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Cardiac Responses during Picture Viewing in Young Male Patients with Schizophrenia

Cardiac Responses during Picture Viewing in Young Male Patients with Schizophrenia Hindawi Publishing Corporation Cardiovascular Psychiatry and Neurology Volume 2012, Article ID 858562, 11 pages doi:10.1155/2012/858562 Clinical Study Cardiac Responses during Picture Viewing in Young Male Patients with Schizophrenia 1, 2 3 1 1 Roelie J. Hempel, Julian F. Thayer, Christian H. Roder, ¨ Hugo G. van Steenis, 1 1 Nico J. M. van Beveren, andJokeH.M.Tulen Department of Psychiatry, Erasmus University Medical Center, ‘s Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands School of Psychology, University of Southampton, University Road, Southampton SO17 1BJ, UK Department of Psychology, Ohio State University, Psychology Building, 1835 Neil Avenue Mall, Columbus, OH 43210, USA Correspondence should be addressed to Joke H. M. Tulen, j.h.m.tulen@erasmusmc.nl Received 26 July 2012; Accepted 16 October 2012 Academic Editor: Heimo ViinamaKi Copyright © 2012 Roelie J. Hempel et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Previous research investigating the emotion recognition ability in patients with schizophrenia has mainly focused on the recognition of facial expressions. To broaden our understanding of emotional processes in patients with schizophrenia, this study aimed to investigate whether these patients experience and process other emotionally evocative stimuli differently from healthy participants. To investigate this, we measured the cardiac and subjective responses of 33 male patients (9 with and 24 without antipsychotic medication) and 40 male control subjects to emotion-eliciting pictures. Cardiac responses were chosen as an outcome measure because previous research has indicated that these are linked with attentional and emotional processes and provide a more objective measure than self-report measures alone. The differences in cardiac responses between patients and controls were limited to medicated patients: only the medicated patients showed significantly decreased cardiac orienting responses compared with control subjects, regardless of picture contents. These results indicate that medicated patients directed less attention towards emotion-eliciting pictures than controls. Decreased attentional resources while processing emotional evocative stimuli could lead to incorrect appraisals of the environment and may have detrimental emotional and social consequences, contributing to chronic stress levels and an increased risk for cardiovascular disease. 1. Introduction patients reported that they experienced the same amount of pleasant emotions as healthy controls, but greater amounts An extensive amount of research papers has been published of unpleasant emotions in response to emotion-eliciting on the impaired emotional functioning of patients with stimuli [10, 11]. It has also been found that schizophrenic schizophrenia. Most of this research has focused on the patients experience less positive emotions and more negative impaired ability of these patients to recognize emotions emotions in response to daily stressors [12] and emotion- from facial expressions [1], which is crucial for forming and eliciting pictures [13], compared with healthy control maintaining interpersonal relationships [2, 3], and patients subjects. This apparent discrepancy between the impaired with schizophrenia are known to experience difficulties with ability of schizophrenic patients to recognize and express social functioning [4, 5]. emotional facial expressions, yet with intact experience of emotions, needs further investigation. If schizophrenic Although schizophrenic patients seem impaired in their ability to recognize and express emotional facial expressions, patients experience emotions in a way similar to healthy they do appear to experience emotions in a way similar to control subjects, they are expected to perceive the emotion- healthy controls. Several studies have found that patients eliciting stimuli in a similar way as well. This could imply that and controls did not differ in their subjective ratings of the disturbances in emotion recognition in schizophrenic pleasantness and arousal when presented with emotion- patients are restricted to facial stimuli, as opposed to more eliciting pictures [6–9]. In two other studies, schizophrenic general emotion-eliciting stimuli. 2 Cardiovascular Psychiatry and Neurology Another aspect of emotions is the psychophysiological their first psychotic episode or were receiving treatment response that accompanies them [14]. Psychophysiological for the first time. In order to assess symptom severity, the responses offer a more objective measure of emotional Dutch translation of the Positive and Negative Syndrome and cognitive processes than self-report alone. Only a few Scale (PANSS; [21]) was used. As can be seen in Table 1, studies have investigated the cardiac responses of patients antipsychotic-free patients had higher scores for all subscales with schizophrenia during the viewing of emotion-eliciting as well as the total score of the PANSS than medicated pictures. Two of these studies did not find any differences patients (positive: t[28] = 2.4,P< 0.05; negative t[28] = 2.6, between the patients and healthy controls with regard to P< 0.05; general psychopathology t[28] = 2.5, P< 0.05; their cardiac responses [7, 9]. However, both studies used total score t[28] = 3.5, P< 0.01). The other difference the averaged heart rate response during slide viewing relative between these two groups was that the duration of illness was to a 1- or 2-second baseline before picture onset, without significantly shorter in antipsychotic-free versus medicated taking into account the triphasic pattern of the cardiac patients (t[25.96] = 3.3, P< 0.01). response (deceleration-acceleration-deceleration [14]). Yee Antipsychotic treatment was administered according to et al. [15] did take this pattern into account and found that the clinical treatment protocol of the Erasmus MC Clinic only prodromal patients differed significantly from healthy for psychotic disorders, which is congruent with both the controls and patients with schizophrenia in their heart rate schizophrenia treatment guidelines of the Dutch Psychiatric deceleration, that is, orienting response (OR), which was Association and the American Psychiatric Association. The more pronounced in these patients. In a study previously details on medication use are shown in Table 2. conducted by our group [16], we found that patients with Controls were recruited by means of advertisements. All schizophrenia hardly showed any OR to emotion-eliciting controls were healthy and drug free at the time of testing pictures. Instead, we found a substantial increase in the heart as assessed by means of a short phone interview and a rate in patients with schizophrenia that was evoked by erotic structured questionnaire. None of the controls or their first- pictures, indicating an activation of the sympathetic nervous degree relatives had experienced past or current psychiatric system, which could either mean a defensive reaction to illnesses. Exclusion criteria for both patients and controls these stimuli, suggesting stimulus rejection [17], or a strong were respiratory diseases, cardiovascular diseases, and the use appetitive reaction. Summarizing, thus far mixed results of medication that could influence the autonomic nervous regarding cardiac responding in schizophrenia have been system. There were significantly more smokers in both reported. However, none of these studies have taken medica- patient groups than in the control group (χ = 27.78, P< tion use into account, while it has previously been found that 0.001). atypical antipsychotics decrease physiological responding to After the subjects were given a complete description emotion-eliciting stimuli [18]. of the study, written informed consent was obtained. The The aim of the present study is to broaden our knowledge study was approved by the Medical Ethics Committee of the about the cardiac responding and underlying motivations of Erasmus MC, University Medical Center Rotterdam, and was patients with schizophrenia while viewing emotion-eliciting carried out in accordance with the Declaration of Helsinki. pictures. Based on previous research [16], we hypothesized that the patients with schizophrenia would show diminished OR responses in general, reflecting a deficit in the intake 2.2. Procedure. All experimental sessions took place between process of stimulus information. Because of the potential 09.00 and 11.00 hrs in the morning. The subject sat in importance of antipsychotic medication use on psychophys- a comfortable chair in a small, sound-attenuated dimly iological responses, we analysed our data separately for lit room. The experimenter was in the room with the medicated and antipsychotic-free patients, while controlling participants at all times to ensure their safety and to for baseline levels of heart rate and heart rate variability, make sure they understood and complied with the task smoking, mood, and age. instructions. Both patients and controls were asked not to use any coffee or cigarettes before and during testing on the day of the experimental session. Before the application of 2. Methods the electrodes participants were asked to complete a Dutch 2.1. Subjects. In this study, 33 male patients with schizophre- shortened version of the Profile of Mood States (POMS; [22]. nia (9 antipsychotic free and 24 medicated) and 40 male Electrodes for the recordings of the heart rate were applied control subjects participated. The demographic details of according to the standard laboratory procedures. After the the participants are shown in Table 1. The patients were application of the electrodes, the experimental session began recruited from the early psychosis unit at the Department with a rest period of five minutes in which subjects were of Psychiatry of the Erasmus MC, University Medical asked to relax and not to speak. After this first rest period, Center Rotterdam. All patients were screened by a senior the headphones were put on and the emotional picture task clinical psychiatrist using the Comprehensive Assessment of was explained. The duration of the task was approximately Symptoms and History (CASH; [19]), and included in the 25 minutes. After completion, all electrodes were removed study if they were diagnosed as suffering from schizophrenia from the subjects and they were asked to do the subjective according to the criteria of the DSM-IV [20]. All patients rating task, which lasted approximately 15 minutes. All tasks experienced a psychotic episode at the time of the study. All were designed using E-prime (Psychology Software Tools, patients were inpatients and most of them were experiencing Inc., 2002). Cardiovascular Psychiatry and Neurology 3 Table 1: Demographic characteristics of the patient and control groups. Medicated patients (n = 24) Antipsychotic-free patients (n = 9) Controls (n = 40) Age (mean ± Sd) 22 ±421 ±623 ± 4 Smokers (Yes/No) 20/4 7/2 8/32 Duration of illness (months ± Sd) 16 ± 19 3 ± 3 Duration of current medication use (weeks ± Sd) 4 ± 4 PANSS (mean ± Sd) Positive symptoms 17 ±623 ± 6 Negative symptoms 15 ±521 ± 5 General psychopathology 33 ±943 ± 12 Total 65 ± 16 87 ± 14 PANSS: positive and negative syndrome scale; Sd: standard deviation. There were significantly more smokers in both patient groups than in the control group (χ = 27.78,P< 0.001). The duration of illness was significantly shorter in antipsychotic-free versus medicated patients (t[25.96] = 3.3,P< 0.01). Antipsychotic-free patients had higher PANSS scores for all subscales than medicated patients (positive: t[28] = 2.4,P< 0.05; negative t[28] = 2.6,P< 0.05; general psychopathology t[28] = 2.5,P< 0.05; total score t[28] = 3.5,P< 0.01). Table 2: Mean dosages and duration of current antipsychotic treatment of the patient group. Antipsychotic n Mean dosage (mg) ± Sd Comedication No Antipsychotic 9 Lorazepam (n = 3) Lorazepam (n = 2) Olanzapine 8 16.3 ± 6.9 Oxazepam (n = 1) Lorazepam (n = 1) Risperidone 6 3.0 ± 0.8 Oxazepam (n = 1) Haloperidol 4 2.8 ± 1.5 Lorazepam (n = 2) Clozapine 4 300.0 ± 81.6 Lorazepam (n = 3) Quetiapine 2 450.0 ± 212.13 — Sd: standard deviation. 2.3. Experimental Tasks pictures were presented using a Dell Dimension M200a Personal Computer with a Pentium processor and a 17-inch 2.3.1. Emotional Picture Task. Subjects were seated approx- Samsung SyncMaster monitor. imately 75 cm from the computer screen. All subjects were Each picture was presented during 6 seconds, with an asked to relax, to breathe regularly, and not to speak during intertrial interval (ITI) ranging from 12 to 25 seconds. A total the task. The emotional picture task was a part of a larger of 48 pictures were presented; during 12 of these pictures (4 study in which we also investigated acoustic startle responses. positive, 4 neutral, and 4 negative) no startle stimulus was Thesubjectsweretoldthattheywereabout to view aseries presented. During the remaining 36 pictures, startle stimuli of different pictures and that loud noises were occasionally were presented either 300, 800, 1300, or 3800 ms after picture presented through the headphones. They were asked to onset in such a way that each of these latency conditions look at the pictures the entire time they were presented occurred 3 times during the viewing of positive, neutral, on the screen, but that they did not have to respond. and negative pictures. In addition, 12 startle stimuli were Forty-eight pictures were selected from the International randomly presented during the inter trial intervals. Thus, a Affective Picture System (IAPS [23]). (Positive IAPS pictures: total of 48 pictures and 48 startle stimuli were presented. All pictures and startle stimuli were presented completely at 4220, 4290, 4608, 4660, 4670, 4680, 5260, 5470, 5621, 5910, random so that each subject was presented with a different 8030, 8170, 8490, 8501. Neutral IAPS pictures: 5120, 5260, order of stimuli. For the purpose of this paper, we will 5510, 5530, 5535, 5711, 5731, 5740, 5900, 7000, 7002, 7004, only report the cardiac responses to the pictures that were 7006, 7009, 7010, 7020, 7025. Negative IAPS pictures: 3000, presented without a startle stimulus. 3010, 3060, 3069, 3080, 3102, 3120, 3170, 6200, 6212, 6230, 6260, 6300, 6313, 6350, 6550.) The stimuli were chosen on the basis of their normative ratings provided with the 2.3.2. Subjective Rating Task. The pictures that were pre- IAPS and could be divided into six different categories, sented during the startle task were again presented in the based on their contents. The positive pictures had erotic subjective rating task, using a randomized order different and adventure contents, the neutral pictures showed nature from that of the startle task. The participants were asked to scenes and household objects, and the negative pictures rate how they felt during the viewing of the pictures. They contained pictures with mutilation and threat contents. The responded with their dominant hand using the numbers 4 Cardiovascular Psychiatry and Neurology on the keyboard. A fixation cross was presented for 3 tests. To assess whether there were any differences between seconds on a 17-inch computer screen, followed by a 6- the three groups (medicated, antipsychotic free, and con- second presentation of a picture. After picture offset, the trols), the Kruskal-Wallis test was used. When significant subjects were asked to rate each picture using the SAM differences were found, we proceeded to investigate which (Self-Assessment Manikin; [24]. The SAM consisted of two groups differed from each other using the Mann-Whitney subsequent screens, each containing five figures. On the first tests and to correct for multiple testing, the alpha was screen, the figures represented the degree of pleasantness reduced to 0.016. The maximal scores for each of the scales of the pictures—ranging from very unpleasant to very were as follows: depression 32, fatigue 24, tension 24, anger pleasant—on a scale from 1 to 9. On the second screen, each 28, and vigour 20. The Total Mood Disturbance (TMD) score figure represented the degree of arousal associated with each was calculated by subtracting the vigour score from the sum picture—ranging from very calm to very arousing—also on of all the other scores (i.e., depression + fatigue + tension a scale from 1 to 9. After their response, the fixation cross +anger − vigour = TMD), so that a higher positive score appeared again for 3 seconds, followed by the next picture. represented a more negative mood state. 2.4.2. Cardiac Responses 2.3.3. Cardiac Responses. During the experiment, continu- ous measurements were made of the heart rate (HR). HR Baseline. The mean HR level and the ln(HF-HRV) of the was recorded using a precordial lead and was sampled at three groups during 3 minutes of resting baseline before 512 Hz. All data were sampled and stored on a flashcard the onset of the tasks were compared using an analysis of by means of a portable digital recorder (Vitaport System; variance (ANOVA) with Group (medicated, antipsychotic- TEMEC Instruments B.V., Kerkrade, The Netherlands). free, and controls) as the between subjects factor. Upon completion of the recording, all physiological data were imported and processed on a Personal Computer Cardiac Response to Picture Stimuli. For the analysis of using a Vitascore software module (TEMEC Instruments cardiac responses to the emotional stimuli, we developed BV, Kerkrade, The Netherlands). Subsequently, the interbeat an hierarchical linear model (HLM) using MlWin software intervals were calculated using R-top detection. A low pass [28], with Subject, Time, and Picture Type entered as filtered cardiac event series (LPFCES; [25]) was calculated, repeated variables. The fixed factors in the HLM were using a low pass filter of 0.5 Hz. This method is based on the Group (medication free, medicated, and control), Time (0– Integral Pulse Frequency Modulation model [25]. 6 seconds, in half second bins) with its linear and quadratic The responses to the 12 pictures that were presented polynomials, Picture Type (negative, neutral, and positive), without a startle stimulus were used for the analyses of the Group × Time, Group × Picture Type, Time × Picture Type, cardiac responses. Data series for each individual stimulus and Group × Time × Picture Type. The following covariates were extracted for the pictures starting 2 seconds before stim- were entered smoking (number of cigarettes per day), age, ulus onset and ending 6 seconds after stimulus onset. Cardiac illness duration (months), medication duration (weeks), responses for each stimulus were calculated by subtracting POMS TMD score, baseline ln(HF-HRV), and baseline HR. the 6 seconds after stimulus onset from the 2-second baseline We also entered the following interaction effects: ln(HF- period before each stimulus. This resulted in time series HRV) × Time and baseline HR × Time; these were included consisting of difference scores for each separate stimulus. to examine whether they were related to a different cardiac responding to startle stimuli, since we previously found that schizophrenic patients generally experience decreased levels 2.3.4. Baseline HR and Heart Rate Variability (HRV). Mean of HF-HRV [29], which could explain overall decreased HR was calculated over a 3-minute period of rest. Addi- cardiac responsivity to stimuli. All factors and covariates tionally, this HR time series was subjected to a discrete Fourier transform (CARSPAN program, Groningen, The were entered in the model and the best fit for the model was sought using the log-likelihood method. Significant interac- Netherlands [26, 27]), to yield power spectra of the rhythmic tion effects were followed up by separate linear models. oscillations over a frequency range of 0.02–0.50 Hz, with a resolution of 0.01 Hz. The power was calculated for the 2.4.3. SAM Ratings. Since the Kolmogorov-Smirnov tests high frequency band (HF-HRV: 0.15–0.5 Hz). Because of indicated that the distributions of the SAM rating of pleasure the skewed distribution, a natural log transformation was and arousal were normally distributed within the groups (P applied to HF-HRV. values ranged from 0.13 to 1.00), we performed two repeated measures ANOVA’s with Pleasure or Arousal rating as the 2.4. Statistical Analyses. All analyses were conducted using dependent variable, Group (medicated, antipsychotic-free SPSS version 13.0 and MlWin 2.10 [28]. All alpha’s were set at and controls) as the between subjects factor, and Picture Type 0.05 unless otherwise specified. All self-report responses were as the within subjects factor. used as a manipulation check and to make sure participants had complied with the task instructions. 3. Results 2.4.1. Profile of Mood States (POMS). To investigate the 3.1. Profile of Mood States (POMS). The POMS scores of the subjective mood state of the participants at the time of three groups are reported in Table 3. Because the Kruskal- testing, we analysed their POMS scores using nonparametric Wallis test showed that there were significant differences Cardiovascular Psychiatry and Neurology 5 Table 3: Profile of mood states scores per group. Medicated patients (n = 24) Antipsychotic-free patients (n = 9) Controls (n = 40) POMS mean ± Sd (range) ∗ ∗ Depression 7 ± 7 (0–22) 8 ± 9 (0–28) 1 ± 2 (0–6) Fatigue 6 ± 6 (0–18) 8 ± 5 (1–15) 3 ± 3 (0–11) ∗ ∗ Tension 6 ± 5 (0–16) 6 ± 4 (0–12) 2 ± 2 (0–9) ∗ ∗ Anger 5 ± 5 (0–17) 7 ± 5 (0–16) 1 ± 2 (0–10) Vigour 11 ± 5 (2–18) 7 ± 5 (0–13) 12 ± 3 (5-18) ∗ ∗ TMD 12 ± 20 (−15–60) 21 ± 22 (2–68) −5 ± 7(−14–14) Sd: standard deviation; TMD: total mood disturbance; significant difference compared to controls, P < 0.01. between the three groups in mood scores (depression χ = overall HR level: with all other variables being constant, the 2 2 28.0, P< 0.001; fatigue χ = 9.7, P< 0.01; tension χ = 22.0, medicated patients showed the least deceleration, followed 2 2 2 2 P< 0.001; anger χ = 16.9, P< 0.001; vigor χ = 6.8, by the controls, while the antipsychotic-free patients showed 2 2 P< 0.05; TMD score χ = 23.2, P< 0.001), we used the most deceleration overall. As expected, the main effect the Mann-Whitney tests to further explore these differences. for Picture Type (joint χ = 11.04, P< 0.01) indicated that (1) The medicated and antipsychotic-free patients did not differ the HR decelerations were significantly larger for negative significantly in their mood scores for any of the subscales and positive pictures compared to neutral pictures. The (all P’s were 0.10 or higher). However, compared to control significant main effect of Time linear showed that HR subjects, the antipsychotic-free patients showed significantly decreased over time. decreased mood on all subscales and the TMD score (all P’s < The significant interaction effect of Group × Picture 0.01), and the medicated patients had significantly decreased Type (joint χ = 23.50, P< 0.01) indicated that the HR (1) mood scores for depression, tension, anger, and the TMD responses to the various picture types of the patient groups score (all P’s < 0.001). were less differentiated than the HR responses of the control group. For example, the difference in HR deceleration between negative and neutral pictures was smaller in the 3.2. Heart Rate and HF-HRV at Baseline. Data was lost for medicated group compared to the control group, while the one medicated patient due to excessive movements during difference in HR response between positive and neutral pic- baseline. We found a significant Group effect when we tures was smaller in the antipsychotic-free group compared investigated whether the resting HR of patients who were to the control group. Also, the medicated patients showed not under current antipsychotic medication (n = 9) and more HR deceleration to positive versus negative pictures, medicated patients (n = 23) differed from the resting HR whereas both the antipsychotic-free patients and the controls of the control group (n = 40), F[2, 69] = 8.26, P = 0.001, did not. The significant interaction effect of Group × Time partial η = 0.19. The mean HR of medicated patients was (joint χ = 10.80, P< 0.01) indicated that medicated (1) 83 ± 16 bpm, of antipsychotic-free patients 75 ± 13 bpm, patients showed significantly less HR deceleration over time and of controls 69 ± 11 bpm. The Bonferroni post hoc tests than antipsychotic-free patients and healthy controls. The indicated that only the mean HR of the medicated patients Picture Type by Time (joint χ = 24.98, P< 0.01) (1) was significantly higher than that of the control subjects interaction effect confirmed that HR decelerates more over (mean difference = 14.05, sd = 3.46, P< 0.001). time for negative and positive pictures than neutral pictures. We also found a significant Group effect for the natural With regard to the covariates, the significant effect of logarithm of HF-HRV, F[2, 69] = 6.07,P< 0.01, partial η = Age indicated that the HR increased with age, whereas 0.15. The Bonferroni post-hoc test (mean difference = 1.08, the significant effects of duration of medication use and sd = 0.31, P< 0.01) showed that medicated patients had a illness duration indicated more deceleration with longer significantly lower HF-HRV (6.21 ± 1.59) than the control antipsychotic medication use and/or longer illness duration. subjects (7.29 ± 0.92), while the antipsychotic-free patients We also found that Baseline HR was negatively related to did not differ significantly from either groups (7.18 ± 1.17). cardiac response: a higher HR at baseline is related to more HR deceleration during picture viewing, and ln(HF-HRV) 3.3. Cardiac Response to Picture Stimuli. The following significantly interacted with Time , indicating that increases factors did not contribute significantly to the model and in cardiac vagal activity during rest were related to an were therefore removed: the three-way interaction between increased cardiac response. Finally, increased negative mood Group × Time × Picture Type, Smoking, and the interaction was related to a cardiac increase, as shown by the significant between baseline HR × Time. effects of the POMS TMD score. All beta-coefficients for this model are reported in Table 4, and the cardiac responses of each of the three groups are shown in Figures 1(a)–1(c). The significant main 3.4. Follow-Up Analyses per Group. Because of the significant effect for Group (joint χ = 94.41, P< 0.01) indicated two-way interaction effects with Group and because the (1) that all three groups differed from each other in terms of figures suggested a decreased orienting response in the 6 Cardiovascular Psychiatry and Neurology Table 4: Beta coefficients of the HLM for cardiac responses to emotion-eliciting pictures in medication free patients, medicated patients, and healthy control subjects. Factor Comparison between GroAFPs Comparison between picture types Beta coefficient Standard error Z-score Constant −0.13 1.11 −0.12 AFP versus C −0.88 0.43 −2.04 Group MP versus C 1.60 0.36 4.51 MP versus AFP 2.51 0.45 5.57 Neg. versus Neu. −2.12 0.24 −8.76 Picture type Pos. versus Neu. −1.79 0.24 −7.39 Pos. versus Neg. 0.33 0.24 1.37 Time −5.63 1.72 −3.27 Time −0.03 1.72 −0.02 AFP versus C Neg. versus Neu. 0.59 0.56 1.05 MP versus C Neg. versus Neu. 1.54 0.40 3.86 MP versus AFP Neg. versus Neu. 0.92 0.60 1.54 AFP versus C Pos. versus Neu. 1.65 0.56 2.93 Group × Picture Type MP versus C Pos. versus Neu. 0.69 0.40 1.72 MP versus AFP Pos. versus Neu. −1.02 0.60 −1.71 AFP versus C Pos. versus Neg. 1.06 0.56 1.89 MP versus C Pos. versus Neg. −0.86 0.40 −2.15 MP versus AFP Pos. versus Neg. −1.92 0.60 −3.20 AFP versus C −0.60 0.83 −0.72 Group × Time MP versus C 1.85 0.64 2.92 MP versus AFP 2.46 0.91 2.70 AFP versus C −0.69 0.83 −0.83 Group × Time MP versus C −1.00 0.64 −1.57 MP versus AFP −0.30 0.91 −0.33 Neg. versus Neu. −3.15 0.65 −4.85 Picture Type × Time Pos. versus Neu. −2.26 0.65 −3.48 Pos. versus Neg. 0.90 0.65 1.38 Neg. versus Neu. 0.26 0.65 0.40 Picture Type × Time Pos. versus Neu. 0.37 0.65 0.56 Pos. versus Neg. 0.11 0.65 0.17 Age 0.10 0.02 4.95 Medication duration −0.17 0.03 −5.09 Illness duration −0.02 0.01 −2.88 HR baseline −0.03 0.01 −3.71 Ln(HRV HF) −0.09 0.08 −1.09 Ln(HRV HF) × Time 0.82 0.23 3.62 Ln(HRV HF) × Time 0.18 0.23 0.79 POMS TMD score 0.01 0.01 2.33 Numbers expressed in bold indicate significant effects at the 0.05 level. HR: heart rate; Ln(HF-HRV): natural logarithm of high frequency heart rate variability; POMS: profile of mood states; TMD: total mood disturbance; AFP: antipsychotic-free patients; C: control; MP: medicated patients; Neg: negative pictures; Neu: neutral pictures; Pos: positive pictures. Cardiovascular Psychiatry and Neurology 7 Cardiac reponses to picture stimuli Cardiac responses to picture stimuli Medicated patients (n = 23) Antipsychotic free patients (n = 9) 2 2 Time (s) 0 0 0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.5 6 −1 0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.5 6 −1 Time (s) −2 −2 −3 −3 −4 −4 −5 −5 Negative Negative Neutral Neutral Positive Positive (a) (b) Cardiac reponses to picture stimuli Healthy controls (n = 40) Time (s) 0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.5 6 −1 −2 −3 −4 −5 Negative Neutral Positive (c) Figure 1: Time series of mean cardiac responses to negative, neutral, and positive picture stimuli in (a) antipsychotic-free patients, (b) medicated patients, and (c) healthy control participants during the 6 seconds of picture presentation. patient groups to positive and negative compared to neutral η = 0.72). The positive pictures were rated as most pictures, we further investigated this with follow-up HLM pleasant, followed by the neutral pictures, and the negative models for each group, only including the cardiac responses pictures were rated as least pleasant (positive versus neutral: during the first 3 seconds of picture viewing. F[1, 71] = 47.32, P< 0.001, partial η = 0.40; positive versus Within the antipsychotic free patient group, the Time × negative: F[1, 71] = 296.50, P< 0.001, partial η = 0.81; Picture Type interaction effect was significant (joint χ = neutral versus negative: F[1, 71] = 136.00, P< 0.001, partial (1) 9.31, P< 0.01), indicating that the heart rate decreased η = 0.66). No significant main or interaction effects for more over time for negative than for positive pictures, that Group were found. is, the antipsychotic-free patients showed a larger orienting For the arousal ratings a significant main effect for response to negative versus positive pictures. Within the PictureTypewas found(F[1.6; 108.5] = 28.68, P< 0.001, medicated patient group, the main effect for Picture Type partial η = 0.29). The negative and positive pictures were was significant (joint χ = 5.33, P< 0.01), indicating that rated as more arousing than the neutral pictures, whereas (1) the heart rate of the medicated patients was lower during no difference in arousal ratings was found between positive the first 3 seconds for positive compared to neutral pictures. and negative pictures (negative versus positive: F[1, 70] = Within the control group, the main effects for Time (Z = 1.23, P = 0.27; negative versus neutral: F[1, 70] = 39.38, −3.92, P< 0.01) and Picture Type (joint χ = 22.47, P< (1) P< 0.001, partial η = 0.36; positive versus neutral: 0.01). As can be seen in Figure 1(c), the HR of the controls F[1, 71] = 74.17, P< 0.001, partial η = 0.51). The main decreased more for positive and negative than for neutral effect for Group was also significant (F[2, 70] = 3.61, P< pictures. The interaction effect of Time × Picture Type (joint 0.05, partial η = 0.09). The Games-Howell test showed χ = 6.30, P< 0.01) was also significant, although pairwise (1) that the arousal ratings of the medicated patients group comparisons were not. tended to be higher than those of the antipsychotic-free and control groups (medicated versus antipsychotic-free: mean 3.5. Subjective Ratings. In Figures 2(a) and 2(b), the mean difference = 0.98, sd = 0.44, P = 0.09; medicated versus SAM ratings for pleasure and arousal are presented. For control: mean difference = 0.83, sd = 0.37, P = 0.07). The the pleasure ratings, we found a significant main effect for interaction effect between Picture Type and Group almost Picture Type (F[1.7; 121.6] = 178.88, P< 0.001, partial reached significance (F[3.1; 108.5] = 2.49, P = 0.06, partial Cardiac response (bpm) Cardiac response (bpm) Cardiac response (bpm) 8 Cardiovascular Psychiatry and Neurology Arousal ratings Pleasure ratings 4 4 2 2 0 0 Antipsychotic free Medicated Controls Antipsychotic free Medicated Controls Positive Positive Neutral Neutral Negative Negative (a) (b) Figure 2: (a) Pleasure and (b) Arousal ratings of antipsychotic-free patients, medicated patients, and healthy control subjects for positive, neutral, and negative pictures. η = 0.07). The antipsychotic-free patients tended to show status [36–40]. Indeed, we found that the power of high less differentiation in arousal ratings between the negative frequency HRV was lower in medicated patients compared and neutral, and positive and neutral pictures compared with healthy control subjects, but not antipsychotic-free with both the medicated and control groups (negative versus patients. The initial HR deceleration related to orienting neutral: F[2, 70] = 3.87, P< 0.05, partial η = 0.10; positive is generally considered to be under vagal control [41–43]. versus neutral: F[2, 70] = 3.46, P< 0.05, partial η = 0.09). The autonomic nervous system (ANS) is considered the link between the central nervous system and the body, and so the 4. Discussion ANS mediates the relationship between centrally occurring events such as emotions and bodily changes such as heart rate The aim of this study was to investigate whether male variability [44]. Thus, generally reduced cardio-vagal control patients with schizophrenia differed from healthy control in patients may have caused the reduced OR rather than this subjects in their psychophysiological responses to emotion- being a result of decreased emotional experience or attention eliciting pictures. A distinction was made between patients in response to emotion-eliciting pictures. However, after who were taking antipsychotic medication and patients who controlling for reduced cardio-vagal control by including were not. HRV as a covariate in our analyses the differences between While the healthy control subjects and antipsychotic-free the medicated and control groups were still significant, patients showed the expected triphasic pattern (i.e., decrease- suggesting that a difference in central processing was at increase-decrease) for cardiac responses to positive and least partially responsible for the different cardiac responses negative pictures—albeit somewhat less pronounced for pos- between groups. itive pictures in antipsychotic-free patients—the medicated patients did not show an initial decrease for any of the picture Second, the sample size for the antipsychotic-free types, suggesting a lack of orientation towards the pictures. patients was very small, so the lack of a significant difference The orientation response (OR), the initial deceleration of the between antipsychotic-free patients and healthy control heart rate, is considered to be the basic cardiac response to subjects could be due to a lack of statistical power. Although perceptual stimuli and tends to be greatest for unpleasant we cannot rule out this possibility, Figures 1(a)–1(c) suggest pictures. The cardiac OR is thought to reflect the intake of that antipsychotic-free patients had heart rate decelerations stimulus information [30–32]. Our results suggest that in during picture viewing comparable to controls, and a medicated patients with schizophrenia this OR is lacking previous study [15] showed an almost identical pattern of a finding that is consistent with the existing literature on cardiac responses to emotion-eliciting pictures in a group of attentional deficits in these patients [33–35]. However, we prodromal patients (n = 12, of which 8 are antipsychotic did not find this lack of OR in antipsychotic-free patients. free). Third, the use of antipsychotic medication may have It seems paradoxical that the antipsychotic-free patients caused side effects such as sedation and/or drowsiness. showed overall decreased mood scores and more severe However, the medicated patients did not differ significantly symptom scores yet physiologically they seemed to respond in their subjective fatigue and vigour scores of the POMS more similarly to healthy control subjects than the medicated when compared to healthy controls. Thus, a number of factors could have caused this difference between medicated patients. A number of factors could account for this finding. First, a difference in sympathovagal balance in the patient and antipsychotic-free patients, but with our current data we group could account for the difference in ORs. Previous are unable to answer this question satisfactorily. We therefore studies have consistently found a decrease in cardiovagal con- propose that future research should focus more on the trol in patients with schizophrenia, regardless of medication difference in emotional responding between medicated and Pleasure rating Arousal rating Cardiovascular Psychiatry and Neurology 9 antipsychotic-free patients with schizophrenia to disentangle the scope of this study would be required to control for medication side effects from emotional processing deficits. respiratory variations in the cardiac time series [48]. Medicated and antipsychotic-free patients differed signif- icantly with regard to the subjective arousal ratings of the 5. Conclusions and Implications pictures. Medicated patients tended to show overall higher Our results indicate that the main difference between arousal ratings than antipsychotic-free patients and controls, patients with schizophrenia and healthy control subjects lies a finding that is in line with the previous study of Schlenker in the reduced amount of attentional resources available in et al. [7]. We also found that antipsychotic-free patients medicated patients while viewing emotion-eliciting pictures. showed less differentiation in their arousal scores of neutral No interaction effects between emotional picture contents versus negative and positive pictures than medicated patients and groups were found, indicating that this is a general effect and healthy controls. Whether this finding is caused by and not caused by any specific picture content. These results increased arousal ratings to neutral pictures or decreased are in line with previous studies in which no differences arousal ratings to positive and negative pictures is not clear at in cardiac responding between patients and controls were the moment. All three groups rated the pictures similarly in found [7, 9]. terms of pleasure, with positive pictures receiving the highest We replicated our previous findings regarding the lack of and unpleasant pictures receiving the lowest pleasure scores. orienting responses in patients with schizophrenia [16]. The There were some limitations to our study. For example, decreased OR we found in our patient sample is in line with we only included male participants in this study, which findings that patients with schizophrenia gather little infor- reduces the generalization of our results. Also, we did not mation before responding to certain tasks, a response style differentiate between paranoid and nonparanoid patients termed “jumping to conclusions” [51, 52]. Abnormalities in our analyses. Rather, we chose to investigate a more in the identification of emotionally salient information may heterogeneous patient sample to be able to generalize our lead to misinterpretations of the intentions of others, which results to a patient population that suffered from recent- may increase or exacerbate paranoid thoughts and result in onset schizophrenia, regardless of specific symptoms, that is, dysfunctions in social behaviour [53]. patients with predominantly positive, negative, or disorga- Medicated patients also showed emotionally dampened nized symptoms were all included in this study. responses: that is, not only did they show a reduced or absent As it is a common practice in studies investigating OR but they also had less differentiation in their responses to psychophysiological responses to emotion-eliciting pictures, the emotion-eliciting pictures. McCubbin et al. [54]propose we sampled and analysed the cardiac responses only for that emotional dampening could increase psychological the time period in which the picture was presented, that distress via inappropriate social interactions with family is, for 6 seconds. However, because we did not analyse the members, friends, and coworkers. In addition, emotional cardiac responses after picture offset it is possible we have dampening has been found to be related to increased risk for missed potential differences between groups. Previous stud- cardiovascular disease, most notably hypertension [54]. ies measuring different types of responses (i.e., behavioural, Summarizing the combination of decreased stimulus startle, and fMRI) have found evidence to suggest that intake, jumping to conclusions and emotional dampening although patients’ responses do not differ from healthy can all contribute to chronic stress levels in patients with control subjects while an emotionally evocative stimulus is schizophrenia, resulting in difficulties in social and emo- present, they do appear to have difficulties in maintaining tional functioning and an increased risk for cardiovascular the elicited emotional response once the stimulus disappears disease. [45–47], thereby reducing their ability to use emotions to help them select the most appropriate behavioural response. References Because we asked our participants to give their subjective ratings immediately after picture offsetwewereunableto [1] A. E. Pinkham, R. E. 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Cardiac Responses during Picture Viewing in Young Male Patients with Schizophrenia

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Copyright © 2012 Roelie J. Hempel et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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Hindawi Publishing Corporation Cardiovascular Psychiatry and Neurology Volume 2012, Article ID 858562, 11 pages doi:10.1155/2012/858562 Clinical Study Cardiac Responses during Picture Viewing in Young Male Patients with Schizophrenia 1, 2 3 1 1 Roelie J. Hempel, Julian F. Thayer, Christian H. Roder, ¨ Hugo G. van Steenis, 1 1 Nico J. M. van Beveren, andJokeH.M.Tulen Department of Psychiatry, Erasmus University Medical Center, ‘s Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands School of Psychology, University of Southampton, University Road, Southampton SO17 1BJ, UK Department of Psychology, Ohio State University, Psychology Building, 1835 Neil Avenue Mall, Columbus, OH 43210, USA Correspondence should be addressed to Joke H. M. Tulen, j.h.m.tulen@erasmusmc.nl Received 26 July 2012; Accepted 16 October 2012 Academic Editor: Heimo ViinamaKi Copyright © 2012 Roelie J. Hempel et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Previous research investigating the emotion recognition ability in patients with schizophrenia has mainly focused on the recognition of facial expressions. To broaden our understanding of emotional processes in patients with schizophrenia, this study aimed to investigate whether these patients experience and process other emotionally evocative stimuli differently from healthy participants. To investigate this, we measured the cardiac and subjective responses of 33 male patients (9 with and 24 without antipsychotic medication) and 40 male control subjects to emotion-eliciting pictures. Cardiac responses were chosen as an outcome measure because previous research has indicated that these are linked with attentional and emotional processes and provide a more objective measure than self-report measures alone. The differences in cardiac responses between patients and controls were limited to medicated patients: only the medicated patients showed significantly decreased cardiac orienting responses compared with control subjects, regardless of picture contents. These results indicate that medicated patients directed less attention towards emotion-eliciting pictures than controls. Decreased attentional resources while processing emotional evocative stimuli could lead to incorrect appraisals of the environment and may have detrimental emotional and social consequences, contributing to chronic stress levels and an increased risk for cardiovascular disease. 1. Introduction patients reported that they experienced the same amount of pleasant emotions as healthy controls, but greater amounts An extensive amount of research papers has been published of unpleasant emotions in response to emotion-eliciting on the impaired emotional functioning of patients with stimuli [10, 11]. It has also been found that schizophrenic schizophrenia. Most of this research has focused on the patients experience less positive emotions and more negative impaired ability of these patients to recognize emotions emotions in response to daily stressors [12] and emotion- from facial expressions [1], which is crucial for forming and eliciting pictures [13], compared with healthy control maintaining interpersonal relationships [2, 3], and patients subjects. This apparent discrepancy between the impaired with schizophrenia are known to experience difficulties with ability of schizophrenic patients to recognize and express social functioning [4, 5]. emotional facial expressions, yet with intact experience of emotions, needs further investigation. If schizophrenic Although schizophrenic patients seem impaired in their ability to recognize and express emotional facial expressions, patients experience emotions in a way similar to healthy they do appear to experience emotions in a way similar to control subjects, they are expected to perceive the emotion- healthy controls. Several studies have found that patients eliciting stimuli in a similar way as well. This could imply that and controls did not differ in their subjective ratings of the disturbances in emotion recognition in schizophrenic pleasantness and arousal when presented with emotion- patients are restricted to facial stimuli, as opposed to more eliciting pictures [6–9]. In two other studies, schizophrenic general emotion-eliciting stimuli. 2 Cardiovascular Psychiatry and Neurology Another aspect of emotions is the psychophysiological their first psychotic episode or were receiving treatment response that accompanies them [14]. Psychophysiological for the first time. In order to assess symptom severity, the responses offer a more objective measure of emotional Dutch translation of the Positive and Negative Syndrome and cognitive processes than self-report alone. Only a few Scale (PANSS; [21]) was used. As can be seen in Table 1, studies have investigated the cardiac responses of patients antipsychotic-free patients had higher scores for all subscales with schizophrenia during the viewing of emotion-eliciting as well as the total score of the PANSS than medicated pictures. Two of these studies did not find any differences patients (positive: t[28] = 2.4,P< 0.05; negative t[28] = 2.6, between the patients and healthy controls with regard to P< 0.05; general psychopathology t[28] = 2.5, P< 0.05; their cardiac responses [7, 9]. However, both studies used total score t[28] = 3.5, P< 0.01). The other difference the averaged heart rate response during slide viewing relative between these two groups was that the duration of illness was to a 1- or 2-second baseline before picture onset, without significantly shorter in antipsychotic-free versus medicated taking into account the triphasic pattern of the cardiac patients (t[25.96] = 3.3, P< 0.01). response (deceleration-acceleration-deceleration [14]). Yee Antipsychotic treatment was administered according to et al. [15] did take this pattern into account and found that the clinical treatment protocol of the Erasmus MC Clinic only prodromal patients differed significantly from healthy for psychotic disorders, which is congruent with both the controls and patients with schizophrenia in their heart rate schizophrenia treatment guidelines of the Dutch Psychiatric deceleration, that is, orienting response (OR), which was Association and the American Psychiatric Association. The more pronounced in these patients. In a study previously details on medication use are shown in Table 2. conducted by our group [16], we found that patients with Controls were recruited by means of advertisements. All schizophrenia hardly showed any OR to emotion-eliciting controls were healthy and drug free at the time of testing pictures. Instead, we found a substantial increase in the heart as assessed by means of a short phone interview and a rate in patients with schizophrenia that was evoked by erotic structured questionnaire. None of the controls or their first- pictures, indicating an activation of the sympathetic nervous degree relatives had experienced past or current psychiatric system, which could either mean a defensive reaction to illnesses. Exclusion criteria for both patients and controls these stimuli, suggesting stimulus rejection [17], or a strong were respiratory diseases, cardiovascular diseases, and the use appetitive reaction. Summarizing, thus far mixed results of medication that could influence the autonomic nervous regarding cardiac responding in schizophrenia have been system. There were significantly more smokers in both reported. However, none of these studies have taken medica- patient groups than in the control group (χ = 27.78, P< tion use into account, while it has previously been found that 0.001). atypical antipsychotics decrease physiological responding to After the subjects were given a complete description emotion-eliciting stimuli [18]. of the study, written informed consent was obtained. The The aim of the present study is to broaden our knowledge study was approved by the Medical Ethics Committee of the about the cardiac responding and underlying motivations of Erasmus MC, University Medical Center Rotterdam, and was patients with schizophrenia while viewing emotion-eliciting carried out in accordance with the Declaration of Helsinki. pictures. Based on previous research [16], we hypothesized that the patients with schizophrenia would show diminished OR responses in general, reflecting a deficit in the intake 2.2. Procedure. All experimental sessions took place between process of stimulus information. Because of the potential 09.00 and 11.00 hrs in the morning. The subject sat in importance of antipsychotic medication use on psychophys- a comfortable chair in a small, sound-attenuated dimly iological responses, we analysed our data separately for lit room. The experimenter was in the room with the medicated and antipsychotic-free patients, while controlling participants at all times to ensure their safety and to for baseline levels of heart rate and heart rate variability, make sure they understood and complied with the task smoking, mood, and age. instructions. Both patients and controls were asked not to use any coffee or cigarettes before and during testing on the day of the experimental session. Before the application of 2. Methods the electrodes participants were asked to complete a Dutch 2.1. Subjects. In this study, 33 male patients with schizophre- shortened version of the Profile of Mood States (POMS; [22]. nia (9 antipsychotic free and 24 medicated) and 40 male Electrodes for the recordings of the heart rate were applied control subjects participated. The demographic details of according to the standard laboratory procedures. After the the participants are shown in Table 1. The patients were application of the electrodes, the experimental session began recruited from the early psychosis unit at the Department with a rest period of five minutes in which subjects were of Psychiatry of the Erasmus MC, University Medical asked to relax and not to speak. After this first rest period, Center Rotterdam. All patients were screened by a senior the headphones were put on and the emotional picture task clinical psychiatrist using the Comprehensive Assessment of was explained. The duration of the task was approximately Symptoms and History (CASH; [19]), and included in the 25 minutes. After completion, all electrodes were removed study if they were diagnosed as suffering from schizophrenia from the subjects and they were asked to do the subjective according to the criteria of the DSM-IV [20]. All patients rating task, which lasted approximately 15 minutes. All tasks experienced a psychotic episode at the time of the study. All were designed using E-prime (Psychology Software Tools, patients were inpatients and most of them were experiencing Inc., 2002). Cardiovascular Psychiatry and Neurology 3 Table 1: Demographic characteristics of the patient and control groups. Medicated patients (n = 24) Antipsychotic-free patients (n = 9) Controls (n = 40) Age (mean ± Sd) 22 ±421 ±623 ± 4 Smokers (Yes/No) 20/4 7/2 8/32 Duration of illness (months ± Sd) 16 ± 19 3 ± 3 Duration of current medication use (weeks ± Sd) 4 ± 4 PANSS (mean ± Sd) Positive symptoms 17 ±623 ± 6 Negative symptoms 15 ±521 ± 5 General psychopathology 33 ±943 ± 12 Total 65 ± 16 87 ± 14 PANSS: positive and negative syndrome scale; Sd: standard deviation. There were significantly more smokers in both patient groups than in the control group (χ = 27.78,P< 0.001). The duration of illness was significantly shorter in antipsychotic-free versus medicated patients (t[25.96] = 3.3,P< 0.01). Antipsychotic-free patients had higher PANSS scores for all subscales than medicated patients (positive: t[28] = 2.4,P< 0.05; negative t[28] = 2.6,P< 0.05; general psychopathology t[28] = 2.5,P< 0.05; total score t[28] = 3.5,P< 0.01). Table 2: Mean dosages and duration of current antipsychotic treatment of the patient group. Antipsychotic n Mean dosage (mg) ± Sd Comedication No Antipsychotic 9 Lorazepam (n = 3) Lorazepam (n = 2) Olanzapine 8 16.3 ± 6.9 Oxazepam (n = 1) Lorazepam (n = 1) Risperidone 6 3.0 ± 0.8 Oxazepam (n = 1) Haloperidol 4 2.8 ± 1.5 Lorazepam (n = 2) Clozapine 4 300.0 ± 81.6 Lorazepam (n = 3) Quetiapine 2 450.0 ± 212.13 — Sd: standard deviation. 2.3. Experimental Tasks pictures were presented using a Dell Dimension M200a Personal Computer with a Pentium processor and a 17-inch 2.3.1. Emotional Picture Task. Subjects were seated approx- Samsung SyncMaster monitor. imately 75 cm from the computer screen. All subjects were Each picture was presented during 6 seconds, with an asked to relax, to breathe regularly, and not to speak during intertrial interval (ITI) ranging from 12 to 25 seconds. A total the task. The emotional picture task was a part of a larger of 48 pictures were presented; during 12 of these pictures (4 study in which we also investigated acoustic startle responses. positive, 4 neutral, and 4 negative) no startle stimulus was Thesubjectsweretoldthattheywereabout to view aseries presented. During the remaining 36 pictures, startle stimuli of different pictures and that loud noises were occasionally were presented either 300, 800, 1300, or 3800 ms after picture presented through the headphones. They were asked to onset in such a way that each of these latency conditions look at the pictures the entire time they were presented occurred 3 times during the viewing of positive, neutral, on the screen, but that they did not have to respond. and negative pictures. In addition, 12 startle stimuli were Forty-eight pictures were selected from the International randomly presented during the inter trial intervals. Thus, a Affective Picture System (IAPS [23]). (Positive IAPS pictures: total of 48 pictures and 48 startle stimuli were presented. All pictures and startle stimuli were presented completely at 4220, 4290, 4608, 4660, 4670, 4680, 5260, 5470, 5621, 5910, random so that each subject was presented with a different 8030, 8170, 8490, 8501. Neutral IAPS pictures: 5120, 5260, order of stimuli. For the purpose of this paper, we will 5510, 5530, 5535, 5711, 5731, 5740, 5900, 7000, 7002, 7004, only report the cardiac responses to the pictures that were 7006, 7009, 7010, 7020, 7025. Negative IAPS pictures: 3000, presented without a startle stimulus. 3010, 3060, 3069, 3080, 3102, 3120, 3170, 6200, 6212, 6230, 6260, 6300, 6313, 6350, 6550.) The stimuli were chosen on the basis of their normative ratings provided with the 2.3.2. Subjective Rating Task. The pictures that were pre- IAPS and could be divided into six different categories, sented during the startle task were again presented in the based on their contents. The positive pictures had erotic subjective rating task, using a randomized order different and adventure contents, the neutral pictures showed nature from that of the startle task. The participants were asked to scenes and household objects, and the negative pictures rate how they felt during the viewing of the pictures. They contained pictures with mutilation and threat contents. The responded with their dominant hand using the numbers 4 Cardiovascular Psychiatry and Neurology on the keyboard. A fixation cross was presented for 3 tests. To assess whether there were any differences between seconds on a 17-inch computer screen, followed by a 6- the three groups (medicated, antipsychotic free, and con- second presentation of a picture. After picture offset, the trols), the Kruskal-Wallis test was used. When significant subjects were asked to rate each picture using the SAM differences were found, we proceeded to investigate which (Self-Assessment Manikin; [24]. The SAM consisted of two groups differed from each other using the Mann-Whitney subsequent screens, each containing five figures. On the first tests and to correct for multiple testing, the alpha was screen, the figures represented the degree of pleasantness reduced to 0.016. The maximal scores for each of the scales of the pictures—ranging from very unpleasant to very were as follows: depression 32, fatigue 24, tension 24, anger pleasant—on a scale from 1 to 9. On the second screen, each 28, and vigour 20. The Total Mood Disturbance (TMD) score figure represented the degree of arousal associated with each was calculated by subtracting the vigour score from the sum picture—ranging from very calm to very arousing—also on of all the other scores (i.e., depression + fatigue + tension a scale from 1 to 9. After their response, the fixation cross +anger − vigour = TMD), so that a higher positive score appeared again for 3 seconds, followed by the next picture. represented a more negative mood state. 2.4.2. Cardiac Responses 2.3.3. Cardiac Responses. During the experiment, continu- ous measurements were made of the heart rate (HR). HR Baseline. The mean HR level and the ln(HF-HRV) of the was recorded using a precordial lead and was sampled at three groups during 3 minutes of resting baseline before 512 Hz. All data were sampled and stored on a flashcard the onset of the tasks were compared using an analysis of by means of a portable digital recorder (Vitaport System; variance (ANOVA) with Group (medicated, antipsychotic- TEMEC Instruments B.V., Kerkrade, The Netherlands). free, and controls) as the between subjects factor. Upon completion of the recording, all physiological data were imported and processed on a Personal Computer Cardiac Response to Picture Stimuli. For the analysis of using a Vitascore software module (TEMEC Instruments cardiac responses to the emotional stimuli, we developed BV, Kerkrade, The Netherlands). Subsequently, the interbeat an hierarchical linear model (HLM) using MlWin software intervals were calculated using R-top detection. A low pass [28], with Subject, Time, and Picture Type entered as filtered cardiac event series (LPFCES; [25]) was calculated, repeated variables. The fixed factors in the HLM were using a low pass filter of 0.5 Hz. This method is based on the Group (medication free, medicated, and control), Time (0– Integral Pulse Frequency Modulation model [25]. 6 seconds, in half second bins) with its linear and quadratic The responses to the 12 pictures that were presented polynomials, Picture Type (negative, neutral, and positive), without a startle stimulus were used for the analyses of the Group × Time, Group × Picture Type, Time × Picture Type, cardiac responses. Data series for each individual stimulus and Group × Time × Picture Type. The following covariates were extracted for the pictures starting 2 seconds before stim- were entered smoking (number of cigarettes per day), age, ulus onset and ending 6 seconds after stimulus onset. Cardiac illness duration (months), medication duration (weeks), responses for each stimulus were calculated by subtracting POMS TMD score, baseline ln(HF-HRV), and baseline HR. the 6 seconds after stimulus onset from the 2-second baseline We also entered the following interaction effects: ln(HF- period before each stimulus. This resulted in time series HRV) × Time and baseline HR × Time; these were included consisting of difference scores for each separate stimulus. to examine whether they were related to a different cardiac responding to startle stimuli, since we previously found that schizophrenic patients generally experience decreased levels 2.3.4. Baseline HR and Heart Rate Variability (HRV). Mean of HF-HRV [29], which could explain overall decreased HR was calculated over a 3-minute period of rest. Addi- cardiac responsivity to stimuli. All factors and covariates tionally, this HR time series was subjected to a discrete Fourier transform (CARSPAN program, Groningen, The were entered in the model and the best fit for the model was sought using the log-likelihood method. Significant interac- Netherlands [26, 27]), to yield power spectra of the rhythmic tion effects were followed up by separate linear models. oscillations over a frequency range of 0.02–0.50 Hz, with a resolution of 0.01 Hz. The power was calculated for the 2.4.3. SAM Ratings. Since the Kolmogorov-Smirnov tests high frequency band (HF-HRV: 0.15–0.5 Hz). Because of indicated that the distributions of the SAM rating of pleasure the skewed distribution, a natural log transformation was and arousal were normally distributed within the groups (P applied to HF-HRV. values ranged from 0.13 to 1.00), we performed two repeated measures ANOVA’s with Pleasure or Arousal rating as the 2.4. Statistical Analyses. All analyses were conducted using dependent variable, Group (medicated, antipsychotic-free SPSS version 13.0 and MlWin 2.10 [28]. All alpha’s were set at and controls) as the between subjects factor, and Picture Type 0.05 unless otherwise specified. All self-report responses were as the within subjects factor. used as a manipulation check and to make sure participants had complied with the task instructions. 3. Results 2.4.1. Profile of Mood States (POMS). To investigate the 3.1. Profile of Mood States (POMS). The POMS scores of the subjective mood state of the participants at the time of three groups are reported in Table 3. Because the Kruskal- testing, we analysed their POMS scores using nonparametric Wallis test showed that there were significant differences Cardiovascular Psychiatry and Neurology 5 Table 3: Profile of mood states scores per group. Medicated patients (n = 24) Antipsychotic-free patients (n = 9) Controls (n = 40) POMS mean ± Sd (range) ∗ ∗ Depression 7 ± 7 (0–22) 8 ± 9 (0–28) 1 ± 2 (0–6) Fatigue 6 ± 6 (0–18) 8 ± 5 (1–15) 3 ± 3 (0–11) ∗ ∗ Tension 6 ± 5 (0–16) 6 ± 4 (0–12) 2 ± 2 (0–9) ∗ ∗ Anger 5 ± 5 (0–17) 7 ± 5 (0–16) 1 ± 2 (0–10) Vigour 11 ± 5 (2–18) 7 ± 5 (0–13) 12 ± 3 (5-18) ∗ ∗ TMD 12 ± 20 (−15–60) 21 ± 22 (2–68) −5 ± 7(−14–14) Sd: standard deviation; TMD: total mood disturbance; significant difference compared to controls, P < 0.01. between the three groups in mood scores (depression χ = overall HR level: with all other variables being constant, the 2 2 28.0, P< 0.001; fatigue χ = 9.7, P< 0.01; tension χ = 22.0, medicated patients showed the least deceleration, followed 2 2 2 2 P< 0.001; anger χ = 16.9, P< 0.001; vigor χ = 6.8, by the controls, while the antipsychotic-free patients showed 2 2 P< 0.05; TMD score χ = 23.2, P< 0.001), we used the most deceleration overall. As expected, the main effect the Mann-Whitney tests to further explore these differences. for Picture Type (joint χ = 11.04, P< 0.01) indicated that (1) The medicated and antipsychotic-free patients did not differ the HR decelerations were significantly larger for negative significantly in their mood scores for any of the subscales and positive pictures compared to neutral pictures. The (all P’s were 0.10 or higher). However, compared to control significant main effect of Time linear showed that HR subjects, the antipsychotic-free patients showed significantly decreased over time. decreased mood on all subscales and the TMD score (all P’s < The significant interaction effect of Group × Picture 0.01), and the medicated patients had significantly decreased Type (joint χ = 23.50, P< 0.01) indicated that the HR (1) mood scores for depression, tension, anger, and the TMD responses to the various picture types of the patient groups score (all P’s < 0.001). were less differentiated than the HR responses of the control group. For example, the difference in HR deceleration between negative and neutral pictures was smaller in the 3.2. Heart Rate and HF-HRV at Baseline. Data was lost for medicated group compared to the control group, while the one medicated patient due to excessive movements during difference in HR response between positive and neutral pic- baseline. We found a significant Group effect when we tures was smaller in the antipsychotic-free group compared investigated whether the resting HR of patients who were to the control group. Also, the medicated patients showed not under current antipsychotic medication (n = 9) and more HR deceleration to positive versus negative pictures, medicated patients (n = 23) differed from the resting HR whereas both the antipsychotic-free patients and the controls of the control group (n = 40), F[2, 69] = 8.26, P = 0.001, did not. The significant interaction effect of Group × Time partial η = 0.19. The mean HR of medicated patients was (joint χ = 10.80, P< 0.01) indicated that medicated (1) 83 ± 16 bpm, of antipsychotic-free patients 75 ± 13 bpm, patients showed significantly less HR deceleration over time and of controls 69 ± 11 bpm. The Bonferroni post hoc tests than antipsychotic-free patients and healthy controls. The indicated that only the mean HR of the medicated patients Picture Type by Time (joint χ = 24.98, P< 0.01) (1) was significantly higher than that of the control subjects interaction effect confirmed that HR decelerates more over (mean difference = 14.05, sd = 3.46, P< 0.001). time for negative and positive pictures than neutral pictures. We also found a significant Group effect for the natural With regard to the covariates, the significant effect of logarithm of HF-HRV, F[2, 69] = 6.07,P< 0.01, partial η = Age indicated that the HR increased with age, whereas 0.15. The Bonferroni post-hoc test (mean difference = 1.08, the significant effects of duration of medication use and sd = 0.31, P< 0.01) showed that medicated patients had a illness duration indicated more deceleration with longer significantly lower HF-HRV (6.21 ± 1.59) than the control antipsychotic medication use and/or longer illness duration. subjects (7.29 ± 0.92), while the antipsychotic-free patients We also found that Baseline HR was negatively related to did not differ significantly from either groups (7.18 ± 1.17). cardiac response: a higher HR at baseline is related to more HR deceleration during picture viewing, and ln(HF-HRV) 3.3. Cardiac Response to Picture Stimuli. The following significantly interacted with Time , indicating that increases factors did not contribute significantly to the model and in cardiac vagal activity during rest were related to an were therefore removed: the three-way interaction between increased cardiac response. Finally, increased negative mood Group × Time × Picture Type, Smoking, and the interaction was related to a cardiac increase, as shown by the significant between baseline HR × Time. effects of the POMS TMD score. All beta-coefficients for this model are reported in Table 4, and the cardiac responses of each of the three groups are shown in Figures 1(a)–1(c). The significant main 3.4. Follow-Up Analyses per Group. Because of the significant effect for Group (joint χ = 94.41, P< 0.01) indicated two-way interaction effects with Group and because the (1) that all three groups differed from each other in terms of figures suggested a decreased orienting response in the 6 Cardiovascular Psychiatry and Neurology Table 4: Beta coefficients of the HLM for cardiac responses to emotion-eliciting pictures in medication free patients, medicated patients, and healthy control subjects. Factor Comparison between GroAFPs Comparison between picture types Beta coefficient Standard error Z-score Constant −0.13 1.11 −0.12 AFP versus C −0.88 0.43 −2.04 Group MP versus C 1.60 0.36 4.51 MP versus AFP 2.51 0.45 5.57 Neg. versus Neu. −2.12 0.24 −8.76 Picture type Pos. versus Neu. −1.79 0.24 −7.39 Pos. versus Neg. 0.33 0.24 1.37 Time −5.63 1.72 −3.27 Time −0.03 1.72 −0.02 AFP versus C Neg. versus Neu. 0.59 0.56 1.05 MP versus C Neg. versus Neu. 1.54 0.40 3.86 MP versus AFP Neg. versus Neu. 0.92 0.60 1.54 AFP versus C Pos. versus Neu. 1.65 0.56 2.93 Group × Picture Type MP versus C Pos. versus Neu. 0.69 0.40 1.72 MP versus AFP Pos. versus Neu. −1.02 0.60 −1.71 AFP versus C Pos. versus Neg. 1.06 0.56 1.89 MP versus C Pos. versus Neg. −0.86 0.40 −2.15 MP versus AFP Pos. versus Neg. −1.92 0.60 −3.20 AFP versus C −0.60 0.83 −0.72 Group × Time MP versus C 1.85 0.64 2.92 MP versus AFP 2.46 0.91 2.70 AFP versus C −0.69 0.83 −0.83 Group × Time MP versus C −1.00 0.64 −1.57 MP versus AFP −0.30 0.91 −0.33 Neg. versus Neu. −3.15 0.65 −4.85 Picture Type × Time Pos. versus Neu. −2.26 0.65 −3.48 Pos. versus Neg. 0.90 0.65 1.38 Neg. versus Neu. 0.26 0.65 0.40 Picture Type × Time Pos. versus Neu. 0.37 0.65 0.56 Pos. versus Neg. 0.11 0.65 0.17 Age 0.10 0.02 4.95 Medication duration −0.17 0.03 −5.09 Illness duration −0.02 0.01 −2.88 HR baseline −0.03 0.01 −3.71 Ln(HRV HF) −0.09 0.08 −1.09 Ln(HRV HF) × Time 0.82 0.23 3.62 Ln(HRV HF) × Time 0.18 0.23 0.79 POMS TMD score 0.01 0.01 2.33 Numbers expressed in bold indicate significant effects at the 0.05 level. HR: heart rate; Ln(HF-HRV): natural logarithm of high frequency heart rate variability; POMS: profile of mood states; TMD: total mood disturbance; AFP: antipsychotic-free patients; C: control; MP: medicated patients; Neg: negative pictures; Neu: neutral pictures; Pos: positive pictures. Cardiovascular Psychiatry and Neurology 7 Cardiac reponses to picture stimuli Cardiac responses to picture stimuli Medicated patients (n = 23) Antipsychotic free patients (n = 9) 2 2 Time (s) 0 0 0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.5 6 −1 0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.5 6 −1 Time (s) −2 −2 −3 −3 −4 −4 −5 −5 Negative Negative Neutral Neutral Positive Positive (a) (b) Cardiac reponses to picture stimuli Healthy controls (n = 40) Time (s) 0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.5 6 −1 −2 −3 −4 −5 Negative Neutral Positive (c) Figure 1: Time series of mean cardiac responses to negative, neutral, and positive picture stimuli in (a) antipsychotic-free patients, (b) medicated patients, and (c) healthy control participants during the 6 seconds of picture presentation. patient groups to positive and negative compared to neutral η = 0.72). The positive pictures were rated as most pictures, we further investigated this with follow-up HLM pleasant, followed by the neutral pictures, and the negative models for each group, only including the cardiac responses pictures were rated as least pleasant (positive versus neutral: during the first 3 seconds of picture viewing. F[1, 71] = 47.32, P< 0.001, partial η = 0.40; positive versus Within the antipsychotic free patient group, the Time × negative: F[1, 71] = 296.50, P< 0.001, partial η = 0.81; Picture Type interaction effect was significant (joint χ = neutral versus negative: F[1, 71] = 136.00, P< 0.001, partial (1) 9.31, P< 0.01), indicating that the heart rate decreased η = 0.66). No significant main or interaction effects for more over time for negative than for positive pictures, that Group were found. is, the antipsychotic-free patients showed a larger orienting For the arousal ratings a significant main effect for response to negative versus positive pictures. Within the PictureTypewas found(F[1.6; 108.5] = 28.68, P< 0.001, medicated patient group, the main effect for Picture Type partial η = 0.29). The negative and positive pictures were was significant (joint χ = 5.33, P< 0.01), indicating that rated as more arousing than the neutral pictures, whereas (1) the heart rate of the medicated patients was lower during no difference in arousal ratings was found between positive the first 3 seconds for positive compared to neutral pictures. and negative pictures (negative versus positive: F[1, 70] = Within the control group, the main effects for Time (Z = 1.23, P = 0.27; negative versus neutral: F[1, 70] = 39.38, −3.92, P< 0.01) and Picture Type (joint χ = 22.47, P< (1) P< 0.001, partial η = 0.36; positive versus neutral: 0.01). As can be seen in Figure 1(c), the HR of the controls F[1, 71] = 74.17, P< 0.001, partial η = 0.51). The main decreased more for positive and negative than for neutral effect for Group was also significant (F[2, 70] = 3.61, P< pictures. The interaction effect of Time × Picture Type (joint 0.05, partial η = 0.09). The Games-Howell test showed χ = 6.30, P< 0.01) was also significant, although pairwise (1) that the arousal ratings of the medicated patients group comparisons were not. tended to be higher than those of the antipsychotic-free and control groups (medicated versus antipsychotic-free: mean 3.5. Subjective Ratings. In Figures 2(a) and 2(b), the mean difference = 0.98, sd = 0.44, P = 0.09; medicated versus SAM ratings for pleasure and arousal are presented. For control: mean difference = 0.83, sd = 0.37, P = 0.07). The the pleasure ratings, we found a significant main effect for interaction effect between Picture Type and Group almost Picture Type (F[1.7; 121.6] = 178.88, P< 0.001, partial reached significance (F[3.1; 108.5] = 2.49, P = 0.06, partial Cardiac response (bpm) Cardiac response (bpm) Cardiac response (bpm) 8 Cardiovascular Psychiatry and Neurology Arousal ratings Pleasure ratings 4 4 2 2 0 0 Antipsychotic free Medicated Controls Antipsychotic free Medicated Controls Positive Positive Neutral Neutral Negative Negative (a) (b) Figure 2: (a) Pleasure and (b) Arousal ratings of antipsychotic-free patients, medicated patients, and healthy control subjects for positive, neutral, and negative pictures. η = 0.07). The antipsychotic-free patients tended to show status [36–40]. Indeed, we found that the power of high less differentiation in arousal ratings between the negative frequency HRV was lower in medicated patients compared and neutral, and positive and neutral pictures compared with healthy control subjects, but not antipsychotic-free with both the medicated and control groups (negative versus patients. The initial HR deceleration related to orienting neutral: F[2, 70] = 3.87, P< 0.05, partial η = 0.10; positive is generally considered to be under vagal control [41–43]. versus neutral: F[2, 70] = 3.46, P< 0.05, partial η = 0.09). The autonomic nervous system (ANS) is considered the link between the central nervous system and the body, and so the 4. Discussion ANS mediates the relationship between centrally occurring events such as emotions and bodily changes such as heart rate The aim of this study was to investigate whether male variability [44]. Thus, generally reduced cardio-vagal control patients with schizophrenia differed from healthy control in patients may have caused the reduced OR rather than this subjects in their psychophysiological responses to emotion- being a result of decreased emotional experience or attention eliciting pictures. A distinction was made between patients in response to emotion-eliciting pictures. However, after who were taking antipsychotic medication and patients who controlling for reduced cardio-vagal control by including were not. HRV as a covariate in our analyses the differences between While the healthy control subjects and antipsychotic-free the medicated and control groups were still significant, patients showed the expected triphasic pattern (i.e., decrease- suggesting that a difference in central processing was at increase-decrease) for cardiac responses to positive and least partially responsible for the different cardiac responses negative pictures—albeit somewhat less pronounced for pos- between groups. itive pictures in antipsychotic-free patients—the medicated patients did not show an initial decrease for any of the picture Second, the sample size for the antipsychotic-free types, suggesting a lack of orientation towards the pictures. patients was very small, so the lack of a significant difference The orientation response (OR), the initial deceleration of the between antipsychotic-free patients and healthy control heart rate, is considered to be the basic cardiac response to subjects could be due to a lack of statistical power. Although perceptual stimuli and tends to be greatest for unpleasant we cannot rule out this possibility, Figures 1(a)–1(c) suggest pictures. The cardiac OR is thought to reflect the intake of that antipsychotic-free patients had heart rate decelerations stimulus information [30–32]. Our results suggest that in during picture viewing comparable to controls, and a medicated patients with schizophrenia this OR is lacking previous study [15] showed an almost identical pattern of a finding that is consistent with the existing literature on cardiac responses to emotion-eliciting pictures in a group of attentional deficits in these patients [33–35]. However, we prodromal patients (n = 12, of which 8 are antipsychotic did not find this lack of OR in antipsychotic-free patients. free). Third, the use of antipsychotic medication may have It seems paradoxical that the antipsychotic-free patients caused side effects such as sedation and/or drowsiness. showed overall decreased mood scores and more severe However, the medicated patients did not differ significantly symptom scores yet physiologically they seemed to respond in their subjective fatigue and vigour scores of the POMS more similarly to healthy control subjects than the medicated when compared to healthy controls. Thus, a number of factors could have caused this difference between medicated patients. A number of factors could account for this finding. First, a difference in sympathovagal balance in the patient and antipsychotic-free patients, but with our current data we group could account for the difference in ORs. Previous are unable to answer this question satisfactorily. We therefore studies have consistently found a decrease in cardiovagal con- propose that future research should focus more on the trol in patients with schizophrenia, regardless of medication difference in emotional responding between medicated and Pleasure rating Arousal rating Cardiovascular Psychiatry and Neurology 9 antipsychotic-free patients with schizophrenia to disentangle the scope of this study would be required to control for medication side effects from emotional processing deficits. respiratory variations in the cardiac time series [48]. Medicated and antipsychotic-free patients differed signif- icantly with regard to the subjective arousal ratings of the 5. Conclusions and Implications pictures. Medicated patients tended to show overall higher Our results indicate that the main difference between arousal ratings than antipsychotic-free patients and controls, patients with schizophrenia and healthy control subjects lies a finding that is in line with the previous study of Schlenker in the reduced amount of attentional resources available in et al. [7]. We also found that antipsychotic-free patients medicated patients while viewing emotion-eliciting pictures. showed less differentiation in their arousal scores of neutral No interaction effects between emotional picture contents versus negative and positive pictures than medicated patients and groups were found, indicating that this is a general effect and healthy controls. Whether this finding is caused by and not caused by any specific picture content. These results increased arousal ratings to neutral pictures or decreased are in line with previous studies in which no differences arousal ratings to positive and negative pictures is not clear at in cardiac responding between patients and controls were the moment. All three groups rated the pictures similarly in found [7, 9]. terms of pleasure, with positive pictures receiving the highest We replicated our previous findings regarding the lack of and unpleasant pictures receiving the lowest pleasure scores. orienting responses in patients with schizophrenia [16]. The There were some limitations to our study. For example, decreased OR we found in our patient sample is in line with we only included male participants in this study, which findings that patients with schizophrenia gather little infor- reduces the generalization of our results. Also, we did not mation before responding to certain tasks, a response style differentiate between paranoid and nonparanoid patients termed “jumping to conclusions” [51, 52]. Abnormalities in our analyses. Rather, we chose to investigate a more in the identification of emotionally salient information may heterogeneous patient sample to be able to generalize our lead to misinterpretations of the intentions of others, which results to a patient population that suffered from recent- may increase or exacerbate paranoid thoughts and result in onset schizophrenia, regardless of specific symptoms, that is, dysfunctions in social behaviour [53]. patients with predominantly positive, negative, or disorga- Medicated patients also showed emotionally dampened nized symptoms were all included in this study. responses: that is, not only did they show a reduced or absent As it is a common practice in studies investigating OR but they also had less differentiation in their responses to psychophysiological responses to emotion-eliciting pictures, the emotion-eliciting pictures. McCubbin et al. [54]propose we sampled and analysed the cardiac responses only for that emotional dampening could increase psychological the time period in which the picture was presented, that distress via inappropriate social interactions with family is, for 6 seconds. However, because we did not analyse the members, friends, and coworkers. In addition, emotional cardiac responses after picture offset it is possible we have dampening has been found to be related to increased risk for missed potential differences between groups. Previous stud- cardiovascular disease, most notably hypertension [54]. ies measuring different types of responses (i.e., behavioural, Summarizing the combination of decreased stimulus startle, and fMRI) have found evidence to suggest that intake, jumping to conclusions and emotional dampening although patients’ responses do not differ from healthy can all contribute to chronic stress levels in patients with control subjects while an emotionally evocative stimulus is schizophrenia, resulting in difficulties in social and emo- present, they do appear to have difficulties in maintaining tional functioning and an increased risk for cardiovascular the elicited emotional response once the stimulus disappears disease. [45–47], thereby reducing their ability to use emotions to help them select the most appropriate behavioural response. References Because we asked our participants to give their subjective ratings immediately after picture offsetwewereunableto [1] A. E. Pinkham, R. E. 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