Altered amygdala activation in schizophrenia patients during emotion processing

Schizophrenia Research 150 (2013) 101–106

Contents lists available at ScienceDirect

Schizophrenia Research journal homepage: www.elsevier.com/locate/schres

Altered amygdala activation in schizophrenia patients during emotion processing Anne Pankow a,⁎,1, Eva Friedel a,1, Philipp Sterzer a, Nina Seiferth a, Henrik Walter a, Andreas Heinz a, Florian Schlagenhauf a,b a b

Department of Psychiatry and Psychotherapy, Charité - Universitätsmedizin Berlin, Charité Campus Mitte, Germany Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany

a r t i c l e

i n f o

Article history: Received 9 December 2012 Received in revised form 15 June 2013 Accepted 5 July 2013 Available online 2 August 2013 Keywords: Schizophrenia Emotion Functional imaging IAPS Amygdala

a b s t r a c t Dysfunctional emotion processing in patients suffering from schizophrenia is a prominent clinical feature of great importance for social functioning and subjective well-being. The neurobiological underpinnings are still poorly understood. Here we investigated a large sample of schizophrenia patients and matched healthy controls with an event-related fMRI task during emotion processing using emotional pictures from the International Affective Picture System (IAPS). Schizophrenia patients revealed stronger right amygdala activation during negative and attenuated response during positive affective picture processing compared to healthy controls. Further analysis indicated that medication status influences activation of the ventral anterior cingulate cortex during negative affective stimuli processing. These results might represent a correlate of altered emotional experience in schizophrenia patients who are known to report less positive and more negative affective states in daily life situations. © 2013 Elsevier B.V. All rights reserved.

1. Introduction Deficits in emotion processing are a key feature of the symptom spectrum in patients suffering from schizophrenia. In day-to-day life schizophrenia patients reported less positive and more negative emotional state and less pleasant events in their daily life compared to controls (Myin-Germeys et al., 2000; Oorschot et al., 2011). However, the neurobiological basis of affective disturbances in schizophrenia is still poorly understood. Functional imaging studies in schizophrenia patients described altered neuronal activation of areas relevant for emotion processing with a pivotal role of the amygdala (Phelps and Ledoux, 2005). However, findings have been inconsistent with studies reporting an amygdala hypoactivation (Schneider et al., 1998; Gur et al., 2002; Li et al., 2010; Taylor et al., 2012), an elevated amygdala activation (Kosaka et al., 2002; Rauch et al., 2010) or an absence of differences (Holt et al., 2005; Sachs et al., 2012). A recent meta-analysis (Anticevic et al., 2012) found a modest under-recruitment in the amygdala during negatively valenced emotional stimulation. Inconsistencies of imaging findings might be due to differences in task design (e.g. emotion discrimination or simply viewing emotional ⁎ Corresponding author at: Department of Psychiatry and Psychotherapy, Charité – Universitätsmedizin Berlin, Campus Mitte, Charitéplatz 1, 10117 Berlin, Germany. Tel.: +49 30 450 517159; fax: +49 30 450 517944. E-mail address: [email protected] (A. Pankow). 1 These authors contributed equally. 0920-9964/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.schres.2013.07.015

stimuli), the type of emotional stimuli (e.g. faces or pictures), clinical heterogeneity (e.g. symptom severity and medication status) as well as methodological differences in analysis strategies. Regarding task design, it has been shown that even simple cognitive tasks, such as a rating of affective valence, can alter mood induction and the underlying neural activation (Taylor et al., 2003). With respect to stimulus material, previous studies primarily used emotional faces (Kosaka et al., 2002; Hempel et al., 2003). However, it was suggested that neuronal responses elicited by face stimuli may be affected by inaccurate recognition and perception of facial expressions in schizophrenia patients (Kohler et al., 2010). In contrast to emotional faces the valence rating for stimuli from the International Affective Picture System (IAPS; Lang et al., 1999) are similar between schizophrenia patients and healthy controls (Herbener et al., 2008; Kring and Moran, 2008). Therefore, IAPS pictures may be well suited to investigate emotional processing in schizophrenia. Given these previous findings, we focused on emotion processing of positive, negative and neutral IAPS pictures in the absence of cognitive demands. We hypothesized altered neuronal activation during emotion processing in the amygdala. Therefore, we tested a valence-by-group interaction in order to assess the contribution of all three emotional conditions to different amygdala activation between schizophrenia patients and healthy controls. Furthermore, the influence of medication status was assessed by comparing unmedicated with medicated schizophrenia patients.

102

A. Pankow et al. / Schizophrenia Research 150 (2013) 101–106

2. Methods and material 2.1. Subjects We examined 35 patients with the diagnosis of schizophrenia according to ICD-10 and DSM IV (mean age: 31.1 ± 9.3 years) and no other comorbid axis I and II disorders according to ICD-10 and 36 healthy controls matched for age (mean age 33.4 ± 10.6 years), verbal IQ, and handedness. Patients were recruited from the inpatient and outpatient facilities of the Department of Psychiatry and Psychotherapy, Charité - Universitätsmedizin Berlin, Campus Mitte. Healthy control participants were recruited from the local community by advertisement. In all subjects, handedness was assessed with the Edinburgh Handedness Inventory, depression symptoms with Beck Depression Inventory (BDI), executive function with the Wisconsin Card Sorting Test (WCST) and verbal IQ with Word Sorting Task (WST) Severity of psychotic symptoms was measured with the Positive and Negative Syndrome Scale (PANSS) (Kay et al., 1987). 16 patients were unmedicated (mean age 28.9 ± 7.2 years) and 19 were medicated (mean age 32.9 ± 10.6 years) with antipsychotics (Table 1). Patients were drug-naïve or did not receive medication for at least 3 month. Healthy controls had no psychiatric axis I or II disorder (SCID I & II-interview). 2.2. fMRI data acquisition Imaging was performed on a 1.5 T Scanner (Magnetom VISION Siemens®) with an Echo Planar Imaging (EPI)-sequence (TR = 2300 ms, TE = 40 ms, flip = 90°, matrix = 64 × 64, voxel size 4 × 4 × 3.3 mm3). An anatomical 3D MPRAGE (Magnetization Prepared Rapid Gradient Echo, TR = 9.7 ms; TE = 4 ms; flip = 12°; matrix = 256 × 256, voxel size 1 × 1 × 1mm3) image data set was acquired. Head movement was minimized by using a vacuum pad. 2.3. fMRI paradigm We used an event-related design with affectively positive, negative and neutral stimuli (Friedel et al., 2009) from the International Affective Picture System (Lang et al., 1999). Subjects viewed 36

stimuli per category, presented for 2 seconds in random order. Half of the pictures were preceded by a cue indicating the valence of the upcoming picture and half of the pictures were preceded by a meaningless cue. A randomly jittered inter-trial interval (1.6–3 s) was used to sample the hemodynamic response at different time points. To keep participants engaged in the task, subjects had to confirm each viewed picture with a button press in order to assess reaction times without further cognitive demands. Valence and arousal were rated on a scale from 1 (unpleasant/low) to 9 (pleasant/high) after the MRI session. 2.4. fMRI data analysis Functional MRI data were analysed in SPM8 (www.fil.ion.ucl.ac. uk/spm). The first three volumes of each functional time series were discarded to remove non-steady-state effects caused by T1 saturation. The remaining images were corrected for differences in slice time acquisition, motion corrected (realigned to the mean volume), spatially normalised to the standard EPI template provided by the Montreal Neurological Institute (MNI template), and spatially smoothed with an 8 mm full-width at half-maximum (FWHM) Gaussian kernel. After preprocessing the data were analysed in the context of the General Linear Model (GLM) as implemented in SPM8 at two levels. On the first single subject level, the picture onsets were modelled separately for each valences (negative, positive or neutral) as well as the different cues as explanatory variables after convolution with the canonical hemodynamic response function. Realignment parameters were included as additional regressors to account for residual movement related variance. Individual contrast images for each picture condition contrasted against the overall mean were computed. The use of these “baseline contrasts” for each of the three picture types allowed us to test for a main effect of valence and a valence-by-group interaction using F contrasts in the context of a factorial ANOVA. The individual contrast images of all three picture conditions against the overall mean were subjected to a second-level random effects model using a flexible ANOVA design with group (healthy controls, medicated schizophrenia patients and unmedicated schizophrenia patients) and picture valence (positive, negative and neutral) as factors including subjects as

Table 1 Group description. Schizophrenia patients medicated (n = 19)

Schizophrenia patients unmedicated (n = 16)

Healthy controls (n = 36)

Sig.

Gender Age (years)

9 female, 10 male 32.9 ± 10.6 (19–50)

4 female, 12 male 28.9 ± 7.2 (18–43)

15 female, 21 male 33.4 ± 10.6 (18–57)

Edinburgh Handedness Inventory

89.8 ± 12 (67–100)

61.31 ± 64.1 (−92–100)

66.7 ± 68.9 (−100–100)

Verbal IQ (WST)

100.7 ± 15.8 (60–125)

107.4 ± 13.4 (81–125)

108.2 ± 11.7 (77–125)

Executive functions (WCST)

31.9 ± 16.5 (0–61)

22.9 ± 20.4 (0–56)

27.9 ± 21.4 (0–99)

BDI

15.1 ± 11 (3–47)

12 ± 8.6 (0–30)

3 ± 3.4 (0–14)

Age of onset (years)

25.3 ± 8.1 (9–42)

27.3 ± 7 (17–39)

–

Duration of illness (years)

7.4 ± 6.2 (0.1–19)

1.8 ± 2.2 (0–7)

–

CGI severity

4.7 ± 1 (3–6)

5.2 ± .7 (4–6)

–

PANSS positive

17 ± 8 (10–39)

22.3 ± 6.4 (13–33)

–

PANSS negative

23.4 ± 8 (7–37)

25.4 ± 7.4 (12–38)

–

PANSS general

39.1 ± 11.8 (22–59)

42.3 ± 10 (25–58)

–

PANSS total

79 ± 23.3 (46–129)

89.4 ± 20.5 (51–116)

–

χ2(2) = .373 F(2,68) = 1.196 p = .309 F(2,49) = 1.308 p = .280 F(2,63) = 1.942 p = .152 F(2, 53) = .657 p = .523 F(2, 58) = 16.873 p b .001 t(29) = .716 p = .479 t(31) = 3.275 p = 0.004 t(23) = 1.451 p = .16 t(32) = 2.107 p = .043 t(33) = .768 p = .448 t(31) = .834 p = .411 t(31) = 1.354 p = .186

A. Pankow et al. / Schizophrenia Research 150 (2013) 101–106

a random factor. The appropriate F-contrasts for the main effect of picture valence and for the group by valence interaction were assessed. Significant findings were followed with post-hoc t-test by extracting parameter estimates from areas showing a significant group by valence interaction. The differential contrasts ‘negative minus neutral pictures’ and ‘positive minus neutral pictures’ were used for separate correlation analyses with psychopathology. Given our a priori hypothesis of an involvement of the amygdala in emotional processing (Phan et al., 2002), correction for multiple testing was performed using the small volume approach with an amygdala VOI derived from the Pick Atlas (Lancaster et al., 2000; Maldjian et al., 2003) (http://www.fmri.wfubmc.edu) (left 68 voxels, right 86 voxels) at p b .05 FWE corrected. Outside the amygdala all results are reported at p b .05 FWE corrected for the whole brain. Explorative analysis comparing unmedicated schizophrenia patients vs. medicated patients are reported at p b .001 uncorrected with a cluster extent of 50 voxels. We correlated the individual maximum fMRI BOLD contrast (beta values) in the Amygdala (VOI) for the contrasts ‘negative minus neutral pictures’ and ‘positive minus neutral pictures’ with the PANSS and BDI using Spearman's linear correlation coefficient.

103

Testing for group differences, a significant group by valence interaction was found in the right amygdala ([20 − 6 −12], F = 7.22, p FWE corrected for amygdala VOI = 0.028) (Fig. 1A and B). This interaction was due to reduced activation in response to positive pictures and heightened response to negative pictures in patients with schizophrenia. Post-hoc t-tests were conducted using the beta values for positive, negative and neutral pictures at the coordinate of the observed group × valence interaction at (x = 20, y = −6, z = −12). Schizophrenia patients showed attenuated response to positive pictures (t (69) = 3.58, puncorrected = .001) and increased response to negative pictures (t (69) = 2.08, puncorrected = .041) compared to controls. Critically, neutral pictures did not differ significantly between controls and patients (p N .2). No significant correlations were found between PANSS scores and amygdala BOLD response for the contrast ‘negative minus neutral pictures’ (p N .2) and ‘positive minus neutral pictures’ (p N .9). Furthermore, there were no correlations between BDI score and amygdala activation for the contrasts ‘positive minus neutral pictures’ (p N .2) nor ‘negative minus neutral’ (p N .4). 3.3. Comparing unmedicated and medicated schizophrenia patients

2.5. Behavioural data analysis Ratings for valence and arousal (on a 9-point Likert scale) were analysed in separate repeated measures 2 × 3 ANOVA using the individual mean score of each picture type with affective valence (positive, negative and neutral) as intrasubject factor and group as intersubject factor using SPSS 18. Reaction time was analysed with a similar repeated measure ANOVA. Post-hoc t-tests were used to establish the direction of significant ANOVA results. 3. Results 3.1. Behavioural data Schizophrenia patients and controls rated the valence of the pictures in the expected direction (main effect of valence: F(1,61) = 260.417, p b .001) with highest valence ratings for positive and lowest for negative. There were no significant differences in valence ratings between patients and controls (main effect of group: F(1,48) = .514, p N .4; interaction valence by group: F(1,61) = .763, p N .4). For arousal ratings, we found a significant main effect of valence (F(2,96) = 76.081, p b .001) and a significant valence by group interaction (F(2,96) = 8.003, p = .002), but no main effect of group (F(1,48) = .377, p N .5). The interaction was due to higher arousal ratings of the neutral pictures in the schizophrenia group compared to controls (post-hoc t-test: t(50) = 3.642, p = .001), while no differences were found for negative and positive picture arousal ratings (p N .4) (Suppl. Fig. 1). Comparing unmedicated and medicated schizophrenia patients there was no significant difference regarding valence ratings (F(1,23) =.802, p N .3) and arousal ratings (F(1,23) = .081, p N .7) (Suppl. Table 1). We found a significant valence effect for reaction times (F(2,132) = 9.711, p b .001), with higher reaction times to negative pictures, compared to positive (t(67) = 3.774, p b .001) and neutral pictures (t(67) = 3.599, p = .001). There were no significant group effect (F(1,66) = .594, p N .4) and no group by valence interaction (F(2,132) = 1.617, p N .2). 3.2. fMRI Data All subjects taken together displayed a significant valence effect in the amygdala bilaterally (L: [−24 − 10 − 16], F = 10.89, pFWE corrected for amygdala VOI b 0.001; R: [24 − 10 −12], F = 15.19, pFWE corrected for amygdala VOI b 0.001). Outside the amygdala VOI, a network comprising the superior temporal gyrus and occipital cortex was activated (for whole brain activation see Supplementary Table 2).

We explored differences between unmedicated and medicated schizophrenia patients and found a significant difference in the perigenual ACC for the valence (positive, negative, neural) by group (medicated vs. unmedicated schizophrenia patients) interaction ([−2 44 −4], F = 10.80, p b .001 uncorrected, cluster extent 87) (Fig. 2A and B). Comparing the parameter estimates at the ACC peak coordinate revealed that this interaction was due to stronger activity during negative picture processing in medicated compared to unmedicated patients (t = 3.657, p b .001) (see also Suppl. Fig. 2). When comparing activation in the amygdala between unmedicated and medicated patients, no significant difference was observed (medication group by valence interaction: F(1, 33) b .9, p N .3). 4. Discussion In this study we found 1) a greater functional activation of the right amygdala during emotional processing of negative pictures and 2) a reduced amygdala activation during processing of positive affective pictures in schizophrenia patients compared to healthy control subjects. 3) Comparing medicated and unmedicated schizophrenia patients we observed a significant effect of medication status in the ventral anterior cingulate cortex (ACC), with higher activation to negative pictures in medicated patients. 4.1. Altered amygdala BOLD response Our finding of greater BOLD response in the right amygdala elicited by negative pictures in schizophrenia patients compared to controls conflicts with the notion of a general under-responsiveness of the amygdala (Anticevic et al., 2012; Taylor et al., 2012). Most previous imaging studies used facial stimuli, which have been shown to reliably activate the amygdala in healthy controls (Hariri et al., 2002). In schizophrenia patients deficits in perception of emotional facial expressions have been described (Kohler et al., 2010). Therefore, it could be speculated that these deficits in schizophrenia patients might influence amygdala activation (Herbener et al., 2008). Previous studies using similar stimulus material (IAPS) reported heterogeneous findings: Paradiso et al. (2003) reported decreased left amygdala cerebral blood flow (CBF) during valence attribution to negative affective pictures in unmedicated SZ compared to controls using [15O]H2O PET. Takahashi et al. (2004) reported a reduced activation in a distributed cortical and subcortical network including the right amygdala in medicated schizophrenia patients compared to controls using a fMRI block design. Besides these methodological differences (block design vs. event related design) in

104

A. Pankow et al. / Schizophrenia Research 150 (2013) 101–106

Fig. 1. Valence effect and group difference between schizophrenia patients and healthy controls in the amygdala during processing of emotional pictures. A: Displayed is the main effect of valence in green and group by valence interaction in red ([20 −6 −12], F = 7.22, p FWE corrected for amygdala VOI = 0.028) (both displayed at p b .001 uncorrected). B: Plot of parameter estimates in the peak voxel of the right amygdala. The boxes have lines at the lower, median, and upper quartile values. Single subject data are displayed as dots.

the latter study (Takahashi et al., 2004) participants were instructed to indicate by button press how each picture made them feel by categorising their subjective emotions into three emotional classes (neutral, unpleasant and pleasant) thus adding cognitive aspects to this emotional task. Given that even simple cognitive task demands can influence neural activation in emotion-associated brain regions (Taylor et al., 2003) this difference in task designs may account for the different findings. In line with our finding, a recent study reported that subjects at increased genetic risk of developing schizophrenia showed amygdala hyperactivity during emotion processing, which suggests aberrant functional activities within the neural circuitry of emotion processing are related to the genetic risk for developing schizophrenia (van Buuren et al., 2011). In a task specifically designed to address emotion and cognition interaction Ursu et al. (2011) found no significant differences in amygdala activation during emotional picture presentation but less activation of the dorsolateral prefrontal cortex during stimulus rating in schizophrenia patients. The latter finding fits in a model of disturbed top-down regulation in which the prefrontal cortex fails to regulate limbic activation (Phan et al., 2002; Ochsner and Gross, 2005; Phelps and Ledoux, 2005). It could be argued that our finding of differences in functional amygdala activation might also be due to a similar dysfunctional

prefrontal control mechanism regulating limbic activation. While the task of Ursu et al. (2011) incorporated a cognitive rating component, our task did not contain any cognitive demands which might influence amygdala activation (Taylor et al., 2003). Further studies should address the possible contributions of stimuli categorisation during scanning on neuronal activation in schizophrenia patients. We did not find medication effects in functional amygdala response to negative and positive affective pictures. Similar to our findings Taylor et al. (2005) did not find any medication effects on functional amygdala activation to affective pictures. Impaired dopamine function in limbic structures has been shown in schizophrenia patients (Heinz and Schlagenhauf, 2010). In healthy controls measures of amygdala dopamine correlated with higher functional activation towards aversive stimuli (Kienast et al., 2008). Therefore, future studies might address the contribution of limbic dopamine dysfunction in schizophrenia and functional activation during emotional processing. 4.2. Difference between medicated and unmedicated patients in the ACC Unmedicated schizophrenia patients displayed strong ventral anterior cingulate cortex activation in response to negative pictures

A. Pankow et al. / Schizophrenia Research 150 (2013) 101–106

105

2011). The valence rating used in our study might not represent subjective experience but rather a cognitive categorisation. However, while no significant differences with respect to the valence rating were found, schizophrenia patients in our study reported higher arousal to neutral pictures compared to healthy controls. Increased arousal may reflect aberrant salience attribution to otherwise neutral stimuli, which may contribute to delusional mood and hence delusion formation in schizophrenia (Heinz, 2002; Kapur, 2003; Pankow et al., 2012). 4.4. Conclusion Our results suggest increased neural response to negative affective stimuli in patients suffering from schizophrenia whereas the response to positive stimuli was found to be decreased. This supports the notion of a bias towards aversive emotion processing in schizophrenia patients and may point to deficits in emotional regulation (Ursu et al., 2011). Furthermore, differences in ACC activation between medicated and unmedicated patients suggest the possibility that antipsychotic medication influences emotion processing. Funding The work was supported by a grant from the German Research Foundation (DFG HE2597/4-3&7-3 to AH; DFG SCHL 1968/1-1 to FS) and by the German Ministry for Education and Research (BMBF 01QG87164 & 01GS08159).

Fig. 2. A: Comparing unmedicated and medicated schizophrenia patients the perigenual ACC was more strongly activated in medicated patients during processing of aversive pictures for the interaction valence by group ([−2 44 −4], F = 10.80, p b 0.001 uncorrected; displayed with a cluster extent N 30 voxels). B: Plot of parameter estimates in the peak voxel showing significant group differences only for negative picture processing with elevated response in medicated compared to unmedicated patients. The boxes have lines at the lower, median, and upper quartile values. Single subject data are displayed as dots.

compared to medicated patients. The ventral ACC is known to be involved in emotion processing and conflict monitoring. A reduced activation in the left ACC was observed in medicated patients with flat affect compared to those without flat affect during negative minus neutral IAPS pictures (Fahim et al., 2005). Our finding indicates that antipsychotic medication might bias ACC processing of affective cues toward aversive stimuli. This finding is limited by the cross sectional nature of our study and the heterogeneous medication state of the medicated schizophrenia group. 4.3. Valence and arousal ratings We observed no significant differences in valence ratings between schizophrenia patients and healthy controls. In line with our study previous results from behavioural and brain imaging studies also indicate that individuals with schizophrenia rate the valence of the pictures as similarly pleasant or unpleasant compared to individuals without schizophrenia (Hempel et al., 2005). Interestingly, a recent meta-analysis found that schizophrenia patients do not show differences in negative valence ratings, but an aversive bias concerning positive and neutral picture ratings compared to controls (Cohen and Minor, 2010). Therefore it has been proposed that the “in-the-moment” experience of emotion might be spared in schizophrenia (Herbener et al., 2008), which would be supported by the absent group differences in valence ratings in our study. On the other hand, schizophrenia patients are known to experience more negative mood states especially anxiety compared to controls during everyday life (Suslow et al., 2003). Indeed, schizophrenia subjects experience more intense negative and less intense positive emotions than healthy subjects using a structured time-sampling technique during daily life (Myin-Germeys et al., 2000). These heterogeneous findings indicate that valence ratings are strongly influenced by the applied methodological approach (Strauss et al.,

Contributors Anne Pankow, Eva Friedel, Philipp Sterzer, Nina Seiferth, Henrik Walter, Andreas Heinz, Florian Schlagenhauf. Conflict of interest The Authors have declared that there are no conflicts of interest in relation to the subject of this study. Acknowledgments We thank Anne Beck, Meline Stoy, and Michael Koslowski for their help during data acquisition and Torsten Wüstenberg for his special support.

Appendix A. Supplementary data Supplementary data to this article can be found online at http:// dx.doi.org/10.1016/j.schres.2013.07.015. References Anticevic, A., Van Snellenberg, J.X., Cohen, R.E., Repovs, G., Dowd, E.C., Barch, D.M., 2012. Amygdala recruitment in schizophrenia in response to aversive emotional material: a meta-analysis of neuroimaging studies. Schizophr. Bull. 38, 608–621. Cohen, A.S., Minor, K.S., 2010. Emotional experience in patients with schizophrenia revisited: meta-analysis of laboratory studies. Schizophr. Bull. 36, 143–150. Fahim, C., Stip, E., Mancini-Marie, A., Mensour, B., Boulay, L.J., Leroux, J.M., Beaudoin, G., Bourgouin, P., Beauregard, M., 2005. Brain activity during emotionally negative pictures in schizophrenia with and without flat affect: an fMRI study. Psychiatry Res. 140, 1–15. Friedel, E., Schlagenhauf, F., Sterzer, P., Park, S.Q., Bermpohl, F., Strohle, A., Stoy, M., Puls, I., Hagele, C., Wrase, J., Buchel, C., Heinz, A., 2009. 5-HTT genotype effect on prefrontalamygdala coupling differs between major depression and controls. Psychopharmacology (Berl) 205, 261–271. 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. Am. J. Psychiatry 159, 1992–1999. Hariri, A.R., Tessitore, A., Mattay, V.S., Fera, F., Weinberger, D.R., 2002. The amygdala response to emotional stimuli: a comparison of faces and scenes. NeuroImage 17, 317–323. Heinz, A., 2002. Dopaminergic dysfunction in alcoholism and schizophrenia– psychopathological and behavioral correlates. Eur. Psychiatry 17, 9–16. Heinz, A., Schlagenhauf, F., 2010. Dopaminergic dysfunction in schizophrenia: salience attribution revisited. Schizophr. Bull. 36, 472–485. Hempel, A., Hempel, E., Schonknecht, P., Stippich, C., Schroder, J., 2003. Impairment in basal limbic function in schizophrenia during affect recognition. Psychiatry Res. 122, 115–124. Hempel, R.J., Tulen, J.H., van Beveren, N.J., van Steenis, H.G., Mulder, P.G., Hengeveld, M.W., 2005. Physiological responsivity to emotional pictures in schizophrenia. J. Psychiatr. Res. 39, 509–518. Herbener, E.S., Song, W., Khine, T.T., Sweeney, J.A., 2008. What aspects of emotional functioning are impaired in schizophrenia? Schizophr. Res. 98, 239–246.

106

A. Pankow et al. / Schizophrenia Research 150 (2013) 101–106

Holt, D.J., Weiss, A.P., Rauch, S.L., Wright, C.I., Zalesak, M., Goff, D.C., Ditman, T., Welsh, R.C., Heckers, S., 2005. Sustained activation of the hippocampus in response to fearful faces in schizophrenia. Biol. Psychiatry 57, 1011–1019. Kapur, S., 2003. Psychosis as a state of aberrant salience: a framework linking biology, phenomenology, and pharmacology in schizophrenia. Am. J. Psychiatry 160, 13–23. Kay, S.R., Fiszbein, A., Opler, L.A., 1987. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr. Bull. 13, 261–276. Kienast, T., Hariri, A.R., Schlagenhauf, F., Wrase, J., Sterzer, P., Buchholz, H.G., Smolka, M.N., Grunder, G., Cumming, P., Kumakura, Y., Bartenstein, P., Dolan, R.J., Heinz, A., 2008. Dopamine in amygdala gates limbic processing of aversive stimuli in humans. Nat. Neurosci. 11, 1381–1382. Kohler, C.G., Walker, J.B., Martin, E.A., Healey, K.M., Moberg, P.J., 2010. Facial emotion perception in schizophrenia: a meta-analytic review. Schizophr. Bull. 36, 1009–1019. Kosaka, H., Omori, M., Murata, T., Iidaka, T., Yamada, H., Okada, T., Takahashi, T., Sadato, N., Itoh, H., Yonekura, Y., Wada, Y., 2002. Differential amygdala response during facial recognition in patients with schizophrenia: an fMRI study. Schizophr. Res. 57, 87–95. Kring, A.M., Moran, E.K., 2008. Emotional response deficits in schizophrenia: insights from affective science. Schizophr. Bull. 34, 819–834. Lancaster, J.L., Woldorff, M.G., Parsons, L.M., Liotti, M., Freitas, C.S., Rainey, L., Kochunov, P.V., Nickerson, D., Mikiten, S.A., Fox, P.T., 2000. Automated Talairach atlas labels for functional brain mapping. Hum. Brain Mapp. 10, 120–131. Lang, P.J., Bradley, M.M., Cuthbert, B.N., 1999. International Affective Picture System (IAPS): Instruction Manual and Affective ratings. University of Florida, Gainesville, Florida. Li, H., Chan, R.C., McAlonan, G.M., Gong, Q.Y., 2010. Facial emotion processing in schizophrenia: a meta-analysis of functional neuroimaging data. Schizophr. Bull. 36, 1029–1039. Maldjian, J.A., Laurienti, P.J., Kraft, R.A., Burdette, J.H., 2003. An automated method for neuroanatomic and cytoarchitectonic atlas-based interrogation of fMRI data sets. NeuroImage 19, 1233–1239. Myin-Germeys, I., Delespaul, P.A., DeVries, M.W., 2000. Schizophrenia patients are more emotionally active than is assumed based on their behavior. Schizophr. Bull. 26, 847–854. Ochsner, K.N., Gross, J.J., 2005. The cognitive control of emotion. Trends Cogn. Sci. 9, 242–249. Oorschot, M., Thewissen, V., van Os, J., Myin-Germeys, I., 2011. Remission in schizophrenia – how the symptomatic remission criterion is reflected in daily life. Schizophr. Bull. 37, 276. Pankow, A., Knobel, A., Voss, M., Heinz, A., 2012. Neurobiological correlates of delusion: beyond the salience attribution hypothesis. Neuropsychobiology 66, 33–43. Paradiso, S., Andreasen, N.C., Crespo-Facorro, B., O'Leary, D.S., Watkins, G.L., Boles Ponto, L.L., Hichwa, R.D., 2003. Emotions in unmedicated patients with schizophre-

nia during evaluation with positron emission tomography. Am. J. Psychiatry 160, 1775–1783. Phan, K.L., Wager, T., Taylor, S.F., Liberzon, I., 2002. Functional neuroanatomy of emotion: a meta-analysis of emotion activation studies in PET and fMRI. NeuroImage 16, 331–348. Phelps, E.A., Ledoux, J.E., 2005. Contributions of the amygdala to emotion processing: from animal models to human behavior. Neuron 48, 175–187. Rauch, A.V., Reker, M., Ohrmann, P., Pedersen, A., Bauer, J., Dannlowski, U., Harding, L., Koelkebeck, K., Konrad, C., Kugel, H., Arolt, V., Heindel, W., Suslow, T., 2010. Increased amygdala activation during automatic processing of facial emotion in schizophrenia. Psychiatry Res. 182, 200–206. Sachs, G., Moser, E., Katschnig, H., Gur, R.C., Gur, R.E., Erfurth, A., 2012. No amygdala attenuation in schizophrenic patients treated with atypical antipsychotics. Psychiatry Res. 202, 168–171. Schneider, F., Weiss, U., Kessler, C., Salloum, J.B., Posse, S., Grodd, W., Muller-Gartner, H.W., 1998. Differential amygdala activation in schizophrenia during sadness. Schizophr. Res. 34, 133–142. Strauss, G.P., Robinson, B.M., Waltz, J.A., Frank, M.J., Kasanova, Z., Herbener, E.S., Gold, J.M., 2011. Patients with schizophrenia demonstrate inconsistent preference judgments for affective and nonaffective stimuli. Schizophr. Bull. 37, 1295–1304. Suslow, T., Roestel, C., Ohrmann, P., Arolt, V., 2003. The experience of basic emotions in schizophrenia with and without affective negative symptoms. Compr. Psychiatry 44, 303–310. Takahashi, H., Koeda, M., Oda, K., Matsuda, T., Matsushima, E., Matsuura, M., Asai, K., Okubo, Y., 2004. An fMRI study of differential neural response to affective pictures in schizophrenia. NeuroImage 22, 1247–1254. Taylor, S.F., Phan, K.L., Decker, L.R., Liberzon, I., 2003. Subjective rating of emotionally salient stimuli modulates neural activity. NeuroImage 18, 650–659. Taylor, S.F., Phan, K.L., Britton, J.C., Liberzon, I., 2005. Neural response to emotional salience in schizophrenia. Neuropsychopharmacology 30, 984–995. Taylor, S.F., Kang, J., Brege, I.S., Tso, I.F., Hosanagar, A., Johnson, T.D., 2012. Meta-analysis of functional neuroimaging studies of emotion perception and experience in schizophrenia. Biol. Psychiatry 71, 136–145. Ursu, S., Kring, A.M., Gard, M.G., Minzenberg, M.J., Yoon, J.H., Ragland, J.D., Solomon, M., Carter, C.S., 2011. Prefrontal cortical deficits and impaired cognition–emotion interactions in schizophrenia. Am. J. Psychiatry 168, 276–285. van Buuren, M., Vink, M., Rapcencu, A.E., Kahn, R.S., 2011. Exaggerated brain activation during emotion processing in unaffected siblings of patients with schizophrenia. Biol. Psychiatry 70, 81–87.