Latent inhibition and schizophrenia: Pavlovian conditioning of autonomic responses

Schizophrenia Research 55 (2002) 147±158

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Latent inhibition and schizophrenia: Pavlovian conditioning of autonomic responses D. Vaitl a,*, O. Lipp b, U. Bauer c, G. SchuÈler c, R. Stark a, M. Zimmermann a, P. Kirsch a a

Department of Clinical and Physiological Psychology, University of Giessen, Otto-Behaghel-Str. 10, D-35394 Giessen, Germany b School of Psychology, University of Queensland, Brisbane, QLD 4072, Australia c Department of Psychiatry, University of Giessen, Am Steg 22, D-35392 Giessen, Germany Received 31 December 2000; accepted 10 April 2001

Abstract Latent inhibition (LI) is an important model for understanding cognitive de®cits in schizophrenia. Disruption of LI is thought to result from an inability to ignore irrelevant stimuli. The study investigated LI in schizophrenic patients by using Pavlovian conditioning of electrodermal responses in a complete within-subject design. Thirty-two schizophrenic patients (16 acute, unmedicated and 16 medicated patients) and 16 healthy control subjects (matched with respect to age and gender) participated in the study. The experiment consisted of two stages: preexposure and conditioning. During preexposure two visual stimuli were presented, one of which served as the to-be-conditioned stimulus (CSp 1 ) and the other one was the not-to-be-conditioned stimulus (CSp 2 ) during the following conditioning ( ˆ acquisition). During acquisition, two novel visual stimuli (CSn 1 and CSn 2 ) were introduced. A reaction time task was used as the unconditioned stimulus (US). LI was de®ned as the difference in response differentiation observed between preexposed and non-preexposed sets of CS 1 and CS 2 . During preexposure, the schizophrenic patients did not differ in electrodermal responding from the control subjects, neither concerning the extent of orienting nor the course of habituation. The exposure to novel stimuli at the beginning of the acquisition elicited reduced orienting responses in unmedicated patients compared to medicated patients and control subjects. LI was observed in medicated schizophrenic patients and healthy controls, but not in acute unmedicated patients. Furthermore LI was found to be correlated with the duration of illness: it was attenuated in patients who had suffered their ®rst psychotic episode. q 2002 Elsevier Science B.V. All rights reserved. Keywords: Latent inhibition; Pavlovian conditioning of autonomic responses; Schizophrenia; Within-subject design

1. Introduction Recent approaches to a better understanding of schizophrenia have placed enhanced emphasis on the cognitive/attentional de®cits observed in the disorder (Braff, 1993; Gray et al., 1991; Hemsley, 1993). * Corresponding author. Tel.: 149-641-99-26080; fax: 149-64199-26099. E-mail address: [email protected] (D. Vaitl).

In particular, the perceived inability of schizophrenic patients to ignore irrelevant, potentially distracting stimulation and to exploit redundancies of the situation has been at the focus of investigations (Braff, 1993). One experimental procedure that is based on the well-documented phenomenon of latent inhibition (LI) is suf®ciently sensitive to ®nd differences in the ability to ignore irrelevant stimuli between patients and participants at risk (e.g. ®rst degree relatives or participants who score high on questionnaire

0920-9964/02/$ - see front matter q 2002 Elsevier Science B.V. All rights reserved. PII: S 0920-996 4(01)00250-X

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D. Vaitl et al. / Schizophrenia Research 55 (2002) 147±158

measures of psychosis proneness) and well controls (Lubow and Gewirtz, 1995). LI is de®ned as the retardation of Pavlovian conditioning after preexposure to the to-be-conditioned stimulus (to-be-CS) prior to its pairing with the unconditional stimulus (US). LI has been observed in a number of different conditioning procedures in a variety of non-human animal species (for a review see Lubow, 1989). In adult human participants LI can be assessed in an instrumental trial-to-criterion procedure (Ginton et al., 1975; Lubow et al., 1992) or during Pavlovian conditioning of autonomic responses (for a review see Vaitl and Lipp, 1997). In both procedures, learning in participants preexposed to the to-be-CS is compared to learning in participants who either received no stimuli during preexposure or were preexposed to experimentally irrelevant stimuli. Learning, measured as trials required to reach a certain criterion or a signi®cant extent of differential autonomic responding, is retarded in participants preexposed to the to-be-CS. The retardation of learning is said to re¯ect a decline in attentional processing of the to-be-CS across repeated presentations of the stimulus on its own (Pearce and Hall, 1980; Lubow, 1989). This lack of attentional processing has to be overcome before learning of an association that involves the CS can be observed. Thus, participants who have an impaired ability to ignore irrelevant, redundant stimulation are not expected to show latent inhibition, but to display learning in spite of to-be-CS preexposure, i.e. the performance of schizophrenic patients should be superior in comparison to well controls. Studies involving animal subjects have repeatedly shown that LI is affected by manipulations that involve the mesolimbic dopaminergic system. LI is reduced in animals treated with amphetamines and enhanced in animals treated with neuroleptics (for reviews see Gray et al., 1991; Weiner, 1990; Weiner and Feldon, 1997). In humans, studies that investigated the relationship between LI and schizophrenia so far have assessed whether LI would be reduced in participants who score highly on questionnaire measures of psychosis proneness and in schizophrenic patients, and whether neuroleptic medication will affect LI as found in animal research. The fact that LI is reduced in participants who score highly on measures of schizotypy or psychoticism has been

shown repeatedly using the trial-to-criterion procedure (e.g. Baruch et al., 1988b; Lubow et al., 1992) and in Pavlovian conditioning (Lipp and Vaitl, 1992; Lipp et al., 1992, 1994). Baruch et al. (1988a) found that acute schizophrenic patients, i.e. patients tested within 14 days of admission to hospital, did not show LI whereas healthy controls and chronic patients did. Moreover, if the acute patients were tested again after a period of 6±7 weeks, LI was found. Gray et al. (1992a) replicated this ®nding. On the basis of these studies it might be argued that the reinstatement of LI is mainly due to the stabilizing effect of long-term neuroleptic medication. This, however, is unlikely to be the case. Gray et al. (1995) demonstrated that the LI performance of neuroleptic-naive schizophrenic patients did not differ from the well controls' performance, but was found to be correlated with the duration of illness in the schizophrenic group. Patients with a longer illness duration (.12 months) showed intact LI, whereas an illness duration of less than 12 months was associated with attenuated LI. Swerdlow et al. (1996), however, failed to replicate the LI disruption in acute medicated schizophrenic patients using the trial-to-criterion procedure and Williams et al. (1998) suggest that the previous reports (Baruch et al. 1988a; Gray et al., 1992a) of disrupted LI in acute medicated patients may be due to the neuroleptic medication itself, rather than the psychotic illness. The effects of pharmacological manipulations on LI in healthy participants were investigated by Gray et al. (1992b), Kumari et al. (1999) and Williams et al. (1996). Gray et al. (1992b) and Kumari et al. (1999) found evidence for reduced LI after treatment with a single dose of d-amphetamine replicating results obtained in animal research. Williams et al. (1996) administered haloperidol to healthy participants and found enhanced LI in comparison to saline controls, a result that conforms with ®ndings from animal studies. The existing literature, however, does not allow a de®nite interpretation of the effects of neuroleptic medication or dose-dependent d-amphetamine administration on LI in human beings. All studies involving patient samples or investigating the effects of medication so far have employed the instrumental trial-to-criterion task. The lack of studies utilising Pavlovian conditioning of autonomic responses mainly re¯ects procedural considerations that seemed to make studies using that paradigm

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rather cumbersome. The use of the Pavlovian conditioning procedure requires controls for two variables: (a) conditioning, i.e. enhanced autonomic responding has to re¯ect associative learning and (b) not some non-associative process like sensitization, and preexposure, i.e. retarded learning has to re¯ect preexposure of the to-be-CS and not a delay of acquisition or preexposure of any stimulus. In previous studies, the presence of conditioning was asserted in either a between-subject comparison, single cue conditioning, or a within-subject comparison, differential conditioning. The effects of preexposure were assessed in between-subject comparisons, contrasting participants preexposed to the to-be-CS with participants who either received no stimulation during a waiting phase of comparable duration or were preexposed to experimentally irrelevant stimuli (for a review see Vaitl and Lipp (1997)). Thus even when using a differential conditioning procedure, a minimum of two groups of patients and two groups of control participants was required to assess differences in LI. Such an approach seemed not feasible for clinical studies that have to contend with small participant samples. Moreover, the heterogeneity of the patient groups reduces the power of any between-group comparison and renders it vulnerable to potential confounds. Thus, a within-subject procedure was developed for the present study. The rationale of the experimental design is as follows: as LI is conceptualised as a retardation in conditioning, that is, reduced CS±US associability, differences between preexposed and non-preexposed conditional stimuli (CS) should occur. A typical LI experiment, therefore, consists of two phases: preexposure and conditioning (or acquisition). During conditioning it is tested, if and to what extent stimulus preexposure retards learning as re¯ected by smaller conditional responses. In the differential conditioning paradigm, the strength of conditioning is determined by subtracting the response magnitude of the non-reinforced stimulus (CS 2 ) from the reinforced stimulus (CS 1 ). This difference (CS 1 minus CS 2 ) representing response differentiation, is expected to be smaller, after preexposure to the CSs compared to novel, non-preexposed CSs. This implies that in a within subject design at least four CSs have to be employed during conditioning (preexposed CS 1 and CS 2 ,

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non-preexposed CS 1 and CS 2 ). In the present experiment, a sample of unmedicated and medicated schizophrenic patients, and a sample of healthy control participants were trained in this within-subject procedure. According to our previous results (Vaitl and Lipp, 1997) we hypothezised that LI is retarded or disrupted in unmedicated schizophrenic patients, whereas medicated schizophrenic patients and healthy control participants show intact LI.

2. Method 2.1. Participants Participants comprised a group of 32 schizophrenics from the Department of Psychiatry, Medical Center of the University of Giessen. The present study included only cases with an unambiguous diagnosis of schizophrenia. All patients ful®lled DSM IV criteria (American Psychiatric Association, 1994) for a diagnosis (295.3 or 295.6) of schizophrenia. N ˆ 13 unmedicated schizophrenic patients were diagnosed as paranoid (295.3) and n ˆ 3 as residual type schizophrenics (295.6). N ˆ 14 medicated schizophrenic patients were diagnosed as paranoid (295.3) and n ˆ 2 as residual type schizophrenics (295.6). No other Axis I diagnoses were present. Diagnostic decisions were made by a psychiatrist on the basis of a careful review of the patients' psychiatric records, a diagnostic interview, an interview with relatives and partners, and psychiatric rating scales (Brief Psychiatric Rating Scale (18 items), BPRS, Overall and Gorham, 1962; Scale for the Assessment of Negative Symptoms, SANS, Andreasen, 1983, Positive and Negative Syndrome Scales, PANSS, Kay et al., 1987). The patient groups consisted of unmedicated (n ˆ 16) and medicated (n ˆ 16) schizophrenic patients. The group of unmedicated patients comprised six drug-naive patients with ®rst episode of the illness and ten patients who were unmedicated for more than 18 days. The medication status was obtained by asking patients and their physicians. The description of patients' characteristics is summarized in Table 1. The medicated patients were on prescribed neuroleptics (n ˆ 11 on typical and n ˆ 5 on atypical) in varying doses which are also reported in Table 1.

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Gender

Age (years)

Duration of illness (years)

BPRS (score)

SANS (score)

PANSS (score)

Medication (f; dose in mg)

Unmedicated (n ˆ 16) Medicated (n ˆ 16)

8 m/8 f 8 m/8 f

33.6 (range: 19±61) 32.1 (range: 20±49)

6.0 (8.4) 6.5 (6.3)

44.4 (9.9) 38.8 (6.8)

46.0 (25.8) 45.2 (18.6)

74.1 (15.8) 67.1 (13.3)

Controls (n ˆ 16)

8 m/8 f

27.9 (range: 18±54)

±

±

±

±

± Haloperidol: 3; 14.7, ¯uphenazine: 8; 10.5, risperidone: 4; 4.8, zotepine: 1; 75 ±

D. Vaitl et al. / Schizophrenia Research 55 (2002) 147±158

Table 1 Healthy control subjects' and schizophrenic patients' demographic and clinical characteristics (means (standard deviations) for unmedicated and medicated schizophrenic patients. BPRS, Brief Psychiatric Rating Scale. SANS, Scale for the assessment of negative symptoms. PANSS, the positive and negative symptoms scale; m ˆ male, f ˆ female)

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The control group consisted of 16 healthy individuals with no history of mental disorder, substance abuse, recreational long use, and schizophrenia in a ®rst-degree relative. Controls were selected after the patient groups had been formed in order to match the patient group with respect to age and gender. The control group consisted of eight females and eight males with a mean age of 27.9 years (range ˆ 18± 54 years). All control participants were paid for their participation.

d . 41 ms: `EXCELLENT'). Participants were not informed with respect to the scaling of the feedback. A detailed description of this procedure is given elsewhere (Lipp and Vaitl, 1990). The visual CS, pictures of a cross, a square, a triangle, and a circle on a green background were presented for 8 s on the computer screen that provided the feedback. The intertrial interval (onset of CS) varied randomly between 24, 28 and 32 s.

2.2. Apparatus and recording methods

All patients completed the experiment between 10:00 am and 1:00 pm whereas the control participants were examined at varying times during the day. The unmedicated schizophrenic patients were examined not later than one day after admission to the hospital and the completion of the diagnostic procedures. The experimental procedure has been approved by the Ethics Committee of the German Psychology Society. The patients and well controls provided informed consent prior to the experiment. Upon arrival at the laboratory, the experimental procedure and the equipment were explained to each participant while the measurement devices were attached. Participants were told that the purpose of the experiment was to examine physiological responses to simple and innocuous stimuli and during performance of a simple reaction time task. Participants were informed that the experiment would start with a series of visual stimuli, some of which would later be presented with the reaction time task. No information was provided about the number and the function of those stimuli. Participants were asked to press the button beneath their index ®nger as quickly as possible whenever the tone was presented. The experimental protocol is summarized in Fig. 1. During preexposure two visual stimuli, e.g. a cross and a square (CSp 1 and CSp 2 ), were presented 20 times each in a randomised order with the restriction that no more than two consecutive stimuli were the same. The duration of each stimulus was 8 s. In the acquisition phase that followed preexposure without interruption, two additional visual stimuli, e.g. a triangle and a circle (CSn 1 and CSn 2 ), were introduced. The offsets of one of the preexposed stimuli (CSp 1 ) and of one of the non-preexposed stimuli (CSn 1 ) coincided with the onset of the tone stimulus (`go' stimulus for the reaction time task), whereas the

The participant was seated in a comfortable armchair in a dimly lit room with air humidity and temperature kept at constant levels (60%, 22±248C). Skin conductance was recorded with a standard 0.5 V circuit (Coulbourne S71-22). Four Ag/AgCl electrodes ®lled with an isotonic electrolyte (0.05 M NaCl) and 8 mm in diameter were attached with adhesive collars to the thenar and hypothenar eminences of the participant's right and left hands. Respiration was recorded using a chest strain gauge (Coulbourne S72-25). An IBM-compatible computer controlled the stimulus sequence and timing, produced the visual and acoustic stimuli, and also recorded reaction times. Physiological data were continuously recorded and stored on a second IBM-compatible computer, with a sampling rate of 10 Hz for electrodermal and respiratory activity. A tone (1000 Hz, 70 dB), presented through headphones, served as the `Go' stimulus for the reaction time task US. Participants were instructed to press a small button located under the index ®nger of their preferred hand as quickly as possible whenever the tone was presented. The tone was terminated by the participant's response or lasted for 3 s. Reaction time was displayed on a computer screen that was located 1.5 m in front of the participant at eye level for 4 s after each presentation. After the ®rst ®ve trials, additional feedback was provided whenever the participant's reaction time was faster than the average reaction time across the previous ®ve trials. Moreover, difference scores (d ˆ average Ð actual reaction time) were computed and additional praise was displayed corresponding to the magnitude of the differences (0 , d , 21 ms: `GOOD'; 20 , d , 41 ms: `VERY GOOD';

2.3. Procedure and experimental design

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Fig. 1. Protocol of the within-subject design. For explanation see text.

remaining two stimuli, CSp 2 and CSn 2 , were presented alone. Each of the four CS was presented eight times during acquisition which resulted in the presentation of 16 CS 1 /US pairings, i.e. eight CSp 1 /US and eight CSn 1 /US, and of 16 CS alone presentations, i.e. eight CSp 2 and eight CSn 2 . 2.4. Response de®nitions Skin conductance responses were analyzed using a computer program developed by Schaefer (1997). In the ®rst step a low pass ®lter with a cut-off frequency of 5 Hz was applied to all electrodermal data in order to reduce artefacts. The program detects the responses by evaluating the gradient of incline at all data points. The detection algorithm is initialized when the incline exceeds a given value. From this data point, the response onset is determined by following the curve backwards to the point of maximal curvature. In the next step, the amplitude is detected by moving forward until the incline of the curve becomes negative. The response amplitude is measured in micro Siemens (mS) as difference between the conductance value at the amplitude and the value at response onset (for more detail see Boucsein, 1992). With this method all electrodermal responses in a time window between 1 and 13 s after CS onset were detected for each participant. Then, as proposed by Prokasy and Kumpfer (1973), the responses were divided for each trial into the ®rst interval response (FIR), the largest response that begins within 1±4 s after CS onset, the second interval response (SIR, not reported here), the largest response that begins within 4±9 s after CS

onset, and the unconditional response (UR), the largest response that begins within 9±13 s after CS onset (or 1±5 s after US onset respectively). Prior to the statistical analysis, changes in skin conductance were log transformed [log SCR] and range corrected by dividing each participant's SCR by her or his maximum response (Lykken and Venables, 1971). Conditioning was de®ned as the difference between the magnitude of electrodermal responses elicited during the reinforced CSs (CS 1 ) and during the non-reinforced CSs (CS 2 ). LI was indicated by larger autonomic response differentiation during non-preexposed CSs, CSn 1 and CSn 2 , than during preexposed CSs, CSp 1 and CSp 2 . 3. Results 3.1. Electrodermal responders vs Non-responders A high percentage of electrodermal non-responders has repeatedly been found among schizophrenic È hman, 1981). The increased likelihood of patients (O electrodermal non-responsiveness among schizophrenic patients poses a potential threat for the validity of the experimental results. In the present study participants were classi®ed as non-responders if they showed no conditioned response during the whole experiment as well as no orienting response to the novel stimuli at the beginning of the preexposureand acquisition phases. Three patients and three well controls met these criteria and were excluded from further analyses. Usually, the rate of non responders among healthy participants ranges between 5 and 10% È hman, 1981). (O 3.2. Unconditional electrodermal responses In order to examine whether the reaction time task used as unconditioned stimulus (US) elicited electrodermal responses and to what extent the responsivity of schizophrenic patients differed from that of well controls, the magnitudes of SCRs 1±5 s after the CS 1 offsets were analyzed in a two-factorial ANOVA (Group x Conditioning). Greenhouse Geisser corrected levels of signi®cance are reported for within subject factors with more than two levels. In these and all subsequent analyses follow-up tests were conducted with t-Tests (independent samples test:

D. Vaitl et al. / Schizophrenia Research 55 (2002) 147±158

Fig. 2. Unconditioned electrodermal response (third interval omission response) in unmedicated and medicated schizophrenic patients and healthy control subjects.

degrees of freedom were adjusted for unequal variances). The level of signi®cance was set to 0.05 for all analyses. All reported P-values are two-tailed unless otherwise mentioned. Responses after CSp 1 and CSn 1 were collapsed as preliminary analyses failed to ®nd a difference between the two conditions. As shown in Fig. 2, the reaction time task elicited reliable unconditional electrodermal responses (URs) in all three groups indicating elevated arousal levels. The ANOVA (Group £ Conditioning) revealed main effects for Group, F(2,45) ˆ 8.13, P , 0.01, and Conditioning, F(1,45) ˆ 251.91, P , 0.01, as well as an interaction `Group £ Conditioning', F(2,45) ˆ 8.20, P , 0.01. Follow-up tests showed that electrodermal URs were larger in well controls than in unmedicated schizophrenic patients, t(30) ˆ 3.42, P , 0.01, and in medicated patients, t(30) ˆ 3.98, P , 0.01, whereas the two patient groups did not differ signi®cantly, t(30) ˆ 0.90, P ˆ 0.38. Although the electrodermal responsivity in schizophrenic patients was reduced, as is frequently observed, this does not imply that they did not respond to arousing conditions and task-relevant actions (key pressing). Moreover, the fact that the URs in unmedicated and medicated patients did not differ supports the notion that neuroleptic medication has not compromised the electrodermal responsivity of the schizophrenic patients. 3.3. Preexposure Electrodermal responses during preexposure were averaged into ®ve blocks of four trials separately for

153

Fig. 3. Electrodermal FIR in the ®rst four trials of preexposure in unmedicated and medicated schizophrenic patients and healthy control subjects.

CSp 1 and CSp 2 . A 3 £ 2 £ 5 (Group £ Stimulus £ Block) factorial ANOVA was performed in order to test whether the groups differed in electrodermal responding during preexposure and to rule out a-priori differences in their responses to the two stimuli. Moreover, the responses during the ®rst trial block were subjected to a 3 £ 2 £ 4 (Group £ Stimulus £ Trial) ANOVA so as to map the course of habituation during the ®rst trials. The ®rst factor in both analyses was between-participants (Groups) and the other factors were within-participants (Stimulus, Block/ Trial). The results are shown in Fig. 3. The analyses indicated that electrodermal responses in block 1 were larger than in all other blocks, F(4,180) ˆ 8.42, P , 0.01. Responses within the ®rst block declined over the ®rst three trials, F(3,135) ˆ 27.79, P , 0.01, all t(47) . 2.5. There were no main effects or interactions involving the factor Group or Stimulus in any of the analyses, indicating that there were no differences in electrodermal orienting or habituation among the three groups, as well as no a-priori differences in the reaction to the two stimuli. 3.4. Orienting to stimulus change (OR) At the onset of acquisition, two novel CSs, CSn 1 and CSn 2 , were introduced that had not been presented during preexposure. This offered an opportunity to assess whether the groups differed in their responses to stimulus change after extended habituation. A 3 £ 2 £ 2 (Group £ Preexposure £ Conditioning) ANOVA was conducted on the electrodermal FIR

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Fig. 4. Electrodermal orienting response in the ®rst four trials of acquisition to preexposed (CSp) and non-preexposed (CSn) stimuli in unmedicated and medicated schizophrenic patients and healthy control subjects.

Fig. 5. Electrodermal FIR in acquisition averaged across trials 2±8 to preexposed (CSp 2 , CSp 1 ) and non-preexposed (CSn 2 , CSn 1 ) stimuli in unmedicated and medicated schizophrenic patients and healthy control subjects.

elicited by preexposed and non-preexposed (novel) CSs. As shown in Fig. 4, electrodermal FIR were larger to novel CSs, F(1,45) ˆ 8.00, P ˆ 0.01 than to preexposed CSs. Moreover, there was a difference across the three groups as indicated by a main effect for Group, F(2,45) ˆ 3.80, P ˆ 0.03, and a Preexposure £ Group interaction, F(2,45) ˆ 4.51, P ˆ 0.02. Subsequent one-tailed t-tests revealed that the novel CSs elicited larger FIR in well controls, t(15) ˆ 2.89, P ˆ 0.01, and medicated schizophrenic patients, t(15) ˆ 1.88, P ˆ 0.04, whereas in unmedicated patients no signi®cant difference between preexposed and non-preexposed CSs was obtained, t(15) ˆ 0.73, P ˆ 0.24.

conditioning effects, that is, signi®cant CS 1 minus CS 2 differences, were limited to the non-preexposed CS condition. Moreover, conditioning was evident in medicated schizophrenic patients, t(15) ˆ 2.67, P ˆ 0.02, and well controls, t(15) ˆ 2.52, P ˆ 0.02, but not in unmedicated schizophrenic patients, t(15) ˆ 0.99, P ˆ 0.34.

3.5. Acquisition The electrodermal FIR were averaged across trials 2±8 and subjected to a 3 £ 2 £ 2 (Group £ Preexposure £ Conditioning) ANOVA. Electrodermal response magnitudes for the two patient samples and well controls are shown in Fig. 5. The ANOVA revealed main effects for Group, F(2,45) ˆ 5.33, P ˆ 0.01 and Conditioning, F(1,45) ˆ 6.23, P ˆ 0.02 as well as a Preexposure £ Conditioning interaction, F(1,45) ˆ 5.88, P ˆ 0.02. As in a previous study (Vaitl and Lipp, 1997), the electrodermal conditional responses in medicated patients were generally smaller than in unmedicated patients, t(30) ˆ 2.09, P ˆ 0.047, and in well controls, t(30) ˆ 2.89, P ˆ 0.01. The Preexposure £ Conditioning interaction is due to the fact that

3.6. Reaction time Reaction time data were available for 14 unmedicated patients, 15 medicated patients and 16 well controls. To reduce the impact of outliers, reaction times slower than 1000 ms and faster than 100 ms were regarded as artefacts and treated as missing data. The corrected reaction time data were averaged into two blocks of four trials (®rst and second half of acquisition) separately for reaction time after the preexposed and the non-preexposed CS 1 and subjected to a 3 £ 2 £ 2 (Group £ Preexposure £ Block) ANOVA. This analysis revealed main effects for Preexposure, F(1,42) ˆ 7.61, P ˆ 0.01, and Block, F(1,42) ˆ 42.19, P , 0.01, as well as a Preexposure £ Block interaction, F(1,42) ˆ 20.16, P , 0.01. There was also a trend towards a main effect for Group, F (2,42) ˆ 2.90, P ˆ 0.07, indicating faster reactions in well controls. As illustrated in Fig. 6, the Block £ Preexposure interaction can be attributed to the fact that reaction time was slower after the preexposed CS 1 than after the non-preexposed CS 1 in block 1, 362 vs. 304 ms, t(44) ˆ 4.56, P , 0.01, but not in block 2, 258 vs. 270 ms, t(44) ˆ 1.33, P ˆ 0.19.

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Fig. 6. Mean reaction time (RT) in two consecutive segments of acquisition (block 1, block 2) for preexposed (CSp) and non-preexposed (CSn) stimuli.

3.7. First psychotic episode and LI To assess whether patients who experience their ®rst episode differed in LI from those who had suffered several, two groups were formed. One comprised nine ®rst-episode participants and the second 23 participants whose psychosis had been manifested several times before, irrespective of the duration of illness. This dichotomous factor was included in a 2 £ 2 £ 2 (Episode £ Preexposure £ Conditioning) ANOVA of the electrodermal FIR, together with the factors Preexposure and Conditioning, revealing a three-way interaction of the factors, F(1,30) ˆ 7.89, P ˆ 0.01. Follow-up t-tests were performed on the CS 1 minus CS 2 differences for preexposed and non-preexposed CSs. In the ®rstepisode group, no signi®cant differences were found for the preexposed, t(8) ˆ 1.44, P ˆ 0.19 and for the non-preexposed CSs, t(8) ˆ 0.16, P ˆ 0.88. In contrast, schizophrenic patients with more than one psychotic episode exhibited LI as revealed by a significant CS 1 minus CS 2 difference (conditioning) only for non-preexposed (novel) CSs, t(22) ˆ 3.26, P , 0.01. For the preexposed CSs the difference was in the opposite direction, indicating stronger reactions to the CS 2 than to the CS 1 in that patient group, t(22) ˆ 2.08, P ˆ 0.049. This result for the group of schizophrenic patients with more than one psychotic episode which is summarized in Fig. 7 holds also true when the duration of illness is taken into account. Schizophrenic patients with both short (,7 years, n ˆ 14) and long (.7 years, n ˆ 9) duration of illness exhibited signi®cant CS 1 minus CS 2

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Fig. 7. Electrodermal FIR in acquisition averaged across trials 2±8 to preexposed (CSp 2 , CSp 1 ) and non-preexposed (CSn 2 , CSn 1 ) stimuli in ®rst-episode and multiple-episode schizophrenic patients.

differences for the non-preexposed CSs, but not for the preexposed CSs. However, these ®ndings need to be con®rmed with a larger sample size in the ®rst episode group, especially with respect to the `conditioning effect' in the preexposed condition which possibly would have reached statistical signi®cance if the group had comprised more patients. 3.8. Clinical symptomatology and LI Non-parametric correlational analyses were calculated to determine the relationship between LI and clinical symptoms in schizophrenic patients. No signi®cant correlations were found between LI indices and clinical symptoms as assessed by BPRS, SANS, and PANSS in unmedicated and medicated schizophrenic patients. 4. Discussion The results of the present study can be summarized as follows. First, the present results con®rmed the utility of the within-subject procedure for the assessment of latent inhibition as indexed by autonomic responses. Employing two sets of CS 1 and CS 2 , one preexposed and the second introduced at the beginning of acquisition, permitted the observation of latent inhibition without the use of a preexposure control group. Moreover, the use of a nonaversive US, a reaction time task, renders this procedure suitable for applications in experimental psychopathology research. Second, LI was evident in both performance

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measures (reaction time task) and autonomic responses. Responding (key pressing) to the imperative signal (tone) was slower to the preexposed CS than responding to novel stimuli. This LI effect was found only during the ®rst half of acquisition phase and did not differ with respect to the groups of participants. Reaction times were equally slower in unmedicated and medicated schizophrenic patients and in well controls. This reduction in response speed level, independent of diagnostic groups, is similar to that found by Kathmann et al. (2000). Third, latent inhibition of Pavlovian conditioning, as indexed by larger electrodermal responses during CSn 1 than during CSn 2 in absence of a difference between CSp 1 and CSp 2 , was present in well controls and in medicated schizophrenic patients, but not in unmedicated patients. The latter group failed to show differential responding to either pair of CS 1 and CS 2 . Fourth, the present study did not ®nd any differences among the three groups in orienting and habituation to novel stimuli as observed during preexposure. Well controls and both patient groups displayed reliable electrodermal orienting responses at the beginning of the experiment which habituated within a few trials as is usually observed in experiments of this type (Lipp et al., 1992). However, the groups differed reliably in the size of orienting to stimulus change observed at the beginning of acquisition (conditioning). Well controls and medicated patients displayed larger electrodermal responses to the novel CS (CSn 1 and CSn 2 ) than to the preexposed CS (CSp 1 and CSp 2 ), whereas there was no such difference in unmedicated schizophrenic patients. The present study has the potential to put to rest concerns that a within-subject Pavlovian conditioning procedure like the present one may not be suited for use with patient samples. Although it is reasonable to assume that the participants differed in the level of motivation, and thus the extent to which they engaged in the non-aversive reaction time task US procedure, such a difference did not affect the overall conditioning performance. Reaction times tended to be slower in patients than in well controls, but this tendency did not affect the conditioning performance. Moreover, a decrease in reaction time across blocks of trials was observed in all three groups. This is an indication that there was no difference in the extent to which the task involved the participants and to which they attempted

to improve their performance as a result of the performance feedback. A second concern that has been raised against the present procedure is the use of electrodermal responses as dependent measure in a sample of schizophrenic patients. This relates to the well documented differences in electrodermal responsiveness that have been reported for schizophrenic È hman, 1981), as well as to concerns patients (O about the effects of medications that may contain anticholinergic components. As evidenced by the electrodermal data from preexposure and the unconditional responses elicited by the reaction time task US, both concerns were ill founded. The patient groups did not comprise more electrodermal nonresponders than did the well control group. Moreover, there was no difference among the groups in orienting during the preexposure phase. Differences in the size of electrodermal responses among the groups were observed during acquisition in that well controls displayed larger unconditional responses than did both patient groups. However, the fact that conditioning was found in one of the two patient groups indicates that this reduction in unconditional responding did not prevent the development of Pavlovian learning. It seems that the within-subject control procedure employed in the present study was suf®ciently sensitive to permit the observation of differential learning effects even if these occurred in the context of an overall diminished responsiveness. In studies using the operant procedure with schizophrenic patients (e.g. Baruch et al., 1988a; Gray et al., 1992a) the absence of LI in acute patients can usually be attributed to equal learning under conditions of prexposure and non-preexposure or enhanced learning in the preexposed condition, whereas the present study failed to provide evidence for learning, i.e. differential electrodermal responses, in either condition in unmedicated patients. This difference across studies may re¯ect idiosyncrasies of the respective procedures. In the operant procedure participants are presented with a small number of target stimuli (36) interspersed among a large number of non-targets (204) and required to respond once the target is identi®ed. In the differential conditioning procedure, the number of targets and non-targets is small and even and differential responding re¯ects both, maintained or enhanced responding to CS 1 and reduced

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responding to CS 2 . The higher number of nontargets in the operant procedure may make their differentiation easier whereas subjects may not have had suf®cient time to learn the differentiation in the present study and continued to respond to both, CS 1 and CS 2 similarly, regardless of whether they had been preexposed or not. The facts, that during acquisition overall responding in the unmedicated group was larger than in the medicated group and that responses were signi®cantly different from Zero are consistent with this interpretation. The second interesting ®nding of the present study is the difference in responding to stimulus change observed among the groups. The three groups did not differ in the extent of orienting or habituation to novel stimuli presented at the beginning of the preexposure phase. This seems to indicate that all subjects identi®ed the preexposed stimuli as novel and, across stimulus repetitions, insigni®cant. However, such an interpretation of the change in electrodermal responding across preexposure seems inappropriate for unmedicated subjects if the pattern of results observed during the initial trials of acquisition is considered. In well controls and medicated patients, the novel stimuli elicited reliably larger responses than did the preexposed stimuli indicating a difference in orienting to and, presumably, processing of the stimuli (for a discussion of orienting as an index of information processing see Siddle, 1991). This was not the case in the unmedicated sample. Participants in this sample displayed signi®cant electrodermal responses that did not differ between novel and preexposed stimuli indicating that there was no difference in the extent to which these stimuli were processed. This observation is consistent with the notion, that schizophrenic patients process redundant stimuli to the same level as novel, informative stimuli (Hemsley, 1993). This interpretation is also consistent with the failure to ®nd differences in conditioning between preexposed and nonpreexposed stimuli during the later stages of acquisition. Contemporary learning theories hold that latent inhibition is mediated by a reduction in the processing of the conditional stimulus after preexposure which is in contrast to the extensive processing that a novel conditional stimulus receives upon its ®rst presentation. Thus, stimuli which are not subjected to extensive processing will not enter as readily into an

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association with an US as will stimuli that are extensively processed (for a review see Lubow, 1989). If, however, CS 1 and CS 2 are processed to the same extent, then differential responding, which is the index of Pavlovian learning in a differential conditioning design, will not emerge. In summary, the present study con®rms the utility of the within subject latent inhibition procedure as a tool for research in psychopathology. In contrast to previous versions of the procedure and in contrast to the operant latent inhibition task, there is no need for a non-preexposed control group in the present procedure. Moreover, by including measurements of orienting to change, the present procedure offers direct support for the proposition that failures to ®nd latent inhibition in nonmedicated patients re¯ect the fact that these patients process preexposed, redundant stimuli in a manner similar to novel stimuli. This ®nding is consistent with current theory of cognitive psychopathology in schizophrenia as well as with results from other experimental paradigms such as evoked potential studies of mismatch negativity (for a review see NaÈaÈtaÈnen, 1992) or sensorimotor gating (Braff, 1993). Acknowledgements This research was supported by a grant to D. Vaitl from the German Research Society (Az. Va 37/32-1). We wish to thank Bertram Walter for assistance in statistical analyses, Prof. Dr Bernd Gallhofer (director of the Psychiatry Department, Medical Center, University of Giessen) for his support, and two anonymous referees for their helpful comments. References American Psychiatric Association, 1994. DSM IV. Washington, DC. Andreasen, N.C., 1983. The scale for the assessment of negative symptoms (SANS). University of Iowa, Iowa City. Baruch, I., Hemsley, D.R., Gray, J.A., 1988a. Differential performance of acute and chronic schizophrenics in a latent inhibition task. J. Nerv. Ment. Dis. 176, 598±606. Baruch, I., Hemsley, D.R., Gray, J.A., 1988b. Latent inhibition and psychotic proneness in normal subjects. Pers. Individ. Diff. 9, 777±783. Braff, D.L., 1993. Information processing and attention dysfunctions in schizophrenia. Schizophr. Bull. 19, 233±259.

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