MEG does not reveal impaired sensory gating in first-episode schizophrenia

Schizophrenia Research 121 (2010) 131–138

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

MEG does not reveal impaired sensory gating in first-episode schizophrenia☆ Silke Bachmann a,⁎, Matthias Weisbrod b, Miriam Röhrig b, Johannes Schröder c, Christine Thomas d, Michael Scherg e, André Rupp e a b c d e

Department of Psychiatry, Psychotherapy and Psychosomatics, University Hospitals Halle/Saale, Julius-Kühn-Str. 7, 06112 Halle (Saale), Germany Section of Experimental Psychopathology, Department of Psychiatry, Center for Psychosocial Medicine, University of Heidelberg, Voss-Str. 4, 69115 Heidelberg, Germany Section of Geriatric Psychiatry, Department of Psychiatry, Center for Psychosocial Medicine, University of Heidelberg, Voss-Str. 4, 69115 Heidelberg, Germany Department of Geriatric Psychiatry, Center for Psychiatry and Psychotherapy, Ev. Hospital Bielefeld-Bethel, Bethesdaweg 12, 33617 Bielefeld, Germany Section of Biomagnetism, Department of Neurology, University of Heidelberg, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany

a r t i c l e

i n f o

Article history: Received 11 January 2009 Accepted 7 March 2010 Available online 5 May 2010 Keywords: MEG AEF P50m N100m Spatio-temporal source analysis Sensory gating Schizophrenia First-episode

a b s t r a c t Objective: The inability to adequately suppress the second of two identical stimuli is called sensory gating deficit and can be studied by recording evoked potentials to auditory stimuli, e.g. the P50 and the N100. It has been considered the physiological correlate of schizophrenia patients' perception of being flooded by sensory impressions. According to the notion that the gating deficit constitutes a genetic trait, we expected to demonstrate the phenomenon in firstepisode schizophrenia patients by using Magnetencephalography (MEG). Methods: Eighteen inpatients in remission of their first psychotic episode and 24 healthy, ageand sex-matched control subjects participated in the study. Diagnoses, psychopathology, and handedness were assessed with established instruments. Stimulation was performed with the double click paradigm (ISI 500 ms, ITI 9–10 s). MEG recordings of 15 patients and 18 controls entered further analyses with the software BESA for spatio-temporal source analyses and statistical analyses with MATLAB. Results: Neither P50 nor N100 responses differed statistically between the groups, which means that gating was not impaired in this sample of first-episode schizophrenia patients. Conclusions: These results are not in line with the majority of studies on sensory gating in schizophrenia, however, studies on first-episode patients are scarce. The most likely reasons for not observing a gating deficit in our study are patients' first-episode status and atypical antipsychotic medication. © 2010 Elsevier B.V. All rights reserved.

1. Introduction Several studies suggest that auditory information processing is impaired in individuals affected with schizophrenia and that specific aspects of this impairment constitute an endophenotype (Cadenhead et al., 2002; Freedman et al., 1991; Siegel et al., 1984). Impairments should therefore be detectable in patients presenting with their first psychotic episode. ☆ Previously presented at the 12th World Congress of Psychophysiology, Thessaloniki, Greece, September 18–23, 2004. ⁎ Corresponding author. E-mail address: [email protected] (S. Bachmann). 0920-9964/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.schres.2010.03.007

Information processing can be documented via the correlates of event-related potentials (ERPs). ERPs are responses to exogenous or endogenous stimuli measured via changes in the electrophysiological activity of the brain by EEG as electric potentials or by MEG as magnetic fields (Picton et al., 2000; Picton et al., 1974). Numerous researchers showed that the auditory evoked P50 in response to two identical auditory stimuli (referred to as S1 and S2), separated by a pause of a few hundred milliseconds, lead to a systematic decrement of the second response (S2) by activation of an inhibitory system (Adler et al., 1982). This amplitude reduction is considered to reflect a basic neurophysiological process called sensory gating which protects the individual against sensory or information overload (Adler et al.,

132

S. Bachmann et al. / Schizophrenia Research 121 (2010) 131–138

1982; Braff and Geyer 1990; Freedman et al., 1983). According to two meta-analyses (Bramon et al., 2004; de Wilde et al., 2007a) with effect sizes of −1.56 and 1.28 this mechanism is disturbed in schizophrenia. Patients' inability to adequately suppress the second stimulus is regarded as the physiological correlate of their perception of being flooded by sensory impressions, hyperawareness of background noises, and lack of concentration (McGhie and Chapman 1961; Venables 1964). The clinical interest in sensory gating arose almost five decades ago (McGhie and Chapman 1961; Venables 1964), and is continuing because the gating deficit seems to constitute an endophenotype and thus reflects a genetic trait in schizophrenia (Cadenhead and Braff 2002; Freedman et al., 1991; Siegel et al., 1984). Moreover, there is interest in gating because recent studies suggest that impaired information processing is related to negative symptoms (Louchart-de la Chapelle et al., 2005; Ringel et al., 2004; Thoma et al., 2003) including cognitive impairment. Thus measures of sensory gating may provide an objective tool for testing the effects of new remedies for these symptoms while taking into consideration the cholinergic nature of P50 (Adler et al., 2005; Adler et al., 2004; Braff and Light 2004; Martin et al., 2004; Potter et al., 2006). P50 is a positive evoked potential (EP) that occurs at about 50 ms following an auditory stimulus. Typically, the P50 is embedded in a sequence of cortical responses ranging from P30 (30 ms post-stimulus) to the N100 (100 ms post-stimulus). The N100 itself is a negative EP following stimulus onset at about 100 ms (Picton et al., 1999). These potentials may reflect the pre-attentive and the early attentive phase of information processing (Braff and Light 2004; Jin et al., 1998; Kisley et al., 2003; Light and Braff 1999; Näätänen et al., 1992; Pekkonen et al., 2002). Sensory gating can be studied reliably with both potentials if paradigms used do not require focused attention (Smith et al., 1994). Like the P50, the distinguishable component N100 is generated in multiple fields of the auditory cortex (AC) including Heschl's gyrus, the planum temporale, and the superior temporal gyrus; it temporally overlaps with P50. Although examined less frequently than P50, N100 has indeed been found abnormal in schizophrenia regarding morphology and latency (Boutros et al., 2004a; Boutros et al., 2004b; Boutros et al., 2006; Budd et al., 1998) pointing at more general abnormalities of sensory gating. Thus, we expected to demonstrate reduced suppression in neuromagnetic P50 (P50m) and N100 (N100m) in first-episode schizophrenia patients. We chose MEG as an adequate means of registration because it provides good differentiation (Scherg 1990), precise location of sources (Mäkelä et al., 1994; Mäkelä and Hari 1990; Mäkelä et al., 1987), and good spatial resolution (Edgar et al., 2003). One of our earlier studies on P50 gating in control subjects showed that MEG compared to EEG data allows for a better fit of individual measurements (Weisser et al., 2001). This is probably due to the fact that magnetic fields are minimally influenced by the conductivities of the different scull compartments. Although MEG picks up the tangential projection of the P50 signal, the comparison has shown that MEG data closely resemble EEG waveforms. Furthermore, Lu et al. (2007) reported that the gating ratio of the magnetic P50 exhibits a higher reliability compared to the electrical counterpart. The additional use of the source analysis with its stable localization

of generators in the left and right auditory cortex provides a method to further increase the signal-to-noise ratio. Finally, less time is needed to prepare MEG compared to EEG measurements (fixing of 32 electrodes). Thus, neuromagnetic recordings were employed to investigate the specific gating effects in schizophrenic patients as reflected by the P50m and N100m. 2. Method 2.1. Patients and control subjects Eighteen Caucasian inpatients at the Department of Psychiatry, University of Heidelberg who were in stable remission – according to clinical assessment as well as to a standardized rating scale – of their first psychotic episode and 24 healthy, age- and sex-matched control subjects participated in the study. Since MEG recordings of 3 patients and 6 controls had to be excluded due to technical problems, data of 15 patients and 18 controls was included in further analysis (see Table 1 for sociodemographic data). Healthy subjects, mainly hospital staff and students, were recruited through local advertisements. All subjects were Caucasians, had no history of or a concomitant severe neurological, medical, or hearing disorder, neither of drug or alcohol abuse in the past 90 days, which was verified by urine toxicology. They had normal hearing as confirmed by audiometric testing. 2.2. Clinical assessment Clinical assessment of patients and controls was performed at the Department of Psychiatry. Diagnoses were established according to the Structured Clinical Interview for DSM−IV (Wittchen et al., 1997), handedness was assessed by the Edinburgh Inventory (Oldfield 1971), family history, regular use of nicotine and alcohol by interview. Patients' symptoms were rated on the Brief Psychiatric Rating Scale

Table 1 Sociodemographic characteristics of first-episode patients and matched controls, clinical data of patients.

Gender (f:m) Age Educational status a 1:2:3:4:5 Family history of schizophrenia yes:no Handedness right:mixed:left Regular use of nicotine yes:no Duration of illness (months) BPRS score b Chlorpromazine equivalents a b

Patients

Controls

Statistics

3:12 30.5 ± 9.2 2:3:5:4:1

7:11 30.2 ± 5.4 0:0:2:4:12

chi-square t-test chi-square

n.s. n.s. p b 0.005

2:13

0:18

chi-square

n.s.

8:4:3

17:1:0

chi-square

p b 0.05

13:2

6:12

chi-square

p b 0.005

4 (range 0–66) 37.3 ± 9.2 666.7 ± 401.6

According to the European Union consent 85/368/EWG, paragraph 2, 2, 1985. Ratings available in 14 patients only.

S. Bachmann et al. / Schizophrenia Research 121 (2010) 131–138

(Overall and Gorham 1962), and duration of illness via clinical interview following the Interview for the Retrospective Assessment of the Onset of Schizophrenia (Häfner et al., 1992). Information on medication was taken from patients' charts. Sociodemographic and clinical data of patients and controls are presented in Table 1. The groups differed regarding handedness, educational, and smoking status. In the patients group, the following diagnoses were ascertained: schizophrenia n = 6, schizophreniform disorder n = 8, schizoaffective disorder n = 1. In addition, the SCIDinterview revealed a history of alcohol and multiple substance use in one patient, and of dysthymia in another. Duration of illness was low as was the level of psychopathological symptoms. Symptom subtyping was not performed as the German version of the BPRS does not allow for this procedure. At the time of assessment, patients received a mean of 666.7 chlorpromazine equivalents (SD 401.6), namely olanzapine (n = 6), clozapine (n = 7), and amisulpride (n = 2). The typical antipsychotics flupentixole and benperidole were administered in addition to atypicals in one patient each while treatment was changed from a typical to an atypical antipsychotic as maintenance medication.

133

rejection tool (ERP module) for rejection of amplitudes exceeding 1000 fT/cm (ocular artifacts). Following these procedures, midlatency complexes were clearly distinguishable from baseline. The remaining data were averaged between 100 ms before (baseline) and 800 ms after stimulus onset. We thus achieved an average of 65.3 trials (SD 14.7) in the patients group and of 73.1 trials (SD 15.8) in the control group for further analysis. Averaged data were analyzed using the BESA spatiotemporal source analysis tool (Scherg 1990)(Fig. 1). First, P50m was identified according to the nomenclature of Picton (Picton et al., 1974) as the second largest positive deflection between 35 and 80 ms post-stimulus. Sources were fitted to the individual's auditory cortices. These fits were held fixed and thereby served as a spatio-temporal filter to obtain source waveforms of the total episode (−100 to 800 ms). Thus, the positive P50m deflection results in a positive dipole moment and the negative N100m peak in a negative dipole moment. These steps were repeated for the N100m in a separate session, where the largest negative deflection following the P50m between 80 and 150 ms post-stimulus was chosen. 2.5. Statistical analyses

2.3. MEG recording MEG recordings were obtained at the Section of Biomagnetism, Department of Neurology of the University of Heidelberg. Prior to recording, the subject's head position was determined by using four coils attached to the scalp. Additionally, 32 surface points on the scalp were digitized to match the MEG head coordinate system. Auditory evoked fields (AEFs) were recorded using a Neuromag-122TM whole head MEG system (Ahonen et al., 1993). Data were sampled at 769 Hz. Stimulation was performed with the double click paradigm, applying 130 paired clicks (S1 and S2) per run. Clicks consisted of square-wave pulses of 0.04 ms duration each; they were presented with an interstimulus interval (ISI) of 500 ms at 60 dB. The intertrial intervals (ITI) varied between 9 and 10 s and were Poisson distributed. The gradients of the magnetic fields were recorded continuously (0.01– 330 Hz) with a Neuromag-122 whole head system (Elekta Neuromag Oy, Helsinki, Finland) inside a magnetically shielded room (IMEDCO, Switzerland). Subjects sat in an upright position, viewed a silent movie of their choice, and listened passively to the acoustic stimuli, i.e., they were instructed not to listen to the stimuli. During testing, they were monitored visually for signs of sleep. Stimuli were generated digitally with a sampling frequency of 44.1 kHz using a PC equipped with an AWE 64 Soundblaster soundcard (Creative Labs, Inc., Metuchen, NJ, USA). The sounds were delivered diotically via Etymotic Research ER-3 phones connected to 90 cm plastic tubes and foam earpieces. Registration lasted for about 30 min. 2.4. Analyses of MEG data Data were analyzed using the software BESA®2000 (MEGIS Software GmbH, Gräfelfing, Germany) (Fig. 1). MEG raw data were visually inspected off-line for artifacts in addition to the application of the BESA semi-automated artifact

Sociodemographic data of patients and controls were compared by chi-square- or Student's t-tests wherever appropriate, using SPSS (Version 12.0, Chicago, IL, USA). Statistical analyses of MEG source waveforms were performed with MATLAB (Version 7.4, MathWorks Inc., Natick, MA, USA). Latencies, amplitudes, and S2/S1 ratios were assessed using bootstrap technique based on critical t-intervals. Bootstrap was used because peaks of the P50m and the N100m could not reliably be picked from all individual data sets. We proceeded as follows: peaks were taken from the bootstrap grand-average resamples (B = 1000 resamples). In a next step, a one-sided t-test was performed in which the standard deviation of the resample distribution (latencies and amplitudes) was multiplied by the critical t-value for α = 5%. We were thus able – via the resulting error – to assess the significance of the differences between groups (Efron and Tibshirani 1993). In other words, a significant difference at the level of α = 5% is present when the error bar (compare Fig. 4) of one group does not reach the mean of another. By using this procedure we were able to compute the S2/S1 ratio without omitting any data set. The study was approved by the ethics committee of the Medical Faculty of the University of Heidelberg and carried out in accordance with the Declaration of Helsinki. Written informed consent was obtained from all participants after the procedures had been fully explained. 3. Results The number of usable trials did not differ statistically between schizophrenia patients and healthy subjects (t(31) = −1.470, n.s.). Figs. 2 and 3 illustrate the grand-average source waveforms of the AEFs separately for patients and controls and for the right and left hemispheres. As shown in Fig. 4, the onesided t-intervals overlap considerably indicating that the groups did not differ statistically with respect to P50m latencies

134

S. Bachmann et al. / Schizophrenia Research 121 (2010) 131–138

Fig. 1. Source analysis using BESA 2000. The example shows seeding of the 2 AC sources for P50.

and amplitudes of S1 and S2 responses. A similar result was achieved for the latencies and amplitudes of the N100m. Furthermore, the S2/S1 ratio for both components, P50m and N100m, did not differ between groups (Fig. 4). Hence, defective gating was not observed in these firstepisode schizophrenia patients.

4. Discussion To our knowledge, this is the first study on AEFs in firstepisode schizophrenia which assessed patients and controls with the traditional double click paradigm. Gating was undisturbed in both groups with respect to P50m as well as

Fig. 2. P50m responses of patients and controls, depicted separately for the left and right hemispheres.

S. Bachmann et al. / Schizophrenia Research 121 (2010) 131–138

135

Fig. 3. N100m responses of patients and controls, depicted separately for the left and right hemispheres.

to N100m. Moreover, patients were comparable to controls regarding P50m and N100m latencies and amplitudes. Both groups exhibited smaller S2 than S1 responses and most importantly, the S2/S1 ratio, which is supposed to directly reflect the gating process, exhibited comparable values for both groups. Thus, our study of first-episode schizophrenia patients did not exhibit a gating deficit measurable with MEG. This finding – in accordance with the previous observation by de Wilde et al. (2007b) – may question the fact that the gating deficit constitutes an endophenotype throughout all disease phases.

Our results are in line with the above indicated study on first-episode patients (de Wilde et al. 2007b) and studies that failed to find P50 gating (Kathmann and Engel 1990) or to detect the gating deficit after correction for patients' temporal variability (Patterson et al., 2000). Also, there is partial conformity between our results and those of Boutros et al. (2004a) in that they reported nonsignificant ratio differences between patients and controls with respect to P50 and N100; solely the provided difference measure for N100 pointed at gating problems at the respective level in schizophrenia. The above authors suggest that gating is a multistage operation,

Fig. 4. Comparison of latencies, amplitudes, and S2/S1 ratios ofpatients and controls.

136

S. Bachmann et al. / Schizophrenia Research 121 (2010) 131–138

which goes with the notion that P50 is embedded in a complex of electric potential- or magnet field-answers of the brain to auditory stimuli. On the other hand it has to be stated that our results are not consistent with the majority of studies on P50, as presented in a recent meta-analysis (Bramon et al., 2004). Another meta-analysis (de Wilde et al., 2007a) in general confirms the result of the previous one, but mentions a major limitation, which may skew the reception of the literature: nearly half of the P50 studies in the literature have been performed by one single group. A recent study on P50 and N100 suppression deserves mention (Brockhaus-Dumke et al., 2008). These authors included a considerable number of subjects in different stages of schizophrenia and at-risk states – all medication-free for at least four weeks – as well as healthy controls, and used EEG to assess S2/S1 ratios. They found differences between healthy controls and all patient groups with respect to P50 suppression. Regarding N100 suppression, all patients but subjects at risk differed from healthy controls. The first-episode patients of that study exhibited more gating impairment than our patients did. This is not likely to be related to methodological discrepancies, e.g., usage of EEG vs. MEG, measurement of ratio vs. latency/ amplitude, but rather to the medication status; patients were medicated in our study and unmedicated in the BrockhausDumke study. Several authors have provided evidence that atypical antipsychotics may normalize gating (Adler et al., 2004; Braff and Light 2004; Light et al., 2000; Nagamoto et al., 1996; Yee et al., 1998). Hence, the extensive use of atypical antipsychotics, especially clozapine, may have led to normal gating in our patient group; only two patients received typical antipsychotics in addition to atypicals. There is strong evidence that atypical compounds positively influence gating, namely cause partial or complete normalization (Adler et al., 2004; Braff and Light 2004; Light et al., 2000; Nagamoto et al., 1996; Yee et al., 1998). The largest improvement is caused by clozapine (Adler et al., 2004; Becker et al., 2004; Potter et al., 2006) due to its action on cholinergic neurotransmission (Adler et al., 2004). These findings are of prognostic relevance. Also, they imply that the gating deficit in schizophrenia may not be fully explained by the trait hypothesis as has already been suggested by Boutros et al. (1993). In our view there are two major reasons for patients' regular gating in our study. One is the first-episode status which is supported by de Wilde et al. (2007b). Unfortunately, the literature included in the existing meta-analyses (Bramon et al., 2004; de Wilde et al., 2007a) did not comprise any first-episode study as none was available at that time. The second reason is the positive influence of the atypical antipsychotics that patients received. One may even speculate that sensory gating fluctuates during the early course of the disease – as do other parameters such as Neurological Soft Signs (NSS) (Bachmann et al., 2005) – due to variations in the disease process or due to medication. A review on animal research even states that sensory gating is undoubtedly affected by an organism's state (Cromwell et al., 2008), thus supporting a state-trait perspective on gating. Interestingly, Brockhaus-Dumke et al. (2008) found more suppression disturbance in chronic as opposed to first-episode patients or at-risk states. As there seems to be an increase in gating deficit during the disease course, this again supports the argument that the gating deficit may not be solely a trait phenomenon. In addition to chronicity, subtypes seem to

influence gating; Ringel et al. (2004), for instance, detected impaired gating in patients with negative symptoms or a hebephrenic subtype. Furthermore, almost all patients in our study used nicotine regularly. We did not require subjects to refrain from smoking prior to MEG measurement, which may constitute a confounder as alpha-7 nicotinic receptor agonists may reverse impaired gating (Leonard et al., 1996; Martin et al., 2004). On the other hand, this effect is lost in chronic smokers – which was the case in our patients – due to receptor desensitization (Leonard et al., 1996; Martin et al., 2004). Additionally, methodological pitfalls may have led to diverging results. Regarding MEG the question arises whether EEG and MEG registration are comparable. Studies comparing amplitudes (Reite et al., 1982) or amplitude and latency measures (Clementz et al., 1997) did not report significant correlations between AEPs and AEFs. Another group (Onitsuka et al., 2000) found different effects of the ISI on P50 vs. P50m and N100 vs. N100m. Yet, the waveforms of AEPs and AEFs are comparable, and some authors positively stated that electric and magnetic sources of the P50 and N100 can be considerably explained by one another (Pekkonen et al., 2002) and reflect the same brain-source activities (Lopes da Silva et al., 1991). Furthermore, Weisser et al. (2001), using simultaneous EEGand MEG recordings and the double click paradigm, clearly showed that electrical and neuromagnetic P50 lead to comparable gating effects. Thus, theoretically, the information required in the presented study, namely whether the second of two identical stimuli leads to an amplitude reduction or a latency change, should be equally rendered by both approaches, as has been reported by the groups who studied EEG and MEG at a time (Ahveninen et al., 2006; Arthur et al., 1991; Thoma et al., 2003; Thoma et al., 2005). Psychopathology may constitute an additional confounder. Patients were not acutely ill but, according to their psychiatrist's judgement, close to discharge, reflected by low BPRS scores. According to Potter et al. (2006) however, most studies failed to show an association between P50 and symptom subscores. Therefore, confounding by psychopathology can most likely be excluded in the presented study.

4.1. Strengths and limitations The patient group was restricted to first-episode subjects which excludes the effects of illness chronicity and longterm medication. Another strength is the assessment of auditory gating via MEG, which is, above all sensitive to tangential activity on the scalp and comprises 122 channels. The most important advantage is the application of spatio-temporal source analysis, which decreased the signal-to-noise ratio considerably. Moreover, the number of averages was higher than in most studies. Quality of signals was high because of a high ITI. Baseline signals were non-ambiguous and EP complexes clearly detectable. The study's limitations are the medium size sample, which nevertheless is comparable to the literature, and the lack of complete restriction to atypical antipsychotic treatment. However, if the gating effect was present in first-episode patients as unequivocally as it has been shown in chronic patients, the indicated limitations would not conceal it.

S. Bachmann et al. / Schizophrenia Research 121 (2010) 131–138

In conclusion, the presented MEG data suggest the presence of normal auditory gating in first-episode patients with low symptom scores for both EPs, P50m and N100m. This contradicts an overall breakdown in selective sensory inhibitory functions in schizophrenia as early as during the first manifestation of the illness. Alternatively, results may support the beneficial effect of atypical antipsychotics on sensory gating. Role of Funding Source This work was supported by grant We 1996/2-1 from the Deutsche Forschungsgemeinschaft (German Research Community) to Matthias Weisbrod. Contributors Silke Bachmann has drafted the article. All coauthors gave their adviceMatthias Weisbrod, Christine Thomas, Miriam Röhrig and Silke Bachmann have performed the MEG assessements. Johannes Schröder has recruited the patients and performed the clinical assessments. Michael Scherg and Silke Bachmann did the spatio-temporal source analyses using BESA. Andre Rupp performed the statistical analyses. As the Head of the Section of Biomagnetism he was involved in every technical aspect of the assessments throughout the whole study. Conflict of Interest Silke Bachmann has no financial or personal relationships, interests, and affiliations relevant to the subject matter of the manuscript. Matthias Weisbrod has no financial or personal relationships, interests, and affiliations relevant to the subject matter of the manuscript. Miriam Röhrig has no financial or personal relationships, interests, and affiliations relevant to the subject matter of the manuscript. Johannes Schröder has no financial or personal relationships, interests, and affiliations relevant to the subject matter of the manuscript. Christine Thomas has no financial or personal relationships, interests, and affiliations relevant to the subject matter of the manuscript. Michael Scherg owns the company BESA which produces the software applied in the study. André Rupp has no financial or personal relationships, interests, and affiliations relevant to the subject matter of the manuscript. Acknowledgements We would like to express our gratitude to the technicians Barbara Burghardt and Esther Tauberschmidt, Heidelberg, for their competent help and their patience. Heidi Baumbauch, Halle, carefully proofread the manuscript.

References Adler, L.E., Cawthra, E.M., Donovan, K.A., Harris, J.G., Nagamoto, H.T., Olincy, A., Waldo, M.C., 2005. Improved P50 auditory gating with ondansetron in medicated schizophrenia patients. Am. J. Psychiatry 162 (2), 386–388. Adler, L.E., Olincy, A., Cawthra, E.M., McRae, K.A., Harris, J.G., Nagamoto, H.T., Waldo, M.C., Hall, M.H., Bowles, A., Woodward, L., Ross, R.G., Freedman, R., 2004. Varied effects of atypical neuroleptics on P50 auditory gating in schizophrenia patients. Am. J. Psychiatry 161 (10), 1822–1828. Adler, L.E., Pachtman, E., Franks, R.D., Pecevic, M., Waldo, M.C., Freedman, R., 1982. Neurophysiological evidence for a defect in neuronal mechanisms involved in sensory gating in schizophrenia. Biol. Psychiatry 17, 639–653. Ahonen, A.I., Hamalainen, M.S., Ilmoniemi, R.J., Kajola, M.J., Knuutila, J.E., Simola, J.T., Vilkman, V.A., 1993. Sampling theory for neuromagnetic detector arrays. IEEE Trans. Biomed. Eng. 40 (9), 859–869. Ahveninen, J., Jaaskelainen, I.P., Osipova, D., Huttunen, M.O., Ilmoniemi, R.J., Kaprio, J., Lonnqvist, J., Manninen, M., Pakarinen, S., Therman, S., Naatanen, R., Cannon, T.D., 2006. Inherited auditory-cortical dysfunction in twin pairs discordant for schizophrenia. Biol. Psychiatry 60 (6), 612–620. Arthur, D.L., Lewis, P.S., Medvick, P.A., Flynn, E.R., 1991. A neuromagnetic study of selective auditory attention. Electr. Clin. Neurophys. 78, 348–360. Bachmann, S., Bottmer, C., Schroeder, J., 2005. Neurological Soft Signs in firstepisode schizophrenia — a follow-up study. Am. J. Psychiatry 162, 1–7.

137

Becker, J., Gomes, I., Ghisolfi, E.S., Schuch, A., Ramos, F.L.P., Ehlers, J.A., Nora, D.B., Lara, D.R., da Costa, J.C., 2004. Clozapine, but not typical antipsychotics, correct P50 suppression deficit in patients with schizophrenia. Clin. Neurophysiol. 115, 396–401. Boutros, N., Zouridakis, G., Rustin, T., Peabody, C., Warner, D., 1993. The P50 component of the auditory evoked potential and subtypes of schizophrenia. Psychiatry Res. 47 (3), 243–254. Boutros, N.N., Korzyukov, O., Jansen, B., Feingold, A., Bell, M., 2004a. Sensory gating deficits during the mid-latency phase of information processing in medicated schizophrenia patients. Psychiatry Res. 126 (3), 203–215. Boutros, N.N., Korzyukov, O., Oliwa, G., Feingold, A., Campbell, D., McClainFurmanski, D., Struve, F., Jansen, B., 2004b. Morphological and latency abnormalities of the mid-latency auditory evoked responses in schizophrenia: a preliminary report. Schizophr Res. 70, 303–313. Boutros, N.N., Trautner, P., Korzyukov, O., Grunwald, T., Burroughs, S., Elger, C.E., Kurthen, M., Rosburg, T., 2006. Mid-latency auditory-evoked responses and sensory gating in focal epilepsy: a preliminary exploration. J. Neuropsychiatry Clin. Neurosci. 18 (3), 409–416. Braff, D.L., Geyer, M.A., 1990. Sensorimotor gating and schizophrenia. Human and animal model studies. Arch. Gen. Psychiatry 47, 181–188. Braff, D.L., Light, G.A., 2004. Preattentional and attentional cognitive deficits as targets for treating schizophrenia. Psychopharmacology 174, 75–85. Bramon, E., Rabe-Hesketh, S., Sham, P., Murray, R.M., Frangou, S., 2004. Metaanalysis of the P300 and P50 waveforms in schizophrenia. Schizophr Res. 70 (2–3), 315–329. Brockhaus-Dumke, A., Schultze-Lutter, F., Mueller, R., Tendolkar, I., Bechdolf, A., Pukrop, R., Klosterkoetter, J., Ruhrmann, S., 2008. Sensory gating in schizophrenia: P50 and N100 gating in antipsychotic-free subjects at risk, first-episode, and chronic patients. Biol. Psychiatry 64 (5), 376–384. Budd, T.W., Barry, R.J., Gordon, E., Rennie, C., Michie, P.T., 1998. Decrement of the N1 auditory event-related potential with stimulus repetition: habituation versus refractoriness. Int. J. Psychophysiol. 31, 51–68. Cadenhead, K.S., Braff, D.L., 2002. Endophenotyping schizotypy: a prelude to genetic studies within the schizophrenia spectrum. Schizophr Res. 54 (1–2), 47–57. Cadenhead, K.S., Light, G.A., Geyer, M.A., McDowell, J.E., Braff, D.L., 2002. Neurobiological measures of schizotypal personality disorder: defining an inhibitory endophenotype? Am. J. Psychiatry 159 (5), 869–871. Clementz, B.A., Blumenfeld, L.D., Cobb, S., 1997. The gamma band response may account for poor P50 suppression in schizophrenia. Neuroreport 8, 3889–3893. Cromwell, H.C., Mears, R.P., Wan, L., Boutros, N.N., 2008. Sensory gating: a translational effort from basic to clinical science. Clin. EEG Neurosci. 39 (2), 69–72. de Wilde, O.M., Bour, L.J., Dingemans, P.M., Koelman, J.H., Linszen, D.H., 2007a. A meta-analysis of P50 studies in patients with schizophrenia and relatives: differences in methodology between research groups. Schizophr Res. 97 (1–3), 137–151. de Wilde, O.M., Bour, L.J., Dingemans, P.M., Koelman, J.H., Linszen, D.H., 2007b. Failure to find P50 suppression deficits in young first-episode patients with schizophrenia and clinically unaffected siblings. Schizophr Bull. 33 (6), 1319–1323. Edgar, J.C., Huang, M.X., Weisend, M.P., Sherwood, A., Miller, G.A., Adler, L.E., Canive, J.M., 2003. Interpreting abnormality: an EEG and MEG study of P50 and the auditory paired-stimulus paradigm. Biol. Psychol. 65 (1), 1–20. Efron, B., Tibshirani, R.J., 1993. An Introduction to the Bootstrap. Chapman and Hall, New York. Freedman, R., Adler, L.E., Waldo, M.C., Pachtman, E., Franks, R.D., 1983. Neurophysiological evidence for a defect in inhibitory pahtways in schizophrenia: comparison of medicated and drug-free patients. Neurophysiological evidence for a defect in inhibitory pahtways in schizophrenia: comparison of medicated and drug-free patients. Biol Psychiatry 18, 537–551. Freedman, R., Waldo, M., Bickford-Wimer, P., Nagamoto, H., 1991. Elementary neuronal dysfunctions in schizophrenia. Schizophr Res. 4, 233–243. Häfner, H., Riecher-Rossler, A., Hambrecht, M., Maurer, K., Meissner, S., Schmidtke, A., Fatkenheuer, B., Loffler, W., van der Heiden, W. 1992. IRAOS: an instrument for the assessment of onset and early course of schizophrenia. Schizophr Res. 6 (3), 209–223. Jin, Y., Bunney, W.E.J., Sandman, C.A., Patterson, J.V., Fleming, K., Moenter, J.R., Kalali, A.H., Hetrick, W.P., Potkin, S.G., 1998. Is P50 suppression a measure of sensory gating in schizophrenia? Biol. Psychiatry 43, 873–878. Kathmann, N., Engel, R.R., 1990. Sensory gating in normals and schizophrenics: a failure to find strong P50 suppression in normals. Biol. Psychiatry 27, 1216–1226. Kisley, M.A., Olincy, A., Robbins, E., Polk, S.D., Adler, L.E., Waldo, M.C., Freedman, R., 2003. Sensory gating impairment associated with schizophrenia persists into REM sleep. Psychophysiology 40 (1), 29–38. Leonard, S., Adams, C., Breese, C.R., Adler, L.E., Bickford, P., Byerley, W., Coon, H., Griffith, J., Miller, C., Myles-Worsley, M., Nagamoto, H.T., Rollins, Y., Stevens,

138

S. Bachmann et al. / Schizophrenia Research 121 (2010) 131–138

K.E., Waldo, M.C., Freedman, R., 1996. Nicotinic receptro function in schizophrenia. Schizophr Bull. 22, 431–445. Light, G.A., Braff, D.L., 1999. Human and animal studies of schizophreniarelated gating deficits. Curr. Psychiatry Rep. 1 (1), 31–40. Light, G.A., Geyer, M.A., Clementz, B.A., Cadenhead, K.S., Braff, D.L., 2000. Normal P50 suppression in schizophrenia patients treated with atypical antipsychotic medications. Am. J. Psychiatry. 157 (5), 767–771. Lopes da Silva, F.H., Wieringa, H.J., Peters, M.J., 1991. Source locatization of EEG versus MEG: empirical comparison using visually evoked responses and theoretical considerations. Brain Topogr. 4 (2), 133–142. Louchart-de la Chapelle, S., Levillain, D., Menard, J.F., Van der Elst, A., Allio, G., Haouzir, S., Dollfus, S., Campion, D., Thibaut, F., 2005. P50 inhibitory gating deficit is correlated with the negative symptomatology of schizophrenia. Psychiatry Res. 136 (1), 27–34. Lu, B.Y., Edgar, J.C., Jones, A.P., Smith, A.K., Huang, M.X., Miller, G.A., Canive, J.M., 2007. Improved test–retest reliability of 50-paired-click auditory gating using magnetoencephalography source modeling. Psychophysiology 44 (1), 86–90. Mäkelä, J.P., Hämäläinen, M., Hari, R., McEvoy, L., 1994. Whole-head mapping of middle-latency auditory evoked magnetic fields. Electroencephalogr. Clin. Neurophysiol. 92, 414–421. Mäkelä, J.P., Hari, R., 1990. Long-latency auditory evoked magnetic fields. Adv. Neurol. 54, 177–191. Mäkelä, J.P., Hari, R., Linnankivi, A., 1987. Different analysis of frequency and amplitude modulations of a continuous tone in the human auditory cortex: a neuromagnetic study. Hear Res. 27, 257–264. Martin, L.F., Kem, W.R., Freedman, R., 2004. Alpha-7 nicotinic receptor agonists: potential new candidates for the treatment of schizophrenia. Psychopharmacology 174, 54–64. McGhie, A., Chapman, J., 1961. Disorders of attention and perception in early schizophrenia. Br. J. Med. Psychol. 34, 103–116. Näätänen, R., Teder, W., Alho, K., Lavikainen, J. 1992. Auditory attention and selective input modulation: a topographical ERP study. Neuroreport 3 (6), 493–496. Nagamoto, H.T., Adler, L.E., Hea, R.A., Griffith, J.M., McRea, K.A., Freedman, R., 1996. Gating of auditory P50 in schizophrenia: unique effects of clozapine. Biol. Psychiatry 40, 181–188. Oldfield, R.C., 1971. The assessment and analysis of handedness: the Edinburgh inventory. Neuropsychologia 9 (1), 97–113. Onitsuka, T., Ninomiya, H., Sato, E., Yamamoto, T., Tashiro, N., 2000. The effect of interstimulus intervals and between-block rests on the auditory evoked potential and magnetic field: is the auditory P50 in humans an overlapping potential? Clin. Neurophysiol. 111, 237–245. Overall, J.E., Gorham, D.R., 1962. The Brief Psychiatric Rating Scale (BPRS). Psychol. Rep. 10, 799–812. Patterson, J.V., Jin, Y., Gierczak, M., Hetrick, W.P., Potkin, S., Bunney Jr., W.E., Sandman, C.A., 2000. Effects of temporal variability on P50 and the gating ratio in schizophrenia: a frequency domain adaptive filter single-trial analysis. Arch. Gen. Psychiatry 57 (1), 57–64. Pekkonen, E., Katila, H., Ahveninen, J., Karhu, J., Huotilainen, M., Tiihonen, J., 2002. Impaired temporal lobe processing of preattentive auditory discrimination in schizophrenia. Schizophr Bull. 28 (3), 467–474.

Picton, T.W., Alain, C., Woods, D.L., John, M.S., Scherg, M., Valdes-Sosa, P., Bosch-Bayard, J., Trujillo, N.J., 1999. Intracerebral sources of human auditory-evoked potentials. Audiol. Neurootol. 4, 64–79. Picton, T.W., Bentin, S., Berg, P., Donchin, E., Hillyard, S.A., Johnson Jr., R., Miller, G.A., Ritter, W., Ruchkin, D.S., Rugg, M.D., Taylor, M.J., 2000. Guidelines for using human event-related potentials to study cognition: recording standards and publication criteria. Psychophysiology 37 (2), 127–152. Picton, T.W., Hillyard, S.A., Krausz, H.I., Galambos, R., 1974. Human auditory evoked potentials. I. Evaluation of components. Electroencephalogr. Clin. Neurophysiol. 36 (2), 179–190. Potter, D., Summerfelt, A., Gold, J., Buchanan, R.W., 2006. Review of clinical correlates of P50 sensory gating abnormalities in patients with schizophrenia. Schizophr Bull. 32 (4), 692–700. Reite, M., Zimmermann, J.T., Zimmermann, J.E., 1982. MEG and EEG auditory responses to tone, click and white noise stimuli. Electroencephalogr. Clin. Neurophysiol. 53, 643–651. Ringel, T.M., Heidrich, A., Jacob, C., Fallgatter, A.J., 2004. Sensory gating deficit in a subtype of chronic schizophrenic patients. Psychiatry Res. 125, 237–245. Scherg, M., 1990. Fundamentals of dipole source analysis. In: Grandori, M., Hoke, M., Romani, G.L. (Eds.), Auditory Evoked Magnetic Fields and Electric Potentials. Karger, Basel, pp. 40–69. Siegel, C., Waldo, M., Mizner, G., Adler, L.E., Freedman, R., 1984. Deficits in sensory gating in schizophrenic patients and their relatives. Evidence obtained with auditory evoked responses. Arch. Gen. Psychiatry 41 (6), 607–612. Smith, D.A., Boutros, N.N., Schwarzkopf, S.B., 1994. Reliability of P50 auditory event-related potential indices of sensory gating. Psychophysiology 31 (5), 495–502. Thoma, R.J., Hanlon, F.M., Moses, S.N., Edgar, J.C., Huang, M.X., Weisend, M.P., Irwin, J., Sherwood, A., Paulson, K., Bustillo, J., Adler, L.E., Miller, G.A., Canive, J.M., 2003. Lateralization of auditory sensory gating and neuropsychological dysfunctionin schizophrenia. Am. J. Psychiatry 160, 1595–1605. Thoma, R.J., Hanlon, F.M., Moses, S.N., Ricker, D., Huang, M., Edgar, C., Irwin, J., Torres, F., Weisend, M.P., Adler, L.E., Miller, G.A., Canive, J.M., 2005. M50 sensory gating predicts negative symptoms in schizophrenia. Schizophr Res. 73 (2–3), 311–318. Venables, P.H., 1964. Input dysfunction in schizophrenia. Prog. Exp. Pers. Res. 72, 1–47. Weisser, R., Weisbrod, M., Roehrig, M., Rupp, A., Schroeder, J., Scherg, M., 2001. Is frontal lobe involved in the generation of auditory evoked P50? Neuroreport 12 (15), 3303–3307. Wittchen, H.U., Wunderlich, U., Gruschwitz, S., Zaudig, M., 1997. SKID-I. Strukturiertes klinisches Interview für DSM-IV [SCID for DSM-IV], Hogrefe, Göttingen, Bern, Toronto, Seattle. . Yee, C.M., Nuechterlein, K.H., Morris, S.E., White, P.M., 1998. P50 suppression in recent-onset schizophrenia: clinical correlates and risperidone effects. J. Abnorm. Psychol. 107 (4), 691–698.