- Email: [email protected]
Increased amygdala activation during automatic processing of facial emotion in schizophrenia
Psychiatry Research: Neuroimaging 182 (2010) 200–206
Contents lists available at ScienceDirect
Psychiatry Research: Neuroimaging j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / p s yc h r e s n s
Increased amygdala activation during automatic processing of facial emotion in schizophrenia Astrid Veronika Raucha,c,⁎,1, Maraike Rekera,1, Patricia Ohrmanna, Anya Pedersena, Jochen Bauera, Udo Dannlowskia,c, Liv Hardinga, Katja Koelkebecka, Carsten Konradc,d, Harald Kugelb, Volker Arolta, Walter Heindelb, Thomas Suslowa,⁎ a
Department of Psychiatry, School of Medicine, University of Muenster, Albert-Schweitzer-Str. 11, 48149 Muenster, Germany Department of Clinical Radiology, School of Medicine, University of Muenster, Albert-Schweitzer-Str. 33, 48149 Muenster, Germany c IZKF-Research Group 4, IZKF Muenster, University of Muenster, Domagkstr.3, 48149 Muenster, Germany d Department of Psychiatry, School of Medicine, University of Marburg, Rudolf-Bultmann-Str. 8, 35039 Marburg, Germany b
a r t i c l e
i n f o
Article history: Received 5 June 2008 Received in revised form 17 February 2010 Accepted 11 March 2010 Keywords: fMRI Automatic emotion processing Limbic system Psychopathology Neuroimaging
a b s t r a c t Schizophrenia patients show abnormalities in the processing of facial emotion. The amygdala is a central part of a brain network that is involved in the perception of facial emotions. Previous functional neuroimaging studies on the perception of facial emotion in schizophrenia have focused almost exclusively on controlled processing. In the present study, we investigated the automatic responsivity of the amygdala to emotional faces in schizophrenia and its relationship to clinical symptomatology by applying an affective priming task. 3-T fMRI was utilized to examine amygdala responses to sad and happy faces masked by neutral faces in 12 schizophrenia patients and 12 healthy controls. The Positive and Negative Syndrome Scale (PANSS) was administered to assess current symptomatology. Schizophrenia patients exhibited greater automatic amygdala responses to sad and happy faces relative to controls. Amygdala responses to masked sad and happy expressions were positively correlated with the negative subscale of the PANSS. Schizophrenia patients appear to be characterized by amygdalar hyperresponsiveness to negative and positive facial expressions on an automatic processing level. Heightened automatic amygdala responsivity could be involved in the development and maintenance of negative symptoms in schizophrenia. © 2010 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Patients suffering from schizophrenia show impairments in the perception of facial expressions of emotions (Schneider et al., 1998; Phillips et al., 1999; Holt et al., 2006; Das et al., 2007). Since facial expressions serve as important social signals of imminent environmental conditions, it is not surprising that dysfunction in emotion recognition has been found to be a key determinant for psychosocial outcomes in schizophrenia patients (Kee et al., 2003). Functional neuroimaging and lesion studies have identified the amygdala as a central component of a subcortical–cortical network that is involved in the perception of facial emotions (Adolphs et al., 1999; Kesler-West et al., 2001; Phillips et al., 2004; Sato et al., 2004) and in generating negative emotional experiences (Abercrombie et al.,
⁎ Corresponding authors. Department of Psychiatry, University of Muenster, AlbertSchweitzer-Str. 11, 48149 Muenster, Germany. Tel.: +49 251 8356601; fax: +49 251 8356612. E-mail addresses: [email protected] (A.V. Rauch), [email protected] (T. Suslow). 1 This is to indicate that Astrid Veronika Rauch and Maraike Reker contributed equally to this work and should, therefore, both be considered first authors. 0925-4927/$ – see front matter © 2010 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.pscychresns.2010.03.005
1998; Schaefer et al., 2002). There is evidence that the amygdala plays a crucial role in processing fearful faces (Morris et al., 1998a), but it is also involved in the perception of the facial expressions of other negative emotions, such as anger and sadness (Wang et al., 2005; Fitzgerald et al., 2006). The amygdala may even be involved in the perception of faces expressing positive emotions (Breiter et al., 1996; Yang et al., 2002). Results from experiments in which facial expression was presented subliminally consistently suggest an automatic activation of the amygdala in response to consciously imperceptible emotional faces (Morris et al., 1998b, 1999; Whalen et al., 1998; Liddell et al., 2005). It has been argued that the thalamoamygdaloid pathway allows a very rapid evaluation of incoming stimuli, which can trigger immediate adaptive (behavioral and autonomic) responses of the organism without requiring controlled information processing (LeDoux, 1998). In a number of neuroimaging studies examining controlled emotion processing, lowered or failed activation of the amygdala was observed in schizophrenia patients compared with healthy subjects (Schneider et al., 1998; Phillips et al., 1999; Gur et al., 2002; Taylor et al., 2002; Hempel et al., 2003; Paradiso et al., 2003; Takahashi et al., 2004; Williams et al., 2004; Johnston et al., 2005; Das et al., 2007; Williams et al., 2007). However, the findings of Kosaka et al. (2002)
A.V. Rauch et al. / Psychiatry Research: Neuroimaging 182 (2010) 200–206
indicate heightened amygdala activation during controlled emotion processing in schizophrenia. Similarly, Holt et al. (2006) found that schizophrenia patients exhibit greater amygdala activation relative to control subjects during first encounters with fearful and neutral faces (within an experiment). Discrepancies among previous results appear to be due to differences in the applied emotion tasks and methods of data analysis (e.g., baseline condition, type of experimental design (block or event-related)). Gur et al. (2007) used an event-related analysis to reveal that the amygdala response to fearful faces in schizophrenia patients was associated with impaired emotional identification and strongly correlated with flat affect expression. Evidence from psychological research indicates that the reduced facial expressiveness of schizophrenia patients does not necessarily reflect a diminished subjective experience of emotion, but instead could be due to selective impairments in the expression of emotions (Berenbaum and Oltmanns, 1992; Kring et al., 1993; Kring and Neale, 1996). However, schizophrenia patients' flat affect expression could also represent an attempt to control and downregulate the intensity of their own emotional experience (Flack et al., 1998) and could disturb, or even disrupt, interpersonal communication (Krause et al., 1992). In everyday life, schizophrenia patients experience more negative emotions (fear in particular) than healthy individuals (Myin-Germeys et al., 2000; Suslow et al., 2003b). Based on the latter observation, it could be expected that schizophrenia patients manifest stronger amygdala responses to emotion-eliciting stimuli than do healthy individuals. Taylor et al. (2002) reported a significant positive correlation between amygdala activity and positive symptoms, which is consistent with the neurobiological theory that the amygdala might drive positive symptoms (Moore et al., 1999). Amygdala activity could directly cause positive symptoms such as hostility, suspiciousness, and excitement. Few studies have investigated automatic emotion processing in schizophrenia. A robust phenomenon of automatic emotion processing is the emotion-congruent influence of facial expressions shown below conscious awareness on subsequent judgments regarding neutral stimuli (Niedenthal, 1990; Murphy and Zajonc, 1993; Rotteveel et al., 2001). That is, subliminally presented angry faces, for example, bias judgments of neutral (mask) stimuli in a negative direction compared to neutral primes. It is assumed that the amygdala could be crucially involved in negative affective priming effects (Winkielman et al., 2007). In a sample of healthy subjects, amygdala responses to masked negative faces were correlated with automatic negative evaluation shifts elicited by negative facial expression in an affective priming experiment (Dannlowski et al., 2007). Using behavioral affective priming tasks, it was shown that schizophrenia patients exhibit a heightened perceptual sensitivity to negative facial emotion and a lowered sensitivity to positive faces on an automatic processing level (Höschel and Irle, 2001). Thus far, only one fMRI study has investigated automatic emotion processing in schizophrenia (Das et al., 2007). Patients showed an impaired connectivity between components of the subcortical and cortical amygdala pathways during different levels of awareness (conscious and nonconscious perception of fear). A major limitation of Das et al.'s study was the fact that, prior to the experiment, subjects were informed about the presence of masked facial expression. Since it is widely accepted that emotions are generally involuntarily elicited (Bargh and Chartrand, 1999), the investigation of automatic response characteristics is of special interest for the understanding of normal and abnormal emotional reactions and cognitive biases. In this study, 3-T fMRI was used to investigate automatic amygdalar responsivity to facial emotions in schizophrenia patients compared to healthy individuals. To this aim, an affective priming experiment was applied in which happy, sad, and neutral facial expressions were masked by neutral faces in order to block participants' conscious recognition. Measures of subjective and
201
objective awareness of facial emotion were administered. We hypothesized that schizophrenia patients would demonstrate enhanced amygdala activation to masked sad and masked happy faces. Our previous behavioral affective priming study (Suslow et al., 2003a) was also based on sad and happy facial expressions. Expressions of sadness and happiness signal both an invitation for social interaction and approach. Happy expressions are invitations for the perceiver to approach the expresser. Sadness is a signal that the expresser needs to be cared for (Knutson, 1996). The investigation of responsivity to approach-related interpersonal signals is of special interest in schizophrenia since many patients are socially isolated and withdrawn (Müller et al., 1998; Salokangas et al., 2001). We conducted an explorative analysis of the correlations between automatic amygdala responses to facial emotion and clinical symptomatology in schizophrenia patients. We expected to find positive correlations of schizophrenia patients' amygdala responsivity and masked emotional expression with the extent of negative and positive symptoms.
2. Methods 2.1. Subjects Participants comprised 12 schizophrenia patients and 12 healthy control subjects. Demographic and clinical characteristics of study participants are listed in Table 1. Patients were recruited from the inpatient service of the University of Muenster's Department of Psychiatry. Diagnoses were determined using the German version of the Structured Clinical Interview for DSM-IV (Wittchen et al., 1997). Controls were screened for a previous history of Axis I disorder via the same interview. They were excluded if they met the criteria for an Axis I disorder. Exclusion criteria for both groups were psychiatric comorbidity (DSM-IV), left handedness, exposure to electroconvulsive therapy (ECT), abnormal vision, past history of substance dependence, and neurological disorder. Handedness was defined by the Handedness Questionnaire (Raczkowski et al., 1974). Patients' psychopathological status was assessed by an experienced clinical investigator using the German version of the Positive and Negative Syndrome Scale (Kay et al., 1987). The Beck Depression Inventory (Beck and Steer, 1987; Hautzinger et al., 1995) and the State-Trait Anxiety Inventory (Spielberger et al., 1970; Laux et al., 1981) were administered to measure state depressivity and trait anxiety, respectively. All schizophrenia patients were receiving neuroleptic treatment. Five patients received only one atypical neuroleptic medication, four patients received a combination of two atypical
Table 1 Demographic and clinical characteristics of study participants. Characteristics
Gender (female/male) Age (years) Neuroleptic dosage (mg)a PANSS Positive scoreb PANSS Negative score c PANSS General score d BDI score e STAI-T score f
Schizophrenia patients
Control subjects
(N = 12)
(N = 12)
3/9 27.7 (7.5) 902.1 (603.2) 14.4 (3.1) 18.9 (5.2) 34.9 (5.9) 17.2 (8.6) 50.4 (9.7)
5/7 26.9 (6.1)
0.9 (1.1) 31.6 (6.8)
Values are presented as means (with standard deviations in parentheses) or frequencies. a CPZ equivalent dose (Riederer et al., 1998; Laux and Ditmaier, 2006). b Positive subscale score of the Positive and Negative Syndrome Scale. c Negative subscale score of the Positive and Negative Syndrome Scale. d General psychopathology subscale score of the Positive and Negative Syndrome Scale. e Beck Depression Inventory sum score. f State-Trait-Anxiety Inventory sum score (trait form).
202
A.V. Rauch et al. / Psychiatry Research: Neuroimaging 182 (2010) 200–206
neuroleptic medications, and three patients were treated with a combination of atypical and typical medication. All subjects gave informed, written consent to participate in the study, which was approved by the institutional ethics committee according to The Code of Ethics of the World Medical Association (Declaration of Helsinki) for experiments involving humans. Controls received 20 € after their participation in the fMRI experiment. 2.2. Stimulus materials and procedure Participants viewed grey-scale normalized face stimuli that were selected from a standardized picture set (Ekman and Friesen, 1976) containing five female and five male individuals with sad, happy, neutral, and erased facial expressions. In the erased condition, neutral faces were shown without central facial features (i.e., eyes, nose, and mouth), which had been replaced by a surface without contours. A fixation cross of 800 ms preceded the facial emotion stimuli, which were presented for 33 ms and followed immediately by a 467 ms neutral expression and a black screen. The duration of each trial was 9 s. The overall presentation time was 12 min. The subjects were instructed to view a series of faces. They were asked to evaluate the briefly shown neutral (mask) face on a 4-point scale and were not informed about the presence of a prime stimulus. Immediately after presentation of the mask face, a blank screen was shown for 7.700 ms. During this time period participants rated the mask face as expressing rather negative (−0.5, −1.5) or rather positive (+ 0.5, +1.5) feelings by pressing a button. Two fixed random orders were presented. One-half of the samples gave positive responses with the left hand while the other half used the right hand for positive responses. The experiment was programmed using the software package Inquisit (2007). The type of evaluative responses and reaction latencies was registered. Face stimuli were presented via a projector (Sharp XG-PC10XE with additional HF shielding). The head position was stabilized with a vacuum head cushion. To determine the success of masking emotional faces, subjects were questioned after the fMRI experiment as to whether they had noticed anything out of the ordinary and whether they had seen anything just before the neutral faces. In addition, a detection task was administered to assess objective awareness of the facial emotions shown in the fMRI experiment (see Section 2.5). None of the participants reported noticing sad or happy facial expressions (before the neutral faces). 2.3. fMRI acquisition T2⁎ functional data were acquired with a 3-Tesla scanner (Gyroscan Intera 3 T, Philips Medical Systems, Best, NL) using a single-shot gradient-echo EPI sequence with parameters selected to minimize distortion while retaining adequate signal to noise ratio and T2⁎ sensitivity (according to suggestions made by Robinson et al. (2004)). 40 axial slices were acquired (matrix 642, resolution 3.5 mm × 3.5 mm× 3.5 mm; TR= 3 s, TE = 35 ms, α = 90°). In addition, to display morphology with high resolution, a T1-weighted 3D sequence (multishot non-equilibrium gradient-echo sequence with preceding inversion recovery pulse, (‘Turbo Field Echo’-sequence, TFE) was applied to acquire isotropic voxels of 0.5 mm edge length of the whole head (TR = 7.6 s, TE= 3.5 ms, FA= 9°, TR(IR)= 832 ms, TI= 437 ms, reconstructed matrix 512 × 408 × 320, fh× ap× lr). 2.4. fMRI analyses Functional imaging data were analyzed using Statistical Parametric Mapping (SPM2, Wellcome Department of Imaging Neuroscience, London, UK). Images were motion corrected (using a set of six rigid body transformations determined for each image), spatially normalized to standard MNI space (Montreal Neurological Institute), and
smoothed (Gaussian kernel, 6 mm full width at half-maximum). Statistical analysis was performed by modeling the different conditions (sad, happy, neutral, and erased) as variables within the context of the general linear model (convolved with a standard hemodynamic response function). The amygdala (Tzourio-Mazoyer et al., 2002) was selected as the a priori region of interest (ROI) using the WFU Pickatlas (Maldjian et al., 2003). The hippocampus was chosen as the subcortical control region. The hippocampus is not primarily involved in the subliminal perception of emotion stimuli. Consistent with previous studies using nonconscious emotion stimuli (e.g., Killgore and Yurgelun-Todd, 2004; Das et al., 2007), ROI analyses were conducted with significance levels set at P b 0.05 (corrected for search volume) and clusters defined by at least 10 contiguous voxels of significant response. Relations between amygdala activation during processing of masked facial emotion and clinical symptoms were evaluated using simple regression as implemented in SPM2. This was done to test the null hypothesis that the variable b in the linear regression model equals 0 (with y = a + bx; where y is the value of the contrast and x for example the PANSS subscale score). Voxels within the whole amygdala were correlated with clinical and priming variables. In addition, mean activation of the left and right amygdala in response to masked emotional faces as compared with masked neutral faces was correlated with clinical symptoms and priming scores (using Spearman's Rho (rs), two-tailed). In the second analysis, voxel values of the whole amygdala were extracted, summarized by mean (separately for the left and right amygdala), and tested among the different conditions using the MarsBaR toolbox (TzourioMazoyer et al., 2002). By focusing the analyses on the contrast emotional faces vs. neutral faces, the effect of emotionality in facial expression on brain activity could be determined and related to actual clinical symptomatology. 2.5. Detection task A detection task was designed to assess objective awareness of the facial emotions shown in the fMRI experiment. After the fMRI session, a detection task based on the facial stimuli applied in the fMRI experiment was administered outside of the scanner on a microcomputer in a quiet room free of auditory and visual distractions. Each of the 40 trials consisted of the following routine: After a fixation cross appeared for 800 ms, a prime face was presented for 33 ms and was directly followed by a neutral target face for 467 ms. Each prime expression (sad, happy, and neutral) and the no-facial expression control condition (erased) was presented 10 times in a fixed random order. Participants were instructed to indicate which of the four conditions was briefly displayed as prime. The chance level for correct answers was 25%. 3. Results 3.1. Detection task The mean hit rate for masked sad faces was 29.2% (SD: 21.5%) for schizophrenia patients and 20.8% (SD: 11.6%) for control subjects, which reflects near or below chance levels of performance. The mean false alarm rate for masked sad faces was 25.8% (SD: 14.6%) for schizophrenia patients and 18.6% (SD: 16.3%) for control subjects. The mean hit rate for masked happy faces was 28.3% (SD: 19.4%) in the schizophrenia group and 37.5% (SD: 33.3%) in the control group. Control subjects' detection rate for happy faces was not statistically different from chance level of performance (one sample t-test, p N .22). The mean false alarm rate for masked happy faces was 20.8% (SD: 10.4%) for schizophrenia patients and 14.7% (SD: 8.8%) for control subjects. Hit rate for masked neutral faces was 48.3% (SD: 15.3%) in the schizophrenia group and 50.0% (SD: 20.0%) in the control group. For neutral faces, the false alarm rate was 37.8% (SD: 13.5) for
A.V. Rauch et al. / Psychiatry Research: Neuroimaging 182 (2010) 200–206
schizophrenia patients and 42.8% (SD: 25.4) for control subjects, indicating that both groups frequently tended to erroneously choose the neutral expression condition as a response. Finally, to assess recognition accuracy of the study groups, we used a composite measure that was calculated as hit rate minus false alarm rate (i.e., corrected hit probability). In the schizophrenia group, corrected hit probabilities were 0.03 (SD: 0.12) for sad faces, 0.08 (SD: 0.17) for happy faces, and 0.11 (SD: 0.19) for neutral faces. In the control group, corrected hit probabilities were 0.02 (SD: 0.16) for sad faces, 0.22 (SD: 0.28) for happy faces, and 0.07 (SD: 0.12) for neutral faces. There were no significant differences between study groups in detection performance (hit rate, false alarm rate, or corrected hit probability) for sad, happy, and neutral faces (Ps N 0.13). 3.2. Behavioral data: evaluative ratings and affective priming scores For schizophrenia patients, mean evaluative ratings were −0.08 (SD: 0.27) for sad faces, −0.10 (SD: 0.29) for happy faces, −0.03 (SD: 0.30) for neutral faces, and −0.04 (SD: 0.24) for the no-prime condition. Healthy subjects' mean evaluative scores were 0.05 (SD: 0.27) for sad faces, 0.05 (SD: 0.23) for happy faces, 0.01 (SD: 0.26) for neutral faces, and −0.03 (SD: 0.21) for the no-prime condition. To examine whether evaluative ratings in the fMRI experiment differed as a function of group and prime condition, ANOVAs with one between-subject factor (group) and one within-subject factor (prime condition: sad prime, happy prime, neutral prime, no-face) were calculated. No significant main effect of prime condition (F (3,20) = 0.17, P = 0.91) or group (F (1,22) = 0.77, P = 0.39) was found, and no interaction effect of group and prime condition on evaluative ratings was observed (F (3,20) = 1.83, P = 0.17). Two affective priming scores were calculated on the basis of subjects' mean evaluative ratings. The affective priming score for happy faces was calculated by subtracting the mean evaluation score for neutral faces from the mean evaluation score for happy faces. Affective priming for sad faces was determined by subtracting the mean evaluation score for sad faces from the mean evaluation score for neutral faces. Thus, positive scores in both cases indicate prime valence congruent affective priming. Neither the affective priming score for happy faces (−0.013, S.D. = 0.17) nor the affective priming score for sad faces (0.003, S.D. = 0.19) were significantly different from zero, as indicated by the results of the one-sample t-tests (Ps N 0.05). 3.3. fMRI results 3.3.1. Automatic response of the amygdala and the hippocampus to facial expression: between-group comparison Comparisons between the two study groups revealed greater activation in the left amygdala for schizophrenia patients relative to controls for the happy versus neutral, sad versus neutral, and sad versus erased contrasts. In addition, greater right amygdala responses to sad faces (compared to neutral and erased faces) and to happy faces (compared with erased faces) were observed in schizophrenia patients relative to controls (see Table 2 and Fig. 1 for details). When compared to schizophrenia patients, control subjects did not show stronger amygdala activation to masked emotional faces compared to masked neutral or masked erased faces. However, control subjects exhibited greater amygdala activation than patients to neutral faces compared to erased faces (see Table 2). The between-group comparison of activation in the subcortical control region of the hippocampus in response to masked emotional faces revealed a result pattern that was markedly different from that in the amygdala. Schizophrenia patients exhibited stronger hippocampal responses to masked sad faces compared to neutral faces (peak voxel xyz, 30, −7, − 22 (Talairach coordinates), cluster size: 23, Z-score = 2.49, P b 0.01), but they did not demonstrate stronger hippocampal responses to masked sad faces compared with erased
203
Table 2 Differences between schizophrenia patients and control subjects in automatic amygdala response to sad and happy facial expressions compared with neutral and erased faces. Emotion condition
Sad N neutral
Happy N neutral Sad N erased
Happy N erased Neutral N erased
Talairach coordinates x
y
z
− 28 34 – − 18 – − 26 34 – 34 – – − 16
−5 −3 – −3 – −5 −3 – −3 – – −7
− 13 − 23 – − 15 – − 15 − 23 – − 23 – – − 15
Size
Zscore
P value
Direction of difference
22 32 – 14 – 25 22 – 15 – – 14
2.21 2.31 – 2.28 – 2.46 2.82 – 2.78 – – 2.29
0.014 0.010 – 0.011 – 0.007 0.002 – 0.003 – – 0.011
Schizophrenia N control Schizophrenia N control Control N schizophrenia Schizophrenia N control Control N schizophrenia Schizophrenia N control Schizophrenia N control Control N schizophrenia Schizophrenia N control Control N schizophrenia Schizophrenia N control Control N schizophrenia
Note: coordinates of the maximal point of activation and the associated Z-values are shown. The activations in the amygdala (a priori region of interest) are significant at P b 0.05 (corrected for search volume); cluster threshold size of 10.
faces when compared with controls. Control subjects instead exhibited greater hippocampal activation to masked sad faces compared to erased faces than did patients (peak voxel xyz, 32, − 37, 2 (Talairach coordinates), cluster size: 33, Z-score = 2.68, P b 0.01; peak voxel xyz, −24, −15, −19, cluster size: 14, Z-score = 2.36, P b 0.01; peak voxel xyz, − 32, − 37, −2, cluster size: 10, Z-score: 2.25, P b 0.05; and peak voxel xyz, −34, −26, −9, cluster size: 12, Z-score: 1.91, P b 0.05). Furthermore, schizophrenia patients exhibited stronger responses in parts of the hippocampus to masked happy faces compared to neutral faces (peak voxel xyz, 20, −16, −13 (Talairach coordinates), cluster size: 16, Z-score = 2.83, P b 0.01). Yet, when compared with controls, they did not demonstrate stronger hippocampal responses to masked happy faces compared to erased faces. Finally, controls manifested greater responses in parts of the hippocampus to masked happy faces compared to neutral faces (peak voxel xyz, 22, −16, −9 (Talairach coordinates), cluster size: 12, Z-score = 2.42, P b 0.01) when compared to schizophrenia patients. They also exhibited greater hippocampal activation to masked happy faces compared to erased faces (peak voxel xyz, 14, −36, 9 (Talairach coordinates), cluster size: 16, Z-score = 3.51, P b 0.001; peak voxel xyz, −22, −9, −20, cluster size: 69, Z-score = 2.73, P b 0.01; peak voxel xyz, − 26, −26, −10, cluster size: 22, Z-score = 2.38, P b 0.01; peak voxel xyz, −34, − 18, −11, cluster size: 11, Z-score: 1.87, P b 0.05). Thus, our amygdala findings appear not to reflect general response characteristics of the brain during masked emotion processing. 3.3.2. Automatic amygdala response to emotional faces: correlation with psychopathology and other clinical variables The voxel-wise region of interest approach revealed several correlations between automatic amygdala responsivity to facial emotions and schizophrenia patients' current psychopathology (as measured by the PANSS). Amygdala activation in response to sad and happy expressions was positively correlated with the negative and positive subscales, but not the general psychopathology subscale, of the PANSS (see Table 3). Further inspection of the correlations between amygdala activation and single items on the negative and positive subscales of the PANSS showed that the correlations were not restricted to specific symptoms. According to the averaged region of interest data, amygdala activation in response to masked facial emotions (compared to masked neutral faces) did not correlate with the positive and the general subscale of the PANSS. Activation of the left and right amygdala in response to masked sad faces were significantly correlated with the PANSS negative subscale (rs = 0.54 and 0.58, P b 0.05). In addition, right amygdala activation to masked happy faces
204
A.V. Rauch et al. / Psychiatry Research: Neuroimaging 182 (2010) 200–206
Fig. 1. Voxel-wise ROI analysis: between-group differences in amygdala response to masked sad faces compared to erased faces. Enhanced activation in the amygdalae of schizophrenia patients in relation to normal controls (peak voxel xyz, − 26, − 5, − 15 (Talairach coordinates), cluster size: 25, Z-score = 2.46, P b 0.01; peak voxel xyz, 34, − 3, − 23 (Talairach coordinates), cluster size: 22, Z-score = 2.82, P b 0.01). Blood oxygenation level-dependent responses of the amygdalae are superimposed over averaged structural T1 data. Reader's right is subjects' right.
was also related to the PANSS negative subscale (rs = 0.50, P b 0.05). Inspection of the correlations between amygdala activation and single items of the PANSS negative subscale revealed that the item “blunted affect” was correlated with left and right amygdala activation to masked sad faces (rs = 0.59 and 0.58, P b 0.05) and with right amygdala activation to masked happy faces (rs = 0.63, P b 0.05). The item “lack of spontaneity and flow of conversation” was also significantly related to right amygdala activation to masked sad and masked happy faces (rs = 0.66, P b 0.01; 0.61, P b 0.05). Finally, the PANSS item “poor rapport” was correlated with right amygdala activation to masked sad faces (rs = 0.55, P b 0.05). We found no significant correlations between automatic amygdala responsivity to facial emotions and state depressivity (as assessed with the BDI) or trait anxiety (as assessed with the STAI), neither in the whole sample nor in the group of patients. Medication (neuroleptic dosage) was also not significantly related to automatic amygdala responsivity to facial emotions. Hit rate for masked sad faces did not correlate with (left or right) amygdala response to Table 3 Correlation of amygdala response to facial emotions with the positive and negative subscale scores of the PANSS. PANSS
Talairach coordinates
Subscale
x
y
z
Positive Subscale Negative Subscale
− 26 32 − 24 26 − 26 28
−3 −3 −5 −5 −5 −1
− 18 − 15 − 20 − 15 − 20 − 15
Size
Zscore
P value
Emotion condition
20 24 14 18 23 52
2.27 2.25 2.20 2.50 2.78 2.72
0.012 0.012 0.014 0.006 0.003 0.003
Sad N neutral Happy N neutral Sad N neutral Sad N neutral Happy N neutral Happy N neutral
Note: coordinates of the maximal point of activation and the associated Z-values are shown. The activations in the amygdala (a priori region of interest) are significant at P b 0.05 (corrected for search volume); cluster threshold size of 10.
masked sad faces (compared to neutral faces) in the whole sample. In contrast, hit rate for masked happy faces was significantly correlated with the amygdala response to masked happy faces (compared to neutral faces) in the whole sample (peak voxel xyz, 26, −1, −23 (Talairach coordinates), cluster size: 15, Z-score = 2.52, P b 0.01). 4. Discussion In the present fMRI study, automatic amygdala responsivity to facial emotions was examined in schizophrenia patients and healthy controls. We measured neural responses associated with the automatic processing of masked emotional facial expression, plus those associated with the explicit evaluation of neutral masking faces. As hypothesized, schizophrenia patients showed greater amygdala responses than controls to masked sad faces in particular, but also to masked happy facial expressions. The observed activation differences were largely independent of the baseline condition (neutral faces or erased facial expression). Thus, patients suffering from schizophrenia appear to be characterized by an amygdalar hyperresponsiveness to negative and positive emotional stimuli on an automatic processing level. Our findings are consistent with the results of Holt et al. (2006), who observed an increased amygdala activation during the initial perception of (overtly presented) fearful facial expressions. However, our results contrast with those from the majority of the neuroimaging studies examining controlled processing of facial emotion. These studies found lowered activation of the amygdala in schizophrenia patients relative to normal controls (Schneider et al., 1998; Phillips et al., 1999; Gur et al., 2002; Taylor et al., 2002; Hempel et al., 2003; Paradiso et al., 2003; Takahashi et al., 2004; Williams et al., 2004; Johnston et al., 2005; Das et al., 2007; Williams et al., 2007). One explanation of this pattern of results could be a dissociation of automatic (unconscious) and controlled (conscious) emotional information processing in schizophrenia. However, Holt et al. (2006) highlighted the problem of the
A.V. Rauch et al. / Psychiatry Research: Neuroimaging 182 (2010) 200–206
baseline condition in measuring amygdala activity in schizophrenia patients. The authors observed increased amygdala responses to emotionally neutral facial expressions in schizophrenia patients relative to normal controls. Neuroimaging studies that examined the controlled processing of facial emotion and used neutral faces as a baseline condition (Schneider et al., 1998; Gur et al., 2002; Das et al., 2007) could therefore have underestimated responses to emotional faces in schizophrenia patients. The amygdalae appear to be critical for lending emotional significance to stimuli and generating negative emotional experience (Abercrombie et al., 1998; Schaefer et al., 2002). Our finding of an amygdalar hyperresponsiveness to masked sad and happy stimuli supports a model of generalized emotional hyperresponsivity in schizophrenia. Data from behavioral studies have shown a heightened perceptual sensitivity to negative facial expression and an aversive perception of positive facial expression in schizophrenia patients on an automatic processing level (Höschel and Irle, 2001; Suslow et al., 2003a). Amygdalar hyperresponsiveness in schizophrenia may underlie the heightened frequency of negative emotions felt in schizophrenia patients relative to healthy individuals (Myin-Germeys et al., 2000; Suslow et al., 2003b). To our knowledge, this is the first neuroimaging study to investigate automatic emotion processing as a function of psychopathology in schizophrenia. Confirming our hypotheses (at least in part), the correlation analysis revealed that schizophrenia patients' amygdala response during the automatic perception of sad (and happy) faces is primarily associated with negative and possibly also positive symptomatology. In the following section, we will focus on the correlation between amygdala responsivity and negative clinical symptoms since this relationship was observed in the voxel-wise and averaged region of interest correlation analyses. According to our data, patients manifesting high automatic amygdalar responsivity to emotional faces are characterized by more intense negative symptoms. In particular, amygdala activation was found to be positively related to the PANSS items “blunted affect” and “lack of spontaneity and flow of conversation”. Thus, it appears that an automatic amygdalar hyperresponsiveness to emotional stimuli could be involved in the development of diminished emotional responsiveness (as characterized by a reduction in facial expression, modulation of feelings, and communicative gestures) and diminished fluidity and productivity of the verbal interactional process. According to Grossberg (Grossberg, 2000), flat affect in schizophrenia can ensue from an overaroused limbic system. Our correlational findings are consistent with those from a recent neuroimaging study (Gur et al., 2007) that found a robust positive correlation of amygdala activation with flat affect expression in schizophrenia. Gur et al. (Gur et al., 2007) suggested that the association between amygdala activation and flat affect expression could be an adaptation for faulty signaling from the amygdala. Interestingly, in a psychophysiological study Schlenker et al. (1995) revealed a positive association between affective flattening and potentiation of the startle reflex to unpleasant visual stimuli in schizophrenia patients. It has been shown that the extent of startle potentiation is related to the activation of the amygdalae, which are thought to be a central part of the neural system modulating startle during negative affect (Pissiota et al., 2003). Our neuroimaging data suggest that schizophrenia patients' amygdalae are especially responsive to the approach-related interpersonal signals of happiness and sadness. Surprisingly at first glance, this reactivity is not related to intense emotional expression, but instead to a diminished emotional expressiveness and a lack of fluid interpersonal interaction. Flat affect expression in schizophrenia patients could represent an attempt to cope with a high perceptual sensitivity and a negative evaluative bias, down-regulating the density of interpersonal communication as well as indirectly the intensity of emotional experience. Inexpressiveness is known to lead to a down-regulation of emotional expression in the interaction
205
partners (Krause et al., 1992) and to be destructive to social interaction (Flack et al., 1998). Javitt (2001) has also argued that emotional withdrawal, lack of openness in conversation, or lack of spontaneity could be consequences of an increased preoccupation with internal experiences of being flooded with emotionally-charged events. Thus, amygdalar hyperresponsivity could function as important factor contributing to social withdrawal and isolation in schizophrenia patients. Certain limitations of the present investigation should be acknowledged. The generalizability of our conclusions is limited due to the small number of subjects. Thus, the replication of our findings is important in terms of increasing confidence in the data. A second limitation is due to the fact that the schizophrenia patients participating in our study were all medicated. Even though no relationship between signal intensity in the amygdala and neuroleptic dose was observed, it is important to investigate amygdala responsivity in unmedicated patients in order to control for medication effects. In addition, only responsivity to sad and happy faces was examined in the present study. Further research must clarify whether schizophrenia patients also show enhanced automatic amygdala responses to facial expressions of other negative emotions, such as anger, fear, or disgust. The present pattern of results regarding the perception of facial emotion in schizophrenia necessitates further research on the relationship between automatic and controlled information processing. Acknowledgement The preparation of this article was facilitated by a grant from the IZKF (University of Muenster) awarded to AVR. References Abercrombie, H.C., Schaefer, S.M., Larson, C.L., Oakes, T.R., Lindgren, K.A., Holden, J.E., Perlman, S.B., Turski, P.A., Krahn, D.D., Benca, R.M., Davidson, R.J., 1998. Metabolic rate in the right amygdala predicts negative affect in depressed patients. Neuroreport 9 (14), 3301–3307. Adolphs, R., Tranel, D., Hamann, S., Young, A.W., Calder, A.J., Phelps, E.A., Anderson, A., Lee, G.P., Damasio, A.R., 1999. Recognition of facial emotion in nine individuals with bilateral amygdala damage. Neuropsychologia 37 (10), 1111–1117. Bargh, J.A., Chartrand, T.L., 1999. The unbearable automaticity of being. American Psychologist 54 (7), 462–479. Beck, A.T., Steer, R.A., 1987. BDI, Beck Depression Inventory: Manual. Psychological Corp, San Antonio, TX. Berenbaum, H., Oltmanns, T.F., 1992. Emotional experience and expression in schizophrenia and depression. Journal of Abnormal Psychology 101 (1), 37–44. Breiter, H.C., Etcoff, N.L., Whalen, P.J., Kennedy, W.A., Rauch, S.L., Buckner, R.L., Strauss, M.M., Hyman, S.E., Rosen, B.R., 1996. Response and habituation of the human amygdala during visual processing of facial expression. Neuron 17 (5), 875–887. Dannlowski, U., Ohrmann, P., Bauer, J., Kugel, H., Arolt, V., Heindel, W., Suslow, T., 2007. Amygdala reactivity predicts automatic negative evaluations for facial emotions. Psychiatry Research: Neuroimaging 154 (1), 13–20. Das, P., Kemp, A.H., Flynn, G., Harris, A.W., Liddell, B.J., Whitford, T.J., Peduto, A., Gordon, E., Williams, L.M., 2007. Functional disconnections in the direct and indirect amygdala pathways for fear processing in schizophrenia. Schizophrenia Research 90 (1–3), 284–294. Ekman, P., Friesen, W.F., 1976. Pictures of Facial Affect. Consulting Psychologists Press, Palo Alto, CA. Fitzgerald, D.A., Angstadt, M., Jelsone, L.M., Nathan, P.J., Phan, K.L., 2006. Beyond threat: amygdala reactivity across multiple expressions of facial affect. NeuroImage 30 (4), 1441–1448. Flack, W.F., Laird, J.D., Cavallaro, L.A., Miller, D.R., 1998. Emotional expression and experience. A psychosocial perspective on schizophrenia. In: Flack, W.F., Laird, J.D. (Eds.), Emotions in Psychopathology. Theory and Research. Oxford University Press, Oxford, pp. 315–322. Grossberg, S., 2000. The imbalanced brain: from normal behavior to schizophrenia. Biological Psychiatry 48 (2), 81–98. 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 (12), 1992–1999. Gur, R.E., Loughead, J., Kohler, C.G., Elliott, M.A., Lesko, K., Ruparel, K., Wolf, D.H., Bilker, W.B., Gur, R.C., 2007. Limbic activation associated with misidentification of fearful faces and flat affect in schizophrenia. Archives of General Psychiatry 64 (12), 1356–1366. Hautzinger, M., Baile, M., Worall, H., 1995. Beck-Depressions-Inventar (BDI). Testhandbuch. Hans Huber, Bern, CH.
206
A.V. Rauch et al. / Psychiatry Research: Neuroimaging 182 (2010) 200–206
Hempel, A., Hempel, E., Schonknecht, P., Stippich, C., Schroder, J., 2003. Impairment in basal limbic function in schizophrenia during affect recognition. Psychiatry Research: Neuroimaging 122 (2), 115–124. Holt, D.J., Kunkel, L., Weiss, A.P., Goff, D.C., Wright, C.I., Shin, L.M., Rauch, S.L., Hootnick, J., Heckers, S., 2006. Increased medial temporal lobe activation during the passive viewing of emotional and neutral facial expressions in schizophrenia. Schizophrenia Research 82 (2–3), 153–162. Höschel, K., Irle, E., 2001. Emotional priming of facial affect identification in schizophrenia. Schizophrenia Bulletin 27 (2), 317–327. Inquisit, 2007. 2.0.61004.4 Computer software. Millisecond Software LLC, Seattle, WA. Javitt, D.C., 2001. Management of negative symptoms of schizophrenia. Current Psychiatry Reports 3 (5), 413–417. Johnston, P.J., Stojanov, W., Devir, H., Schall, U., 2005. Functional MRI of facial emotion recognition deficits in schizophrenia and their electrophysiological correlates. European Journal of Neuroscience 22 (5), 1221–1232. Kay, S.R., Fiszbein, A., Opler, L.A., 1987. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophrenia Bulletin 13 (2), 261–276. Kee, K.S., Green, M.F., Mintz, J., Brekke, J.S., 2003. Is emotion processing a predictor of functional outcome in schizophrenia? Schizophrenia Bulletin 29 (3), 487–497. Kesler-West, M.L., Andersen, A.H., Smith, C.D., Avison, M.J., Davis, C.E., Kryscio, R.J., Blonder, L.X., 2001. Neural substrates of facial emotion processing using fMRI. Brain Research: Cognitive Brain Research 11 (2), 213–226. Killgore, W.D.S., Yurgelun-Todd, D.A., 2004. Activation of the amygdala and anterior cingulate during non-conscious processing of sad versus happy faces. NeuroImage 21 (4), 1215–1223. Knutson, B., 1996. Facial expressions of emotion influence interpersonal trait inferences. Journal of Nonverbal Behavior 20 (3), 165–182. 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. Schizophrenia Research 57 (1), 87–95. Krause, R., Steimer-Krause, E., Hufnagel, H., 1992. Expression and experience of affects in paranoid schizophrenia. European Review of Applied Psychology 42 (2), 131–138. Kring, A.M., Neale, J.M., 1996. Do schizophrenic patients show a disjunctive relationship among expressive, experiential, and psychophysiological components of emotion? Journal of Abnormal Psychology 105 (2), 249–257. Kring, A.M., Kerr, S.L., Smith, D.A., Neale, J.M., 1993. Flat affect in schizophrenia does not reflect diminished subjective experience of emotion. Journal of Abnormal Psychology 102 (4), 507–517. Laux, G., Ditmaier, O., 2006. Praktische Psychopharmakotherapie. fifth ed. ELSEVIER, Urban & Fischer, München. Laux, L., Glanzmann, P., Schaffner, P., 1981. Das State-Trait Angstinventar. Weinheim, Beltz. LeDoux, J.E., 1998. Cognitive-emotional interactions in the brain. Cognition and Emotion 3 (4), 267–289. Liddell, B.J., Brown, K.J., Kemp, A.H., Barton, M.J., Das, P., Peduto, A., Gordon, E., Williams, L.M., 2005. A direct brainstem-amygdala-cortical ‘alarm’ system for subliminal signals of fear. NeuroImage 24 (1), 235–243. 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 (3), 1233–1239. Moore, H., West, A.R., Grace, A.A., 1999. The regulation of forebrain dopamine transmission: relevance to the pathophysiology and psychopathology of schizophrenia. Biological Psychiatry 46 (1), 40–55. Morris, J.S., Friston, K.J., Buchel, C., Frith, C.D., Young, A.W., Calder, A.J., Dolan, R.J., 1998a. A neuromodulatory role for the human amygdala in processing emotional facial expressions. Brain 121 (Pt 1), 47–57. Morris, J.S., Öhman, A., Dolan, R.J., 1998b. Conscious and unconscious emotional learning in the human amygdala. Nature 393 (6684), 467–470. Morris, J.S., Öhman, A., Dolan, R.J., 1999. A subcortical pathway to the right amygdala mediating “unseen” fear. Proceedings of the National Academy of Sciences of the United States of America 96 (4), 1680–1685. Müller, P., Gaebel, W., Bandelow, B., Köpcke, W., Linden, M., Müller-Spahn, F., Pietzcker, A., Tegeler, J., 1998. Zur sozialen Situation schizophrener Patienten. Nervenarzt 69 (3), 204–209. Murphy, S.T., Zajonc, R.B., 1993. Affect, cognition, and awareness: affective priming with optimal and suboptimal stimulus exposures. Journal of Personality and Social Psychology 64 (5), 723–739. Myin-Germeys, I., Delespaul, P.A., deVries, M.W., 2000. Schizophrenia patients are more emotionally active than is assumed based on their behavior. Schizophrenia Bulletin 26 (4), 847–854. Niedenthal, P.M., 1990. Implicit perception of affective information. Journal of Experimental Social Psychology 26 (6), 505–527. 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 schizophrenia
during evaluation with positron emission tomography. American Journal of Psychiatry 160 (10), 1775–1783. Phillips, M.L., Williams, L., Senior, C., Bullmore, E.T., Brammer, M.J., Andrew, C., Williams, S.C., David, A.S., 1999. A differential neural response to threatening and non-threatening negative facial expressions in paranoid and non-paranoid schizophrenics. Psychiatry Research: Neuroimaging 92 (1), 11–31. Phillips, M.L., Williams, L.M., Heining, M., Herba, C.M., Russell, T., Andrew, C., Bullmore, E.T., Brammer, M.J., Williams, S.C., Morgan, M., Young, A.W., Gray, J.A., 2004. Differential neural responses to overt and covert presentations of facial expressions of fear and disgust. Neuroimage 21 (4), 1484–1496. Pissiota, A., Frans, Ö., Michelgard, A., Appel, L., Langstrom, B., Flaten, M.A., Fredrikson, M., 2003. Amygdala and anterior cingulate cortex activation during affective startle modulation: a PET study of fear. European Journal of Neuroscience 18 (5), 1325–1331. Raczkowski, D., Kalat, J.W., Nebes, R., 1974. Reliability and validity of some handedness questionnaire items. Neuropsychologia 12 (1), 43–47. Riederer, P., Laux, G., Pöldinger, W., 1998. Neuro-Psychopharmaka. Ein TherapieHandbuch, Band 4: Neuroleptika, second ed. Springer, Wien. Robinson, S., Windischberger, C., Rauscher, A., Moser, E., 2004. Optimized 3 T EPI of the amygdalae. Neuroimage 22 (1), 203–210. Rotteveel, M., de Groot, P., Geutskens, A., Phaf, R.H., 2001. Stronger suboptimal than optimal affective priming? Emotion 1 (4), 348–364. Salokangas, R.K.R., Honkonen, T., Stengard, E., Koivisto, A.M., 2001. To be or not to be married—that is the question of quality of life in men with schizophrenia. Social Psychiatry and Psychiatric Epidemiology 36 (8), 381–390. Sato, W., Yoshikawa, S., Kochiyama, T., Matsumura, M., 2004. The amygdala processes the emotional significance of facial expressions: an fMRI investigation using the interaction between expression and face direction. NeuroImage 22 (2), 1006–1013. Schaefer, S.M., Jackson, D.C., Davidson, R.J., Aguirre, G.K., Kimberg, D.Y., ThompsonSchill, S.L., 2002. Modulation of amygdalar activity by the conscious regulation of negative emotion. Journal of Cognitive Neuroscience 14 (6), 913–921. Schlenker, R., Cohen, R., Hopmann, G., 1995. Affective modulation of the startle relfex in schizophrenic patients. European Archives of Psychiatry and Clinical Neuroscience 245 (6), 309–318. 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. Schizophrenia Research 34 (3), 133–142. Spielberger, C.D., Gorsuch, R.L., Lushene, R.E., 1970. Manual for the State-Trait Anxiety Inventory. Consulting Psychologists Press, Palo Alto, CA. Suslow, T., Roestel, C., Arolt, V., 2003a. Affective priming in schizophrenia with and without affective negative symptoms. European Archives of Psychiatry and Clinical Neuroscience 253 (6), 292–300. Suslow, T., Roestel, C., Ohrmann, P., Arolt, V., 2003b. The experience of basic emotions in schizophrenia with and without affective negative symptoms. Comprehensive Psychiatry 44 (4), 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 (3), 1247–1254. Taylor, S.F., Liberzon, I., Decker, L.R., Koeppe, R.A., 2002. A functional anatomic study of emotion in schizophrenia. Schizophrenia Research 58 (2–3), 159–172. Tzourio-Mazoyer, N., Landeau, B., Papathanassiou, D., Crivello, F., Etard, O., Delcroix, N., Mazoyer, B., Joliot, M., 2002. Automated anatomical labeling of activations in SPM using a macroscopic anatomical parcellation of the MNI MRI single-subject brain. Neuroimage 15 (1), 273–289. Wang, L., McCarthy, G., Song, A.W., LaBar, K.S., 2005. Amygdala activation to sad pictures during high field (4 Tesla) functional magnetic resonance imaging. Emotion 5 (1), 12–22. Whalen, P.J., Rauch, S.L., Etcoff, N.L., McInerney, S.C., Lee, M.B., Jenike, M.A., 1998. Masked presentations of emotional facial expressions modulate amygdala activity without explicit knowledge. Journal of Neuroscience 18 (1), 411–418. Williams, L.M., Das, P., Harris, A.W., Liddell, B.B., Brammer, M.J., Olivieri, G., Skerrett, D., Phillips, M.L., David, A.S., Peduto, A., Gordon, E., 2004. Dysregulation of arousal and amygdala-prefrontal systems in paranoid schizophrenia. American Journal of Psychiatry 161 (3), 480–489. Williams, L.M., Das, P., Liddell, B.J., Olivieri, G., Peduto, A.S., David, A.S., Gordon, E., Harris, A.W., 2007. Fronto-limbic and autonomic disjunctions to negative emotion distinguish schizophrenia subtypes. Psychiatry Research 155 (1), 29–44. Winkielman, P., Knutson, B., Paulus, M., Trujillo, J.L., 2007. Affective influence on judgments and decisions: moving towards core mechanisms. Review of General Psychology 11 (2), 179–192. Wittchen, H.U., Wunderlich, U., Gruschwitz, S., Zaudig, M., 1997. SKID-I. Strukturiertes Klinisches Interview für DSM-IV. Hogrefe, Göttingen. Yang, T.T., Menon, V., Eliez, S., Blasey, C., White, C.D., Reid, A.J., Gotlib, I.H., Reiss, A.L., 2002. Amygdalar activation associated with positive and negative facial expressions. Neuroreport 13 (14), 1737–1741.
Contents lists available at ScienceDirect
Psychiatry Research: Neuroimaging j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / p s yc h r e s n s
Increased amygdala activation during automatic processing of facial emotion in schizophrenia Astrid Veronika Raucha,c,⁎,1, Maraike Rekera,1, Patricia Ohrmanna, Anya Pedersena, Jochen Bauera, Udo Dannlowskia,c, Liv Hardinga, Katja Koelkebecka, Carsten Konradc,d, Harald Kugelb, Volker Arolta, Walter Heindelb, Thomas Suslowa,⁎ a
Department of Psychiatry, School of Medicine, University of Muenster, Albert-Schweitzer-Str. 11, 48149 Muenster, Germany Department of Clinical Radiology, School of Medicine, University of Muenster, Albert-Schweitzer-Str. 33, 48149 Muenster, Germany c IZKF-Research Group 4, IZKF Muenster, University of Muenster, Domagkstr.3, 48149 Muenster, Germany d Department of Psychiatry, School of Medicine, University of Marburg, Rudolf-Bultmann-Str. 8, 35039 Marburg, Germany b
a r t i c l e
i n f o
Article history: Received 5 June 2008 Received in revised form 17 February 2010 Accepted 11 March 2010 Keywords: fMRI Automatic emotion processing Limbic system Psychopathology Neuroimaging
a b s t r a c t Schizophrenia patients show abnormalities in the processing of facial emotion. The amygdala is a central part of a brain network that is involved in the perception of facial emotions. Previous functional neuroimaging studies on the perception of facial emotion in schizophrenia have focused almost exclusively on controlled processing. In the present study, we investigated the automatic responsivity of the amygdala to emotional faces in schizophrenia and its relationship to clinical symptomatology by applying an affective priming task. 3-T fMRI was utilized to examine amygdala responses to sad and happy faces masked by neutral faces in 12 schizophrenia patients and 12 healthy controls. The Positive and Negative Syndrome Scale (PANSS) was administered to assess current symptomatology. Schizophrenia patients exhibited greater automatic amygdala responses to sad and happy faces relative to controls. Amygdala responses to masked sad and happy expressions were positively correlated with the negative subscale of the PANSS. Schizophrenia patients appear to be characterized by amygdalar hyperresponsiveness to negative and positive facial expressions on an automatic processing level. Heightened automatic amygdala responsivity could be involved in the development and maintenance of negative symptoms in schizophrenia. © 2010 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Patients suffering from schizophrenia show impairments in the perception of facial expressions of emotions (Schneider et al., 1998; Phillips et al., 1999; Holt et al., 2006; Das et al., 2007). Since facial expressions serve as important social signals of imminent environmental conditions, it is not surprising that dysfunction in emotion recognition has been found to be a key determinant for psychosocial outcomes in schizophrenia patients (Kee et al., 2003). Functional neuroimaging and lesion studies have identified the amygdala as a central component of a subcortical–cortical network that is involved in the perception of facial emotions (Adolphs et al., 1999; Kesler-West et al., 2001; Phillips et al., 2004; Sato et al., 2004) and in generating negative emotional experiences (Abercrombie et al.,
⁎ Corresponding authors. Department of Psychiatry, University of Muenster, AlbertSchweitzer-Str. 11, 48149 Muenster, Germany. Tel.: +49 251 8356601; fax: +49 251 8356612. E-mail addresses: [email protected] (A.V. Rauch), [email protected] (T. Suslow). 1 This is to indicate that Astrid Veronika Rauch and Maraike Reker contributed equally to this work and should, therefore, both be considered first authors. 0925-4927/$ – see front matter © 2010 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.pscychresns.2010.03.005
1998; Schaefer et al., 2002). There is evidence that the amygdala plays a crucial role in processing fearful faces (Morris et al., 1998a), but it is also involved in the perception of the facial expressions of other negative emotions, such as anger and sadness (Wang et al., 2005; Fitzgerald et al., 2006). The amygdala may even be involved in the perception of faces expressing positive emotions (Breiter et al., 1996; Yang et al., 2002). Results from experiments in which facial expression was presented subliminally consistently suggest an automatic activation of the amygdala in response to consciously imperceptible emotional faces (Morris et al., 1998b, 1999; Whalen et al., 1998; Liddell et al., 2005). It has been argued that the thalamoamygdaloid pathway allows a very rapid evaluation of incoming stimuli, which can trigger immediate adaptive (behavioral and autonomic) responses of the organism without requiring controlled information processing (LeDoux, 1998). In a number of neuroimaging studies examining controlled emotion processing, lowered or failed activation of the amygdala was observed in schizophrenia patients compared with healthy subjects (Schneider et al., 1998; Phillips et al., 1999; Gur et al., 2002; Taylor et al., 2002; Hempel et al., 2003; Paradiso et al., 2003; Takahashi et al., 2004; Williams et al., 2004; Johnston et al., 2005; Das et al., 2007; Williams et al., 2007). However, the findings of Kosaka et al. (2002)
A.V. Rauch et al. / Psychiatry Research: Neuroimaging 182 (2010) 200–206
indicate heightened amygdala activation during controlled emotion processing in schizophrenia. Similarly, Holt et al. (2006) found that schizophrenia patients exhibit greater amygdala activation relative to control subjects during first encounters with fearful and neutral faces (within an experiment). Discrepancies among previous results appear to be due to differences in the applied emotion tasks and methods of data analysis (e.g., baseline condition, type of experimental design (block or event-related)). Gur et al. (2007) used an event-related analysis to reveal that the amygdala response to fearful faces in schizophrenia patients was associated with impaired emotional identification and strongly correlated with flat affect expression. Evidence from psychological research indicates that the reduced facial expressiveness of schizophrenia patients does not necessarily reflect a diminished subjective experience of emotion, but instead could be due to selective impairments in the expression of emotions (Berenbaum and Oltmanns, 1992; Kring et al., 1993; Kring and Neale, 1996). However, schizophrenia patients' flat affect expression could also represent an attempt to control and downregulate the intensity of their own emotional experience (Flack et al., 1998) and could disturb, or even disrupt, interpersonal communication (Krause et al., 1992). In everyday life, schizophrenia patients experience more negative emotions (fear in particular) than healthy individuals (Myin-Germeys et al., 2000; Suslow et al., 2003b). Based on the latter observation, it could be expected that schizophrenia patients manifest stronger amygdala responses to emotion-eliciting stimuli than do healthy individuals. Taylor et al. (2002) reported a significant positive correlation between amygdala activity and positive symptoms, which is consistent with the neurobiological theory that the amygdala might drive positive symptoms (Moore et al., 1999). Amygdala activity could directly cause positive symptoms such as hostility, suspiciousness, and excitement. Few studies have investigated automatic emotion processing in schizophrenia. A robust phenomenon of automatic emotion processing is the emotion-congruent influence of facial expressions shown below conscious awareness on subsequent judgments regarding neutral stimuli (Niedenthal, 1990; Murphy and Zajonc, 1993; Rotteveel et al., 2001). That is, subliminally presented angry faces, for example, bias judgments of neutral (mask) stimuli in a negative direction compared to neutral primes. It is assumed that the amygdala could be crucially involved in negative affective priming effects (Winkielman et al., 2007). In a sample of healthy subjects, amygdala responses to masked negative faces were correlated with automatic negative evaluation shifts elicited by negative facial expression in an affective priming experiment (Dannlowski et al., 2007). Using behavioral affective priming tasks, it was shown that schizophrenia patients exhibit a heightened perceptual sensitivity to negative facial emotion and a lowered sensitivity to positive faces on an automatic processing level (Höschel and Irle, 2001). Thus far, only one fMRI study has investigated automatic emotion processing in schizophrenia (Das et al., 2007). Patients showed an impaired connectivity between components of the subcortical and cortical amygdala pathways during different levels of awareness (conscious and nonconscious perception of fear). A major limitation of Das et al.'s study was the fact that, prior to the experiment, subjects were informed about the presence of masked facial expression. Since it is widely accepted that emotions are generally involuntarily elicited (Bargh and Chartrand, 1999), the investigation of automatic response characteristics is of special interest for the understanding of normal and abnormal emotional reactions and cognitive biases. In this study, 3-T fMRI was used to investigate automatic amygdalar responsivity to facial emotions in schizophrenia patients compared to healthy individuals. To this aim, an affective priming experiment was applied in which happy, sad, and neutral facial expressions were masked by neutral faces in order to block participants' conscious recognition. Measures of subjective and
201
objective awareness of facial emotion were administered. We hypothesized that schizophrenia patients would demonstrate enhanced amygdala activation to masked sad and masked happy faces. Our previous behavioral affective priming study (Suslow et al., 2003a) was also based on sad and happy facial expressions. Expressions of sadness and happiness signal both an invitation for social interaction and approach. Happy expressions are invitations for the perceiver to approach the expresser. Sadness is a signal that the expresser needs to be cared for (Knutson, 1996). The investigation of responsivity to approach-related interpersonal signals is of special interest in schizophrenia since many patients are socially isolated and withdrawn (Müller et al., 1998; Salokangas et al., 2001). We conducted an explorative analysis of the correlations between automatic amygdala responses to facial emotion and clinical symptomatology in schizophrenia patients. We expected to find positive correlations of schizophrenia patients' amygdala responsivity and masked emotional expression with the extent of negative and positive symptoms.
2. Methods 2.1. Subjects Participants comprised 12 schizophrenia patients and 12 healthy control subjects. Demographic and clinical characteristics of study participants are listed in Table 1. Patients were recruited from the inpatient service of the University of Muenster's Department of Psychiatry. Diagnoses were determined using the German version of the Structured Clinical Interview for DSM-IV (Wittchen et al., 1997). Controls were screened for a previous history of Axis I disorder via the same interview. They were excluded if they met the criteria for an Axis I disorder. Exclusion criteria for both groups were psychiatric comorbidity (DSM-IV), left handedness, exposure to electroconvulsive therapy (ECT), abnormal vision, past history of substance dependence, and neurological disorder. Handedness was defined by the Handedness Questionnaire (Raczkowski et al., 1974). Patients' psychopathological status was assessed by an experienced clinical investigator using the German version of the Positive and Negative Syndrome Scale (Kay et al., 1987). The Beck Depression Inventory (Beck and Steer, 1987; Hautzinger et al., 1995) and the State-Trait Anxiety Inventory (Spielberger et al., 1970; Laux et al., 1981) were administered to measure state depressivity and trait anxiety, respectively. All schizophrenia patients were receiving neuroleptic treatment. Five patients received only one atypical neuroleptic medication, four patients received a combination of two atypical
Table 1 Demographic and clinical characteristics of study participants. Characteristics
Gender (female/male) Age (years) Neuroleptic dosage (mg)a PANSS Positive scoreb PANSS Negative score c PANSS General score d BDI score e STAI-T score f
Schizophrenia patients
Control subjects
(N = 12)
(N = 12)
3/9 27.7 (7.5) 902.1 (603.2) 14.4 (3.1) 18.9 (5.2) 34.9 (5.9) 17.2 (8.6) 50.4 (9.7)
5/7 26.9 (6.1)
0.9 (1.1) 31.6 (6.8)
Values are presented as means (with standard deviations in parentheses) or frequencies. a CPZ equivalent dose (Riederer et al., 1998; Laux and Ditmaier, 2006). b Positive subscale score of the Positive and Negative Syndrome Scale. c Negative subscale score of the Positive and Negative Syndrome Scale. d General psychopathology subscale score of the Positive and Negative Syndrome Scale. e Beck Depression Inventory sum score. f State-Trait-Anxiety Inventory sum score (trait form).
202
A.V. Rauch et al. / Psychiatry Research: Neuroimaging 182 (2010) 200–206
neuroleptic medications, and three patients were treated with a combination of atypical and typical medication. All subjects gave informed, written consent to participate in the study, which was approved by the institutional ethics committee according to The Code of Ethics of the World Medical Association (Declaration of Helsinki) for experiments involving humans. Controls received 20 € after their participation in the fMRI experiment. 2.2. Stimulus materials and procedure Participants viewed grey-scale normalized face stimuli that were selected from a standardized picture set (Ekman and Friesen, 1976) containing five female and five male individuals with sad, happy, neutral, and erased facial expressions. In the erased condition, neutral faces were shown without central facial features (i.e., eyes, nose, and mouth), which had been replaced by a surface without contours. A fixation cross of 800 ms preceded the facial emotion stimuli, which were presented for 33 ms and followed immediately by a 467 ms neutral expression and a black screen. The duration of each trial was 9 s. The overall presentation time was 12 min. The subjects were instructed to view a series of faces. They were asked to evaluate the briefly shown neutral (mask) face on a 4-point scale and were not informed about the presence of a prime stimulus. Immediately after presentation of the mask face, a blank screen was shown for 7.700 ms. During this time period participants rated the mask face as expressing rather negative (−0.5, −1.5) or rather positive (+ 0.5, +1.5) feelings by pressing a button. Two fixed random orders were presented. One-half of the samples gave positive responses with the left hand while the other half used the right hand for positive responses. The experiment was programmed using the software package Inquisit (2007). The type of evaluative responses and reaction latencies was registered. Face stimuli were presented via a projector (Sharp XG-PC10XE with additional HF shielding). The head position was stabilized with a vacuum head cushion. To determine the success of masking emotional faces, subjects were questioned after the fMRI experiment as to whether they had noticed anything out of the ordinary and whether they had seen anything just before the neutral faces. In addition, a detection task was administered to assess objective awareness of the facial emotions shown in the fMRI experiment (see Section 2.5). None of the participants reported noticing sad or happy facial expressions (before the neutral faces). 2.3. fMRI acquisition T2⁎ functional data were acquired with a 3-Tesla scanner (Gyroscan Intera 3 T, Philips Medical Systems, Best, NL) using a single-shot gradient-echo EPI sequence with parameters selected to minimize distortion while retaining adequate signal to noise ratio and T2⁎ sensitivity (according to suggestions made by Robinson et al. (2004)). 40 axial slices were acquired (matrix 642, resolution 3.5 mm × 3.5 mm× 3.5 mm; TR= 3 s, TE = 35 ms, α = 90°). In addition, to display morphology with high resolution, a T1-weighted 3D sequence (multishot non-equilibrium gradient-echo sequence with preceding inversion recovery pulse, (‘Turbo Field Echo’-sequence, TFE) was applied to acquire isotropic voxels of 0.5 mm edge length of the whole head (TR = 7.6 s, TE= 3.5 ms, FA= 9°, TR(IR)= 832 ms, TI= 437 ms, reconstructed matrix 512 × 408 × 320, fh× ap× lr). 2.4. fMRI analyses Functional imaging data were analyzed using Statistical Parametric Mapping (SPM2, Wellcome Department of Imaging Neuroscience, London, UK). Images were motion corrected (using a set of six rigid body transformations determined for each image), spatially normalized to standard MNI space (Montreal Neurological Institute), and
smoothed (Gaussian kernel, 6 mm full width at half-maximum). Statistical analysis was performed by modeling the different conditions (sad, happy, neutral, and erased) as variables within the context of the general linear model (convolved with a standard hemodynamic response function). The amygdala (Tzourio-Mazoyer et al., 2002) was selected as the a priori region of interest (ROI) using the WFU Pickatlas (Maldjian et al., 2003). The hippocampus was chosen as the subcortical control region. The hippocampus is not primarily involved in the subliminal perception of emotion stimuli. Consistent with previous studies using nonconscious emotion stimuli (e.g., Killgore and Yurgelun-Todd, 2004; Das et al., 2007), ROI analyses were conducted with significance levels set at P b 0.05 (corrected for search volume) and clusters defined by at least 10 contiguous voxels of significant response. Relations between amygdala activation during processing of masked facial emotion and clinical symptoms were evaluated using simple regression as implemented in SPM2. This was done to test the null hypothesis that the variable b in the linear regression model equals 0 (with y = a + bx; where y is the value of the contrast and x for example the PANSS subscale score). Voxels within the whole amygdala were correlated with clinical and priming variables. In addition, mean activation of the left and right amygdala in response to masked emotional faces as compared with masked neutral faces was correlated with clinical symptoms and priming scores (using Spearman's Rho (rs), two-tailed). In the second analysis, voxel values of the whole amygdala were extracted, summarized by mean (separately for the left and right amygdala), and tested among the different conditions using the MarsBaR toolbox (TzourioMazoyer et al., 2002). By focusing the analyses on the contrast emotional faces vs. neutral faces, the effect of emotionality in facial expression on brain activity could be determined and related to actual clinical symptomatology. 2.5. Detection task A detection task was designed to assess objective awareness of the facial emotions shown in the fMRI experiment. After the fMRI session, a detection task based on the facial stimuli applied in the fMRI experiment was administered outside of the scanner on a microcomputer in a quiet room free of auditory and visual distractions. Each of the 40 trials consisted of the following routine: After a fixation cross appeared for 800 ms, a prime face was presented for 33 ms and was directly followed by a neutral target face for 467 ms. Each prime expression (sad, happy, and neutral) and the no-facial expression control condition (erased) was presented 10 times in a fixed random order. Participants were instructed to indicate which of the four conditions was briefly displayed as prime. The chance level for correct answers was 25%. 3. Results 3.1. Detection task The mean hit rate for masked sad faces was 29.2% (SD: 21.5%) for schizophrenia patients and 20.8% (SD: 11.6%) for control subjects, which reflects near or below chance levels of performance. The mean false alarm rate for masked sad faces was 25.8% (SD: 14.6%) for schizophrenia patients and 18.6% (SD: 16.3%) for control subjects. The mean hit rate for masked happy faces was 28.3% (SD: 19.4%) in the schizophrenia group and 37.5% (SD: 33.3%) in the control group. Control subjects' detection rate for happy faces was not statistically different from chance level of performance (one sample t-test, p N .22). The mean false alarm rate for masked happy faces was 20.8% (SD: 10.4%) for schizophrenia patients and 14.7% (SD: 8.8%) for control subjects. Hit rate for masked neutral faces was 48.3% (SD: 15.3%) in the schizophrenia group and 50.0% (SD: 20.0%) in the control group. For neutral faces, the false alarm rate was 37.8% (SD: 13.5) for
A.V. Rauch et al. / Psychiatry Research: Neuroimaging 182 (2010) 200–206
schizophrenia patients and 42.8% (SD: 25.4) for control subjects, indicating that both groups frequently tended to erroneously choose the neutral expression condition as a response. Finally, to assess recognition accuracy of the study groups, we used a composite measure that was calculated as hit rate minus false alarm rate (i.e., corrected hit probability). In the schizophrenia group, corrected hit probabilities were 0.03 (SD: 0.12) for sad faces, 0.08 (SD: 0.17) for happy faces, and 0.11 (SD: 0.19) for neutral faces. In the control group, corrected hit probabilities were 0.02 (SD: 0.16) for sad faces, 0.22 (SD: 0.28) for happy faces, and 0.07 (SD: 0.12) for neutral faces. There were no significant differences between study groups in detection performance (hit rate, false alarm rate, or corrected hit probability) for sad, happy, and neutral faces (Ps N 0.13). 3.2. Behavioral data: evaluative ratings and affective priming scores For schizophrenia patients, mean evaluative ratings were −0.08 (SD: 0.27) for sad faces, −0.10 (SD: 0.29) for happy faces, −0.03 (SD: 0.30) for neutral faces, and −0.04 (SD: 0.24) for the no-prime condition. Healthy subjects' mean evaluative scores were 0.05 (SD: 0.27) for sad faces, 0.05 (SD: 0.23) for happy faces, 0.01 (SD: 0.26) for neutral faces, and −0.03 (SD: 0.21) for the no-prime condition. To examine whether evaluative ratings in the fMRI experiment differed as a function of group and prime condition, ANOVAs with one between-subject factor (group) and one within-subject factor (prime condition: sad prime, happy prime, neutral prime, no-face) were calculated. No significant main effect of prime condition (F (3,20) = 0.17, P = 0.91) or group (F (1,22) = 0.77, P = 0.39) was found, and no interaction effect of group and prime condition on evaluative ratings was observed (F (3,20) = 1.83, P = 0.17). Two affective priming scores were calculated on the basis of subjects' mean evaluative ratings. The affective priming score for happy faces was calculated by subtracting the mean evaluation score for neutral faces from the mean evaluation score for happy faces. Affective priming for sad faces was determined by subtracting the mean evaluation score for sad faces from the mean evaluation score for neutral faces. Thus, positive scores in both cases indicate prime valence congruent affective priming. Neither the affective priming score for happy faces (−0.013, S.D. = 0.17) nor the affective priming score for sad faces (0.003, S.D. = 0.19) were significantly different from zero, as indicated by the results of the one-sample t-tests (Ps N 0.05). 3.3. fMRI results 3.3.1. Automatic response of the amygdala and the hippocampus to facial expression: between-group comparison Comparisons between the two study groups revealed greater activation in the left amygdala for schizophrenia patients relative to controls for the happy versus neutral, sad versus neutral, and sad versus erased contrasts. In addition, greater right amygdala responses to sad faces (compared to neutral and erased faces) and to happy faces (compared with erased faces) were observed in schizophrenia patients relative to controls (see Table 2 and Fig. 1 for details). When compared to schizophrenia patients, control subjects did not show stronger amygdala activation to masked emotional faces compared to masked neutral or masked erased faces. However, control subjects exhibited greater amygdala activation than patients to neutral faces compared to erased faces (see Table 2). The between-group comparison of activation in the subcortical control region of the hippocampus in response to masked emotional faces revealed a result pattern that was markedly different from that in the amygdala. Schizophrenia patients exhibited stronger hippocampal responses to masked sad faces compared to neutral faces (peak voxel xyz, 30, −7, − 22 (Talairach coordinates), cluster size: 23, Z-score = 2.49, P b 0.01), but they did not demonstrate stronger hippocampal responses to masked sad faces compared with erased
203
Table 2 Differences between schizophrenia patients and control subjects in automatic amygdala response to sad and happy facial expressions compared with neutral and erased faces. Emotion condition
Sad N neutral
Happy N neutral Sad N erased
Happy N erased Neutral N erased
Talairach coordinates x
y
z
− 28 34 – − 18 – − 26 34 – 34 – – − 16
−5 −3 – −3 – −5 −3 – −3 – – −7
− 13 − 23 – − 15 – − 15 − 23 – − 23 – – − 15
Size
Zscore
P value
Direction of difference
22 32 – 14 – 25 22 – 15 – – 14
2.21 2.31 – 2.28 – 2.46 2.82 – 2.78 – – 2.29
0.014 0.010 – 0.011 – 0.007 0.002 – 0.003 – – 0.011
Schizophrenia N control Schizophrenia N control Control N schizophrenia Schizophrenia N control Control N schizophrenia Schizophrenia N control Schizophrenia N control Control N schizophrenia Schizophrenia N control Control N schizophrenia Schizophrenia N control Control N schizophrenia
Note: coordinates of the maximal point of activation and the associated Z-values are shown. The activations in the amygdala (a priori region of interest) are significant at P b 0.05 (corrected for search volume); cluster threshold size of 10.
faces when compared with controls. Control subjects instead exhibited greater hippocampal activation to masked sad faces compared to erased faces than did patients (peak voxel xyz, 32, − 37, 2 (Talairach coordinates), cluster size: 33, Z-score = 2.68, P b 0.01; peak voxel xyz, −24, −15, −19, cluster size: 14, Z-score = 2.36, P b 0.01; peak voxel xyz, − 32, − 37, −2, cluster size: 10, Z-score: 2.25, P b 0.05; and peak voxel xyz, −34, −26, −9, cluster size: 12, Z-score: 1.91, P b 0.05). Furthermore, schizophrenia patients exhibited stronger responses in parts of the hippocampus to masked happy faces compared to neutral faces (peak voxel xyz, 20, −16, −13 (Talairach coordinates), cluster size: 16, Z-score = 2.83, P b 0.01). Yet, when compared with controls, they did not demonstrate stronger hippocampal responses to masked happy faces compared to erased faces. Finally, controls manifested greater responses in parts of the hippocampus to masked happy faces compared to neutral faces (peak voxel xyz, 22, −16, −9 (Talairach coordinates), cluster size: 12, Z-score = 2.42, P b 0.01) when compared to schizophrenia patients. They also exhibited greater hippocampal activation to masked happy faces compared to erased faces (peak voxel xyz, 14, −36, 9 (Talairach coordinates), cluster size: 16, Z-score = 3.51, P b 0.001; peak voxel xyz, −22, −9, −20, cluster size: 69, Z-score = 2.73, P b 0.01; peak voxel xyz, − 26, −26, −10, cluster size: 22, Z-score = 2.38, P b 0.01; peak voxel xyz, −34, − 18, −11, cluster size: 11, Z-score: 1.87, P b 0.05). Thus, our amygdala findings appear not to reflect general response characteristics of the brain during masked emotion processing. 3.3.2. Automatic amygdala response to emotional faces: correlation with psychopathology and other clinical variables The voxel-wise region of interest approach revealed several correlations between automatic amygdala responsivity to facial emotions and schizophrenia patients' current psychopathology (as measured by the PANSS). Amygdala activation in response to sad and happy expressions was positively correlated with the negative and positive subscales, but not the general psychopathology subscale, of the PANSS (see Table 3). Further inspection of the correlations between amygdala activation and single items on the negative and positive subscales of the PANSS showed that the correlations were not restricted to specific symptoms. According to the averaged region of interest data, amygdala activation in response to masked facial emotions (compared to masked neutral faces) did not correlate with the positive and the general subscale of the PANSS. Activation of the left and right amygdala in response to masked sad faces were significantly correlated with the PANSS negative subscale (rs = 0.54 and 0.58, P b 0.05). In addition, right amygdala activation to masked happy faces
204
A.V. Rauch et al. / Psychiatry Research: Neuroimaging 182 (2010) 200–206
Fig. 1. Voxel-wise ROI analysis: between-group differences in amygdala response to masked sad faces compared to erased faces. Enhanced activation in the amygdalae of schizophrenia patients in relation to normal controls (peak voxel xyz, − 26, − 5, − 15 (Talairach coordinates), cluster size: 25, Z-score = 2.46, P b 0.01; peak voxel xyz, 34, − 3, − 23 (Talairach coordinates), cluster size: 22, Z-score = 2.82, P b 0.01). Blood oxygenation level-dependent responses of the amygdalae are superimposed over averaged structural T1 data. Reader's right is subjects' right.
was also related to the PANSS negative subscale (rs = 0.50, P b 0.05). Inspection of the correlations between amygdala activation and single items of the PANSS negative subscale revealed that the item “blunted affect” was correlated with left and right amygdala activation to masked sad faces (rs = 0.59 and 0.58, P b 0.05) and with right amygdala activation to masked happy faces (rs = 0.63, P b 0.05). The item “lack of spontaneity and flow of conversation” was also significantly related to right amygdala activation to masked sad and masked happy faces (rs = 0.66, P b 0.01; 0.61, P b 0.05). Finally, the PANSS item “poor rapport” was correlated with right amygdala activation to masked sad faces (rs = 0.55, P b 0.05). We found no significant correlations between automatic amygdala responsivity to facial emotions and state depressivity (as assessed with the BDI) or trait anxiety (as assessed with the STAI), neither in the whole sample nor in the group of patients. Medication (neuroleptic dosage) was also not significantly related to automatic amygdala responsivity to facial emotions. Hit rate for masked sad faces did not correlate with (left or right) amygdala response to Table 3 Correlation of amygdala response to facial emotions with the positive and negative subscale scores of the PANSS. PANSS
Talairach coordinates
Subscale
x
y
z
Positive Subscale Negative Subscale
− 26 32 − 24 26 − 26 28
−3 −3 −5 −5 −5 −1
− 18 − 15 − 20 − 15 − 20 − 15
Size
Zscore
P value
Emotion condition
20 24 14 18 23 52
2.27 2.25 2.20 2.50 2.78 2.72
0.012 0.012 0.014 0.006 0.003 0.003
Sad N neutral Happy N neutral Sad N neutral Sad N neutral Happy N neutral Happy N neutral
Note: coordinates of the maximal point of activation and the associated Z-values are shown. The activations in the amygdala (a priori region of interest) are significant at P b 0.05 (corrected for search volume); cluster threshold size of 10.
masked sad faces (compared to neutral faces) in the whole sample. In contrast, hit rate for masked happy faces was significantly correlated with the amygdala response to masked happy faces (compared to neutral faces) in the whole sample (peak voxel xyz, 26, −1, −23 (Talairach coordinates), cluster size: 15, Z-score = 2.52, P b 0.01). 4. Discussion In the present fMRI study, automatic amygdala responsivity to facial emotions was examined in schizophrenia patients and healthy controls. We measured neural responses associated with the automatic processing of masked emotional facial expression, plus those associated with the explicit evaluation of neutral masking faces. As hypothesized, schizophrenia patients showed greater amygdala responses than controls to masked sad faces in particular, but also to masked happy facial expressions. The observed activation differences were largely independent of the baseline condition (neutral faces or erased facial expression). Thus, patients suffering from schizophrenia appear to be characterized by an amygdalar hyperresponsiveness to negative and positive emotional stimuli on an automatic processing level. Our findings are consistent with the results of Holt et al. (2006), who observed an increased amygdala activation during the initial perception of (overtly presented) fearful facial expressions. However, our results contrast with those from the majority of the neuroimaging studies examining controlled processing of facial emotion. These studies found lowered activation of the amygdala in schizophrenia patients relative to normal controls (Schneider et al., 1998; Phillips et al., 1999; Gur et al., 2002; Taylor et al., 2002; Hempel et al., 2003; Paradiso et al., 2003; Takahashi et al., 2004; Williams et al., 2004; Johnston et al., 2005; Das et al., 2007; Williams et al., 2007). One explanation of this pattern of results could be a dissociation of automatic (unconscious) and controlled (conscious) emotional information processing in schizophrenia. However, Holt et al. (2006) highlighted the problem of the
A.V. Rauch et al. / Psychiatry Research: Neuroimaging 182 (2010) 200–206
baseline condition in measuring amygdala activity in schizophrenia patients. The authors observed increased amygdala responses to emotionally neutral facial expressions in schizophrenia patients relative to normal controls. Neuroimaging studies that examined the controlled processing of facial emotion and used neutral faces as a baseline condition (Schneider et al., 1998; Gur et al., 2002; Das et al., 2007) could therefore have underestimated responses to emotional faces in schizophrenia patients. The amygdalae appear to be critical for lending emotional significance to stimuli and generating negative emotional experience (Abercrombie et al., 1998; Schaefer et al., 2002). Our finding of an amygdalar hyperresponsiveness to masked sad and happy stimuli supports a model of generalized emotional hyperresponsivity in schizophrenia. Data from behavioral studies have shown a heightened perceptual sensitivity to negative facial expression and an aversive perception of positive facial expression in schizophrenia patients on an automatic processing level (Höschel and Irle, 2001; Suslow et al., 2003a). Amygdalar hyperresponsiveness in schizophrenia may underlie the heightened frequency of negative emotions felt in schizophrenia patients relative to healthy individuals (Myin-Germeys et al., 2000; Suslow et al., 2003b). To our knowledge, this is the first neuroimaging study to investigate automatic emotion processing as a function of psychopathology in schizophrenia. Confirming our hypotheses (at least in part), the correlation analysis revealed that schizophrenia patients' amygdala response during the automatic perception of sad (and happy) faces is primarily associated with negative and possibly also positive symptomatology. In the following section, we will focus on the correlation between amygdala responsivity and negative clinical symptoms since this relationship was observed in the voxel-wise and averaged region of interest correlation analyses. According to our data, patients manifesting high automatic amygdalar responsivity to emotional faces are characterized by more intense negative symptoms. In particular, amygdala activation was found to be positively related to the PANSS items “blunted affect” and “lack of spontaneity and flow of conversation”. Thus, it appears that an automatic amygdalar hyperresponsiveness to emotional stimuli could be involved in the development of diminished emotional responsiveness (as characterized by a reduction in facial expression, modulation of feelings, and communicative gestures) and diminished fluidity and productivity of the verbal interactional process. According to Grossberg (Grossberg, 2000), flat affect in schizophrenia can ensue from an overaroused limbic system. Our correlational findings are consistent with those from a recent neuroimaging study (Gur et al., 2007) that found a robust positive correlation of amygdala activation with flat affect expression in schizophrenia. Gur et al. (Gur et al., 2007) suggested that the association between amygdala activation and flat affect expression could be an adaptation for faulty signaling from the amygdala. Interestingly, in a psychophysiological study Schlenker et al. (1995) revealed a positive association between affective flattening and potentiation of the startle reflex to unpleasant visual stimuli in schizophrenia patients. It has been shown that the extent of startle potentiation is related to the activation of the amygdalae, which are thought to be a central part of the neural system modulating startle during negative affect (Pissiota et al., 2003). Our neuroimaging data suggest that schizophrenia patients' amygdalae are especially responsive to the approach-related interpersonal signals of happiness and sadness. Surprisingly at first glance, this reactivity is not related to intense emotional expression, but instead to a diminished emotional expressiveness and a lack of fluid interpersonal interaction. Flat affect expression in schizophrenia patients could represent an attempt to cope with a high perceptual sensitivity and a negative evaluative bias, down-regulating the density of interpersonal communication as well as indirectly the intensity of emotional experience. Inexpressiveness is known to lead to a down-regulation of emotional expression in the interaction
205
partners (Krause et al., 1992) and to be destructive to social interaction (Flack et al., 1998). Javitt (2001) has also argued that emotional withdrawal, lack of openness in conversation, or lack of spontaneity could be consequences of an increased preoccupation with internal experiences of being flooded with emotionally-charged events. Thus, amygdalar hyperresponsivity could function as important factor contributing to social withdrawal and isolation in schizophrenia patients. Certain limitations of the present investigation should be acknowledged. The generalizability of our conclusions is limited due to the small number of subjects. Thus, the replication of our findings is important in terms of increasing confidence in the data. A second limitation is due to the fact that the schizophrenia patients participating in our study were all medicated. Even though no relationship between signal intensity in the amygdala and neuroleptic dose was observed, it is important to investigate amygdala responsivity in unmedicated patients in order to control for medication effects. In addition, only responsivity to sad and happy faces was examined in the present study. Further research must clarify whether schizophrenia patients also show enhanced automatic amygdala responses to facial expressions of other negative emotions, such as anger, fear, or disgust. The present pattern of results regarding the perception of facial emotion in schizophrenia necessitates further research on the relationship between automatic and controlled information processing. Acknowledgement The preparation of this article was facilitated by a grant from the IZKF (University of Muenster) awarded to AVR. References Abercrombie, H.C., Schaefer, S.M., Larson, C.L., Oakes, T.R., Lindgren, K.A., Holden, J.E., Perlman, S.B., Turski, P.A., Krahn, D.D., Benca, R.M., Davidson, R.J., 1998. Metabolic rate in the right amygdala predicts negative affect in depressed patients. Neuroreport 9 (14), 3301–3307. Adolphs, R., Tranel, D., Hamann, S., Young, A.W., Calder, A.J., Phelps, E.A., Anderson, A., Lee, G.P., Damasio, A.R., 1999. Recognition of facial emotion in nine individuals with bilateral amygdala damage. Neuropsychologia 37 (10), 1111–1117. Bargh, J.A., Chartrand, T.L., 1999. The unbearable automaticity of being. American Psychologist 54 (7), 462–479. Beck, A.T., Steer, R.A., 1987. BDI, Beck Depression Inventory: Manual. Psychological Corp, San Antonio, TX. Berenbaum, H., Oltmanns, T.F., 1992. Emotional experience and expression in schizophrenia and depression. Journal of Abnormal Psychology 101 (1), 37–44. Breiter, H.C., Etcoff, N.L., Whalen, P.J., Kennedy, W.A., Rauch, S.L., Buckner, R.L., Strauss, M.M., Hyman, S.E., Rosen, B.R., 1996. Response and habituation of the human amygdala during visual processing of facial expression. Neuron 17 (5), 875–887. Dannlowski, U., Ohrmann, P., Bauer, J., Kugel, H., Arolt, V., Heindel, W., Suslow, T., 2007. Amygdala reactivity predicts automatic negative evaluations for facial emotions. Psychiatry Research: Neuroimaging 154 (1), 13–20. Das, P., Kemp, A.H., Flynn, G., Harris, A.W., Liddell, B.J., Whitford, T.J., Peduto, A., Gordon, E., Williams, L.M., 2007. Functional disconnections in the direct and indirect amygdala pathways for fear processing in schizophrenia. Schizophrenia Research 90 (1–3), 284–294. Ekman, P., Friesen, W.F., 1976. Pictures of Facial Affect. Consulting Psychologists Press, Palo Alto, CA. Fitzgerald, D.A., Angstadt, M., Jelsone, L.M., Nathan, P.J., Phan, K.L., 2006. Beyond threat: amygdala reactivity across multiple expressions of facial affect. NeuroImage 30 (4), 1441–1448. Flack, W.F., Laird, J.D., Cavallaro, L.A., Miller, D.R., 1998. Emotional expression and experience. A psychosocial perspective on schizophrenia. In: Flack, W.F., Laird, J.D. (Eds.), Emotions in Psychopathology. Theory and Research. Oxford University Press, Oxford, pp. 315–322. Grossberg, S., 2000. The imbalanced brain: from normal behavior to schizophrenia. Biological Psychiatry 48 (2), 81–98. 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 (12), 1992–1999. Gur, R.E., Loughead, J., Kohler, C.G., Elliott, M.A., Lesko, K., Ruparel, K., Wolf, D.H., Bilker, W.B., Gur, R.C., 2007. Limbic activation associated with misidentification of fearful faces and flat affect in schizophrenia. Archives of General Psychiatry 64 (12), 1356–1366. Hautzinger, M., Baile, M., Worall, H., 1995. Beck-Depressions-Inventar (BDI). Testhandbuch. Hans Huber, Bern, CH.
206
A.V. Rauch et al. / Psychiatry Research: Neuroimaging 182 (2010) 200–206
Hempel, A., Hempel, E., Schonknecht, P., Stippich, C., Schroder, J., 2003. Impairment in basal limbic function in schizophrenia during affect recognition. Psychiatry Research: Neuroimaging 122 (2), 115–124. Holt, D.J., Kunkel, L., Weiss, A.P., Goff, D.C., Wright, C.I., Shin, L.M., Rauch, S.L., Hootnick, J., Heckers, S., 2006. Increased medial temporal lobe activation during the passive viewing of emotional and neutral facial expressions in schizophrenia. Schizophrenia Research 82 (2–3), 153–162. Höschel, K., Irle, E., 2001. Emotional priming of facial affect identification in schizophrenia. Schizophrenia Bulletin 27 (2), 317–327. Inquisit, 2007. 2.0.61004.4 Computer software. Millisecond Software LLC, Seattle, WA. Javitt, D.C., 2001. Management of negative symptoms of schizophrenia. Current Psychiatry Reports 3 (5), 413–417. Johnston, P.J., Stojanov, W., Devir, H., Schall, U., 2005. Functional MRI of facial emotion recognition deficits in schizophrenia and their electrophysiological correlates. European Journal of Neuroscience 22 (5), 1221–1232. Kay, S.R., Fiszbein, A., Opler, L.A., 1987. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophrenia Bulletin 13 (2), 261–276. Kee, K.S., Green, M.F., Mintz, J., Brekke, J.S., 2003. Is emotion processing a predictor of functional outcome in schizophrenia? Schizophrenia Bulletin 29 (3), 487–497. Kesler-West, M.L., Andersen, A.H., Smith, C.D., Avison, M.J., Davis, C.E., Kryscio, R.J., Blonder, L.X., 2001. Neural substrates of facial emotion processing using fMRI. Brain Research: Cognitive Brain Research 11 (2), 213–226. Killgore, W.D.S., Yurgelun-Todd, D.A., 2004. Activation of the amygdala and anterior cingulate during non-conscious processing of sad versus happy faces. NeuroImage 21 (4), 1215–1223. Knutson, B., 1996. Facial expressions of emotion influence interpersonal trait inferences. Journal of Nonverbal Behavior 20 (3), 165–182. 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. Schizophrenia Research 57 (1), 87–95. Krause, R., Steimer-Krause, E., Hufnagel, H., 1992. Expression and experience of affects in paranoid schizophrenia. European Review of Applied Psychology 42 (2), 131–138. Kring, A.M., Neale, J.M., 1996. Do schizophrenic patients show a disjunctive relationship among expressive, experiential, and psychophysiological components of emotion? Journal of Abnormal Psychology 105 (2), 249–257. Kring, A.M., Kerr, S.L., Smith, D.A., Neale, J.M., 1993. Flat affect in schizophrenia does not reflect diminished subjective experience of emotion. Journal of Abnormal Psychology 102 (4), 507–517. Laux, G., Ditmaier, O., 2006. Praktische Psychopharmakotherapie. fifth ed. ELSEVIER, Urban & Fischer, München. Laux, L., Glanzmann, P., Schaffner, P., 1981. Das State-Trait Angstinventar. Weinheim, Beltz. LeDoux, J.E., 1998. Cognitive-emotional interactions in the brain. Cognition and Emotion 3 (4), 267–289. Liddell, B.J., Brown, K.J., Kemp, A.H., Barton, M.J., Das, P., Peduto, A., Gordon, E., Williams, L.M., 2005. A direct brainstem-amygdala-cortical ‘alarm’ system for subliminal signals of fear. NeuroImage 24 (1), 235–243. 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 (3), 1233–1239. Moore, H., West, A.R., Grace, A.A., 1999. The regulation of forebrain dopamine transmission: relevance to the pathophysiology and psychopathology of schizophrenia. Biological Psychiatry 46 (1), 40–55. Morris, J.S., Friston, K.J., Buchel, C., Frith, C.D., Young, A.W., Calder, A.J., Dolan, R.J., 1998a. A neuromodulatory role for the human amygdala in processing emotional facial expressions. Brain 121 (Pt 1), 47–57. Morris, J.S., Öhman, A., Dolan, R.J., 1998b. Conscious and unconscious emotional learning in the human amygdala. Nature 393 (6684), 467–470. Morris, J.S., Öhman, A., Dolan, R.J., 1999. A subcortical pathway to the right amygdala mediating “unseen” fear. Proceedings of the National Academy of Sciences of the United States of America 96 (4), 1680–1685. Müller, P., Gaebel, W., Bandelow, B., Köpcke, W., Linden, M., Müller-Spahn, F., Pietzcker, A., Tegeler, J., 1998. Zur sozialen Situation schizophrener Patienten. Nervenarzt 69 (3), 204–209. Murphy, S.T., Zajonc, R.B., 1993. Affect, cognition, and awareness: affective priming with optimal and suboptimal stimulus exposures. Journal of Personality and Social Psychology 64 (5), 723–739. Myin-Germeys, I., Delespaul, P.A., deVries, M.W., 2000. Schizophrenia patients are more emotionally active than is assumed based on their behavior. Schizophrenia Bulletin 26 (4), 847–854. Niedenthal, P.M., 1990. Implicit perception of affective information. Journal of Experimental Social Psychology 26 (6), 505–527. 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 schizophrenia
during evaluation with positron emission tomography. American Journal of Psychiatry 160 (10), 1775–1783. Phillips, M.L., Williams, L., Senior, C., Bullmore, E.T., Brammer, M.J., Andrew, C., Williams, S.C., David, A.S., 1999. A differential neural response to threatening and non-threatening negative facial expressions in paranoid and non-paranoid schizophrenics. Psychiatry Research: Neuroimaging 92 (1), 11–31. Phillips, M.L., Williams, L.M., Heining, M., Herba, C.M., Russell, T., Andrew, C., Bullmore, E.T., Brammer, M.J., Williams, S.C., Morgan, M., Young, A.W., Gray, J.A., 2004. Differential neural responses to overt and covert presentations of facial expressions of fear and disgust. Neuroimage 21 (4), 1484–1496. Pissiota, A., Frans, Ö., Michelgard, A., Appel, L., Langstrom, B., Flaten, M.A., Fredrikson, M., 2003. Amygdala and anterior cingulate cortex activation during affective startle modulation: a PET study of fear. European Journal of Neuroscience 18 (5), 1325–1331. Raczkowski, D., Kalat, J.W., Nebes, R., 1974. Reliability and validity of some handedness questionnaire items. Neuropsychologia 12 (1), 43–47. Riederer, P., Laux, G., Pöldinger, W., 1998. Neuro-Psychopharmaka. Ein TherapieHandbuch, Band 4: Neuroleptika, second ed. Springer, Wien. Robinson, S., Windischberger, C., Rauscher, A., Moser, E., 2004. Optimized 3 T EPI of the amygdalae. Neuroimage 22 (1), 203–210. Rotteveel, M., de Groot, P., Geutskens, A., Phaf, R.H., 2001. Stronger suboptimal than optimal affective priming? Emotion 1 (4), 348–364. Salokangas, R.K.R., Honkonen, T., Stengard, E., Koivisto, A.M., 2001. To be or not to be married—that is the question of quality of life in men with schizophrenia. Social Psychiatry and Psychiatric Epidemiology 36 (8), 381–390. Sato, W., Yoshikawa, S., Kochiyama, T., Matsumura, M., 2004. The amygdala processes the emotional significance of facial expressions: an fMRI investigation using the interaction between expression and face direction. NeuroImage 22 (2), 1006–1013. Schaefer, S.M., Jackson, D.C., Davidson, R.J., Aguirre, G.K., Kimberg, D.Y., ThompsonSchill, S.L., 2002. Modulation of amygdalar activity by the conscious regulation of negative emotion. Journal of Cognitive Neuroscience 14 (6), 913–921. Schlenker, R., Cohen, R., Hopmann, G., 1995. Affective modulation of the startle relfex in schizophrenic patients. European Archives of Psychiatry and Clinical Neuroscience 245 (6), 309–318. 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. Schizophrenia Research 34 (3), 133–142. Spielberger, C.D., Gorsuch, R.L., Lushene, R.E., 1970. Manual for the State-Trait Anxiety Inventory. Consulting Psychologists Press, Palo Alto, CA. Suslow, T., Roestel, C., Arolt, V., 2003a. Affective priming in schizophrenia with and without affective negative symptoms. European Archives of Psychiatry and Clinical Neuroscience 253 (6), 292–300. Suslow, T., Roestel, C., Ohrmann, P., Arolt, V., 2003b. The experience of basic emotions in schizophrenia with and without affective negative symptoms. Comprehensive Psychiatry 44 (4), 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 (3), 1247–1254. Taylor, S.F., Liberzon, I., Decker, L.R., Koeppe, R.A., 2002. A functional anatomic study of emotion in schizophrenia. Schizophrenia Research 58 (2–3), 159–172. Tzourio-Mazoyer, N., Landeau, B., Papathanassiou, D., Crivello, F., Etard, O., Delcroix, N., Mazoyer, B., Joliot, M., 2002. Automated anatomical labeling of activations in SPM using a macroscopic anatomical parcellation of the MNI MRI single-subject brain. Neuroimage 15 (1), 273–289. Wang, L., McCarthy, G., Song, A.W., LaBar, K.S., 2005. Amygdala activation to sad pictures during high field (4 Tesla) functional magnetic resonance imaging. Emotion 5 (1), 12–22. Whalen, P.J., Rauch, S.L., Etcoff, N.L., McInerney, S.C., Lee, M.B., Jenike, M.A., 1998. Masked presentations of emotional facial expressions modulate amygdala activity without explicit knowledge. Journal of Neuroscience 18 (1), 411–418. Williams, L.M., Das, P., Harris, A.W., Liddell, B.B., Brammer, M.J., Olivieri, G., Skerrett, D., Phillips, M.L., David, A.S., Peduto, A., Gordon, E., 2004. Dysregulation of arousal and amygdala-prefrontal systems in paranoid schizophrenia. American Journal of Psychiatry 161 (3), 480–489. Williams, L.M., Das, P., Liddell, B.J., Olivieri, G., Peduto, A.S., David, A.S., Gordon, E., Harris, A.W., 2007. Fronto-limbic and autonomic disjunctions to negative emotion distinguish schizophrenia subtypes. Psychiatry Research 155 (1), 29–44. Winkielman, P., Knutson, B., Paulus, M., Trujillo, J.L., 2007. Affective influence on judgments and decisions: moving towards core mechanisms. Review of General Psychology 11 (2), 179–192. Wittchen, H.U., Wunderlich, U., Gruschwitz, S., Zaudig, M., 1997. SKID-I. Strukturiertes Klinisches Interview für DSM-IV. Hogrefe, Göttingen. Yang, T.T., Menon, V., Eliez, S., Blasey, C., White, C.D., Reid, A.J., Gotlib, I.H., Reiss, A.L., 2002. Amygdalar activation associated with positive and negative facial expressions. Neuroreport 13 (14), 1737–1741.