Sensory Gating in Schizophrenia: P50 and N100 Gating in Antipsychotic-Free Subjects at Risk, First-Episode, and Chronic Patients

Sensory Gating in Schizophrenia: P50 and N100 Gating in Antipsychotic-Free Subjects at Risk, First-Episode, and Chronic Patients Anke Brockhaus-Dumke, Frauke Schultze-Lutter, Ralf Mueller, Indira Tendolkar, Andreas Bechdolf, Ralf Pukrop, Joachim Klosterkoetter, and Stephan Ruhrmann Background: Abnormal sensory gating in schizophrenia has frequently been reported; however, only limited data on unmedicated patients and patients at risk to develop a psychosis have, as yet, been available. Methods: P50 and N100 suppression were assessed with an auditory double-click paradigm in five groups: 18 at-risk subjects who did not develop a full psychosis within the follow-up period of 2 years, 21 truly prodromal subjects who developed frank psychosis within the follow-up period, 46 antipsychotic-naïve subjects with first-episode schizophrenia, 20 antipsychotic-free subjects with chronic schizophrenia, and 46 healthy control subjects. Results: P50 and N100 suppression indices differed significantly between groups and were lowest in chronic schizophrenia patients. Compared with healthy control subjects, P50 suppression was significantly impaired in at-risk subjects, truly prodromal and first-episode patients (stimulus 2 [S2]/stimulus 1 [S1] P50 amplitude ratio), and chronic schizophrenia patients (difference and ratio), and N100 suppression was significantly reduced in truly prodromal and first-episode patients (S1–S2 difference) and in chronic schizophrenia patients (difference and ratio) but not at-risk subjects. At-risk subjects with and without conversion to psychosis did not significantly differ on any test parameter. Conclusions: Sensory gating is already impaired in early stages of schizophrenia, though this is most prominent in chronic stages. Future studies will have to clarify the type and impact of variables modifying sensory gating disturbances, such as illness progression and genetic load. Furthermore, the meaning and nature of differences between P50 and N100 suppression need further elucidation. Key Words: Early recognition, EEG, event-related potentials, first episode, prodrome, schizophrenia, sensory gating

M

idlatency auditory evoked potentials (e.g., the P50 component that appears about 50 msec after stimulus onset) have been used in studies of auditory information processing in schizophrenia. Their core finding is that, in a conditioning-testing paradigm, decreased attenuation of the P50 component to the second of two clicks occurs in schizophrenia patients, which can be related to a deficit in sensory gating (1–5). This was also supported by a recent meta-analysis (6). Nonetheless, overall results are less consistent than for other neurophysiological parameters, such as the P300 amplitude, since some studies failed to show differences in P50 suppression between schizophrenia patients and control subjects (7–10). Yet, there is indication that P50 gating is associated with a disorganized subtype of schizophrenia and prominent negative symptoms, respectively (10 –15). Recent research has focused on the evaluation of P50 suppression as an endophenotype of schizophrenia. As such, it should be heritable, i.e., show a familial co-segregation with illness and be present in some unaffected relatives, and stateindependent (16). So far, a reduced P50 suppression has been linked to several gene loci (17) and was found in healthy

From the Department of Psychiatry and Psychotherapy (AB-D, FS-L, RM, AB, RP, JK, SR), University of Cologne, Cologne, Germany; and Department of Psychiatry (IT), University Medical Center Nijmegen, University of Nijmegen, Nijmegen, Netherlands. Address reprint requests to Anke Brockhaus-Dumke, M.D., Department of Psychiatry and Psychotherapy, University of Cologne, Kerpener Str. 62, D-50924 Cologne, Germany; E-mail: [email protected]. Received June 7, 2007; revised February 7, 2008; accepted February 7, 2008.

0006-3223/08/$34.00 doi:10.1016/j.biopsych.2008.02.006

relatives of schizophrenia patients (18 –25) and in schizotypal personality disorder (26). Myles-Worsley et al. (27) compared a genetically defined high-risk group and a clinically defined sample of at-risk adolescents and showed that P50 suppression was impaired in both groups. Yet, in the genetically high-risk group, P50 suppression abnormalities were found only in those with clinically defined prodromal symptoms (27). Recently, Cadenhead et al. (28) showed that subjects at risk of developing a psychosis had modestly lower levels of P50 suppression relative to control subjects, in particular, if they had a first-degree relative with schizophrenia (28). This difference was nonsignificant, probably due to 1) the fact that a mixed sample was investigated (less than half of the at-risk group was predicted to develop a psychotic episode at least in the next future), and 2) the fact that one third of the group was receiving an atypical antipsychotic that might have “normalized” P50 suppression. The effects of antipsychotic medication on the modulation of the P50 are still not elucidated. Under treatment with firstgeneration antipsychotics (FGAs), a reduction of the P50 suppression was described that was not present under treatment with second-generation antipsychotics (SGAs) (2,4,5). However, a review of the effects of antipsychotics on sensory gating concluded that there was little evidence to suggest that FGAs adversely affect sensory gating (15). And although clozapine might normalize P50 gating, there is scarce evidence of a restorative effect on sensory gating for other SGAs (15). However, to preclude possible confounding effects of antipsychotic medication, only subjects free of antipsychotic medication at the time of recordings were included in the current study. Recent results have extended the findings of reduced P50 suppression in schizophrenia to later event-related potential (ERP) components. Accordingly, sensory gating appears as a pervasive abnormality in schizophrenia patients that is not limited to BIOL PSYCHIATRY 2008;64:376 –384 © 2008 Society of Biological Psychiatry

BIOL PSYCHIATRY 2008;64:376 –384 377

A. Brockhaus-Dumke et al. the preattentive phase of information processing but also present in later stages as reflected by the N100 and the P200 (29,30). Compared with reliability measures of P50 parameters, the N100 component and the N100 derived gating parameters were equally reliable, while the reliability of the suppression ratio of N100 was even superior to that of the corresponding P50 parameter (31). Therefore, in the present study, we investigated both P50 and N100 components using a double-click paradigm in at-risk subjects without transition to psychosis, in truly prodromal patients who subsequently developed psychosis within the 2-year follow-up period, in antipsychotic-naïve first-episode schizophrenia patients, in antipsychotic-free chronic schizophrenia patients, and in healthy control subjects. We expected reduced gating parameters (difference and ratio) in truly prodromal patients and both schizophrenia patient groups compared with control subjects. In addition, we explored possible differences between at-risk subjects with and without conversion to psychosis within the follow-up period.

Methods and Materials Subjects Thirty-nine outpatients of the Early Recognition and Intervention Centre for mental crises (FETZ) at the Department of Psychiatry and Psychotherapy of the University of Cologne meeting prodromal criteria were included. Eighteen of these at-risk subjects (46.2%) did not develop a full-blown psychotic episode within the 24-month follow-up period (at-risk patients [AR]). Twenty-one (53.8%) developed a psychotic disorder according to DSM-IV criteria within the 24-month follow-up period

(truly prodromal patients [PP]): 95.2% developed a schizophrenic psychosis (of these, 65% a paranoid subtype and 35% an undifferentiated subtype), and 4.8% developed a schizoaffective disorder. A prodromal state has been defined by the presence of at least any two of nine self-experienced and self-reported subtle subclinical cognitive disturbances, i.e., basic symptoms, as assessed with the Bonn Scale for the Assessment of Basic Symptoms (BSABS) (32) and the Schizophrenia Proneness Instrument, Adult Version (SPI-A) (33,34), respectively. In the prospective Cologne Early Recognition (CER) study evaluating the predictive value of basic symptoms (35), the high-risk criterion cognitive disturbances (COGDIS) had shown a sensitivity of .67, a specificity of .83, and good positive (.79) and negative (.72) predictive values (36). Of the 18 at-risk subjects, 10 (55.56%) had met the COGDIS criterion only, whereas of the 21 truly prodromal subjects, 9 subjects (42.86%) had met the COGDIS criterion only. The remaining subjects had additionally presented with attenuated positive symptoms (APS) and brief limited intermittent psychotic symptoms (BLIPS) according to the ultra-high risk (UHR) criteria (37). Details are presented in Table 1. Exclusion criteria of the at-risk and the prodromal groups were 1) a present or past psychotic episode according to Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I) criteria (38); 2) the presence of symptoms that reached psychotic intensity for more than 1 week according to the consensus criterion for a transition to psychosis (37), 3) current substance abuse or cannabis use, and 4) a physical illness that may account for the symptoms. The schizophrenia patients (46 antipsychotic-naïve first-epi-

Table 1. Demographic and Clinical Data of Healthy Control Subjects, High-Risk Subjects, and True Prodromal, First-Episode, and Chronic Schizophrenia Patients

Age (years) Gender (male/female) School Education (years) Duration of Illness (years) Age at Onset (years) Number of Episodes Smoking (yes/no) Genetic Load (yes /no)a Subtype (paranoid/ disorganized) APS (yes/no)b BLIPS (yes/no)c PANSS Positive Scored PANSS Negative Scored PANSS Sum Scored

First Episode (FE) (n ⫽ 46) (mean/SD)

Chronic Schizophrenia (CS) (n ⫽ 20) (mean/SD)

Statistics [F (df)/p]c [␹2 (df)/p]d

21.76 (4.15) 18/3

28.0 (7.16) 30/16

27.35 (8.75) 18/2

3.60 (4,146)/.008e 8.73 (4)/nse

11.79 (1.36)

11.58 (2.39)

11.25 (1.62)

5.23 (4,138)/.001e

1.18 (1.30) 28.05 (7.06) 18/28 1/45

5.39 (4.16) 22.89 (6.44) 5.29 (9.48) 12/8 0/20

38/8

19/1

19.78 (3.27) 21.63 (5.98) 84.46 (13.56)

24.59 (9.72) 24.94 (8.53) 93.71 (25.10)

Control Subjects (C) (n ⫽ 46) (mean/SD)

High- Risk (HR) (n ⫽ 18) (mean/SD)

Prodromal Patients (PP) (n ⫽ 21) (mean/SD)

26.22 (5.29) 28/18

25.61 (6.27) 12/6

12.9 (.68)

12.18 (1.33)

2/44

6/12 1/17

6/15 8/13

8/10 2/16 14.0 (5.1) 17.0 (6.13) 63.20 (15.57)

9/12 8/13 14.57 (3.61) 20.07 (5.06) 71.07 (16.28)

36.62 (1,60)/.000e 7.38 (1,60)/.009e 25.30 (4)/.000f 25.21 (3)/.000f 1.82 (1)/nsf .92 (1)/nsf 3.70 (1)/nsf 10.43 (3,64)/.000e 3.25 (3,64)/.027e 27.15 (3,59)/.000e

ANOVA, analysis of variance; APS, attenuated positive symptoms; BLIPS, brief limited psychotic episodes; C, healthy control subjects; CS, chronic schizophrenia patients; FE, first-episode patients; HR, high-risk subjects; ns, not significant (p ⬎.05); p, level of significance; PANSS, Positive and Negative Syndrome Scale; PP, prodromal patients; SD, standard deviation. a Genetic load: at least one first-degree family member with psychosis. b Attenuated positive symptoms (APS). c Brief limited psychotic episodes (BLIPS) (Phillips et al. [37]). d Psychopathology assessed by the Positive and Negative Syndrome Scale (PANSS) (Kay et al. [41]). e ANOVA. f Chi-square test.

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Table 2. P50 and N100 Amplitudes, Latencies, Amplitude Differences (S1–S2), and Suppression Indices

P50 S1 Amplitude (␮V) P50 S2 Amplitude (␮V) P50 S1 Latency (␮V) P50 S2 Latency (␮V) P50 Difference (S1–S2) (␮V) P50 Ratio (S2/S1) N100 S1 Amplitude (␮V) N100 S2 Amplitude (␮V) N100 S1 Latency (␮V) N100 S2 Latency (␮V) N100 Difference (S1–S2) (␮V) N100 Ratio (S2/S1)

HC (n ⫽ 6)

HR (n ⫽ 18)

PP (n ⫽ 21)

FE (n ⫽ 46)

CS (n ⫽ 20)

Chi- Square (df ⫽ 4)

p Value

3.12 (1.50) n ⫽ 41 1.44 (1.06) n ⫽ 35 60.10 (5.17) n ⫽ 41 59.74 (6.79) n ⫽ 35 1.87 (1.34) n ⫽ 35 .43 (.28) n ⫽ 35 6.28 (4.00) n ⫽ 44 1.74 (2.05) n ⫽ 42 101.89 (11.99) n ⫽ 44 103.52 (13.09) n ⫽ 42 4.49 (3.20) n ⫽ 40 .24 (.38) n ⫽ 40

3.0 (1.58) n ⫽ 15 2.06 (.84) n ⫽ 14 60.8 (5.89) n ⫽ 15 62.94 (7.64) n ⫽ 14 1.10 (1.27) n ⫽ 14 .67 (.34) n ⫽ 13 4.05 (1.92) n ⫽ 17 1.67 (1.50) n ⫽ 17 101.18 (6.56) n ⫽ 17 95.82 (11.71) n ⫽ 17 2.39 (1.19) n ⫽ 17 .37 (.28) n ⫽ 17

2.84 (1.25) n ⫽ 19 1.75 (.90) n ⫽ 17 63.47 (5.58) n ⫽ 19 62.94 (6.20) n ⫽ 17 1.16 (.97) n ⫽ 17 .64 (.26) n ⫽ 17 3.35 (1.70) n ⫽ 20 1.31 (1.52) n ⫽ 20 103.45 (11.71) n ⫽ 20 100.95 (12.72) n ⫽ 20 2.27 (1.46) n ⫽ 19 .23 (.37) n ⫽ 18

3.14 (1.75) n ⫽ 29 1.96 (1.32) n ⫽ 21 60.62 (8.36) n ⫽ 29 62.52 (8.08) n ⫽ 21 1.43 (1.68) n ⫽ 21 .65 (.38) n ⫽ 21 3.41 (2.53) n ⫽ 45 1.13 (1.37) n ⫽ 46 101.42 (11.79) n ⫽ 45 97.89 (13.63) n ⫽ 46 2.23 (2.35) n ⫽ 44 .25 (.49) n ⫽ 41

2.00 (.84) n ⫽ 14 1.89 (1.39) n ⫽ 13 59.86 (9.26) n ⫽ 14 61.46 (10.87) n ⫽ 13 .21 (.77) n ⫽ 12 .85 (.42) n ⫽ 12 2.88 (1.35) n ⫽ 17 1.62 (1.37) n ⫽ 17 96.47 (9.33) n ⫽ 17 101.24 (13.53) n ⫽ 17 1.03 (1.63) n ⫽ 16 .69 (.66) n ⫽ 16

7.649

ns

5.91

ns

5.05

ns

3.38

ns

16.79

.002

15.85

.003

18.22

.001

3.00

ns

4.51

ns

6.32

ns

20.21

.000

9.82

.043

Mean values and standard deviations (SD) of P50 and N100 amplitude and latency elicited by stimulus 1 (S1) and stimulus 2 (S2), difference (S1 amplitude minus S2 amplitude), and ratio (amplitude S2/amplitude S 1; i.e., the higher the ratio, the lower is the gating) in healthy control subjects (HC), high-risk subjects without transition to psychosis (HR), true prodromal patients with transition to psychosis (PP), antipsychotic-naive patients with first-episode schizophrenia (FE), and actually antipsychotic-free patients with chronic schizophrenia (CS). Chi-square and p values obtained by the nonparametric test according to Kruskal-Wallis are given in the last two columns. CS, chronic schizophrenia patients; FE, first-episode patients; HC, healthy control subjects; HR, high-risk subjects; ns, not significant; PP, prodromal patients; S1, stimulus 1; S2, stimulus 2; SD, standard deviation.

sode patients [FE], 20 chronic schizophrenia patients [CS] free of antipsychotic medication at time of recordings for at least 4 weeks) were recruited from the Department of Psychiatry and Psychotherapy of the University of Cologne. Actual drug intake was ruled out by urine analyses in first-episode and chronic schizophrenia patients. All met criteria for schizophrenia according to DSM-IV. For clinical data, see Table 1. The exclusion criteria for both schizophrenia groups were the same as for the at-risk and prodromal groups, except for the exclusion of psychosis. Furthermore, schizophrenia patients fulfilling criteria of any other Axis 1 disorder (double diagnosis) were excluded. Additionally, 46 healthy control subjects were recruited. Exclusion criteria included past or current psychiatric diagnosis including substance use and/or dependence, current physical illness, and family history of psychiatric illness in first-degree biological relatives. All participants gave their written informed consent prior to assessments after the procedure was fully explained. During the diagnostic interview and the explanation of the study, the first author assessed that no impairment of decision-making capability was present in any of the included subjects. Smokers refrained from smoking 1 hour prior to and during recordings. Measurement of P50 and N100 Event-Related Potentials Subjects were seated in a comfortable recliner in a quiet, dim lighted room, wearing headphones for presentation of auditory stimuli. A hearing test, but no audiometric test, was performed prior to recordings to exclude severe hearing deficits. Subjects www.sobp.org/journal

were instructed to relax, to keep their eyes open, and to focus on a fixation point. All subjects were monitored for signs of drowsiness by visual observation and electroencephalogram (EEG) monitoring. Sintered Ag/AgCl electrodes were used (Falk Minow Services, Herrsching, Germany), and all electrode resistances were less than 5 k⍀. Eye movements were recorded by using electrooculography (EOG) with placement of Ag/AgCl electrodes at the outer canthi of both eyes for horizontal eye movements, as well as above and below the right eye for vertical movements. Electrodes were used at 32 recording sites according to the 10-20 system with a forehead ground and referenced to the vertex electrode (Cz). Offline data were computed to a linked mastoid reference. Stimuli were generated by the STIM system (Neuroscan, El Paso, Texas). The auditory clicks consisted of broadband square waves of 1-msec duration with an average resulting click of 90 A-weighted decibels (dB[A]). The stimuli were 96 click pairs (stimulus 1 [S1] and stimulus 2 [S2]) with a 500-msec interval between S1 and S2. The interval between click pairs was 10 seconds. The EEG/EOG was continuously recorded using a 16-bit analog-to-digital (A/D) converter with a resolution of .168 ␮V/bit (Synamps, Neuroscan, El Paso, Texas); the sampling rate was 500 Hz using a 70 Hz low-pass and a .1 Hz high-pass filter. Offline processing and peak evaluation were performed with the Brain Vision Analyzer (Brain Products GmbH, Gilching, Germany) in a fully automated procedure. Additionally, epochs were visually screened for artifacts by raters blind to group membership. Epochs of 250 msec including a 100 msec baseline separately

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Figure 1. P50 and N100 amplitude difference (S1–S2) and ratio (S2/S1). The two upper graphs show the amplitude differences (S1 amplitude minus S2 amplitude, in ␮V) for the P50 (upper left panel) and the N100 (upper right panel). The two lower graphs show the ratio (S2/S1) for the P50 (lower left panel) and the N100 (lower right panel). The bars reflect the mean values in electrode position Cz; the error bars indicate the confidence intervals (95%). Levels of significance are given (*** p ⬍ .001, ** p ⬍ .01, * p ⬍ .05). Please, be aware of the different scaling for P50 and N100 differences. Cz, vertex electrode; S1, stimulus 1; S2, stimulus 2.

for S1 and S2 stimuli were filtered using 1) a 10 Hz high-pass filter for the analysis of the P50 and 2) a Butterworth zero-phase filter (.5305 Hz–70 Hz, 12-dB/octave high- and low-pass slopes) for the N100. After baseline correction, an ocular artifact correction according to the algorithm proposed by Gratton et al. (39) was calculated for the N100 component, whereas P50 component epochs containing ocular artifact were excluded from the analyses. All EEG epochs were screened for artifacts, and trials containing artifacts (⫾50 ␮V EEG channel deflection) were not included in the waveform averaging. Sixty artifact-free epochs were averaged separately for S1 and S2 stimuli. The P50 component was identified as the most positive deflection within 40 to 80 msec after stimulus presentation. The P50 amplitude elicited by S2 was identified as the most positive deflection within ⫾10 msec of the latency of the corresponding P50 component elicited by S1. The P50 amplitude was defined as the absolute difference between the P50 peak and the preceding negative trough (40). Data from the vertex (Cz) are reported. The P50 suppression was calculated as the ratio S2 amplitude/S1 amplitude; this means that a lower value of the

ratio indicates a higher suppression of S2 compared with S1 (i.e., the gating). A maximum of 2 (or 100% facilitation) was used to prevent outliers from disproportionately affecting the group means, consistent with the methods of Nagamoto et al. (40). The P50 amplitude difference was calculated as the difference between S1 and S2 amplitudes. The N100 component was identified as the most negative deflection within 80 to 130 msec after stimulus presentation. The N100 amplitude was defined as the absolute difference between the N100 peak and baseline. The N100 ratio (S2/S1) and the N100 amplitude (S1–S2) difference were calculated in analogy to the P50 suppression parameters. Data Analysis All variables were normally distributed (one-sample Kolmogorov-Smirnov test), but as the distribution of data was more or less skewed, nonparametric statistics were employed. Multiple group comparisons were made by Kruskal-Wallis test. Post hoc, Mann-Whitney U tests were used to elucidate differences between individual groups. Correlations between ERP data as well www.sobp.org/journal

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Figure 2. P50 and N100 amplitudes. The left panel shows the P50 amplitudes, the right panel shows the N100 amplitudes (in ␮V) of the individuals. Amplitudes elicited by the first click (S1) are represented by full black triangles, amplitudes elicited by the second click (S2) by empty black triangles. The black horizontal lines indicate the group means of the respective amplitude. Please, be aware of the different scaling for P50 and N100. S1, stimulus 1; S2, stimulus 2.

as with age, age of onset, duration of illness, and Positive and Negative Syndrome Scale (PANSS) scores were assessed using the two-tailed Spearman rank correlation test. A two-tailed ␣ level of 5% was considered significant throughout. Bonferroni procedure was applied to adjust for multiple comparisons. All tests were calculated using SPSS 14 (SPSS GmbH, München, Germany).

Results The P50 gating differed significantly between groups (P50 difference: p ⬍ .002; P50 ratio: p ⬍ .003, for details see Table 2). Post hoc tests revealed that chronic schizophrenia patients (CS) showed lower P50 difference than all other groups (see Figure 1, upper left panel), i.e., compared with control subjects (HC; p ⫽ .000), with at-risk subjects (AR; p ⫽ .036), with truly prodromal subjects (PP; p ⫽ .004), and with first-episode patients (FE; p ⫽ .030). After Bonferroni correction for 10 post hoc tests, the difference between HC and CS maintained significance (p ⬍ .05), but the difference between PP and SC receded to a statistical trend (p ⬍ .10). P50 ratio was significantly impaired in all other groups compared with control subjects (see Figure 1, lower left panel). Control subjects (HC) had lower P50 ratio compared with AR (p ⫽ .011), with PP (p ⫽ .007), with FE (p ⫽ .035), and with CS (p ⫽ .004). After Bonferroni correction for 10 post hoc tests, the difference between HC and PP and that between HC and CS reached statistically a trend level (p ⬍ .10). The P50 amplitudes and latencies elicited by S1 and S2 did not differ significantly between groups. The N100 gating measured either as the N100 amplitude difference (p ⬍ .000) or as the N100 ratio (p ⬍ .05) differed significantly between groups (details are given in Table 2). Post hoc tests revealed that the N100 differences (S1–S2) were significantly reduced in PP (p ⫽ .031), FE (p ⫽ .001), and CS (p ⫽ .000) but not AR (p ⫽ .052) when compared with HC (Figure 1, upper right panel). However, only the differences between HC and FE (p ⬍ .05) and HC and CS (p ⬍ .01) withstood Bonferroni correction for 10 post hoc tests. The N100 ratio was significantly reduced in CS compared with all other groups (HC: p ⫽ .003; AR: www.sobp.org/journal

p ⫽ .049; PP: p ⫽ .025; FE: p ⫽ .006; see Figure 1, lower right panel). After Bonferroni correction for 10 post hoc tests, the differences between HC and CS, as well as PP and CS, receded to trend level (p ⬍ .10). In line with the N100 difference, the N100 amplitude elicited by S1 was significantly reduced in PP (p ⫽ .006), FE (p ⫽ .001), and CS (p ⫽ .002) but not AR (p ⫽ .102) when compared with HC. After Bonferroni correction for 10 post hoc tests, the differences between HC and FE, as well as between HC and CS, remained significant (p ⬍ .05); the difference between HC and PP decreased to a trend (p ⬍ .10). The N100 amplitude elicited by S2, as well as N100 latencies elicited by S1 and S2, did not differ significantly between groups. Figure 2 displays the distribution of P50 amplitudes (left panel) and N100 amplitudes (right panel) and the mean amplitudes of S1 and S2, demonstrating the variation and the overlap between groups, as well as the differences described above. Grand average waveforms of P50 (Figure 3) and N100 (Figure 4) clearly show the reduction of the S1 amplitudes in FE and CS, as well as the deficient reduction of the S2 response (especially P50 in truly prodromals). Significant results of correlation analyses are shown in Table 3. The P50 S1 amplitude was significantly correlated with the P50 S2 amplitude and the P50 difference (p ⬍ .05 after Bonferroni correction for 80 tests). Furthermore, the P50 ratio was significantly correlated with the P50 S2 amplitude and the P50 difference (p ⬍ .05 after Bonferroni correction for 80 tests). The same pattern was present for N100 amplitudes and gating scores. No significant correlations were present between ERP parameters and clinical data or PANSS scores except significant though weak correlations between age and P50 amplitude to S2 as well as between age and the P50 ratio that both did not withstand Bonferroni correction (Table 3).

Discussion Event-related potentials are not yet fully understood for their neurophysiological underpinnings. Yet, especially the P50 suppression is discussed as a potential neurophysiological endophenotype of schizophrenia. As such, it should, among others, have

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BIOL PSYCHIATRY 2008;64:376 –384 381 been described by Myles-Worsly et al. (27) in a sample of Palauan high-risk adolescents. With regard to recent-onset schizophrenia patients, limited data (5) show a disruption in P50 suppression during the early stages of illness. No data on antipsychotic-naïve first-episode patients have been reported up to now. Currently, the neurophysiological underpinnings leading to sensory gating and its disturbance in schizophrenia are not yet fully understood, and two etiological hypotheses prevail: reduced gating may be due to either 1) a reduction of the S1 amplitude or 2) an impaired inhibition of the S2 response (13,30,43,44). Thus, it has been supposed that two processes contribute to the gating deficit, i.e., a reduced sensory registration (S1 amplitude reduction) and a reduced ability to habituate to repeated auditory stimulation (lack of reduction of S2 amplitude). In our study, the S1–S2 difference was highly correlated with the S1 amplitude (P50 and N100) but only weakly with the S2 amplitude (P50, not N100); thus, our data primarily but not solely support the first hypothesis, i.e., the assumption that the S1–S2

Figure 3. Grand averages of the P50 component. The ERP elicited by the first click (S1) is represented by the dark black line; the gray line represents the ERP elicited by the second click (S2). The x axis represents the time axis (raging from ⫺100 msec to ⫹150 msec, time 0 msec indicates stimulus onset), the y axis represents the amplitude (raging from ⫺5 ␮V to ⫹3.5 ␮V, positive values are plotted up). The P50 component (S1 and S2 amplitude) is markedly, though statistically not significantly, reduced in CS; there is nearly no difference between S1 and S2 amplitude, reflected by significantly reduced S1–S2 amplitude difference and increased ratio in CS compared with the four other groups (compare with Figure 1). HC, healthy controls; AR, at-risk subjects; PP, true prodromal patients; FE, first episode; CS, chronic schizophrenia patients; ERP, event-related potential; S1, stimulus 1; S2, stimulus 2.

the property of state independence (42). Therefore, we evaluated differences of sensory gating in antipsychotic-naïve patients at risk to develop a full-blown psychosis and in patients at early and later stages of schizophrenia free of antipsychotic medication. Thus, P50 and N100 gating were investigated in at-risk subjects (AR) that did not develop a full-blown psychosis within a 2-year follow-up, truly prodromal patients (PP) who developed psychosis within this period, antipsychotic-naive patients with a first psychotic episode (FE), antipsychotic-free patients with chronic schizophrenia (CS), and healthy control subjects (HC). As expected, a P50 and a N100 gating deficit reflected by the S1–S2 amplitude difference and the ratio (S2 amplitude/S1 amplitude) were clearly present in antipsychotic-free CS. These results are in line with previous work on mixed samples—mixed in terms of antipsychotic medication (medicated and unmedicated samples) and stage of illness (first-episode and chronic schizophrenia patients), respectively (29,30). Furthermore, PP and FE were also significantly impaired in sensory gating as reflected by an increased P50 ratio and reduced N100 differences as compared with HC. These data indicate an association between an inhibitory neurophysiological deficit and early clinical symptomatology. Corresponding findings have also

Figure 4. Grand averages of the N100 component. The ERP elicited by the first click (S1) is represented by the dark black line; the gray line represents the ERP elicited by the second click (S2). The x axis represents the time axis (raging from ⫺100 msec to ⫹150 msec, time 0 msec indicates stimulus onset); the y axis represents the amplitude (raging from ⫺5 ␮V to ⫹3.5 ␮V, positive values are plotted up). The N100 amplitude elicited by the first click (S1) is significantly reduced in prodromal subjects and first-episode and chronic patients compared with control subjects, whereas the S2 amplitude does not differ between groups. Correspondingly, the S1–S2 amplitude difference is significantly reduced in prodromal subjects and first-episode and chronic patients compared with control subjects and the suppression index is significantly reduced in chronic patients compared with control subjects, prodromal subjects, and first-episode patients (compare with Figure 1). HC, healthy controls; AR, at-risk subjects; PP, true prodromal patients; FE, first episode; CS, chronic schizophrenia patients; ERP, event-related potential; S1, stimulus 1; S2, stimulus 2.

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Table 3. Summary of the Correlation Analyses P50 S2 P50

S1

S2

Diff

.539(***)a .000 100

Diff .594(***)a .000 99 ⫺.254(*)c .011 99

N100 Ratio

S1

S2

Diff

Ratio

Age

ns

.232(*)c .014 112

ns

.300(**)c .002 107

ns

ns

.720(***)a .000 98 ⫺.789(***)a .000 98

ns

ns

ns

ns

⫺.217(*)c .030 100

.276(**)c .007 94

ns

.331(**)b .001 90

ns

ns

ns

⫺.230(*)c .023(*) 98

ns

ns

Ratio ns N100

S1

ns .492(***)a .000 107

ns .809(***)a .000 107

S2 ns Diff

.756(***)a .000 104 ⫺.549(***)a .000 104

ns

ns

Ratio ns Spearman correlation coefficient (first row), significance level p (second row), and sample size n (third row) of the correlation analysis of ERP parameter and clinical data. ***p ⬍ .000; **p ⬍ .001; *p ⬍ .05 prior to Bonferroni correction. Age, age at recordings (in years); diff, difference S1 amplitude minus S2 amplitude (in ␮V); ratio, ratio S2 amplitude/S1 amplitude; S1, first click; S2, second click; ERP, event-related potential. a After Bonferroni correction for 80 tests still significant (p ⬍ .05; dark yellow). b after Bonferroni correction for 80 tests still a trend (p ⬍ .01); light yellow). c after Bonferroni correction for 80 tests not significant (ns; light green).

amplitude difference mainly, but not exclusively, mirrors smaller stimulus registration reflected by the S1 amplitude. The S2/S1 ratio, on the other hand, seems to primarily reflect the reduced gating, as the S2/S1 ratio was strongly correlated with the S2 amplitude but not with the S1 amplitude (Table 3). However, the S1–S2 difference and the S2/S1 ratio were significantly interrelated as well. Thus, it can be concluded that the S1–S2 difference reflects both impairment in stimulus registration and—to a probably lesser extent— gating or habituation to repeated stimulation, whereas the S2/S1 ratio is predominately an expression of gating and to a lesser extent of stimulus registration. Analyses of correlations between P50 and N100 revealed weak to moderate correlations of the P50 S1 amplitude and the P50 S1–S2 difference with N100 S1 amplitude and N100 S1–S2 difference. By contrast, the S2 amplitudes and the ratio of P50 and N100 did not show significant correlations across the two test parameters but within their respective parameter (Table 3), thus indicating that both P50 and N100 reflect stimulus registration in similar ways but gating or habituation to repeated stimulation in different ways. In the future, understanding of these phenomena will benefit from the growing knowledge on stimulus encoding via the primary thalamic nuclei to the primary auditory cortex and its modulation by prefrontal, limbic, and thalamic structures such as the reticular thalamic nucleus. Thus, the co-investigation of the oscillatory brain activity underlying ERP components is strongly recommended, especially as P50 is associated with higher frequencies of the gamma band and N100 is associated with lower frequencies in the alpha and theta bands (45). www.sobp.org/journal

Another aim of our study was testing for state independence of deficits in auditory information processing. We found the reduction of the suppression index, i.e., the lack of suppression of the S2 amplitude, most prominent in our sample of chronic schizophrenia patients. Thus, it appeared to be associated with illness progression, despite the lack of significant correlation between illness duration and evoked potentials. However, significant impairments of the P50 ratio, the N100 S1 amplitude, and the S1–S2 difference of the N100 component have already been present in prodromal and first-episode patients, i.e., the early stages of the illness. Thus, these phenomena might be less affected by illness duration. Additionally, we did not find a significant difference between at-risk subjects, truly prodromal patients, and first-episode patients for any one of the ERP components, difference, or ratio. Consequently, our results are more compatible with the notion that deficits in midlatency auditory ERPs are a state marker of the expression of the illness or at least “influenced by state-dependent factors” (42) rather than with the predominant hypothesis that P50 gating is a marker of genetic risk for schizophrenia or an endophenotype. These results are in line with recent results of de Wilde et al. (46), who did not find significant P50 gating differences in first-episode patients and their unaffected siblings. However, there is evidence of gating deficits in all groups but to different degrees. Longitudinal follow-up studies that also evaluate medication effects are needed to clarify this issue. This is the first study reporting sensory gating data on at-risk subjects who were proven to be truly prodromal by subsequently

A. Brockhaus-Dumke et al. developing a psychosis and antipsychotic-naïve first-episode patients. Notwithstanding, the study is limited due to unequal sample sizes, the unequal mean age of the groups with lowest age in the prodromal group, the unequal distribution of nicotine consumption with only two smokers in the control group, and the unequal distribution of relatives suffering from schizophrenia that is highest in the true prodromal sample. Thus, we preferred the nonparametric statistical approach in combination with Bonferroni corrections instead of a parametric approach after a normalization procedure because the analysis of potentially confounding factors is rather limited due to their unequal distribution. However, in line with previous results (21,46,47), we found only a weak correlation of age with P50 gating and none with N100 gating (Table 3), indicating little if any influence of age in our sample. The effects of nicotine consumption and of genetic load have to be addressed in a subsequent study. The investigation of auditory sensory gating implies several methodological problems such as the signal-to-noise ratio or variation of peak latencies. To assure a reasonable signal-tonoise ratio in the ERPs and prevent the single trial latency jitter to disproportionally affect the ERP amplitudes (48), we used a fixed number of 60 trials per average. However, we cannot exclude that this approach may have introduced yet another bias in the ERP evaluation. Another potential source of error is the variation of peak latencies in the patient groups. The pattern of blurred waveform with a general amplitude reduction in FE and CS, especially in the P50 grand averages (Figure 3), might be caused by a higher latency variance of the P50 S1 and S2 peaks without significant differences of the corresponding amplitude (Table 2). The alternative or additional possibility that the waveforms might have been affected by the individual latency variation could have been ruled out by single trial analyses (48), but signal-to-noise ratio may be too low to reliably identify P50 in individual trials. In summary, to the best of our knowledge, this is the first time that a sensory gating deficit in selected samples of truly prodromal patients with later transition to psychosis and drug-naïve first-episode patients was demonstrated by a higher P50 S2/S1 ratio and a reduced N100 amplitude difference in these samples. These findings support the hypothesis that the S2/S1 ratio and S1–S2 amplitude difference of midlatency auditory ERPs are associated with disturbances in sensory registration and sensory gating and reflect stable trait and risk indicators of schizophrenia that are already present in prodromal and early stages of schizophrenia. The lack of significant differences between at-risk subjects, truly prodromal patients, and first-episode patients in combination with the pronounced deficit in chronic schizophrenia patients, however, is inconsistent with a complete state independence. It rather indicates that suppression of midlatency auditory ERPs—in addition to its early presence during the development of schizophrenia—might increase with the progressive illness. However, future longitudinal follow-up studies will have to address this issue conclusively. P50 recordings were supported by the Koeln Fortune Program/Faculty of Medicine, University of Cologne at project number 38/1998 awarded to AB-D. Follow-up of at-risk subjects was supported by the Koeln Fortune Program/Faculty of Medicine, University of Cologne at project numbers 8/2005 and 27/2006 awarded to FS-L. We thank all participants whose willingness to participate made the study possible. All authors report no biomedical financial interests or potential conflicts of interest.

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