reached borderline significance. At the neurophysiological level, our study showed that parietal P3 amplitude was significantly modulated as a function of target class in both healthy control groups, but not in recent onset or chronic schizophrenia patients. The pattern of parietal modulation of P3 amplitude in healthy controls and the failure to modulate P3 in schizophrenia replicate findings from our previous studies (Neuhaus et al., 2007, 2010a). These findings are extended in that we found comparable patterns of P3 modulation in young and older controls, thus arguing against an influence of age on P3 modulation with target class, which is also supported by correlation analysis. Moreover, the failure of both patient groups to modulate P3 amplitude provides evidence that this deficit is independent of duration of illness. Likewise, deficient P3 modulation could not be accounted for by age, antipsychotic medication, or clinical disparities such as number of episodes or duration of illness. The fact that duration of illness does not seem to affect the deficient P3 modulation in our patient sample is well in line with other findings. Although it has been found that a longer DOI is associated with decreased performance of frontal lobe functions (Liddle and Morris, 1991), the majority of studies arrive at the conclusion that neurocognitive deficits, once present at the onset of schizophrenia, do not further deteriorate in the course of illness (DeLisi et al., 1995; Goldberg et al., 1993; Heaton et al., 2001). A wealth of studies has investigated absolute P3 amplitudes in schizophrenia that are usually obtained using an auditory oddball paradigm. The P3 amplitude deficit in schizophrenia is a longstanding and most consistent finding (e.g. Braff, 1993; Ford et al., 2004; Roth and Cannon, 1972; van der Stelt et al., 2005). However, despite the reliability of P3 abnormalities in schizophrenia, this deficit is not specific to this disorder. Among other disorders, P3 deficits have been found in depression (e.g. Gangadhar et al., 1993; Urretavizcaya et al., 2003) and bipolar disorder (O'Donnell et al., 2004; Salisbury et al., 1999). On the other hand, the amplitude modulation of the visual P3 was absent in schizophrenia, but comparable between healthy controls and depressive patients, suggesting a more specific deficit than absolute P3 amplitude (Neuhaus et al., 2010a). Our results are well in line with previous research on P3 amplitude modulation in normative samples as well as in schizophrenia. In healthy controls, an amplitude modulation of parietal P3 as a function of Go/NoGo conditions has been described in other studies that employed variants of a Go/NoGo paradigm (Ford et al., 2004; Jonkman et al., 2003; Knott et al., 1999; Pass et al., 1980). Interestingly, earlier studies already identified diminished parietal P3 amplitude modulations, i.e. Go/NoGo differences, in different samples of schizophrenic patients, i.e. acute (Pass et al., 1980), chronic (Knott et al., 1999), and mixed in- and outpatients (Ford et al., 2004). By testing recent onset and chronic schizophrenic patients within the same study design, the present study is able to confirm trait marker properties of parietal P3 modulation. The comparability of P3 data obtained from recent onset and chronic schizophrenic patients also argues against state or residual marker properties. Different explanations have been brought forward to enhance our understanding of underlying cognitive mechanisms of P3 modulation and its deficits in schizophrenia. Knott et al. (1999) have argued that schizophrenic patients may insufficiently allocate attentional resources, which may be reflected in minimal target/non-target differences. Jonkman et al. (2003) hypothesized that parietal Go/ NoGo differences might reflect an investment of effort in updating task-relevant information as a protection against interference effects. However, as schizophrenic patients and controls exhibit similar
behavioral performances in terms of ANT effects, especially inhibition, in our study, both explanations imply less expenditure of effort (allocation of attention or context updating, respectively) and thus superior performance of schizophrenic patients relative to healthy controls. Ford et al. (2004) have also argued in favor of a context updating model postulating that repetitive presentations of the same target lead to a P3 decrease, because context updating is not necessary, whereas the presentation of a different target leads to a P3 increase via context updating. This notion, however, cannot explain our data, given that all targets occurred at the same frequency and were presented in a pseudo-randomized order. A potential explanation for P3 amplitude modulation may arise from the very general finding that P3 amplitude is attenuated when task difficulty increases (Hagen et al., 2006; Polich, 1987). Considering that rationale, P3 modulation in controls may reflect graded target detection processes owing to different degrees of difficulty depending on the flankers presented together with the target. In our data, inhibition, i.e. overcoming of conflict induced by incompatible flankers, is associated with the highest P3 attenuation, consistent with the idea of P3 modulation by demanding cognitive operations. The lack of P3 modulation in schizophrenia may indicate a failure to detect or to differentially process varying degrees of task difficulty, i.e. the flanking condition. This hypothesis is consistent with recent research on visual processing deficits in schizophrenia. Specifically, schizophrenia has been theoretically linked with an impaired ability to utilize contextual information for stimulus interpretation (Hemsley, 2005; Phillips and Silverstein, 2003). Impaired visual context processing has also been shown in experiments with schizotypal subjects (Uhlhaas et al., 2004) and with schizophrenic patients (Dakin et al., 2005; Must et al., 2004; Yoon et al., 2009). Interestingly and consistent with our paradigm, in the latter study schizophrenic patients exhibited altered suppression of contextual information that was horizontally oriented while vertically arranged context information yielded no difference to healthy controls. Our data thus support the assumption that schizophrenia is associated with a relative failure to combine stimulus features into coherent object presentations, as outlined earlier by Uhlhaas and Mishara (2007). Coherent object presentations, however, are a necessary prerequisite to generate distinct down-stream neural activity, such as P3 modulation. In summary, incompatible flanking conditions necessitating inhibition may underlie parietal P3 modulation in controls while the relative inability to fully process flanking conditions may cause deficient parietal P3 modulation in schizophrenic patients. In spite of providing a first step in answering the question whether P3 modulation may serve as a trait marker of schizophrenia, this study is limited by the lack of longitudinal data. Several assessments of the same sample over time would be of particular importance. Nevertheless, the present study is in good accordance with previous research and may therefore serve as an approximation. As another limitation, medication status was not systematically controlled for, limiting the ability to address the role of antipsychotic agents within our study design; however, no correlation was found between CPZ equivalents and our crucial P3 measures. Furthermore, it cannot be excluded that the lack of parietal P3 modulation in schizophrenia patients is, at least partially, due to a general P3 amplitude decrease that may lead to a floor effect. Here, the application of simpler target arrays could prove helpful in determining whether the P3 modulation deficit is specific to the study design or the illness. Last, when investigating potential trait markers of schizophrenia, the inclusion of unmedicated first-episode or even prodromal subjects is desirable. In this regard, the current study can only serve as an approximation and cannot strictly prove, but only suggest trait marker properties of P3 modulation. In sum, conclusive evidence is presented that modulation of parietal P3 amplitude as a function of target class is reduced in schizophrenia, independent of duration of illness. Against the background of recent
A.H. Neuhaus et al. / Schizophrenia Research 130 (2011) 210–215
data on the specificity of the P3 amplitude modulation deficit, this ERP measure merits further investigation as a potential trait marker of schizophrenia. Role of funding source None. Contributors Authors AHN, EH, and MD designed the study. Author CU wrote the experimental protocol. Authors CH, TMT, and AHN analyzed the data. Author COR managed the literature searches and analyses. Author AHN wrote the first draft of the manuscript. All authors contributed to and have approved the final manuscript. Conflict of interest All authors declare that they have no conflicts of interest. Acknowledgement The authors thank all participants who contributed their time and effort to this study.
References AhnAllen, C.G., Nestor, P.G., Shenton, M.E., McCarley, R.W., Niznikiewicz, M.A., 2008. Early nicotine withdrawal and transdermal nicotine effects on neurocognitive performance in schizophrenia. Schizophr. Res. 100 (1–3), 261–269. Braff, D.L., 1993. Information processing and attention dysfunctions in schizophrenia. Schizophr. Bull. 19 (2), 233–259. Carter, C.S., Mintun, M., Nichols, T., Cohen, J.D., 1997. Anterior cingulate dysfunction and selective attention deficits in schizophrenia: [15O]H2O PET study during single-trial Stroop task performance. Am. J. Psychiatry 154 (12), 1670–1675. Dakin, S., Carlin, P., Hemsley, D., 2005. Weak suppression of context in chronic schizophrenia. Curr. Biol. 15 (20), R822–R824. DeLisi, L.E., Tew, W., Xie, S., Hoff, A.L., Sakuma, M., Kushner, M., Lee, G., Shedlack, K., Smith, A.M., Grimson, R., 1995. A prospective follow-up study of brain morphology and cognition in first episode schizophrenia patients: preliminary findings. Biol. Psychiatry 38 (6), 349–360. Ehlis, A.C., Reif, A., Herrmann, M.J., Lesch, K.P., Fallgatter, A.J., 2007. Impact of catechol-Omethyltransferase on prefrontal brain functioning in schizophrenia spectrum disorders. Neuropsychopharmacology 32 (1), 162–170. Fan, J., McCandliss, B.D., Sommer, T., Raz, A., Posner, M.I., 2002. Testing the efficiency and independence of attentional networks. J. Cogn. Neurosci. 14 (3), 340–347. Fan, J., McCandliss, B.D., Fossella, J., Flombaum, J.I., Posner, M.I., 2005. The activation of attentional networks. Neuroimage 26 (2), 471–479. Ford, J.M., Gray, M., Whitfield, S.L., Turken, A.U., Glover, G., Faustman, W.O., Mathalon, D.H., 2004. Acquiring and inhibiting prepotent responses in schizophrenia: event-related brain potentials and functional magnetic resonance imaging. Arch. Gen. Psychiatry 61 (2), 119–129. Gangadhar, B.N., Ancy, J., Janakiramaiah, N., Umapathy, C., 1993. P300 amplitude in non-bipolar, melancholic depression. J. Affect. Disord. 28 (1), 57–60. Goldberg, T.E., Hyde, T.M., Kleinman, J.E., Weinberger, D.R., 1993. Course of schizophrenia: neuropsychological evidence for a static encephalopathy. Schizophr. Bull. 19 (4), 797–804. Hagen, G.F., Gatherwright, J.R., Lopez, B.A., Polich, J., 2006. P3a from visual stimuli: task difficulty effects. Int. J. Psychophysiol. 59 (1), 8–14. Heaton, R.K., Gladsjo, J.A., Palmer, B.W., Kuck, J., Marcotte, T.D., Jeste, D.V., 2001. Stability and course of neuropsychological deficits in schizophrenia. Arch. Gen. Psychiatry 58 (1), 24–32. Hemsley, D.R., 2005. The schizophrenic experience: out of context? Schizophr. Bull. 31 (1), 43–53. Hepp, H.H., Maier, S., Hermle, L., Spitzer, M., 1996. The Stroop effect in schizophrenic patients. Schizophr. Res. 22 (3), 187–195. Jonkman, L.M., Lansbergen, M., Stauder, J.E.A., 2003. Developmental differences in behavioral and event-related brain responses associated with response preparation and inhibition in a go/nogo task. Psychophysiology 40 (5), 752–761.
215
Jung, T.P., Makeig, S., Westerfield, M., Townsend, J., Courchesne, E., Sejnowski, T.J., 2000. Removal of eye activity artifacts from visual event-related potentials in normal and clinical subjects. Clin. Neurophysiol. 111 (10), 1745–1758. Knott, V., Mahoney, C., Labelle, A., Ripley, C., Cavazzoni, P., Jones, B., 1999. Event-related potentials in schizophrenic patients during a degraded stimulus version of the continuous performance task. Schizophr. Res. 35 (3), 263–278. Liddle, P.F., Morris, D.L., 1991. Schizophrenic syndromes and frontal lobe performance. Br. J. Psychiatry 158 (3), 340–345. Minzenberg, M.J., Laird, A.R., Thelen, S., Carter, C.S., Glahn, D.C., 2009. Meta-analysis of 41 functional neuroimaging studies of executive dysfunction in schizophrenia. Arch. Gen. Psychiatry 66 (8), 811–822. Must, A., Janka, Z., Benedek, G., Keri, S., 2004. Reduced facilitation effect of collinear flankers on contrast detection reveals impaired lateral connectivity in the visual cortex of schizophrenia patients. Neurosic. Lett. 357 (2), 131–134. Neuhaus, A.H., Koehler, S., Opgen-Rhein, C., Urbanek, C., Hahn, E., Dettling, M., 2007. Selective anterior cingulate cortex deficit during conflict solution in schizophrenia: an event-related potential study. J. Psychiatr. Res. 41 (8), 635–644. Neuhaus, A.H., Trempler, N.R., Hahn, E., Luborzewski, A., Karl, C., Hahn, C., Opgen-Rhein, C., Urbanek, C., Schaub, R., Dettling, M., 2010a. Evidence of specificity of a visual P3 amplitude modulation deficit in schizophrenia. Schizophr. Res. 124 (1–3), 119–126. Neuhaus, A.H., Urbanek, C., Opgen-Rhein, C., Hahn, E., Ta, T.M.T., Koehler, S., Gross, M., Dettling, M., 2010b. Event-related potentials associated with Attention Network Test. Int. J. Psychophysiol. 76 (2), 72–79. O'Donnell, B.F., Vohs, J.L., Hetrick, W.P., Carroll, C.A., Shekhar, A., 2004. Auditory eventrelated potential abnormalities in bipolar disorder and schizophrenia. Int. J. Psychophysiol. 53 (1), 45–55. Opgen-Rhein, C., Neuhaus, A.H., Urbanek, C., Hahn, E., Sander, T., Dettling, M., 2008. Executive attention in schizophrenic males and the impact of COMT val108/ 158met genotype on performance on the attention network test. Schizophr. Bull. 34 (6), 1231–1239. Pass, H.L., Klorman, R., Salzman, L.F., Klein, R.H., Kaskey, G.B., 1980. The late positive component of the evoked response in acute schizophrenics during a test of sustained attention. Biol. Psychiatry 115 (1), 9–20. Phillips, W.A., Silverstein, S.M., 2003. Convergence of biological and psychological perspectives on cognitive coordination in schizophrenia. Behav. Brain Sci. 26 (1), 65–82. Polich, J., 1987. Task difficulty, probability, and inter-stimulus interval as determinants of P300 from auditory stimuli. Electroencephal. Clin. Neurophysiol. 68 (4), 311–320. Roth, W.T., Cannon, F.H., 1972. Some features of the auditory event-related response in schizophrenia. Arch. Gen. Psychiatry 27 (4), 466–471. Salisbury, D.F., Shenton, M.E., McCarley, R.W., 1999. P300 topography differs in schizophrenia and manic psychosis. Biol. Psychiatry 45 (1), 98–106. Uhlhaas, P.J., Mishara, A.L., 2007. Perceptual anomalies in schizophrenia: integrating phenomenology and cognitive neuroscience. Schizophr. Bull. 33 (1), 142–156. Uhlhaas, P.J., Silverstein, S.M., Phillips, W.A., Lovell, P.G., 2004. Evidence for impaired visual context processing in schizotypy with thought disorder. Psychiatry Res. 68 (2–3), 249–260. Urbanek, C., Neuhaus, A.H., Opgen-Rhein, C., Strathmann, S., Wieseke, N., Schaub, R., Hahn, E., Dettling, M., 2009. Attention network test (ANT) reveals gender-specific alterations of executive function in schizophrenia. Psychiatry Res. 168 (2), 102–109. Urretavizcaya, M., Moreno, I., Benlloch, L., Cardoner, N., Serrallonga, J., Menchon, J.M., Vallejo, J., 2003. Auditory event-related potentials in 50 melancholic patients: increased N100, N200 and P300 latencies and diminished P300 amplitude. J. Affect. Disord. 74 (3), 293–297. Van der Stelt, O., Lieberman, J.A., Belger, A., 2005. Auditory P300 in high-risk, recent onset and chronic schizophrenia. Schizophr. Res. 77 (2–3), 309–320. Wang, K., Fan, J., Dong, Y., Wang, C.Q., Lee, T.M., Posner, M.I., 2005. Selective impairment of attentional networks of orienting and executive control in schizophrenia. Schizophr. Res. 78 (2–3), 235–241. Yoon, J.H., Rokem, A.S., Silver, M.A., Minzenberg, M.J., Ursu, S., Ragland, J.D., Carter, C.S., 2009. Diminished orientation-specific surround suppression of visual processing in schizophrenia. Schizophr. Bull. 35 (6), 1078–1084.