Exploration of somatosensory P50 gating in schizophrenia spectrum patients: reduced P50 amplitude correlates to social anhedonia

Psychiatry Research 125 (2004) 147–160

Exploration of somatosensory P50 gating in schizophrenia spectrum patients: reduced P50 amplitude correlates to social anhedonia Sidse M. Arnfreda,*, Andrew C.N. Chenb a

Department of Psychiatry, Hvidovre Hospital, University Hospital of Copenhagen, Brøndbyøstervej 160, DK-2605 Brøndby, Denmark b Human Brain Mapping and Cortical Imaging Laboratory, Aalborg University, DK-9220 Aalborg, Denmark Received 27 May 2003; received in revised form 30 September 2003; accepted 16 December 2003

Abstract Originally, the hypothesis of a sensory gating defect in schizophrenia evolved from studies of somatosensory evoked potentials (SEP), although the idea has primarily been pursued in the auditory modality. Gating is the relative attenuation of amplitude following the second stimulus in a stimulus pair. Recently, SEP P50 gating was seen when recording the SEP P50 in a paradigm similar to the one used for auditory P50 gating. Hypothetically, abnormality of somatosensory information processing could be related to anhedonia, which is considered a core feature of schizophrenia. Twelve unmedicated, male, schizophrenia spectrum patients (seven schizophrenic and five schizotypal personality disorder patients) and 14 age-matched healthy men participated in recordings of pair-wise presented auditory and median nerve stimuli. The patients had smaller amplitudes of the SEP P50 at the first stimulus, but no gating defect. The reduced amplitude was particularly evident in subjects with high scores on the Revised Social Anhedonia Scale. Early somatosensory information processing seems abnormal in schizophrenia spectrum patients. This could be in agreement with the theory of loss of the benefit of regularity in schizophrenia, while the results are in-conclusive regarding sensory gating theory. 䊚 2003 Elsevier Ireland Ltd. All rights reserved. Keywords: Information processing; Auditory P50 gating; Evoked potentials; Social anhedonia; Schizophrenia

1. Introduction In studies of somatosensory evoked potentials (SEP) in schizophrenia, findings of increased mean amplitudes in the early SEP and decreased *Corresponding author. Present address: Bispebjerg Bakke 23, Copenhagen NV, Denmark. Tel.: q45-35-31-26-61yq4524-62-75-12; fax: q45-35-31-39-53. E-mail address: [email protected] (S.M. Arnfred).

amplitude in the late SEP (Shagass, 1976; Buchsbaum, 1977; Shagass, 1977; Shagass et al., 1977, 1978, 1979) led Shagass to formulate the theory of an impaired sensory filtering mechanism leading to inefficient functioning of later stages of processing (Shagass, 1977). Based on this and other findings within early information processing and the description of disturbed perception of young schizophrenic patients (McGhie and Chapman,

0165-1781/04/$ - see front matter 䊚 2003 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.psychres.2003.12.008

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1961), the sensorimotor (or sensory) gating theory (Braff, 1993) has become one of the major hypotheses regarding early information processing in schizophrenia of the last decade. The deficiency in auditory P50 gating seen in schizophrenia (Adler et al., 1982; Freedman et al., 1983, 1987; Nagamoto et al., 1989) has been one of the experimental findings that have supported sensory gating theory. P50 gating is a measure of the attenuation of the auditory evoked potential (AEP) P50 in a paired stimulus paradigm: Two identical clicks of short duration are delivered binaurally with an interstimulus interval (ISI) of 500 ms, followed by a interpair pause of approximately 10 s. The second positive peak of the AEP is the P50 component. The repetition effect on (or gating of) the midlatency components of the somatosensory evoked potential (SEP) has not been extensively studied (McLaughlin and Kelly, 1993), but recently midlatency SEPs were investigated in a paradigm similar to the auditory P50 gating paradigm (Arnfred et al., 2001b). The vertex SEP P50 showed a decrement ratio of 0.59 in healthy men (Arnfred et al., 2001b). A mixed modality paradigm in which paired median nerve stimuli and paired clicks are presented in a fixed loop in total lasting 12 s from one identical first stimulus (of a pair) to the next (Arnfred et al., 2001a). This modification to the standard auditory P50 gating paradigm yielded no change of either P50 amplitude or P50 gating in the two modalities, and it was concluded that the recovery of the stimulus one (S1) P50 component was modality specific and the paradigm could be useful when examining gating in more than one modality (Arnfred et al., 2001a). The idea of investigating somatosensory processing derived from the above-mentioned findings of Shagass and the hypothesis put forward by Sandor Rado in 1953 regarding the core deficits in schizophrenia (Rado, 1953). Although a psychoanalytically oriented psychiatrist, he suggested that schizophrenia derives from a basic proprioceptive disorder of ‘the circular response pattern of self-awareness and willed action’ – and a basic ‘integrative pleasure deficiency’ or anhedonia. The basic proprioceptive disorder could possibly be disclosed in the investigation of simple somatosen-

sory stimuli. However, as we postulate an early somatosensory information-processing defect, it seems that the ‘integrative pleasure deficiency’ might just as well be a consequence of the information-processing defect as separate from it. Hypothetically, a link between anhedonia and electrophysiological measurement could be a lack of somatosensory readiness degrading the fine tuning of proprioception or bodily empathy leading to aversive experiences of un-preparedness, secondarily followed by withdrawal and anxiety. Thus the hypothesis of the present study is that we would find a somatosensory P50 gating defect in the schizophrenia spectrum patients that would be correlated to the auditory P50 gating defect and to anhedonia. A precise quantification of anhedonia as a specific symptom can be obtained by the use of the self-administered questionnaires developed by Chapman and Chapman (Chapman et al., 1976): The revised Physical Anhedonia Scale (PhysAn) and the revised Social Anhedonia Scale (SocAn) (Eckblad et al., 1982) were aimed at identifying schizophrenia-prone individuals. The scales consist of 40–60 items that are frequencygraded examples of the same aspect of pleasurable experiences. The PhysAn has items about the pleasures of eating, touching, feeling, sex, temperature movement, smell and sound. The SocAn has items of interpersonal pleasure like talking, playing games and having intimate relations (Chapman et al., 1976; Eckblad et al., 1982). In short, we aimed at (1) investigating gating in the somatosensory modality in schizophrenia spectrum patients; (2) testing for correlation between somatosensory information processing and anhedonia measured by Chapman and Chapmans self-rating questionnaires; and (3) replication of the findings of parallel auditory P50 gating measures in the mixed modality and the standard gating paradigm in a sample including patients and testing for correlations between P50 gating in the two modalities. 2. Methods 2.1. Subjects Twelve patients and 14 age-matched healthy men were included. The patients (SCH) were

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included if they had a diagnosis of schizophrenia or schizotypal personality disorder (SPD), age 18– 50 years, no current medication, no substantial abuse except tobacco and the ability to participate in 3 days of experimental sessions without admittance. DSM-IV diagnoses (American Psychiatric Association, 1994) were assessed by the semistructured interview Schedules for Clinical Assessment in Neuropsychiatry (SCAN version 2.1) (Wing et al., 1990, 1998). The interview was conducted similarly in the healthy controls (CON) as in the SCH. The patients were referred from all the hospitals and outpatient clinics of Copenhagen from January 2000 to February 2002. They were all without psychopharmacological medication at the time of testing. Diagnoses and DSM-IV codes were: 295.20 schizophrenia, Catatonic type: 1; 295.30 schizophrenia, Paranoid type: 2; 295.60 schizophrenia, Residual type 1; 295.70: 1; 295.90 schizophrenia, Undifferentiated type: 2; 301.22 Schizotypal Personality. Disorder: 5 (American Psychiatric Association, 1994). Seven schizophrenic patients were a sub-sample of the patients demonstrating normal auditory P50-gating in (Arnfred et al., 2003). Three of the patients were drug¨ four had been medication free for more than naıve, 24 months and only three patients had received antipsychotic medication within the last 3 months. None of the patients used minor tranquilizers habitually. As was expected, the SCH were more anhedonic than the CON as measured by the Chapman and Chapman questionnaire scores. The number of wrong answers to the infrequency items was not different in the two groups. This implies that the groups did not differ as to self-rating compliance. See Table 1 for characteristics of the sample. CON were recruited by board advertisement. They could have no current abuse other than tobacco, no family history of psychiatric disease (first degree relatives) and no personal history of former contact with a psychologist for more than 10 consultations or of any contact with a psychiatrist or former psychopharmacological treatment. All controls were screened for schizotypal symptoms, more than two symptoms being grounds for exclusion. One healthy subject was excluded due to this criterion.

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Table 1 Sample characteristics

Age (years) Education** (years) Smoking (cigyw) PhysAn* (sum score) SocAn** (sum score) Infreq (sum score)

CON

SCH

SCH only

29.9 (9.7) 16.5 (3.5) 28.6 (52.7) 11.8 (5.7) 4.9 (3.1) 1.9 (0.8)

30.7 (9.4) 12.0 (2.1) 55.8 (68.8) 19.3 (10.5) 15.8 (7.6) 1.9 (1.6)

Illness duration (years) Antipsy. duration (months) Antipsy. pause噛 (months) Positive (mean score) Negative (mean score) Disorganised (mean score)

7.9 (7.9) 6.4 (7.8) 50.4 (76.0) 1.7 (1.1) 2.0 (0.7) 0.8 (0.9)

Mean values (S.D.) in the two groups. Healthy controls (CON) Ns14, schizophrenia spectrum patients (SCH) Ns12. Duration of antipsychotic medication (antipsy) is lifetime total duration of all types (old and new) of antipsychotic medication. Illness duration is years since first psychiatric contact. SAPS and SANS scores are used for computation of symptom dimension scores: Positive (global hallucinationsqglobal delusionsy2), negative (all global scores of the SANS except attentiony5) or disorganised symptomatology (global formal thought disorderqglobal bizarre behaviorqSANS item inappropriate affecty3). In the revised Social Anhedonia Scale (SocAn) maximum pathology is 40, in the revised Physical Anhedonia Scale (PhysAn) maximum is 61, and the Infrequency items (Infreq), total 13, which are interspersed in the computerised item presentation to check that the subjects read ¨ Three the items. (噛) Ns9, as three patients were drug naıve. patients had only been treated with typical antipsychotics, two patients only with atypical antipsychotics (risperidone andyor olanzapine), and four patients had been treated with both types. Significant group difference (*) Ps0.04; (**) P-0.0001 (Wilcoxon Signed Rank Test, two-tailed).

No urine screenings were performed. All subjects were right-handed and none of the subjects complained of hearing problems. All subjects gave informed written consent as approved by the Ethics Committee and they were paid to participate in the experiment. 2.2. Psychopathological ratings The SCAN was performed regarding present state—the last 4 weeks—and lifetime. Psychopathology was rated with the Scale for Assessment of Positive Symptoms (SAPS) (Andreasen, 1984b) and Scale for the Assessment of Negative Symptoms (SANS) (Andreasen, 1984a, 1989). The

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SAPS and SANS were performed regarding the last 3 months. All interviews and ratings were performed by the principal investigator (a senior resident in psychiatry), who had completed the official SCAN training program and who performed SAPS joint ratings with the other investigators at the department every second month. The Chapman and Chapman scales (SocAn and PhysAn) and the Infrequency Scale (measuring if the subject is reading the items) was translated into Danish and then secondarily re-translated into English. The re-translation was approved by Prof. Thomas Kwapil’s group, University of North Carolina, Greensboro, one of several groups continuing the work of the Chapmans. The items were introduced, one at a time, in a fixed intermixed order on a PC for the subject to click on true or false. This was accomplished within 40 min in all subjects. 2.3. Procedure After the interview, the subjects were enrolled in a fixed schedule of experimental sessions and breaks. Each session encompassed approximately eight runs of recording. Several experimental paradigms were presented in a fixed order alternating between the standard auditory gating paradigm, the mixed modality paradigm and active (P300y reaction time) tests, which will not be further described here. During recording, the subjects were seated comfortably upright, with closed eyes, in dim light and with background masking low level white noise (73 dB SPL) in adjacent loudspeakers. Subjects were allowed to smoke during the breaks and the number of cigarettes smoked during the period was recorded. They were allowed to drink their habitual tea or coffee at home in the morning of the recording day, but they were only offered xanthine-free beverages during the day (Ghisolfi et al., 2002). 2.4. Evoked potentials Auditory stimuli were 104-dB peak SPL clicks (20 Hz–10 kHz) of 1.6-ms duration. They were delivered binaurally through earphones. For the nerve stimulation, 25-mm disposable electrodes

(3M) were placed 2 cm apart, cathode proximal, at the median nerve on the right wrist. The level of stimulation was set 10 digital units (approx. 0.6 mA) lower than the thumb muscle twitch threshold. The stimulus was a square wave of 0.2-ms duration. The EOG were monitored on-line in the first period while checking for startle reactions. The mixed modality paradigm consists of 4 runs of 40 loops of paired clicks and paired median nerve stimulation. In each loop the identical pairs were separated by a 12-s interpair interval (Arnfred et al., 2001a). Seven scalp electrodes were positioned according to the international 10–20 system and referenced to linked earlobes: Fp1, Fp2, Fz, Cz, Pz, C39 and C49 (the last two positioned 2 cm posterior to C3yC4 to optimize recording from somatosensory cortex). Recording with a sampling frequency of 1000 Hz, equipment and set-up was identical to earlier recordings in our laboratory except for an increase in analog band pass width to 1–300 Hz (Arnfred et al., 2001b). The EEG was recorded continuously, epoched off-line and afterwards the Psylab䉷 files were converted for further processing in Neuroscan䉷 Edit (v 4.21) software (El Paso, Texas). The epochs were y40 to 290 ms. Sweeps were rejected if the EOG exceeded "70 mV. The baseline was corrected by the mean of 40 pre-stimulus samples. Lastly, a digital filter with a bandpass of 10–50 Hz (12 dByoctave roll-off) was applied (White and Yee, 1997). 2.5. Data reduction and data analyses The waveforms were inspected systematically, but unblinded to subject group or stimulus condition. In the AEP the vertex recording was examined; in the SEP the vertex and contralateral parietal channel (C39) was examined. In the AEP the maximum positive peak amplitude in the latency range 40–70 ms was identified as P50. If in doubt as to the stimulus-two (S2) P50 peak, the stimulus-one (S1) waveform was superimposed. In the SEP the N30 (latency range 20–40 ms) of S1 were identified at the vertex electrode as starting point. Following that, the S1 vertex components P50 (latency range 40–70 ms), N65 (50– 100 ms) and P80 (70–120 ms) were identified.

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The S2 were superimposed and similar components recognised. If no obvious component was seen, amplitude at the latency of the S1 component was reported. The same procedure was followed at C39 starting at S1 N30 (latency range 15–35 ms) and reporting P50 (latency range 30–60 ms) and N65 (50–100 ms). Using the Waveboard䉷 function, the peak-to-peak amplitudes were measured relative to the preceding peak. When no recognizable peak was detected, a missing data point was reported. If a preceding though was missing, the baseline-to-peak measure was used as peak-to-peak amplitude. Peak-to-peak amplitude less than 0.5 mV in a S1 component was treated as a missing data point. Peak-to-peak amplitudes less than 0.5 mV in S2 were set to 0.01 mV. Gating is reported as the ratio of amplitudes S2yS1 and the difference in amplitudes S1yS2. Both peak-to-peak amplitudes and baseline-to-peak amplitude are reported. The data were exported to statistical software (SPSS v. 11) for further analysis. The auditory amplitudes, the gating data and the Chapman and Chapman questionnaire scores had a non-parametric distribution and only non-parametric tests were performed on these. Wilcoxon Signed Rank Test was used to test for significance of difference by group, paradigm and stimulus condition. Cohen’s Kappa coefficient was computed for agreement between subjects categorised by gating ratio (gatingsratio-0.5). Spearman correlations were computed for the relationship between the parameters of the two paradigms, the gating in the two modalities, and the electrophysiological measures and symptom scores. Additionally, subjects were stratified by the SocAn score. Stratification cutpoints were determined by the median of the SocAn score in the two diagnostic groups: Low score 0–4; Intermediate score 5–14; High score 15–30. The remainder of the data had a parametric distribution and they were examined by repeated measures analysis of variance (r.m. ANOVA) having stimulus condition as within-subjects factor and diagnostic group as between-subjects factor. Post hoc, two-tailed Student’s t-test was applied. P-values were not corrected for multiple comparisons. All results are reported as means and standard

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Table 2 Latencies of the mid-latency somatosensory evoked potential at the vertex and contralateral parietal lead

N30

Cz C39

P50

Cz C39

N65*

Cz* C39*

P80

Cz

S1

S2

S1

S2

34.1 (3.4) 29.1 (7.2) 48.3 (4.8) 47.1 (4.6) 67.4 (6.2) 68.2 (5.5) 87.4 (8.5)

34.1 (4.5) 30.2 (7.1) 48.0 (4.7) 45.9 (4.5) 63.0 (5.1) 65.1 (6.6) 81.9 (7.0)

33.8 (4.5) 33.3 (6.4) 48.1 (5.8) 45.8 (3.4) 63.9 (8.8) 67.5 (6.0) 86.6 (9.8)

33.8 (4.2) 32.9 (6.0) 45.7 (4.2) 45.7 (3.3) 60.0 (7.6) 68.2 (7.5) 84.1 (9.8)

Mean (S.D.) group latencies reported in ms. S1: stimulus 1 of a pair of equal intensity right median nerve stimuli, ISI 500 ms. S2: stimulus 2. CON: healthy controls (Ns14); SCH: schizophrenia spectrum patients (Ns12). Cz: vertex electrode. C39: contra-lateral parietal electrode. (*) marks the component where the latency was significantly shorter in S2 (P-0.01). In the other components no significant effect of stimulus condition or diagnostic group was observed.

deviations (S.D.) to facilitate comparisons to earlier works in the field. 3. Results 3.1. Mid-latency somatosensory evoked potentials N30, P50, N60 and P80 components were observed at the vertex electrode and N30, P50 and N65 components were observed at the contralateral parietal electrode, see Table 2, for mean latency values at these electrode positions in the two stimulus conditions. The grand average waveforms are shown in Fig. 1. Latencies were not affected by diagnostic group. Latency of N30, P50 and P80 did not change with stimulus condition. Latency of N65 was shorter in S2. SEP P50, N65 or P80 gating did not differ between the two diagnostic groups. Baseline-topeak amplitudes, peak-to-peak amplitudes and ‘gating’ of the somatosensory components are shown in Table 3. No main effect of diagnostic group was seen on the amplitude measures, but an

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amplitude of vertex S1 P50 in the SCH group (CON: mean 1.10 mV, S.D. 0.89; SCH mean 0.38 mV, S.D. 0.73, Ps0.04). At the vertex electrode N30 baseline-to-peak amplitude (F1,24s17.985, Ps0.0001) and P80 baseline-to-peak amplitude (F1,24s18.969, P0.0001) decreased from S1 to S2. P50 and N65 baseline-to-peak amplitudes were not affected by stimulus condition. The same pattern was seen at the parietal contralateral electrode and in analysis of the peak-to-peak values, except from the vertex P50 peak-to-peak amplitude, which decreased from S1 to S2 (F1,22s3.389, Ps0.001). The interaction effect between diagnostic group and stimulus condition seen at the vertex P50 baseline-to-peak amplitude was not seen in the otherwise identical analysis of peak-to-peak amplitudes. No effect of diagnostic group was observed at the contra-lateral parietal P50. The effect of diagnostic group on the vertex S1 P50 baseline-to-peak amplitude was tested against confounding effects of several subject variables: No associations were found with number of sweeps included, age, stimulus intensity or number of cigarettes either weekly or during the recording day. Number of included sweeps in the individual SEPs ranged between 76 and 160; the mean number of sweeps included in CON was 146 (S.D. 25) and in SCH 138 (S.D. 24). Only 1 EPs (NTotals52) were based on fewer than 90 sweeps. No group differences were significant. Mean intensity of nerve stimulation did not differ between groups; it was in CON 4.8 mA (S.D. 1.7) and in SCH 5.0 mA (S.D. 2.5). Fig. 1. Stimulus one somatosensory evoked potential in schizophrenia spectrum patients and healthy controls. Grand averages of the SEP of the first right median nerve stimulus of a pair recorded in the mixed modality paradigm. Schizophrenia spectrum patients (Ns12) dotted line; healthy controls (Ns 14) solid line. Positive potential downward. Sagittal marker at stimulus onset. Epoch y10 to 90 ms. Arrowhead points to the vertex (Cz) P50, where difference between groups were significant (Ps0.04). Only contralateral parietal electrode (C39) and Cz were analysed.

interaction between stimulus condition and diagnostic group affected the vertex P50 baseline-topeak amplitude (F1,22s6.632, Ps0.01). Post hoc testing showed that this was due to a smaller

3.2. Symptom correlation A negative correlation between social anhedonia (SocAn scores) and vertex S1 P50 baseline-topeak amplitude was seen (rSsy0.41, Ps0.05). The stratification of the total sample by social anhedonia yielded a lower amplitude when comparing the high and the intermediate scoring group (High SocAn: 0.03 mV, S.D. 0.88, Intermediate SocAn 1.0 mV, S.D. 0.92, Ps0.03). See Fig. 2. No correlations were seen to physical anhedonia (PhysAn), the symptom dimensions rated in SAPS and SANS or illness duration.

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Table 3 Amplitudes and ‘gating’ of the mid-latency somatosensory evoked potential at the vertex and contralateral parietal lead CON

N30

Cz** C39**

P50

Cz Cz P-P**

S1

S2

S1

S2

y0.83 (0.42) y0.14 (0.57) 1.10* (0.89) 1.92 (0.83)

y0.40 (0.52) 0.05 (0.69) 0.75 (0.58) 1.10 (0.45)

y1.47 (1.45) y0.23 (1.20) 0.38* (0.73) 1.85 (1.79)

y0.52 (0.99) 0.34 (0.84) 0.78 (0.62) 1.29 (1.25)

Cz S1yS2

0.82 (0.78) 0.67 (0.37)

Cz S2yS1 P50

C3’ C39 P-P**

2.18 (0.90) 2.32 (0.93)

C39 S1yS2

Cz Cz P-P

C39 P-P

Cz ** Cz P-P** Cz S1yS2 Cz S2yS1

y0.75 (0.69) y1.13 (0.64)

y0.65 (1.55) y2.34 (1.88)

2.16 (2.06) 2.62 (1.41)

y1.35 (0.95) y3.44 (1.53)

y0.78 (0.64) y2.93 (1.36) y0.41 (1.13) 0.96 (0.47)

1.02 (0.92) 1.50 (1.17) 1.12 (1.47) 0.62 (0.54)

y0.67 (0.42) y1.44 (0.67) 0.31 (0.59) 1.52 (0.90)

y1.65 (2.51) 0.67 (0.36)

C39 S2yS1

2.15 (0.93) 1.81 (1.08) 0.41 (1.22) 1.07 (0.67)

y0.48 (0.74) y1.27 (0.72)

y1.82 (1.17) y3.99 (1.87)

C39 S1yS2

P80

1.99 (0.97) 2.22 (1.71)

y0.46 (1.19) 0.97 (0.64)

Cz S2yS1 C39

1.69 (0.67) 1.65 (0.99)

y0.53 (0.95) y1.73 (0.95)

Cz S1yS2

N65

0.56 (1.05) 0.81 (0.80)

0.68 (1.14) 0.97 (1.20)

C39 S2yS1 N65

SCH

2.31 (1.72) 3.06 (2.13)

1.02 (0.91) 1.69 (1.05) 1.37 (1.53) 0.68 (0.40)

Description of middle latency SEP components in the two groups. Mean (S.D.) group values. Cz: vertex electrode baseline-topeak amplitude, C39: contra-lateral-parietal ditto; P-P denotes peak-to-peak amplitudes. The difference (S1yS2) and ratio (S2yS1) gating is based on peak-to-peak amplitudes. Amplitudes and differences are in microvolts. Preceding through to N30 was not identified, which is the reason for the sole measure of amplitudes in that component. P80 was not identified at the parietal site. The only parameter differing between diagnostic groups is the vertex P50 S1 amplitude marked by *. Components demonstrating significant difference from stimulus 1 (S1) to stimulus 2 (S2) are marked by ** (P-0.03). CON: healthy controls (Ns12–14). SCH: schizophrenia spectrum patients (Ns12).

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0.001) and in the CON (rSs0.87, Ps0.0002), but not in the SCH group. This was probably an effect of the correlation seen between the peak-to-peak S2 amplitudes (rSs0.55, Ps0.005), while the other amplitude measures were without correlation. 4. Discussion

Fig. 2. Stimulus one somatosensory P50 amplitude arranged by social anhedonia score category. Social Anhedonia scores determine group membership on the x-axis. Left: subjects scoring 0–4; Middle: subjects scoring 5–14; Right: subjects scoring 15–30. The difference between the patients scoring 15–30 and the mixed group scoring 5–14 is significant (Ps0.03). Markers are arranged by subject group: SCH: schizophrenia spectrum patients (Ns12); CON: healthy controls (Ns14).

3.3. Auditory P50 gating in the mixed modality paradigm Auditory P50 gating was obvious as all amplitudes (both peak-to-peak and peak-to-baseline) decreased from S1 to S2. The slightly reduced gating in the SCH subjects was not significantly different from CON (SCH: 0.61, S.D. 0.67; CON: 0.42, S.D. 0.20, Ps0.74). Of the P50 parameters shown in Table 4, none of the measures differed between the two groups. The results were in correspondence with the results of the standard gating paradigm in an extension of the same sample (Arnfred et al., 2003); see Fig. 3. The difference and amplitude measures across the two paradigms were correlated (rS ranges0.54–0.73, P-0.004). See Fig. 4. Agreement as to gating classification was poor (ks0.38, P;0.06) and correlation between gating ratio was non-significant. The number of sweeps included in the averages ranged from 101 to 160 without difference between groups. AEP P50 and SEP P50 gating ratios were correlated across the whole sample (rSs0.63, Ps

The major findings were that gating was similar in the two modalities across the whole sample and that no gating defect was observed in the somatosensory modality in these unmedicated schizophrenic and clinical SPD patients. However, the lack of an auditory gating defect in the same sample (Arnfred et al., 2003) makes it difficult to be conclusive regarding lack of somatosensory gating generally in schizophrenia. A specific attenuation of the S1 SEP P50 amplitude was observed indicating that early somatosensory information processing is affected in schizophrenia spectrum patients and the result is supported by the correlation between lower amplitudes and higher social anhedonia scores. The utility of the mixed modality paradigm could seem questionable due to the poor agreement and lack of correlation between auditory gating ratios obtained by this paradigm Table 4 Auditory P50 gating in the mixed modality gating paradigm

S1 (mV) S2 (mV) S1pp (mV) S2pp (mV) S1yS2 (mV) Ratio S2yS1

CON

SCH

2.48 (1.26) 0.63 (0.99) 2.68 (1.59) 1.19 (0.99) 1.50 (0.80) 0.42 (0.20)

2.66 (0.94) 1.10 (0.51) 2.57 (1.40) 1.18 (0.80) 1.39 (1.23) 0.61 (0.67)

Group mean values (S.D.). S1y2 denotes baseline-to-peak amplitude in stimulus1y2, S1 or S2pp is the corresponding peak-to-peak amplitude, which is the value used in the difference (S1yS2) and ratio (S2yS1) gating measures. All differences from S1 to S2 are highly significant (P-0.0001). No differences across diagnostic group are significant. CON: healthy controls (Ns14). SCH: schizophrenia spectrum patients (Ns12).

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due to a correlation between S2 amplitudes. In the following, these results are discussed in separate paragraphs.

Fig. 3. Vertex auditory evoked potential in the standard and the mixed modality gating paradigm. Grand averages of the mid-latency AEP in the top panel (a) recorded in the standard paradigm and in the bottom panel (b) recorded in the mixed modality paradigm. Stimulus 1 solid line; stimulus 2 dotted line. Positive potential downward. Arrowheads point to the P50 component. Stimulus onset at y-axis. Epoch y40 to 120 ms. Gating is obvious in both groups and in both paradigms. SCH: schizophrenia spectrum patients (Ns12); CON: healthy controls (Ns14).

and the standard paradigm. However, the amplitudes were highly correlated. Furthermore, the P50 gating ratios in the two modalities were correlated

Fig. 4. Scatterplot of auditory P50 amplitudes comparing the standard and the mixed modality gating paradigms. The standard paradigm amplitude is at the x-axis; the mixed modality paradigm, at the y-axis. Top panel (a) shows the AEP P50 amplitudes at stimulus one (S1); bottom panel (b), the amplitudes at stimulus two (S2). Markers are arranged by subject group: SCH: schizophrenia spectrum patients (Ns12); CON: healthy controls (Ns14). At both stimuli Spearman correlations are significant (P-0.004).

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4.1. Somatosensory evoked potentials (P50) The configuration of the mid-latency SEP in the present study is similar to the configuration seen in previous studies on healthy volunteers obtained from recordings both in the standard gating paradigm (Arnfred et al., 2001b) and the mixed modality paradigm (Arnfred et al., 2001a). In the grand averages, a N20yP30yN35yP50yN65yP100 configuration is seen at the contralateral parietal electrode and a N30yP50yN65yP80 configuration is seen at vertex. N30 is maximal at the frontal electrode, and P50 is maximal at the contralateral electrode; this polarity shift between the electrode location above the contralateral somatosensory cortex and the frontal central region is a well-known phenomenon and it is still debated whether the configuration is due to a dipole formation inherent in the folding structure of the central sulcus or to two different foci of activation, one in the somatosensory cortex and one more frontal in the supplementary motor area (Stevens, 2002). The lack of a SEP gating defect in the schizophrenia spectrum patients was contrary to expectation, but it was in agreement with the lack of gating defect in the auditory modality (Arnfred et al., 2003). Accordingly, it is not possible to conclude that the gating defect in schizophrenia is a particular auditory phenomenon. It is noteworthy that as it is the peak-to-peak amplitude that is included in the gating computation, the somatosensory gating observed at vertex P50 is the manifestation of reduced N30 baseline-to-peak amplitude more than of reduced P50 baseline-to-peak amplitude at S2. The attenuation of the P50 amplitude is in opposition to the earlier findings of increased mean amplitudes of the short latency SEPs (-100 ms) in schizophrenic patients (Shagass, 1976). The mean amplitude measure of selected latency periods is a cruder measure than the peak amplitude as it arbitrarily divides the components. However, it is the only amplitude measure in the earlier reports on schizophrenia. The high frequency stimulus rate of the earlier recordings (Shagass, 1976) could be the source of the discrepancy between the present results and the earlier findings. The amplitude attenuation is only seen in relation to

the baseline to peak measures, and it could be argued that this reflects a slower underlying neural potential and not the P50 deflection per se as measured in the peak-to-peak amplitude. However, while it is traditional to examine the P50 as a peak-to-peak amplitude, this is not theoretically meaningful due to the mixture of components evaluated in the peak-to-peak measure (Picton et al., 1974; Chiappa, 1997; Cardenas et al., 1993). Furthermore, the reliability of the peakto-peak amplitude measure has been questioned due to the low reliability of the peak-to-peak measures compared with baseline-to-peak amplitudes (Cardenas et al., 1993; Smith et al., 1994). The peak-to-peak amplitude of P50 is a composite measure of the amplitude of the frontal N30 and the more central P50, two components that may have quite different generators and habituation patterns. The SEP P50 amplitude has been shown to be increased when attention is on the stimulus (Desmedt and Tomberg, 1989; Josiassen et al., 1990; Garcia-Larrea et al., 1995). This is assumed to be a cortical modulation due to readiness to respond (Desmedt et al., 1984), so-called priming (Desmedt et al., 1983) or spatially directed attention (Desmedt and Tomberg, 1989; Josiassen et al., 1990; Garcia-Larrea et al., 1995). In this sense, the smaller S1 P50 amplitude observed in the patients could be a manifestation of less spatial attentional readinessycortical priming. Attenuated S1 P50 amplitude in schizophrenia has also been a frequent finding in auditory P50 gating studies (Freedman et al., 1987; Judd et al., 1992; Jin et al., 1997, 1998; Patterson et al., 2000; Clementz and Blumenfeld, 2001) and it is also seen in controls when a visual distracter is added to the experiment (Jin and Potkin, 1996). As no difference was observed in the somatosensory S2 P50 amplitude, the somatosensory abnormality cannot be interpreted as a gating defect, i.e. a decrease of an inhibitory mechanism initiated by S1 and executed on S2. However, it could be interpreted within the theories of loss of the effect of regularities or context (Shakow, 1977; Hemsley, 1996; Gray, 1998): the patients do not have the neuronal readiness to develop the normal P50 amplitude at

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the first stimulus, although the cycle of stimuli is regular and totally predictable. The contralateral parietal P45, which is the equivalent of the component called P50 in the present study, is restricted to the contralateral parietal scalp and not measured pre-sulcally (Desmedt et al., 1983). Still, it has been suggested, that the repetition effects on P50 and P100 measured in scalp recordings are due to summation with activity either from prefrontal central or subcortical processes (Kekoni et al., 1997). The lack of group differences at the parietal electrode could in a sense support this idea of a compound component where only the central—sub-cortical—part is compromised in schizophrenia. This is speculative and as abnormalities in laterality have been a major issue in schizophrenia research (Gruzelier and Raine, 1994), this would have to be taken into consideration as well. The findings of hemisphere differences both regarding variability, amplitude and latencies of SEPs are rather inconsistent (Roemer et al., 1979; Shagass et al., 1983; Tress et al., 1983; Cooper et al., 1985; Furlong et al., 1990; Allen et al., 1991) 4.2. Anhedonia and somatosensory information processing The correlation between early somatosensory information processing and social anhedonia was in accordance with the major hypothesis of the study, while the lack of correlation to physical anhedonia (PhysAn) was unexpected. SocAn has seldom been correlated to electrophysiological measures of early information processing. In a population sample of students having high scores of social anhedonia, no difference was seen on the emotion-modulated acoustic startle response (Gooding et al., 2002). In the present study the correlation between SocAn and electrophysiological abnormality is only seen in the somatosensory modality, which has not been investigated before, while no correlations are seen to the AEP measures in accordance with the lack of acoustic startle differences. Perhaps the loss of reward from social and bodily interaction is accompanied by generally reduced bodily attention and secondarily reduced somatosensory priming, or, as was our primary

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hypothesis, see Section 1, the other way around. Only prospective studies could illuminate the sequence of events. 4.3. Auditory P50 gating in two paradigms Decreased S1 and decreased gating have been observed when the subject is distracted by visual stimulation (Jin and Potkin, 1996) or with verbalisation of an arithmetic task (White and Yee, 1997). Schizophrenic patients frequently have problems with distraction and this could pose a problem when using the mixed modality paradigm. The patients could be relatively more distracted by the somatosensory stimuli in the pause between the auditory stimuli than the normal controls. This was not the case, as we found no difference between the two paradigms in the S1 amplitudes, which were highly correlated in both subject groups. As we did not find any difference in gating between the healthy controls and the schizophrenia spectrum patients in any of the auditory paradigms (Arnfred et al., 2003), it is not possible to conclude that the mixed modality paradigm is reliable in detecting defects in gating as has been observed in schizophrenic patients (Adler et al., 1982; Freedman et al., 1983, 1987; Nagamoto et al., 1989). However, the replication of the good correspondence between amplitudes seen in (Arnfred et al., 2001a) in the patients makes it likely that the mixed modality paradigm would be sensitive to abnormalities in gating. The correlation between AEP and SEP gating is in disagreement with the initial study in healthy men, where gating in the two modalities was without correlation (Arnfred et al., 2001b). As those recordings were made separately, the lack of correlation could be due to a generally lower reliability of gating across runs (Smith et al., 1994), compared with the present recordings in the mixed paradigm where SEP and AEP gating is recorded simultaneously. 5. Conclusion The present study has some representative limitations due to the low number of included patients; the priority was to include unmedicated patients.

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As it is the first report of the finding of SEP amplitude attenuation, caution is needed regarding these findings and the results need replication in another unmedicated sample before a final conclusion can be reached. Only seven patients were schizophrenic, they were all male and they were stable out-patients with no history of aggressive behaviour. Particularly the latter implies that they might have different results from a patient sample obtained from hospital wards. However, as the focus was on trait-like schizophrenia characteristics, it was relevant to examine a sample without acute psychotic exacerbation. The present study does not support the idea of a defect in somatosensory gating in schizophrenia. The specific attenuation of the SEP P50 amplitude following the first stimulus is best understood within the information-processing theory of a loss of effect of regularity in schizophrenia. The result is supported by the correlation between lower SEP amplitudes and higher social anhedonia scores, which could be the consequence of a lack of expectancy. Acknowledgments The study was supported by a Ph.D. grant to the first author by the Faculty of Health Sciences, University of Copenhagen, as well as unrestricted grants from the Lundbeck Foundation, the Ivan Nielsen Foundation for Rare Psychiatric Disorders, the Schizophrenia Foundation of 1986, the Copenhagen Hospital Corporation Research Foundation and the Danish Hospital Foundation for Medical Research, Region of Copenhagen, The Faroe Islands and Greenland. References Adler, L.E., Pachtman, E., Franks, R.D., Pecevich, M., Waldo, M.C., Freedman, R., 1982. Neurophysiological evidence for a defect in neuronal mechanisms involved in sensory gating in schizophrenia. Biological Psychiatry 17, 639–654. Allen, J.E., Jenner, A., Stevens, J.C., 1991. Early cortical tactile-evoked potentials, laterality and schizophrenia. British Journal of Psychiatry 158, 529–533. American Psychiatric Association, 1994. Diagnostic and Statistical Manual of Mental Disorders. Author, Washington, DC.

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