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Interaction of negative olfactory stimulation and working memory in schizophrenia patients: Development and evaluation of a behavioral neuroimaging task
Psychiatry Research 144 (2006) 123 – 130 www.elsevier.com/locate/psychres
Interaction of negative olfactory stimulation and working memory in schizophrenia patients: Development and evaluation of a behavioral neuroimaging task Frank Schneider a,*, Kathrin Koch a, Martina Reske a, Thilo Kellermann a, N. Seiferth a, Tony Sto¨cker b, Katrin Amunts b, N. Jon Shah b, Ute Habel a a
Department of Psychiatry and Psychotherapy, University of Aachen, Pauwelsstr. 30, 52074 Aachen, Germany b Institute of Medicine, Research Center, Ju¨lich, Germany Received 21 June 2004; received in revised form 25 October 2004; accepted 16 December 2004
Abstract Negative affect plays a crucial role in the psychopathology of schizophrenia. Although it is known that negative emotion has a strong effect on cognitive performance, this interaction has mainly been studied in healthy volunteers. Hence, working memory was assessed in 24 schizophrenia patients and 24 matched comparison subjects with a 0-back/2-back continuous performance test. Simultaneously, negative emotion was induced by olfactory stimulation. Although subjective ratings confirmed that stimulation with a negative odor was associated with a significant increase in negative affect in patients and healthy volunteers, working memory performance was affected differentially in healthy volunteers and schizophrenia patients. Whilst a similar trend of a reduced behavioral performance during negative odor stimulation was observed in patients, only controls demonstrated a significantly higher response time and a reduced number of correct reactions during higher working memory demands (2-back). Patients, on the other hand, revealed an increase in false alarms during both conditions. The present data indicate a differential effect of negative mood induction on working memory performance in schizophrenia patients and healthy subjects. D 2005 Elsevier Ireland Ltd. All rights reserved. Keywords: Olfaction; n-back task; Emotion; Mood induction
1. Introduction In schizophrenia, impairments in both emotion and cognition are prominent and characterize its psychopathology. In particular, emotion recognition and experience (Schneider et al., 1994; Li et al., 2002; Malla et al., 2002), as well as attention and working memory (Krae* Corresponding author. Tel.: +49 241 80 89 633; fax: +49 241 80 82 401. E-mail address: [email protected] (F. Schneider).
pelin, 1920; Barr, 2001), are dysfunctional and are accompanied by deficiencies in their corresponding underlying cerebral correlates (Schneider et al., 1995; Barch et al., 2002; Gur et al., 2002; Perlstein et al., 2002). However, interactions between emotion and cognition have not been investigated in greater detail in patients. Similarly, in healthy subjects, there are only a few and rather contradictory studies exploring the effects of emotion on cognitive function (Bartolic et al., 1999; Perlstein et al., 2002; Simpson et al., 2000).
0165-1781/$ - see front matter D 2005 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.psychres.2004.12.013
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Gray (2001) studied the effects of different emotional states (approach, neutral or withdrawal) on working memory performance (verbal and spatial). In the withdrawal condition, subjects made significantly more errors in the verbal task and fewer errors in the spatial task. Thus, emotional–cognitive interaction is not a simple one-way relation but seems to depend both on the type of cognition and the type of emotion. Comparable studies in schizophrenia patients are necessary to increase knowledge of the interfering effects of negative emotion on cognition. Due to its tight anatomical connections to the limbic cortex, olfactory stimulation represents a powerful tool to induce mood (Carmichael and Price, 1994). A number of findings indicate positive emotions in subjects exposed to pleasant odors, as well as negative affect when exposed to negative odors (Knasko, 1995; Schneider et al., 1998, 2000; Chen and Haviland-Jones, 1999). However, in schizophrenia patients, one must be aware of olfactory dysfunctions. These deficits concerning mainly the ability to perceive and identify odors (Stedman and Clair, 1998; Moberg et al., 1999; Brewer et al., 2001) suggest differential olfactory processing mechanisms in schizophrenia. A PET study (Crespo-Facorro et al., 2001) confirms this assumption: schizophrenia patients who, whilst failing to activate limbic regions, showed hyperactivations in several frontal regions during negative odor stimulation. The affective odor judgments, on the other hand, did not differ between patients and healthy controls. We chose fermented yeast, an odor associated with strong negative affect (Schneider et al., 1999, 2000), and tested its influence on cognitive performance in schizophrenia patients and healthy controls by means of a combined 0-back/2-back continuous performance paradigm. In this paradigm, single letters are presented rapidly one after another. The 0-back condition demands an immediate button press following a predefined target (for example, the letter X), whereas the 2back condition asks for a reaction if the last but one letter is the same as the present letter. Since the 2-back condition requires working memory in addition to attentional processes and therefore exhibits increased cognitive demands, we hypothesized a greater impact of negative affect on 2-back performance. Regarding the emotional impairments and associated hypoactivation in subcortical cerebral activation during the experience of negative emotion (Schneider et al., 1998), we expected smaller cognitive disturbances in the schizophrenia patients under negative mood induction than in controls.
Given the fact that interactions between emotional and cognitive processing have rarely been investigated in patients with schizophrenia, the aim of this study was to explore the effect of negative emotion on cognitive processing in schizophrenia patients. 2. Methods 2.1. Subjects Participants included 24 (12 male, 12 female) patients with DSM-IV diagnosis of schizophrenia (American Psychiatric Association, 1994) and 24 healthy subjects who were matched to the patients by gender, age and years of parental education (mean F 2 S.D.). The mean age was 40.1 years (S.D. = 12.3) and the mean parental education was 10.0 years (S.D. = 2.6) in patients and 38.1 years (S.D. =13.1) and 9.5 years (S.D. = 2.7) in controls, respectively. There were no differences between the groups regarding age (t = 0.4, df = 46, NS) or parental education (t = 0.7, df = 46, NS). All subjects gave written informed consent to participate in the study. Mean ratings on the Positive and Negative Syndrome Scale (PANSS, Kay et al., 1987) were 11.5 (S.D. = 6.2) on the Positive Symptom Scale and 15.0 (S.D. = 7.7) on the Negative Symptom Scale. Of the 24 schizophrenia subjects, 15 were receiving atypical medication, 3 typical and 5 both typical and atypical antipsychotic medication. One patient’s medication is presently unknown as he is participating in a doubleblind psychopharmacology study (risperidone vs. haloperidol). In the patient group, 11 were non-smokers; 9 patients smoked fewer than 21 cigarettes per day; the remainder smoked 21 to 40 cigarettes per day. The group of healthy volunteers comprised 16 nonsmokers and 8 smokers; 7 of them smoked fewer than 21 cigarettes per day. Participants were excluded if they had any (comorbid) psychiatric or neurological disease or sensory impairments interfering with performance. 2.2. Procedure Odors were presented with constant temperature, pressure and humidity using a self-designed olfactometer delivering the stimulants by air pressure through several parallel tubings to the subjects’ right nostrils (Schneider et al., 1999, 2000). Stimuli consisted of 20 g of rotten yeast melted in 200 ml of water, which was kept at a constant temperature of 30 8C (86.1 8F) for 1 week.
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each run on the Positive and Negative Affect Schedule (PANAS, Watson et al., 1988), as well as their level of disgust using the corresponding subscale of the Emotional Self-Rating (ESR) scale (1 = not at all, 2 = mildly, 3 = moderately, 4 = quite a lot, 5 = extremely; Schneider et al., 1994) based on a previous study confirming the relevance of disgust in negative olfactory stimulation (Schneider et al., 1999).
The experimental design consisted of two runs, each with eight alternating baseline (30 s) and eight activation blocks (30 s, 0-back, 2-back; Fig. 1). Single letters (A–Z) presented in both baseline and activation phases were shown in random order and appeared for 500 ms. In baseline phases, subjects were simply asked to focus on the letters. Activation phases were 0-back (immediate reaction to the predefined target letter X) and 2-back (reaction if the last but one letter was the same) conditions in alternating order. Thus, the 0-back task demands attentional processes; the 2-back task requires both attentional and working memory capacities. Olfactory stimulation took place only during the 0-back and 2-back conditions every 5 s for 3 s each to minimize habituation effects, with either neutral room air or yeast depending on the run. The order of presentation of neutral room air and yeast was randomized across subjects. Subjects had to react within 900 ms by pressing the space bar of a portable PC for the target letter. The target letter was presented at irregular intervals. The target probability was 0.37 with a ratio of 48 nontargets to 28 targets.
2.4. Statistical analysis Performance was assessed by hits (percent correct), false alarms (commission errors), reaction time, and sensitivity. Sensitivity was calculated corresponding to signal detection theory as a measure of the subject’s ability to discriminate targets from non-targets (Nestor et al., 1990). For the scores on the valence and intensity scales for the negative odor, we performed two-tailed t-tests to investigate whether patients and controls differed in their judgments. For the PANAS and ESR, we conducted two three-way repeated measures analyses of variance (ANOVAs) with group (patients vs. controls) and gender as between-subject factors, and olfaction (neutral room air vs. fermented yeast) as a within-subject factor on the difference score for positive and negative affect of the PANAS and the disgust ratings of the ESR, respectively. Levene tests for the homogeneity of variances revealed unequal variance for most variables. Parametric analyses have nevertheless been applied here, since the ANOVA is relatively robust against violations of equal variances if the sample size is relatively high (between 10 and 20) and groups are of same size (Box, 1954). Both apply to our data. Four overall four-way repeated measure analyses of variance on hits, false alarms, sensitivity and reaction time were
2.3. Valence and intensity scale Before the experimental sessions, subjects were asked to judge the valence of the negative odor on a Likert-type intensity scale ranging from 3 (very unpleasant) to 3 (very pleasant). In addition, subjects had to judge the intensity of the yeast on a scale ranging from 0 (imperceptible) to 6 (extremely intense). Subjects rating the valence of the odor as 0 (neither–nor) or higher and the intensity as 2 (slightly perceptible) or below were excluded. Patients and healthy volunteers were asked to rate their emotional state before and after NEUTRAL ODOR DURING CPT NO ODOR
0 BL
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0
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-2 BL 8 min
NEGATIVE ODOR DURING CPT NO ODOR
-2
0 BL
BL
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Fig. 1. Experimental design. The paradigm consisted of two runs with eight 30 s baseline blocks and eight 30 s activation blocks each and olfactory stimulation during 0-back/2-back.
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performed with group (patients vs. controls) as the between-subject factor and olfaction (neutral room air vs. yeast) and task (0-back/2-back) as the within-subject factors and gender as the covariate to test for the influence of gender on results. Since gender had no contribution to the data (hits, sensitivity, false alarms, and reaction time), sensitivity has been increased by ignoring gender in the further analyses. Hence, threeway ANOVAs were performed with group (patients vs. controls) as the between-subjects factor and olfaction (neutral room air vs. yeast) and task (0-back/2-back) as the within-subject factors. Subsequently, significant effects were decomposed by post-hoc t-tests. Possible confounding effects of medication, psychopathology and smoking were addressed with correlation analyses. Correlations have also been calculated between mood changes and working memory performance.
3.1.3. ESR scores Mean values on the ESR disgust scale were 1.4 (S.D. = 0.9) after neutral olfactory stimulation and 2.4 (S.D. = 1.4) after negative olfactory stimulation for healthy volunteers as well as 1.5 (S.D. = 0.8) and 3.0 (S.D. = 1.5) for schizophrenia patients, respectively (Fig. 2), demonstrating no disgust during neutral and slight to medium disgust during negative odor. The equivalent ANOVA on the ESR scores showed only a significant main effect for olfaction ( F = 37.15, df = 1, 44, P = 0.00). Hence, both patients and healthy volunteers reported a noticeably increased feeling of disgust when stimulated with negative odor in contrast to neutral room air. Furthermore, no group differences could be observed.
3. Results
3.2.1. Overall analysis For descriptive results, see Table 1.
3.2. Hits, sensitivity, reaction time, false alarms
3.1. Valence, intensity, and PANAS and ESR scores
3.1.2. PANAS scores Mean difference values on the PANAS scale (positive minus negative score) were 13.2 (S.D. = 5.0) for the patient group and 10.1 (S.D. = 9.5) for the control group after neutral stimulation. Following negative stimulation, patients and healthy volunteers had a mean difference value of 8.2 (S.D. = 8.3) and 9.3 (S.D. = 9.7), respectively, indicating that both groups experienced an increase in negative affect following stimulation with a negative odor. Accordingly, the three-way repeated measures ANOVA showed a significant main effect for olfaction ( F = 12.87, df = 1, 44, P = 0.00) and a significant interaction between group and olfaction ( F = 6.57, df = 1, 44, P = 0.01). Post-hoc Scheffe´ tests for decomposition of this interaction remained nonsignificant. Hence, patients and controls experienced a similar mood during negative and neutral olfactory stimulation.
3.2.2. Hits The three-way ANOVA revealed a main effect for group ( F = 9.4, df = 1, 46, P = 0.00) indicating higher overall hit rates in controls. A main effect for olfaction ( F = 4.8, df = 1, 46, P = 0.03) and task ( F = 36.8, df = 1, 46, P = 0.00) showed reduced performance during negative odor and higher hit rates during 0-back, respectively. Furthermore, a significant group-by-task interaction ( F = 5.5, df = 1, 46, P = 0.02) emerged. Decomposing the interaction revealed more hits in controls than in patients during the 0-back (t = 3.4, df = 74.8, P = 0.00) and 2-back condition (t = 3.8, df = 72.9, P = 0.00). Regarding the significant main effects and our hypotheses, we nevertheless performed planned comparisons of means for the 0-back and 2back condition separately in each group, testing wheth-
Baseline Neutral odor Negative odor
5
self-rating
3.1.1. Valence and intensity scores No significant difference was found in ratings of unpleasantness for yeast between patients (mean = 2.3, S.D. = 0.9) and healthy volunteers (mean = 2.1, S.D. = 0.8; t = 0.7, df = 46, NS). Similarly, intensity ratings were comparable for patients (mean = 4.4, S.D. = 1.0) and controls (mean = 4.0, SD = 0.2; t = 1.1, df = 46, NS). The degree of rating indicated unpleasant and intense odor perception, respectively. Furthermore, no participant had to be excluded from the analysis due to outlying valence or intensity ratings.
4 3 2 1 Controls
Patients
Fig. 2. Affective ratings. Emotional self-ratings (ESR, means F S.D.) of patients and controls of perceived disgust during baseline, neutral and negative odor.
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Table 1 Hits (correct reactions), false alarms, sensitivity and reaction time (ms) of patients and controls during neutral and negative odor stimulation (mean (M) and standard deviation (S.D.) of 0-back/2-back) 0-back
2-back
Neutral
Hits Hits False alarms False alarms Sensitivity Sensitivity Reaction time (ms) Reaction time (ms)
Neutral
Negative
S.D.
M
S.D.
M
S.D.
M
S.D.
26.58 27.92 0.63 0.21 0.93 0.99 556.81 433.86
1.95 0.28 0.88 0.66 0.08 0.02 327.84 53.96
26.83 27.58 1.04 0.25 0.94 0.97 567.25 431.60
1.79 1.47 1.43 0.53 0.08 0.05 357.26 51.42
20.71 25.42 1.13 0.46 0.92 0.97 557.80 480.23
7.41 3.83 3.23 1.06 0.09 0.04 131.24 86.66
19.71 24.33 1.79 0.29 0.89 0.96 587.99 520.57
7.53 4.28 4.66 0.69 0.11 0.04 150.21 81.08
er these differences could be traced back to both cognitive tasks or – as we hypothesized – to only one. For 0-back, no significant differences between neutral and negative odor could be found in either group (patients: t = 0.5, df = 23, NS; controls: t = 1.1, df = 23, NS). However, for 2-back, significant performance differences were found for controls (t = 2.3, df = 23, P= 0.02) with fewer hits during negative odor; but only a trend emerged for patients (t = 1.3, df = 23, P = 0.10). 3.2.3. Sensitivity The ANOVA demonstrated a significant main effect for group ( F = 11.7, df = 1, 46, P = 0.00) indicating higher sensitivity for controls and a main effect for task ( F = 5.2, df = 1, 46, P = 0.03) with higher sensitivity during 0-back. 3.2.4. Reaction time The equivalent ANOVA revealed a main effect for group ( F = 6.3, df = 1, 46, P = 0.02) and olfaction ( F = 7.4, df = 1, 46, P = 0.01). Hence, controls responded faster than patients, and reactions were also faster during 0-back compared with 2-back. Furthermore, there was a significant olfaction-by-task interaction ( F = 7.6, df = 1, 46, P = 0.01). Decomposing the interaction in each group with two-way repeated measures ANOVAs, a main effect for task ( F = 30.0, df = 1, 23, P = 0.00) and olfaction ( F =5.3, df = 1, 23, P = 0.03) emerged in healthy volunteers, as well as a significant interaction between olfaction and task ( F = 7.5, df = 1, 23, P = 0.01). According to our hypothesis of greater impact of olfaction on the 2-back task, different reaction times were found for 2-back task performance only (2back: t = 2.7, df = 23, P = 0.01; 0-back: t = 0.4, df = 23, NS; Fig. 3). In patients, only a trend for olfaction emerged ( F = 3.0, df = 1, 23, P = 0.10).
3.2.5. False alarms In this ANOVA, a significant olfaction-by-group interaction ( F = 4.6, df = 1, 46, P = 0.04) emerged. More false alarms irrespective of task were found in patients during negative than during neutral stimulation (t = 2.1, df = 23, P = 0.02) while such a difference could not be observed in healthy volunteers (t = 0.5, df = 23, NS). 3.2.6. Corollary analyses Significant correlations emerged between smoking and performance. In controls, hit rates (r = 0.43, P = 0.04) and sensitivity (r = 0.50, P = 0.01) were lower in smokers during the 0-back task and the same applied for patients (0-back: hits: r = 0.45, P = 0.03; sensitivity: 0.49, P = 0.01). In addition, patients’ sensitivity during 2-back showed a significant correlation with smoking (r = 0.42, P = 0.04). Hence, no systematic influence of smoking on results as well as no interactive effects with the influence of emotion on performance were found (our results rely on effects
Neutral odor Negative odor
*
NS
Controls
Patients
600
ms
Patients Controls Patients Controls Patients Controls Patients Controls
Negative
M
500 400
Fig. 3. Behavioral performance for the 2-back task. Reaction times (F S.D.) of patients and controls during neutral and negative odor.
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for 2-back rather than 0-back; furthermore, the strongest effects were found for reaction time and false alarms, not affected by smoking). For patients, no significant associations were obtained between psychopathological ratings (positive, negative and general symptom scores of the PANSS) and all performance measures. Medication (chlorpromazine equivalents) revealed an influence on reaction time during 2-back only (r = 0.54, P = 0.02). A higher dosage was associated with elevated response rates. However, no differential effect of medication on emotion–cognition interactions was observed: Correlations were similar for neutral (r =0.57, P = 0.01) and negative emotions (r = 0.46, P = 0.05). Correlations between mood changes (PANAS neutral–PANAS negative condition) and working memory (difference scores between neutral and negative stimulations for each task) revealed no significant association in controls, but a significant correlation between sensitivity and mood changes in the 2-back task (r = 0.49, P = 0.01) in patients: Increased negative affect (larger difference) was accompanied by higher sensitivity (smaller difference). 4. Discussion As hypothesized, negative olfactory stimulation had impairing effects on working memory performance. Yet, whilst in healthy controls these effects were most prominent for reaction time but also seen for reaction quality (hits), patients with schizophrenia failed to show significant impairments concerning hits and reaction time during negative odor stimulation in contrast to neutral stimulation. However, a trend in the same direction was also obvious in patients. Differential effects of emotion on cognition were indicated in patients by the fact that significant impairing mood effects were found on the false alarm rate irrespective of task condition. 4.1. Subjective ratings Valence and intensity ratings of the odor indicated that patients and controls perceived the negative odor as similarly unpleasant and intense. Thus, the results converge with those of Crespo-Facorro et al. (2001), who found similar affect ratings for the negative odor in schizophrenia patients and healthy volunteers. Furthermore, subjective ratings following each condition corroborate that fermented yeast was effective in inducing negative affect, namely disgust, in both patients and controls.
4.2. Cognitive performance Results on hits, sensitivity and reaction time showed that patients performed significantly worse than healthy participants, demonstrating attentional and working memory deficits irrespective of olfactory stimulation, a finding that has been frequently reported (Barr, 2001; Li et al., 2002; Okada, 2002). 4.3. Influence of emotion on cognition Results demonstrated a deteriorating effect of negative olfactory stimulation, especially on velocity but also on the mean number of correct reactions, as revealed in a hypothesis driven analysis. Results indicated a significantly different performance quality between the 0-back and the 2-back condition during negative affect. With the 2-back condition being far more demanding than the 0-back condition, this difference was according to our expectations, assuming a greater influence of negative emotion on working memory. Given a significant group difference in the overall analysis, we conducted further analyses on hits and reaction times for patients and controls separately. However, the effect of olfactory stimulation was not significant in patients despite data showing a similar trend, namely a similarly impaired performance in the 2-back task under negative olfactory stimulation. Moreover, an increased false alarm rate irrespective of task indicated general impairing negative olfactory stimulation effects in patients too. Hence, negative olfactory stimulation seemed to exert a measurable effect on healthy volunteers leading to a decrease in response speed and correct reactions. While effects for hits and reaction times were similar in direction in patients, although less obvious and weaker despite similar subjective experiences, this did not apply for false alarms. Hence, apparently in patients, negative emotion affected the behavioral style differentially. First, it showed that patients were already affected at lower task demands (0-back) and, second, the negative emotion appeared to exert its influence on working memory by increasing inadequate responses to non-targets. Hence, our results are only partly consistent with our hypothesis that less cognitive disturbance occurs during negative mood in schizophrenia due to emotional impairments. Rather, the measurable impairments in healthy controls, namely a delay in response, could be interpreted as the attempt to adjust and modify their behavior to adequately cope with the increased task demands and adverse effects of negative affect during elevated working memory loads visible in a slightly
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increased error rate. Patients, on the other hand, demonstrated mainly a heightened distractibility and inadequate response patterns already during low cognitive demands. Hence, one can infer that effective behavioral adjustments in view of negative emotions are less effective and dysfunctional in patients, possibly caused by characteristic emotional impairments. Alternatively, in regard to the higher variation in patients, negative olfactory stimulation may lead to more heterogeneous effects in this group than in healthy participants. However, examining the influence of relevant factors such as smoking, psychopathology and medication, no differential effects on this emotion–cognition interaction could be found. Thus, results demonstrating impairment in working memory during olfactory stimulation in controls lend support to the findings of Gray (2001) showing impaired performance in verbal working memory after the induction of negative emotion. In addition, the present findings imply that negative affect influences cortical activity. During olfactory processing and negative affect, the amygdala and the orbitofrontal cortex play a crucial role. According to recent findings (Perlstein et al., 2002), the amygdaloid complex and its connections to orbitofrontal structures exert strong influences on the dorsolateral prefrontal cortex, which is known to be involved in working memory processes, thus being able to affect working memory. With regard to the emotional impairments and associated hypoactivation in subcortical cerebral activation during negative odor stimulation (Crespo-Facorro et al., 2001) and the experience of negative emotion (Schneider et al., 1998), we can speculate that a dysfunctional connectivity and hence a lack of adequate influence of the amygdala on prefrontal areas may be responsible for the characteristic behavioral pattern in patients. However, some methodological constraints have to be taken into account when interpreting the results. In the present study; no detailed examination of olfactory abilities was carried out. Thus, possible deficits in olfactory perception might have gone undetected, but they are not believed to be of influence on the present data. We assessed valence and intensity perception, which guaranteed the intended behavioral effect of the negative odor. Furthermore, the present study relies on behavioral data only. This paradigm which was newly developed for use in behavioral neuroimaging studies, provides exciting opportunities, for studying the interaction between emotion and cognition both in healthy individuals and in schizophrenia patients. Hence, we are in the process
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of implementing the paradigm in behavioral imaging methods. Acknowledgments This work was supported by the German Research Foundation (DFG, Schn 362/13-1 and 13-2), the Research Center Ju¨lich and the Federal Ministry of Education and Research (Brain Imaging Center West, 01GO0204 and Competence Network on Schizophrenia, 01GI9932). We thank Volker Backes, Helen Greenland, and Sabrina Weber for assistance and support. References American Psychiatric Association, 1994. Diagnostic and Statistical Manual of Mental Disorders: DSM-IV. Hogrefe, Go¨ttingen. Barch, D.M., Csernansky, J.G., Conturo, T., Snyder, A.Z., 2002. Working and long-term memory deficits in schizophrenia: is there a common prefrontal mechanism? Journal of Abnormal Psychology 111, 478 – 494. Barr, W.B., 2001. Schizophrenia and attention deficit disorder. Two complex disorders of attention. Annals of the New York Academy of Sciences 931, 239 – 250. Bartolic, E.I., Basso, M.R., Schefft, B.K., Glauer, T., Titanic-Schefft, M., 1999. Effects of experimentally-induced emotional states on frontal lobe cognitive task performance. Neuropsychologia 37, 677 – 683. Box, G.E.P., 1954. Some theorems on quadratic forms applied in the study of analysis of variance problems. Annals of Statistics 25, 290 – 302. Brewer, W.J., Pantelis, C., Anderson, V., Velakoulis, D., Singh, B., Copolov, D.L., McGorry, P.D., 2001. Stability of olfactory identification deficit in neuroleptic-naive patients with first-episode psychosis. American Journal of Psychiatry 158, 107 – 115. Carmichael, S.T., Price, J.L., 1994. Architectonic subdivision of the orbital and medial prefrontal cortex in the macaque monkey. Journal of Comparative Neurology 346, 179 – 207. Chen, D., Haviland-Jones, J., 1999. Rapid mood change and human odors. Physiology and Behavior 68, 241 – 250. Crespo-Facorro, B., Paradiso, S., Andreasen, N.C., O’Leary, D.S., Watkins, G.L., Ponto, L.L., Hichwa, R.D., 2001. Neural mechanisms of anhedonia in schizophrenia: a PET study of response to unpleasant and pleasant odors. JAMA 286, 427 – 435. Gray, J.R., 2001. Emotional modulation of cognitive control: approach–withdrawal states double-dissociate spatial from verbal two-back task performance. Journal of Experimental Psychology: General 130, 436 – 452. Gur, R.E., McGrath, C., Chan, R.M., Schroeder, L., Turner, T., Turetsky, B.I., Kohler, C., Alsop, D., Maldjian, J., Ragland, J.D., Gur, R.C., 2002. An fMRI study of facial emotion processing in patients with schizophrenia. American Journal of Psychiatry 159, 1992 – 1999. Kay, S.R., Opler, L.A., Fiszbein, A., 1987. The Positive and Negative Syndrome Scale (PANSS) for schizophrenia. Schizophrenia Bulletin 13, 261 – 276. Knasko, S.C., 1995. Pleasant odors and congruency: effects on approach behavior. Chemical Senses 20, 479 – 487.
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Schneider, F., Gur, R.C., Gur, R.E., Shtasel, D.L., 1995. Emotional processing in schizophrenia: neurobehavioral probes in relation to psychopathology. Schizophrenia Research 17, 67 – 75. Schneider, F., Weiss, U., Kessler, C., Salloum, J.B., Posse, S., Grodd, W., Mu¨ller-Ga¨rtner, H.W., 1998. Differential amygdala activation in schizophrenia during sadness. Schizophrenia Research 34, 133 – 142. Schneider, F., Weiss, U., Kessler, C., Mu¨ller-Ga¨rtner, H.W., Posse, S., Salloum, J.B., Grodd, W., Himmelmann, F., Gaebel, W., Birbaumer, N., 1999. Subcortical correlates of differential classical conditioning of aversive emotional reactions in social phobia. Biological Psychiatry 45, 863 – 871. Schneider, F., Habel, U., Kessler, C., Posse, S., Grodd, W., Mu¨llerGa¨rtner, H.W., 2000. Functional imaging of conditioned aversive emotional responses in antisocial personality disorder. Neuropsychobiology 42, 192 – 201. ¨ ngu¨r, D., Akbudak, E., Conturo, T.E., Ollinger, J.M., Simpson, J.R., O Snyder, A.Z., Gusnard, D.A., Raichle, M.E., 2000. The emotional modulation of cognitive processing: an fMRI study. Journal of Cognitive Neuroscience 12, 157 – 170. Stedman, T.J., Clair, A.L., 1998. Neuropsychological, neurological and symptom correlates of impaired olfactory identification in schizophrenia. Schizophrenia Research 32, 23 – 30. Watson, D., Clark, L.A., Tellegen, A., 1988. Development and validation of brief measures of positive and negative affect: the PANAS scales. Journal of Personality and Social Psychology 54, 1061 – 1063.
Interaction of negative olfactory stimulation and working memory in schizophrenia patients: Development and evaluation of a behavioral neuroimaging task Frank Schneider a,*, Kathrin Koch a, Martina Reske a, Thilo Kellermann a, N. Seiferth a, Tony Sto¨cker b, Katrin Amunts b, N. Jon Shah b, Ute Habel a a
Department of Psychiatry and Psychotherapy, University of Aachen, Pauwelsstr. 30, 52074 Aachen, Germany b Institute of Medicine, Research Center, Ju¨lich, Germany Received 21 June 2004; received in revised form 25 October 2004; accepted 16 December 2004
Abstract Negative affect plays a crucial role in the psychopathology of schizophrenia. Although it is known that negative emotion has a strong effect on cognitive performance, this interaction has mainly been studied in healthy volunteers. Hence, working memory was assessed in 24 schizophrenia patients and 24 matched comparison subjects with a 0-back/2-back continuous performance test. Simultaneously, negative emotion was induced by olfactory stimulation. Although subjective ratings confirmed that stimulation with a negative odor was associated with a significant increase in negative affect in patients and healthy volunteers, working memory performance was affected differentially in healthy volunteers and schizophrenia patients. Whilst a similar trend of a reduced behavioral performance during negative odor stimulation was observed in patients, only controls demonstrated a significantly higher response time and a reduced number of correct reactions during higher working memory demands (2-back). Patients, on the other hand, revealed an increase in false alarms during both conditions. The present data indicate a differential effect of negative mood induction on working memory performance in schizophrenia patients and healthy subjects. D 2005 Elsevier Ireland Ltd. All rights reserved. Keywords: Olfaction; n-back task; Emotion; Mood induction
1. Introduction In schizophrenia, impairments in both emotion and cognition are prominent and characterize its psychopathology. In particular, emotion recognition and experience (Schneider et al., 1994; Li et al., 2002; Malla et al., 2002), as well as attention and working memory (Krae* Corresponding author. Tel.: +49 241 80 89 633; fax: +49 241 80 82 401. E-mail address: [email protected] (F. Schneider).
pelin, 1920; Barr, 2001), are dysfunctional and are accompanied by deficiencies in their corresponding underlying cerebral correlates (Schneider et al., 1995; Barch et al., 2002; Gur et al., 2002; Perlstein et al., 2002). However, interactions between emotion and cognition have not been investigated in greater detail in patients. Similarly, in healthy subjects, there are only a few and rather contradictory studies exploring the effects of emotion on cognitive function (Bartolic et al., 1999; Perlstein et al., 2002; Simpson et al., 2000).
0165-1781/$ - see front matter D 2005 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.psychres.2004.12.013
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Gray (2001) studied the effects of different emotional states (approach, neutral or withdrawal) on working memory performance (verbal and spatial). In the withdrawal condition, subjects made significantly more errors in the verbal task and fewer errors in the spatial task. Thus, emotional–cognitive interaction is not a simple one-way relation but seems to depend both on the type of cognition and the type of emotion. Comparable studies in schizophrenia patients are necessary to increase knowledge of the interfering effects of negative emotion on cognition. Due to its tight anatomical connections to the limbic cortex, olfactory stimulation represents a powerful tool to induce mood (Carmichael and Price, 1994). A number of findings indicate positive emotions in subjects exposed to pleasant odors, as well as negative affect when exposed to negative odors (Knasko, 1995; Schneider et al., 1998, 2000; Chen and Haviland-Jones, 1999). However, in schizophrenia patients, one must be aware of olfactory dysfunctions. These deficits concerning mainly the ability to perceive and identify odors (Stedman and Clair, 1998; Moberg et al., 1999; Brewer et al., 2001) suggest differential olfactory processing mechanisms in schizophrenia. A PET study (Crespo-Facorro et al., 2001) confirms this assumption: schizophrenia patients who, whilst failing to activate limbic regions, showed hyperactivations in several frontal regions during negative odor stimulation. The affective odor judgments, on the other hand, did not differ between patients and healthy controls. We chose fermented yeast, an odor associated with strong negative affect (Schneider et al., 1999, 2000), and tested its influence on cognitive performance in schizophrenia patients and healthy controls by means of a combined 0-back/2-back continuous performance paradigm. In this paradigm, single letters are presented rapidly one after another. The 0-back condition demands an immediate button press following a predefined target (for example, the letter X), whereas the 2back condition asks for a reaction if the last but one letter is the same as the present letter. Since the 2-back condition requires working memory in addition to attentional processes and therefore exhibits increased cognitive demands, we hypothesized a greater impact of negative affect on 2-back performance. Regarding the emotional impairments and associated hypoactivation in subcortical cerebral activation during the experience of negative emotion (Schneider et al., 1998), we expected smaller cognitive disturbances in the schizophrenia patients under negative mood induction than in controls.
Given the fact that interactions between emotional and cognitive processing have rarely been investigated in patients with schizophrenia, the aim of this study was to explore the effect of negative emotion on cognitive processing in schizophrenia patients. 2. Methods 2.1. Subjects Participants included 24 (12 male, 12 female) patients with DSM-IV diagnosis of schizophrenia (American Psychiatric Association, 1994) and 24 healthy subjects who were matched to the patients by gender, age and years of parental education (mean F 2 S.D.). The mean age was 40.1 years (S.D. = 12.3) and the mean parental education was 10.0 years (S.D. = 2.6) in patients and 38.1 years (S.D. =13.1) and 9.5 years (S.D. = 2.7) in controls, respectively. There were no differences between the groups regarding age (t = 0.4, df = 46, NS) or parental education (t = 0.7, df = 46, NS). All subjects gave written informed consent to participate in the study. Mean ratings on the Positive and Negative Syndrome Scale (PANSS, Kay et al., 1987) were 11.5 (S.D. = 6.2) on the Positive Symptom Scale and 15.0 (S.D. = 7.7) on the Negative Symptom Scale. Of the 24 schizophrenia subjects, 15 were receiving atypical medication, 3 typical and 5 both typical and atypical antipsychotic medication. One patient’s medication is presently unknown as he is participating in a doubleblind psychopharmacology study (risperidone vs. haloperidol). In the patient group, 11 were non-smokers; 9 patients smoked fewer than 21 cigarettes per day; the remainder smoked 21 to 40 cigarettes per day. The group of healthy volunteers comprised 16 nonsmokers and 8 smokers; 7 of them smoked fewer than 21 cigarettes per day. Participants were excluded if they had any (comorbid) psychiatric or neurological disease or sensory impairments interfering with performance. 2.2. Procedure Odors were presented with constant temperature, pressure and humidity using a self-designed olfactometer delivering the stimulants by air pressure through several parallel tubings to the subjects’ right nostrils (Schneider et al., 1999, 2000). Stimuli consisted of 20 g of rotten yeast melted in 200 ml of water, which was kept at a constant temperature of 30 8C (86.1 8F) for 1 week.
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each run on the Positive and Negative Affect Schedule (PANAS, Watson et al., 1988), as well as their level of disgust using the corresponding subscale of the Emotional Self-Rating (ESR) scale (1 = not at all, 2 = mildly, 3 = moderately, 4 = quite a lot, 5 = extremely; Schneider et al., 1994) based on a previous study confirming the relevance of disgust in negative olfactory stimulation (Schneider et al., 1999).
The experimental design consisted of two runs, each with eight alternating baseline (30 s) and eight activation blocks (30 s, 0-back, 2-back; Fig. 1). Single letters (A–Z) presented in both baseline and activation phases were shown in random order and appeared for 500 ms. In baseline phases, subjects were simply asked to focus on the letters. Activation phases were 0-back (immediate reaction to the predefined target letter X) and 2-back (reaction if the last but one letter was the same) conditions in alternating order. Thus, the 0-back task demands attentional processes; the 2-back task requires both attentional and working memory capacities. Olfactory stimulation took place only during the 0-back and 2-back conditions every 5 s for 3 s each to minimize habituation effects, with either neutral room air or yeast depending on the run. The order of presentation of neutral room air and yeast was randomized across subjects. Subjects had to react within 900 ms by pressing the space bar of a portable PC for the target letter. The target letter was presented at irregular intervals. The target probability was 0.37 with a ratio of 48 nontargets to 28 targets.
2.4. Statistical analysis Performance was assessed by hits (percent correct), false alarms (commission errors), reaction time, and sensitivity. Sensitivity was calculated corresponding to signal detection theory as a measure of the subject’s ability to discriminate targets from non-targets (Nestor et al., 1990). For the scores on the valence and intensity scales for the negative odor, we performed two-tailed t-tests to investigate whether patients and controls differed in their judgments. For the PANAS and ESR, we conducted two three-way repeated measures analyses of variance (ANOVAs) with group (patients vs. controls) and gender as between-subject factors, and olfaction (neutral room air vs. fermented yeast) as a within-subject factor on the difference score for positive and negative affect of the PANAS and the disgust ratings of the ESR, respectively. Levene tests for the homogeneity of variances revealed unequal variance for most variables. Parametric analyses have nevertheless been applied here, since the ANOVA is relatively robust against violations of equal variances if the sample size is relatively high (between 10 and 20) and groups are of same size (Box, 1954). Both apply to our data. Four overall four-way repeated measure analyses of variance on hits, false alarms, sensitivity and reaction time were
2.3. Valence and intensity scale Before the experimental sessions, subjects were asked to judge the valence of the negative odor on a Likert-type intensity scale ranging from 3 (very unpleasant) to 3 (very pleasant). In addition, subjects had to judge the intensity of the yeast on a scale ranging from 0 (imperceptible) to 6 (extremely intense). Subjects rating the valence of the odor as 0 (neither–nor) or higher and the intensity as 2 (slightly perceptible) or below were excluded. Patients and healthy volunteers were asked to rate their emotional state before and after NEUTRAL ODOR DURING CPT NO ODOR
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NEGATIVE ODOR DURING CPT NO ODOR
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Fig. 1. Experimental design. The paradigm consisted of two runs with eight 30 s baseline blocks and eight 30 s activation blocks each and olfactory stimulation during 0-back/2-back.
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performed with group (patients vs. controls) as the between-subject factor and olfaction (neutral room air vs. yeast) and task (0-back/2-back) as the within-subject factors and gender as the covariate to test for the influence of gender on results. Since gender had no contribution to the data (hits, sensitivity, false alarms, and reaction time), sensitivity has been increased by ignoring gender in the further analyses. Hence, threeway ANOVAs were performed with group (patients vs. controls) as the between-subjects factor and olfaction (neutral room air vs. yeast) and task (0-back/2-back) as the within-subject factors. Subsequently, significant effects were decomposed by post-hoc t-tests. Possible confounding effects of medication, psychopathology and smoking were addressed with correlation analyses. Correlations have also been calculated between mood changes and working memory performance.
3.1.3. ESR scores Mean values on the ESR disgust scale were 1.4 (S.D. = 0.9) after neutral olfactory stimulation and 2.4 (S.D. = 1.4) after negative olfactory stimulation for healthy volunteers as well as 1.5 (S.D. = 0.8) and 3.0 (S.D. = 1.5) for schizophrenia patients, respectively (Fig. 2), demonstrating no disgust during neutral and slight to medium disgust during negative odor. The equivalent ANOVA on the ESR scores showed only a significant main effect for olfaction ( F = 37.15, df = 1, 44, P = 0.00). Hence, both patients and healthy volunteers reported a noticeably increased feeling of disgust when stimulated with negative odor in contrast to neutral room air. Furthermore, no group differences could be observed.
3. Results
3.2.1. Overall analysis For descriptive results, see Table 1.
3.2. Hits, sensitivity, reaction time, false alarms
3.1. Valence, intensity, and PANAS and ESR scores
3.1.2. PANAS scores Mean difference values on the PANAS scale (positive minus negative score) were 13.2 (S.D. = 5.0) for the patient group and 10.1 (S.D. = 9.5) for the control group after neutral stimulation. Following negative stimulation, patients and healthy volunteers had a mean difference value of 8.2 (S.D. = 8.3) and 9.3 (S.D. = 9.7), respectively, indicating that both groups experienced an increase in negative affect following stimulation with a negative odor. Accordingly, the three-way repeated measures ANOVA showed a significant main effect for olfaction ( F = 12.87, df = 1, 44, P = 0.00) and a significant interaction between group and olfaction ( F = 6.57, df = 1, 44, P = 0.01). Post-hoc Scheffe´ tests for decomposition of this interaction remained nonsignificant. Hence, patients and controls experienced a similar mood during negative and neutral olfactory stimulation.
3.2.2. Hits The three-way ANOVA revealed a main effect for group ( F = 9.4, df = 1, 46, P = 0.00) indicating higher overall hit rates in controls. A main effect for olfaction ( F = 4.8, df = 1, 46, P = 0.03) and task ( F = 36.8, df = 1, 46, P = 0.00) showed reduced performance during negative odor and higher hit rates during 0-back, respectively. Furthermore, a significant group-by-task interaction ( F = 5.5, df = 1, 46, P = 0.02) emerged. Decomposing the interaction revealed more hits in controls than in patients during the 0-back (t = 3.4, df = 74.8, P = 0.00) and 2-back condition (t = 3.8, df = 72.9, P = 0.00). Regarding the significant main effects and our hypotheses, we nevertheless performed planned comparisons of means for the 0-back and 2back condition separately in each group, testing wheth-
Baseline Neutral odor Negative odor
5
self-rating
3.1.1. Valence and intensity scores No significant difference was found in ratings of unpleasantness for yeast between patients (mean = 2.3, S.D. = 0.9) and healthy volunteers (mean = 2.1, S.D. = 0.8; t = 0.7, df = 46, NS). Similarly, intensity ratings were comparable for patients (mean = 4.4, S.D. = 1.0) and controls (mean = 4.0, SD = 0.2; t = 1.1, df = 46, NS). The degree of rating indicated unpleasant and intense odor perception, respectively. Furthermore, no participant had to be excluded from the analysis due to outlying valence or intensity ratings.
4 3 2 1 Controls
Patients
Fig. 2. Affective ratings. Emotional self-ratings (ESR, means F S.D.) of patients and controls of perceived disgust during baseline, neutral and negative odor.
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Table 1 Hits (correct reactions), false alarms, sensitivity and reaction time (ms) of patients and controls during neutral and negative odor stimulation (mean (M) and standard deviation (S.D.) of 0-back/2-back) 0-back
2-back
Neutral
Hits Hits False alarms False alarms Sensitivity Sensitivity Reaction time (ms) Reaction time (ms)
Neutral
Negative
S.D.
M
S.D.
M
S.D.
M
S.D.
26.58 27.92 0.63 0.21 0.93 0.99 556.81 433.86
1.95 0.28 0.88 0.66 0.08 0.02 327.84 53.96
26.83 27.58 1.04 0.25 0.94 0.97 567.25 431.60
1.79 1.47 1.43 0.53 0.08 0.05 357.26 51.42
20.71 25.42 1.13 0.46 0.92 0.97 557.80 480.23
7.41 3.83 3.23 1.06 0.09 0.04 131.24 86.66
19.71 24.33 1.79 0.29 0.89 0.96 587.99 520.57
7.53 4.28 4.66 0.69 0.11 0.04 150.21 81.08
er these differences could be traced back to both cognitive tasks or – as we hypothesized – to only one. For 0-back, no significant differences between neutral and negative odor could be found in either group (patients: t = 0.5, df = 23, NS; controls: t = 1.1, df = 23, NS). However, for 2-back, significant performance differences were found for controls (t = 2.3, df = 23, P= 0.02) with fewer hits during negative odor; but only a trend emerged for patients (t = 1.3, df = 23, P = 0.10). 3.2.3. Sensitivity The ANOVA demonstrated a significant main effect for group ( F = 11.7, df = 1, 46, P = 0.00) indicating higher sensitivity for controls and a main effect for task ( F = 5.2, df = 1, 46, P = 0.03) with higher sensitivity during 0-back. 3.2.4. Reaction time The equivalent ANOVA revealed a main effect for group ( F = 6.3, df = 1, 46, P = 0.02) and olfaction ( F = 7.4, df = 1, 46, P = 0.01). Hence, controls responded faster than patients, and reactions were also faster during 0-back compared with 2-back. Furthermore, there was a significant olfaction-by-task interaction ( F = 7.6, df = 1, 46, P = 0.01). Decomposing the interaction in each group with two-way repeated measures ANOVAs, a main effect for task ( F = 30.0, df = 1, 23, P = 0.00) and olfaction ( F =5.3, df = 1, 23, P = 0.03) emerged in healthy volunteers, as well as a significant interaction between olfaction and task ( F = 7.5, df = 1, 23, P = 0.01). According to our hypothesis of greater impact of olfaction on the 2-back task, different reaction times were found for 2-back task performance only (2back: t = 2.7, df = 23, P = 0.01; 0-back: t = 0.4, df = 23, NS; Fig. 3). In patients, only a trend for olfaction emerged ( F = 3.0, df = 1, 23, P = 0.10).
3.2.5. False alarms In this ANOVA, a significant olfaction-by-group interaction ( F = 4.6, df = 1, 46, P = 0.04) emerged. More false alarms irrespective of task were found in patients during negative than during neutral stimulation (t = 2.1, df = 23, P = 0.02) while such a difference could not be observed in healthy volunteers (t = 0.5, df = 23, NS). 3.2.6. Corollary analyses Significant correlations emerged between smoking and performance. In controls, hit rates (r = 0.43, P = 0.04) and sensitivity (r = 0.50, P = 0.01) were lower in smokers during the 0-back task and the same applied for patients (0-back: hits: r = 0.45, P = 0.03; sensitivity: 0.49, P = 0.01). In addition, patients’ sensitivity during 2-back showed a significant correlation with smoking (r = 0.42, P = 0.04). Hence, no systematic influence of smoking on results as well as no interactive effects with the influence of emotion on performance were found (our results rely on effects
Neutral odor Negative odor
*
NS
Controls
Patients
600
ms
Patients Controls Patients Controls Patients Controls Patients Controls
Negative
M
500 400
Fig. 3. Behavioral performance for the 2-back task. Reaction times (F S.D.) of patients and controls during neutral and negative odor.
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for 2-back rather than 0-back; furthermore, the strongest effects were found for reaction time and false alarms, not affected by smoking). For patients, no significant associations were obtained between psychopathological ratings (positive, negative and general symptom scores of the PANSS) and all performance measures. Medication (chlorpromazine equivalents) revealed an influence on reaction time during 2-back only (r = 0.54, P = 0.02). A higher dosage was associated with elevated response rates. However, no differential effect of medication on emotion–cognition interactions was observed: Correlations were similar for neutral (r =0.57, P = 0.01) and negative emotions (r = 0.46, P = 0.05). Correlations between mood changes (PANAS neutral–PANAS negative condition) and working memory (difference scores between neutral and negative stimulations for each task) revealed no significant association in controls, but a significant correlation between sensitivity and mood changes in the 2-back task (r = 0.49, P = 0.01) in patients: Increased negative affect (larger difference) was accompanied by higher sensitivity (smaller difference). 4. Discussion As hypothesized, negative olfactory stimulation had impairing effects on working memory performance. Yet, whilst in healthy controls these effects were most prominent for reaction time but also seen for reaction quality (hits), patients with schizophrenia failed to show significant impairments concerning hits and reaction time during negative odor stimulation in contrast to neutral stimulation. However, a trend in the same direction was also obvious in patients. Differential effects of emotion on cognition were indicated in patients by the fact that significant impairing mood effects were found on the false alarm rate irrespective of task condition. 4.1. Subjective ratings Valence and intensity ratings of the odor indicated that patients and controls perceived the negative odor as similarly unpleasant and intense. Thus, the results converge with those of Crespo-Facorro et al. (2001), who found similar affect ratings for the negative odor in schizophrenia patients and healthy volunteers. Furthermore, subjective ratings following each condition corroborate that fermented yeast was effective in inducing negative affect, namely disgust, in both patients and controls.
4.2. Cognitive performance Results on hits, sensitivity and reaction time showed that patients performed significantly worse than healthy participants, demonstrating attentional and working memory deficits irrespective of olfactory stimulation, a finding that has been frequently reported (Barr, 2001; Li et al., 2002; Okada, 2002). 4.3. Influence of emotion on cognition Results demonstrated a deteriorating effect of negative olfactory stimulation, especially on velocity but also on the mean number of correct reactions, as revealed in a hypothesis driven analysis. Results indicated a significantly different performance quality between the 0-back and the 2-back condition during negative affect. With the 2-back condition being far more demanding than the 0-back condition, this difference was according to our expectations, assuming a greater influence of negative emotion on working memory. Given a significant group difference in the overall analysis, we conducted further analyses on hits and reaction times for patients and controls separately. However, the effect of olfactory stimulation was not significant in patients despite data showing a similar trend, namely a similarly impaired performance in the 2-back task under negative olfactory stimulation. Moreover, an increased false alarm rate irrespective of task indicated general impairing negative olfactory stimulation effects in patients too. Hence, negative olfactory stimulation seemed to exert a measurable effect on healthy volunteers leading to a decrease in response speed and correct reactions. While effects for hits and reaction times were similar in direction in patients, although less obvious and weaker despite similar subjective experiences, this did not apply for false alarms. Hence, apparently in patients, negative emotion affected the behavioral style differentially. First, it showed that patients were already affected at lower task demands (0-back) and, second, the negative emotion appeared to exert its influence on working memory by increasing inadequate responses to non-targets. Hence, our results are only partly consistent with our hypothesis that less cognitive disturbance occurs during negative mood in schizophrenia due to emotional impairments. Rather, the measurable impairments in healthy controls, namely a delay in response, could be interpreted as the attempt to adjust and modify their behavior to adequately cope with the increased task demands and adverse effects of negative affect during elevated working memory loads visible in a slightly
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increased error rate. Patients, on the other hand, demonstrated mainly a heightened distractibility and inadequate response patterns already during low cognitive demands. Hence, one can infer that effective behavioral adjustments in view of negative emotions are less effective and dysfunctional in patients, possibly caused by characteristic emotional impairments. Alternatively, in regard to the higher variation in patients, negative olfactory stimulation may lead to more heterogeneous effects in this group than in healthy participants. However, examining the influence of relevant factors such as smoking, psychopathology and medication, no differential effects on this emotion–cognition interaction could be found. Thus, results demonstrating impairment in working memory during olfactory stimulation in controls lend support to the findings of Gray (2001) showing impaired performance in verbal working memory after the induction of negative emotion. In addition, the present findings imply that negative affect influences cortical activity. During olfactory processing and negative affect, the amygdala and the orbitofrontal cortex play a crucial role. According to recent findings (Perlstein et al., 2002), the amygdaloid complex and its connections to orbitofrontal structures exert strong influences on the dorsolateral prefrontal cortex, which is known to be involved in working memory processes, thus being able to affect working memory. With regard to the emotional impairments and associated hypoactivation in subcortical cerebral activation during negative odor stimulation (Crespo-Facorro et al., 2001) and the experience of negative emotion (Schneider et al., 1998), we can speculate that a dysfunctional connectivity and hence a lack of adequate influence of the amygdala on prefrontal areas may be responsible for the characteristic behavioral pattern in patients. However, some methodological constraints have to be taken into account when interpreting the results. In the present study; no detailed examination of olfactory abilities was carried out. Thus, possible deficits in olfactory perception might have gone undetected, but they are not believed to be of influence on the present data. We assessed valence and intensity perception, which guaranteed the intended behavioral effect of the negative odor. Furthermore, the present study relies on behavioral data only. This paradigm which was newly developed for use in behavioral neuroimaging studies, provides exciting opportunities, for studying the interaction between emotion and cognition both in healthy individuals and in schizophrenia patients. Hence, we are in the process
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of implementing the paradigm in behavioral imaging methods. Acknowledgments This work was supported by the German Research Foundation (DFG, Schn 362/13-1 and 13-2), the Research Center Ju¨lich and the Federal Ministry of Education and Research (Brain Imaging Center West, 01GO0204 and Competence Network on Schizophrenia, 01GI9932). We thank Volker Backes, Helen Greenland, and Sabrina Weber for assistance and support. References American Psychiatric Association, 1994. Diagnostic and Statistical Manual of Mental Disorders: DSM-IV. Hogrefe, Go¨ttingen. Barch, D.M., Csernansky, J.G., Conturo, T., Snyder, A.Z., 2002. Working and long-term memory deficits in schizophrenia: is there a common prefrontal mechanism? Journal of Abnormal Psychology 111, 478 – 494. Barr, W.B., 2001. Schizophrenia and attention deficit disorder. Two complex disorders of attention. Annals of the New York Academy of Sciences 931, 239 – 250. Bartolic, E.I., Basso, M.R., Schefft, B.K., Glauer, T., Titanic-Schefft, M., 1999. Effects of experimentally-induced emotional states on frontal lobe cognitive task performance. Neuropsychologia 37, 677 – 683. Box, G.E.P., 1954. Some theorems on quadratic forms applied in the study of analysis of variance problems. Annals of Statistics 25, 290 – 302. Brewer, W.J., Pantelis, C., Anderson, V., Velakoulis, D., Singh, B., Copolov, D.L., McGorry, P.D., 2001. Stability of olfactory identification deficit in neuroleptic-naive patients with first-episode psychosis. American Journal of Psychiatry 158, 107 – 115. Carmichael, S.T., Price, J.L., 1994. Architectonic subdivision of the orbital and medial prefrontal cortex in the macaque monkey. Journal of Comparative Neurology 346, 179 – 207. Chen, D., Haviland-Jones, J., 1999. Rapid mood change and human odors. Physiology and Behavior 68, 241 – 250. Crespo-Facorro, B., Paradiso, S., Andreasen, N.C., O’Leary, D.S., Watkins, G.L., Ponto, L.L., Hichwa, R.D., 2001. Neural mechanisms of anhedonia in schizophrenia: a PET study of response to unpleasant and pleasant odors. JAMA 286, 427 – 435. Gray, J.R., 2001. Emotional modulation of cognitive control: approach–withdrawal states double-dissociate spatial from verbal two-back task performance. Journal of Experimental Psychology: General 130, 436 – 452. Gur, R.E., McGrath, C., Chan, R.M., Schroeder, L., Turner, T., Turetsky, B.I., Kohler, C., Alsop, D., Maldjian, J., Ragland, J.D., Gur, R.C., 2002. An fMRI study of facial emotion processing in patients with schizophrenia. American Journal of Psychiatry 159, 1992 – 1999. Kay, S.R., Opler, L.A., Fiszbein, A., 1987. The Positive and Negative Syndrome Scale (PANSS) for schizophrenia. Schizophrenia Bulletin 13, 261 – 276. Knasko, S.C., 1995. Pleasant odors and congruency: effects on approach behavior. Chemical Senses 20, 479 – 487.
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