Multidimensional assessment of empathic abilities: Neural correlates and gender differences

Psychoneuroendocrinology (2010) 35, 67—82

a v a i l a b l e a t w w w. s c i e n c e d i r e c t . c o m

j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / p s y n e u e n

Multidimensional assessment of empathic abilities: Neural correlates and gender differences Birgit Derntl a,b,*, Andreas Finkelmeyer a, Simon Eickhoff a,c, Thilo Kellermann a, Dania I. Falkenberg a, Frank Schneider a,d, Ute Habel a a

Department of Psychiatry and Psychotherapy, RWTH Aachen University, Aachen, Germany Institute for Clinical, Biological and Differential Psychology, University of Vienna, Vienna, Austria c Institute of Neuroscience and Medicine - 4, Research Center Ju ¨lich, Germany d Ju ¨lich Aachen Research Alliance (JARA), Translation Brain Medicine, Germany b

Received 12 August 2009; received in revised form 9 October 2009; accepted 10 October 2009

KEYWORDS Empathy; Gender; Social cognition; Perspective taking; Affective responsiveness; Emotion recognition

Summary Empathy is a multidimensional construct and comprises the ability to perceive, understand and feel the emotional states of others. Gender differences have been reported for various aspects of emotional and cognitive behaviors including theory of mind. However, although empathy is not a single ability but a complex behavioral competency including different components, most studies relied on single aspects of empathy, such as perspective taking or emotion perception. To extend those findings we developed three paradigms to assess all three core components of empathy (emotion recognition, perspective taking and affective responsiveness) and clarify to which extent gender affects the neural correlates of empathic abilities. A functional MRI study was performed with 12 females (6 during their follicular phase, 6 during their luteal phase) and 12 males, measuring these tasks as well as self-report empathy questionnaires. Data analyses revealed no significant gender differences in behavioral performance, but females rated themselves as more empathic than males in the self-report questionnaires. Analyses of functional data revealed distinct neural networks in females and males, and females showed stronger neural activation across all three empathy tasks in emotion-related areas, including the amygdala. Exploratory analysis of possible hormonal effects indicated stronger amygdala activation in females during their follicular phase supporting previous data suggesting higher social sensitivity and thus facilitated socio-emotional behavior. Hence, our data support the assumption that females and males rely on divergent processing strategies when solving emotional tasks: while females seem to recruit more emotion and self-related regions, males activate more cortical, rather cognitive-related areas. # 2009 Elsevier Ltd. All rights reserved.

* Corresponding author at: Department of Psychiatry and Psychotherapy, RWTH Aachen University, Pauwelsstrasse 30, 52074 Aachen, Germany. Tel.: +49 241 8080279; fax: +49 241 8082304. E-mail address: [email protected] (B. Derntl).

1. Introduction Gender differences in different behavioral domains, among them several emotional competencies (Bradley et al., 2001;

0306-4530/$ — see front matter # 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.psyneuen.2009.10.006

68 Grossman and Wood, 1993; Kring and Gordon, 1998) have been documented for a long time. Several studies demonstrated that females frequently report about more intense but also more negative emotions than males (e.g., Fischer et al., 2004; Tobin et al., 2000; Vrana and Rollock, 2002). Despite a general ability in both genders to correctly infer the emotional state of others, some studies suggest that female subjects show significantly better performance in emotion recognition and expression than male participants (e.g., Goos and Silverman, 2002; Hall and Matsumoto, 2004; Montagne et al., 2005). However, a growing body of research demonstrates no gender differences in behavioral parameters but in the underlying neural network, ranging from different activation in frontal regions to subcortical areas such as the amygdala (e.g., Kemp et al., 2004; Lee et al., 2002, 2005). Applying neuroimaging tools, a stronger lateralization of these neural networks in males during emotion processing has frequently been observed (e.g., Kesler-West et al., 2001; Killgore and Yurgelun-Todd, 2001; for metaanalysis see Wager et al., 2003). Some studies also report a significant interaction of emotional valence and gender of participants on neural activation, particularly affecting the amygdala (Schienle et al., 2005; Wrase et al., 2003). Moreover, divergent results regarding activation of the amygdala and orbitofrontal cortex have also been demonstrated in adolescent girls and boys (e.g., McClure et al., 2004). Recently, Li et al. (2008) reported significant attentional and evaluative biases for moderately negative pictures, showing that women might be particularly more sensitive to less salient stimuli. Gender differences have also been observed for the neural correlates of interaction of emotion and cognition (Koch et al., 2007; Seubert et al., 2009) and also for mood induction with happy and sad facial expressions (Schneider et al., 2000), emotional pictures (Hofer et al., 2006) and emotional words (Hofer et al., 2007). These studies indicated that females and males use different neural networks comprising various frontal and temporal regions as well as subcortical areas such as the amygdala for the processing and experiencing of positive and negative emotions. Concerning empathy and empathic behavior, several studies have suggested that females might be more empathic than males, but mostly relied on self-report data (e.g., Baron-Cohen and Wheelwright, 2004; Eisenberg and Lennon, 1983; Hoffman, 1977; Rueckert and Naybar, 2008) possibly prompting gender stereotype responses. The influence of such stereotypes on behavior as well as cerebral responses has been demonstrated impressively (Krendl et al., 2008). Hence, assessments of empathic abilities should avoid stimulating such stereotypes. Besides self-report, gender differences in empathy have also been shown using functional neuroimaging, for example Singer et al. (2006) studied brain activity while female and male subjects underwent mild electric shocks or witnessed a confederate receiving a similar shock. While females showed a response in pain-related areas even when an unfairly behaving confederate received a shock, males exhibited activation in brain regions associated with reward, i.e. nucleus accumbens and orbitofrontal cortex, under this condition. Using EEG, a similar effect has been reported by Fukushima and Hiraki (2006), who observed a medial-frontal negative component in women and men when they lost in a gambling task, but interestingly, women also showed this

B. Derntl et al. pattern when they only observed a negative outcome for their confederate. Additionally, Han et al. (2008) observed a stronger modulation of the long latency response associated with affective empathy in females than males in a pain judgment task. Recently, gender differences have also been reported for the neural correlates of emotional perspective taking (Schulte-Ru ¨ther et al., 2008) using an emotional attribution task. The results suggest that the better performance of females is related to an enhanced recruitment of inferior frontal and superior temporal regions, while males activate the left temporo-parietal junction instead when assessing emotional states of others and themselves. Taken together, these findings suggest that, although males and females may not differ in terms of behavioral and peripheral physiological measures of emotional responsiveness, the two genders may well differ in the recruitment of cerebral networks (e.g., Kemp et al., 2004; Schulte-Ru ¨ther et al., 2008). However, due to the heterogeneity of task demands, neuroimaging tools and data analysis, the nature of these differences remains unclear. While most studies explored empathic abilities using pain-related paradigms (e.g., Singer et al., 2006), only Schulte-Ru ¨ther et al. (2008) explored differences regarding empathic abilities for some basic emotions. To evaluate these previous findings, it is important to mention, that empathy is a multidimensional construct and requires the ability to perceive, understand and feel the emotional states of others. Due to the complexity of the construct empathy has various definitions, but according to most models one can derive at least three core components (Decety and Jackson, 2004): (a) recognition of emotions in oneself and others via facial expressions, speech or behavior, (b) the sharing of emotional states with others, i.e. the ability to experience similar emotions as others while being conscious that this is the simulation of the emotional feeling and it is not one’s own emotion (affective responsiveness), and (c) to take the perspective of another person, though the distinction between self and other remains intact (emotional perspective taking). In light of the heterogeneity of previous studies on gender differences in emotional competencies and their neural correlates, this is the first study to assess the neural network underlying all three defining components of empathy in females and males. This approach enabled a more encompassing and detailed analysis of these emotional competencies, their interactions and possible general and task-specific gender differences. Based on prior results (e.g., Rueckert and Naybar, 2008), we hypothesized higher empathy scores of females in selfreport measures. Moreover, considering previous neuroimaging studies on emotional competencies and separate empathy components, we hypothesized a significant difference between females and males in the cerebral networks underlying the empathy components due to diverging processing strategies and sensitivity to emotional stimuli (e.g., Li et al., 2008; Schulte-Ru ¨ ther et al., 2008). Since the amygdala has been known to be essential for the evaluation and relevance detection of emotional stimuli (cf. Sander et al., 2003) and gender differences in amygdala activation during emotion processing have been reported frequently, we aimed to determine its exact role in the different components of empathy.

Gender and empathy

69

Regarding previous results (e.g, Schulte-Ru ¨ther et al., 2008), we assume that during emotional perspective taking and emotion recognition females will recruit more emotionrelated regions such as the inferior frontal and superior temporal gyrus, while males will exhibit stronger activation in the temporo-parietal junction. Finally, for affective responsiveness we hypothesize overall stronger neural activation in female subjects, and particularly in the superior temporal and medial-frontal regions as well as the amygdala (cf. Hofer et al., 2006, 2007). Due to our preceding results (Derntl et al., 2008a,b) we also conducted exploratory analyses concerning the influence of cycle phase on the activation pattern and suggested more pronounced responses in emotional networks during the follicular phase.

2. Methods and material 2.1. Sample Twelve right handed healthy Caucasian females aged 23—40 years (mean age 28.3 years, SD = 6.6) and twelve right handed healthy Caucasian males aged 21—34 years (mean age 26.3 years, SD = 4.1) participated in the study. They were recruited via advertisements posted at the RWTH Aachen University, Germany. All subjects were paid for their participation and written informed consent was obtained. The study was approved by the local Institutional Review Board and subjects were treated according to the Declaration of Helsinki (1964) regarding treatment of human research participants. The presence of psychiatric disorders (according to DSM IV) was excluded on the basis of the German version of the Structured Clinical Interview for DSM (SCID, Wittchen et al., 1997) conducted by experienced clinical psychologists. The usual exclusion criteria for MRI were also applied. Females

and males were of similar age ( p = .382) and years of education ( p = .675; females, mean = 15.9 years, SD = 2.5; males, mean = 16.3 years, SD = 2.3). Females were not taking oral contraceptives or any other hormone treatment and six females were measured during their follicular phase, the remaining six during their luteal phase. Three questionnaires measuring cognitive and affective empathy were administered: the Questionnaire Measure of Emotional Empathy (QMEE, Mehrabian and Epstein, 1972), the German Questionnaire for Assessment of Empathy, Social Attitude and Aggression (FEEPA, Lukesch, 2006) and the German version of the Interpersonal Reactivity Index (IRI, Davis, 1983). All participants completed tests tapping crystallized verbal intelligence (MWT-B, Lehrl, 1996), executive functions (TMT-A/-B, Reitan, 1956), working memory (digit span, WAIS III, Von Aster et al., 2006), and word fluency (Aschenbrenner et al., 2000). Performance of females and males did not differ in any of the neurocognitive tasks (MWT-B: t = .220, p = .829; TMT-A: t = .382, p = .707; TMT-B: t = .215, p = .832; phonematic word fluency: t = .830, p = .421; semantic word fluency: t = .583, p = .570; working memory: t = .714, p = .487). Demographic and neuropsychological characteristics are shown in Table 1.

2.2. Functional tasks Similar versions of the functional tasks have been validated in a recent behavioral study and are described in more detail there (Derntl et al., 2009a). Briefly, we applied three tasks tapping the three components of empathy separately. 2.2.1. Emotion recognition We presented 60 colored photographs of Caucasian facial identities depicting five basic emotions (happiness, sadness,

Table 1 Overview on demographic and neuropsychological characteristics of females and males including self-report data from the empathy questionnaires. Significant differences in self-report scores are highlighted. Females

Males

Demographics Sample size Age (mean years) Education (mean years)

12 28.3 15.9

12 26.3 17.1

Empathy QMEE FEPAA-E IRI — empathic concern IRI — perspective taking IRI — fantasy IRI — personal distress IRI — empathy

17.83 (3.9) 24.33 (1.8) 16.08 (1.8) 16.25 (1.7) 15.42 (1.9) 10.83 (2.9) 47.75 (3.7)

17.83 (2.4) 23.67 (2.5) 13.33 (2.7) 15.33 (3.1) 13.33 (3.1) 9.00 (2.2) 42.17 (7.4)

Neuropsychology Verbal intelligence (MWT-B) Executive functions (TMT-A, sec) Executive functions (TMT-B, sec) Word fluency — lexical Word fluency — phonemic

31.6 21.9 35.9 16.6 29.4

31.2 20.4 37.2 14.4 26.9

p-Values

.382 .675 1.000 .455 .008 .378 .062 .099 .030 .829 .707 .832 .570 .421

70 anger, fear, disgust) and neutral expressions. Half of the stimuli were used for emotion recognition, the other half for the age discrimination control task. All stimuli were selected from a standardized stimulus set (Gur et al., 2002) that has been used frequently as neurobehavioral probes (e.g., Derntl et al., 2008a,b, 2009b; Fitzgerald et al., 2006; Habel et al., 2007; Moser et al., 2007). Stimuli were comparable with respect to gender, age, intensity, valence, and brightness. Stimulus presentation was randomized with regard to task, emotion and gender but kept constant for all subjects. For emotion recognition subjects were instructed to choose the correct emotion from two possibilities presented on the left and right of the image, by pressing the corresponding button of a response box using the right hand. In the control trials, subjects had to judge which of two age decades was closer to the poser’s age and then press the corresponding button. One of the options was correct and the other was selected at random from all other choices and position of correct choice was balanced for left vs. right button press. Facial expressions were presented maximally for 5 s with a randomized, variable interstimulus interval (ISI) ranging from 8 s to 12 s (during which subjects viewed a blurred face with a central crosshair). Manual responses triggered immediate progression to the next ISI. 2.2.2. Emotional perspective taking Participants viewed 70 items in total depicting scenes showing two Caucasians involved in social interaction thereby portraying five basic emotions. Half of the stimuli were used for emotional perspective taking, the other half for the control task. The face of one person in the scene was masked and participants were asked to infer the corresponding emotional expression of the masked face. These scenes were shown for 4 s and immediately afterwards, responses were made by selecting between two different emotional facial expressions or a neutral expression. Facial alternatives were taken from the same pool of stimuli described above. Again, one option was correct and the alternative was selected at random from the remaining choices. In the control trials, participants had to indicate whether the left or the right face was masked by pressing the corresponding button on the response device after being presented with two response alternatives (‘left’, ‘right’). Stimuli were presented in blocks of five stimuli, each block was preceded by an instruction slide indicating the next task for the block (emotional or control). 2.2.3. Affective responsiveness We presented 70 short written sentences describing real-life situations which are likely to induce the basic emotions described above. Again, half of the stimuli were used for the affective responsiveness task and the other half for the control task. For affective responsiveness, participants were asked to imagine how they would feel if they were experiencing those situations. Stimuli were presented for 4 s and response format was the same as for emotional perspective taking, presenting two facial expressions, one showing the correct emotion and the other was chosen randomly from the other expressions. For the control task, participants had to indicate the number of words forming the sentence and were then presented with two options. Again, subjects were confronted with blocks of stimuli (five stimuli/block) and

B. Derntl et al. informed prior whether an emotional or control block will appear next. Response format was kept maximally similar between tasks allowing comparisons between tasks, i.e. differences could be traced back to different task requirements not to different response formats. Fig. 1 illustrates the three empathy tasks presented in this study. Prior to this study, tasks were validated behaviorally in a group of 55 healthy females and males resulting in a set of items that were correctly recognized by over 70% of all raters. All stimuli were presented using goggles (VisuaStimDigital, Resonance Technology Inc., Los Angeles, CA). The presentation of images, recording of responses and acquisition of scanner triggers was achieved using the Presentation# software package (Neurobehavioral Systems, Inc., Albany, CA).

2.3. Behavioral data analysis Statistical analyses were performed using SPSS 15.0 and level of significance was set at p = .05. The correct responses of each empathy task and the corresponding control task acquired during scanning were analyzed using three repeated-measures ANOVAs with task (empathy vs. control) as within-subject factor and gender as between-subjects factor. Similarly, for analysis of reaction times we used repeated-measures ANOVA with task as within-subject factor and gender as between-subjects factor. For significant effects partial-eta squares are listed as estimates of effect size and Greenhouse-Geisser corrected degrees of freedom and p-values are reported. Gender differences in the empathy questionnaires and the neurocognitive tests were assessed using two-sample t-tests. Correlations between accuracy measures of the empathy paradigms and self-report scores were computed using Pearson correlations since normal distribution of all variables was given, testing one-sided for negative, respective positive correlations. An exploratory analysis to reveal any impact of menstrual cycle phase on behavioral performance was computed applying two-sample t-tests for accuracy and reaction time in the three empathy tasks.

2.4. FMRI acquisition parameters and data processing 2.4.1. Data acquisition All subjects were examined with a 3 T whole-body scanner (Philips, Best, The Netherlands) at the Interdisciplinary Centre for Clinical Research, Medical Faculty of the RWTH Aachen University. Functional imaging was performed using gradientrecalled EPI, and 35 oblique axial slices were acquired using asymmetric k-space sampling (FOV = 24 cm  24 cm, matrix size 64  64, slice thickness 3 mm, slice gap .3 mm, TR = 2200 ms, TE = 31 ms). Each task was divided into two experimental runs of about 10 min acquiring between 220 (emotion recognition and age discrimination paradigm) and 360 slabs (emotional perspective taking and affective responsiveness tasks). Taken together, 6 runs were performed (2 per task), tasks were presented in a randomized and empathy and control items were counterbalanced across each run.

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Figure 1 Illustration of the three newly developed tasks, measuring emotion recognition and age discrimination (a), emotional perspective taking (b), and affective responsiveness (c) as components of the empathic ability. Task instructions are listed next to the example stimuli.

Measurement time was about 60 min. After functional neuroimaging, anatomical images were acquired using standardized T1-weighted and T2-weighted 3D sequences. 2.4.2. Data preprocessing Functional data were preprocessed using SPM5 (http:// www.fil.ion.ucl.ac.uk/spm/spm5.html). Images were slice timing corrected, realigned to the mean image and normalized into the standardized stereotactic space. To increase SNR and allow inferences as to statistical significance, functional data sets were spatially smoothed using an isotropic Gaussian kernel with a full-width-at-half-maximum of 8 mm. For this event-related design, each stimulus type was modeled with a separate regressor convolved with the canonical hemodynamic response function. For the emotional perspective taking task as well as the affective responsiveness task not only each stimulus but also each response option was modeled with a separate regressor allowing the differentiation between task-related neural reactivity and neural activation due to the response format (emotional facial expressions vs. verbal response labels in the control tasks). For the present data analysis, we did not include the response related regressors in our model, thus only focused on the neural activation during stimulus presentation by entering only the stimulus regressors into the analysis.

2.5. FMRI data analysis For the analysis of functional data, we pooled all stimuli across emotions to assess brain responses to each empathy

task/control task leaving a minimum of 30 stimuli per task for statistical analysis (emotion recognition/control task: 30 stimuli; emotional perspective taking/control task: 35 stimuli; affective responsiveness/control task: 35 stimuli). Statistical analysis was performed at the individual and group level. To detect group differences, contrast images from all subjects (condition [emotion/control] vs. rest) were included in a second level random effects analysis. To specifically analyze neural activation during empathy processing we performed a 2 (gender)  6 (task) mixed effects ANOVA with gender as between-subjects factor and task as withinsubject factor. Since we were specifically interested in gender differences in empathic abilities and their neural correlates, we explored neural activation for each empathy task always considering the corresponding control tasks by applying F-contrasts and, if significant, by subsequent post hoc tcontrasts disentangling any gender differences. 2.5.1. ROI analysis We performed a ROI analysis for the amygdala region with the aim of maximizing the sensitivity to gender as well as hemispheric lateralization differences in the amygdala. Furthermore, we aimed to determine its exact role in the different components of empathy. The amygdala has been chosen due to several reasons: it plays a major role in emotion processing, has also been implicated in empathy and has revealed gender differences. Values for amygdala ROIs were extracted using a template based on the probabilistic cytoarchitectonic maps (Amunts et al., 2005), as was available in the Anatomy toolbox in SPM5 (Eickhoff et al., 2005). Mean parameter

72 estimates were extracted for left and right amygdala ROI in each condition (empathy task > control task) and Levene tests for homogeneity of variances indicated homoscedasticity for all parameter estimates of all tasks (emotion recognition left: p = .947, emotion recognition right: p = .756; emotional perspective taking left: p = .298, emotional perspective taking right: p = .770; affective responsiveness left: p = .832, affective responsiveness right: p = .324). A three-way ANOVA was applied with gender as betweensubject factor as well as task and laterality as repeated factors. Greenhouse-Geisser corrected p-values are presented. Moreover, for an exploratory analysis of the influence of menstrual cycle phase of females on amygdala activation during the three empathy tasks we performed a repeatedmeasures ANOVA with task as within-subjects and phase (follicular vs. luteal phase) as between-subjects factor. Again, Greenhouse-Geisser corrected p-values are presented. 2.5.2. Corollary analyses Correlation analysis was performed for each task between performance (% correct and reaction time) and whole brain BOLD effect as well as amygdala parameter estimates (taken from the ROI analysis). Moreover, neural activation was also correlated with performance in the self-report empathy questionnaires. In order to account for multiple comparisons we applied a combined height and extent threshold technique based on Monte-Carlo simulations using AlphaSim (Cox, 1996). According to 1000 simulations based on a height threshold of p < .001 (uncorrected) and the spatial properties of the residual image an extent threshold of 55 contiguous voxels suffices to comply with a family wise error of p < .05. This correction for thresholding will be referred to as ‘‘height and extent threshold’’ (HET) and group results as well as direct comparisons between females and males are demonstrated at this threshold.

B. Derntl et al. performance in the control task, no significant gender difference (F(1,21) = .962, p = .338, ns), and no significant taskby-gender interaction (F(1,21) = .415, p = .526, ns). Again for reaction times a significant task effect (F(1,21) = 87.695, p < .001, partial-eta sq = .807) emerged with faster responses in the control condition but neither a significant gender effect (F(1,21) = 1.610, p = .218, ns) nor a significant task-by-gender interaction (F(1,21) = .045, p = .835, ns) occurred. 3.1.3. Affective responsiveness Data analysis demonstrated a significant task effect (F(1,21) = 5.704, p = .026, partial-eta sq = .214) with better performance during the emotional task, no significant gender effect (F(1,21) = .027, p = .871, ns), and no significant taskby-gender interaction (F(1,21) = .076, p = .786, ns). For reaction times, a significant task effect (F(1,21) = 82.065, p < .001, partial-eta sq = .796) occurred, but again no significant gender effect (F(1,21) = .254, p = .619, ns) nor a significant task-by-gender interaction (F(1,21) = 1.147, p = .296, ns) emerged. Fig. 2 illustrates performance on the three empathy tasks across females and males. Correlation analyses between the empathy tasks revealed significant positive associations between all three tasks (all ps < .001), which has been shown before (Derntl et al., 2009a). Moreover, a significant correlation emerged between performance in affective responsiveness and

3. Results 3.1. Behavioral performance Due to an error of the response device, behavioral data of one male subject were not included in the final analysis. 3.1.1. Emotion recognition Analysis of percent correct demonstrated a significant task effect (F(1,21) = 46.399, p < .001, partial-eta sq = .688), with higher percent correct for the emotion recognition task, no significant gender effect (F(1,21) = 1.179, p = .290, ns), and no significant task-by-gender interaction (F(1,21) = .305, p = .587, ns). Similar for reaction times, a significant task effect (F(1,21) = 237.626, p < .001, partial-eta sq = .919) with faster responses in the age discrimination task, no significant gender effect (F(1,21) = 2.069, p = .165, ns), and no significant task-by-gender interaction (F(1,21) = .230, p = .637, ns) emerged. 3.1.2. Emotional perspective taking Repeated-measures ANOVA revealed a significant task effect (F(1,21) = 5.511, p = .029, partial-eta sq = .208), with better

Figure 2 Performance (% correct with SD, a) and reaction times (b) in emotion recognition (ER), emotional perspective taking (PT), and affective responsiveness (AR) in females and males. Results of data analyses revealed no significant difference between groups.

Gender and empathy verbal intelligence (r = .610, p = .006), but no other correlation between neurocognitive tests and empathy tasks reached significance. Exploratory analysis of any impact of menstrual cycle phase on behavioral performance during scanning revealed no significant result (emotion recognition performance: t(10) = .391, p = .704, emotion recognition reaction time: t(10) = .152, p = .882; perspective taking performance: t(10) = .077, p = .940, perspective taking reaction time: t(10) = .347, p = .736; affective responsiveness performance: t(10) = .192, p = .852, affective responsiveness reaction time: t(10) = .196, p = .848).

73 (t = 2.327, df = 22, p = .030) and the IRI subscale empathic concern (t = 2.914, df = 22, p = .008) in males. However, after correction for multiple comparisons, only the correlation for the IRI subscale empathic concern remains significant ( p < .0083). For all other self-report data no significant differences occurred (all ps > .062). Correlation analyses with our empathy tasks indicated significant correlations between affective responsiveness and the FEEPA (r = .398, p = .030) as well as the IRI total score (r = .458, p = .014). No other correlations reached significance.

3.2. Functional data 3.1.4. Empathy questionnaires Direct comparison of self-report empathy scores demonstrated significantly lower scores in the IRI empathy scale

Separate group analyses for female and male participants showed activation of a widespread cortical-subcortical

Figure 3 Illustration of the neural networks underlying the empathic behavior in females and males (contrast: emotion > rest), showing similar activation in fronto-temporal, occipital regions and brainstem, with pronounced activation in the inferior, middle and superior frontal region bilaterally ( p < .05 HET corrected).

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B. Derntl et al.

network including inferior and middle frontal regions, orbitofrontal cortex, temporal gyri, fusiform gyri, amygdala, hippocampus, inferior parietal cortex, and cingular cortex across all tasks. Fig. 3 illustrates activation patterns for the three tasks for female and male participants separately. Analysis of the whole brain functional data applying a mixed effects ANOVA revealed significant gender differences for all three empathy tasks, directly controlling for the corresponding control condition: For emotion recognition, the F-contrast revealed significant gender differences (F(1,132) = 11.33, p < .05 HET corr.). Post hoc t-contrasts indicated that females recruited the right angular gyrus and the left superior frontal gyrus while males showed higher activation in the rolandic operculum, the right middle cingulate cortex and the left superior frontal gyrus (t = 3.15, p < .05 HET corr., see Table 2 for details). For emotional perspective taking, the F-contrast also demonstrated significant gender differences (F(1,132) = 11.33, p < .05 HET corr.). Post hoc t-contrasts demonstrated that while females showed stronger neural response in a broad network including the right amygdala, both hippo-

campi, superior temporal gyri, calcarine gyri as well as inferior frontal gyri, males only recruited the temporo-parietal junction more strongly (t = 3.15, p < .05 HET corr., see Table 2 for details). Analysis of any gender differences in the neural correlates of affective responsiveness revealed a significant result (F(1,132) = 11.33, p < .001 uncorr. [20]). Post hoc t-contrasts directly comparing neural activation of females with males (and vice versa) revealed stronger activation in females only. Here, females showed particularly stronger neural activation bilaterally in the postcentral gyri, the cerebellum, the anterior cingulate, the hippocampi, the superior frontal gyri and the left insula (t = 3.15, p < .05 HET corr., see Table 2 for details). Table 2 shows MNI coordinates of all the regions that were revealed in the post hoc t-contrasts revealing gender differences in the neural activation underlying the three empathy components. Performing a conjunction analysis across the three empathy tasks (with the task > control contrasts) each represented by the main effect across females and males, we observed neural activation in the inferior frontal gyrus pars

Table 2 Results of the post-hoc tests revealing gender differences for all three empathy tasks. Regions are listed with MNI coordinates, cluster size and t-value (all p < .05 HET corrected). Contrast

MNI coordinates X

Y

Cluster size

Z

t-Value df = 132

L/R

Region

ER F > M (T-contrast)

48 18

64 56

26 36

67 73

4.42 3.99

R L

Angular gyrus Superior frontal gyrus

ER M > F (T-contrast)

62 18 6

6 10 12

10 60 38

176 83 103

4.51 3.72 3.66

R L R

Rolandic operculum Superior frontal gyrus Middle cingulate gyrus

PT F > M (T-contrast)

12 56 4 28 40 32 46 30 36 54

6 34 30 24 46 46 2 66 20 12

8 14 10 2 16 46 14 6 30 8

1017 345 101 147 287 92 67 74 104 76

5.05 4.85 4.45 4.17 4.16 4.06 3.96 3.79 3.76 3.68

R R L L L R R L L L

Amygdala Inferior frontal gyrus Hippocampus

Calcarine gyrus Inferior frontal gyrus Superior temporal gyrus

PT M > F (T-contrast)

54

62

36

76

3.88

R

Temporo-parietal junction

AR F > M (T-contrast)

22 42 14 6 14 20 34 16 22 6 46

34 36 44 16 44 16 10 16 42 16 4

64 54 20 36 22 64 26 24 38 36 0

344 287 323 641 57 164 148 56 183 641 55

4.68 4.63 4.38 4.37 4.36 4.11 3.98 3.92 3.84 3.72 3.68

L R L R R R L R L R L

Postcentral gyrus

AR M > F (T-contrast)

No suprathreshold activation

Medial temporal gyrus Superior temporal gyrus

Cerebellum Anterior cingulate Cerebellum Superior frontal gyrus Hippocampus Superior frontal gyrus Anterior cingulate Insula

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Figure 4 Illustration of the conjunction analysis across all three tasks ( p < .05 HET corrected), revealing activation in the inferior frontal and middle temporal gyri bilaterally, the left superior frontal gyrus and the left posterior as well as middle cingulate gyrus, and the cerebellum.

76 triangularis bilaterally (left: 52, 30, 0, k = 1732, t = 5.00; right: 52, 32, 4, k = 3975, t = 4.99), the inferior temporal gyri extending to the middle temporal gyri (left: 46, 2, 34, k = 1946, t = 3.98; right: 60, 60, 0, k = 2305, t = 3.76), the left superior medial-frontal gyrus (x,y,z: 2, 32, 52, k = 163, t = 2.44), the left posterior (x,y,z: 14, 38, 12, k = 192, t = 2.20) and middle cingulate gyrus (x,y,z: 2, 10, 38, k = 199, t = 2.10) as well as the cerebellum (x,y,z: 14, 40, 18, k = 187, t = 2.03). Gender-specific conjunction analyses revealed only one region for females, the left inferior frontal gyrus (x,y,z: 54, 28, 4, k = 57, t = 3.79), whereas for males only the left middle temporal gyrus (x,y,z: 46, 0, 32, k = 34, t = 3.61) showed activation throughout all empathy tasks > control conditions. See Fig. 4 for illustration of the group conjunction analysis. Correlation analyses in females between self-report empathy score and neural activation during emotion recognition revealed significant positive associations of the insula bilaterally (QMEE: x,y,z: 42, 2, 6, t = 5.20, p < .001 uncorr.; x,y,z: 48, 2, 0, t = 4.51, p < .001 uncorr.), the right superior temporal gyrus (FEPAA: x,y,z: 60, 18, 6, t = 5.39, p < .001 uncorr.), and the left middle temporal gyrus (FEPAA: x,y,z: 42, 16, 30, t = 5.68, p < .001 uncorr.). Moreover, the following neural correlates of emotional perspective taking showed significant negative associations with self-report empathy scores: right middle temporal gyrus (FEPAA: x,y,z: 64, 36, 0, t = 9.60, p < .001 uncorr.) and the left inferior frontal gyrus (FEPAA: x,y,z: 50, 26, 4, t = 5.72, p < .001 uncorr.; IRI: x,y,z: 44, 22, 20, t = 5.44, p < .001 uncorr.). For affective responsiveness, significant positive correlations emerged between empathy scores and the middle temporal gyrus bilaterally (QMEE: x,y,z: 42, 16, 30, t = 5.68, p < .001 uncorr.; x,y,z: 40, 14, 28, t = 4.61, p < .001 uncorr.). For males, significant positive correlations only emerged between FEPAA scores and left inferior temporal gyrus (x,y,z:

B. Derntl et al. 46, 48, 12, t = 5.37, p < .001 uncorr.) during affective responsiveness, and left temporal pole (x,y,z: 50, 12, 0, t = 5.46, p < .001 uncorr.) during emotional perspective taking. Additionally, negative correlations between IRI empathy scores and activation of the left temporo-parietal junction (x,y,z: 42, 38, 36, t = 7.53, p < .001 uncorr.) during emotional perspective taking, as well as the QMEE scores and lingual gyrus activation (x,y,z: 8, 74, 0, t = 6.79, p < .001 uncorr.), and left anterior cingulate (x,y,z: 10, 38, 24, t = 5.91, p < .001 uncorr.) during emotion recognition and emotional perspective taking occurred.

3.3. ROI analysis The ROI analysis demonstrated no significant task effect (F(2,44) = 1.164, p = .322, ns), no significant main effect of laterality (F(1,22) = 3.155, p = .090, ns), but a main effect of gender (F(1,22) = 34.939, p < .001, partial-eta sq = .614), with stronger activation in females compared to males. Moreover, no interaction reached significance (task-by-gender: F(2,44) = 2.397, p = .103, ns; laterality-by-gender: F(1,22) = .032, p = .859, ns; task-by-laterality: F(2,44) = 1.141, p = .329, ns; task-by-gender-by-laterality: F(2,44) = .237, p = .790, ns). After Bonferroni correction for multiple correlations, data analysis demonstrated a significant correlation between amygdala activation across all empathy tasks and the IRI empathy score (r = .598, p = .002). Task-specific analyses revealed a significant correlation between amygdala activation during affective responsiveness and the IRI score for empathic concern (r = .712, p < .001) and the IRI empathy score (r = .590, p = .002), while no other correlation between amygdala activation and self-report data reached significance. For performance accuracy no significant correlation emerged (all ps > .096), however, a significant correlation between reaction time and amygdala activation across all

Figure 5 Result of ROI analysis for the amygdala revealed a significant gender effect ( p < .001) indicating stronger amygdala activation bilaterally in female subjects, in particular during emotional perspective taking and affective responsiveness.

Gender and empathy empathy tasks (r = .525, p = .005) occurred. Fig. 5 illustrates left and right amygdala activation for the three tasks across females and males. Exploratory analysis of the influence of menstrual cycle phase on amygdala activation yielded a trend towards a significant phase effect (F(1,10) = 4.718, p = .055, partialeta sq = .321), indicating higher amygdala activation in the six females who were in their first half of the menstrual cycle. Moreover, neither a significant task effect (F(2,20) = 2.475, p = .128), nor a significant task-by-phase interaction (F(2,20) = .691, p = .476) occurred.

4. Discussion In this fMRI study we investigated the neural networks underlying empathic behavior in healthy females and males. We assessed empathic abilities with three tasks separately tapping the core components of this human competency: (1) emotion recognition, (2) emotional perspective taking, and (3) affective responsiveness. Additionally, we gathered selfreport data from empathy questionnaires. Despite similar behavioral performance, functional data analyses revealed that females and males showed distinct activation patterns, indicating recruitment of different cerebral processing strategies for solving the three tasks.

4.1. Emotion recognition Females and males performed equally well in the emotion recognition task and only a trend for faster recognition in male participants emerged. Moreover, gender differences were detected for the neural correlates supporting previous results (Lee et al., 2002; Wrase et al., 2003; McClure et al., 2004). In particular, females showed stronger activation of the right angular gyrus and the left superior frontal gyrus. We applied an explicit emotion recognition task, thus subject had to select one out of two verbal choices while presented with an emotional face. Thus, our results support the assumption that the angular gyrus acts as a way station between the primary sensory modalities and the speech area (Gschwind, 1965). More recently, Vilberg and Rugg (2009) reported that the angular gyrus seems to establish an ‘‘online’’ representation of episodic information. Furthermore, Abraham et al. (2008) reported activation of the angular gyrus and the superior frontal region to be associated with the recollection as well as prospection of personal events, probably indicating that females rely on autobiographical memory to correctly label the emotional expressions. Males, however, showed stronger activation of the right rolandic operculum as well as the left superior frontal and the right middle cingulate gyrus. The rolandic operculum has mostly been related to speech processing (Tonkonogy and Puente, 2009), and its stronger activation in males might reflect a different neural strategy to solve the explicit emotion recognition task presented here. Regarding emotions, Koelsch et al. (2006) reported rolandic operculum activation during the perception of pleasant music probably reflecting mirror-function mechanisms. Previous studies on emotion recognition mostly applied passive viewing or implicit emotion processing tasks and frequently observed not only stronger lateralization but also

77 elevated activation in males compared to females (e.g., Killgore and Yurgelun-Todd, 2001; Schienle et al., 2005). Explicit emotion recognition like it was investigated here has rarely been investigated. However, in two preceding studies using such explicit emotion recognition tasks we neither observed gender differences in behavior nor in functional activation (Derntl et al., 2009b; Habel et al., 2007), contrary to our present results. However, in these prior studies we relied on an optimized high-resolution EPI sequence with restricted coverage centered on the amygdala, thus functional data analysis was limited to this section of the brain preventing analysis of more cortical regions.

4.2. Emotional perspective taking Comparing neural activation in females and males for emotional perspective taking revealed stronger neural activation in females, in particular in the inferior frontal gyri, the hippocampi, the superior temporal gyri and the calcarine gyri as well as the right amygdala. Activity in the inferior frontal gyrus has been repeatedly observed during various emotional processes (e.g., passive viewing of faces, Dapretto et al., 2006; emotion recognition and evaluation, Carr et al., 2003; Seitz et al., 2008) and only recently has been reported to play a major role in emotional perspective taking (Schulte-Ru ¨ther et al., 2007, 2008) also with females showing stronger activation of this region. Schulte-Ru ¨ther et al. (2007) assume that this activation might mirror the degree of interpersonal emotional involvement, indicating that females much more strongly participate and share affections, while on the behavioral performance level no gender difference is apparent. The superior temporal gyrus (STG) has been described in empathy imaging studies when using visual stimuli (e.g., Carr et al., 2003; Vo ¨llm et al., 2006), and has been associated with attention to facial emotion (Narumoto et al., 2001). Moreover, Vo ¨llm et al. (2006) speculated that the STG is involved in biological stimuli processing, in particular the initial analysis of social cues (here human stimuli) and the detection of intentional activity which is further supported by our data. For emotional perspective taking, males in particular recruited the temporo-parietal junction which is in accordance with previous results from Schulte-Ru ¨ther et al. (2008), who also observed this effect in males during an emotion attribution task. Activation of the temporo-parietal junction has been reported for theory of mind tasks (Frith and Frith, 2003) and is important in the self and other distinction (Decety and Sommerville, 2003; Vogeley et al., 2001). Consequently, Frith and Frith (2003) postulated that temporoparietal junction activation is related to perceptual processing of socially relevant cues that might help to determine the mental states of other people. Here, participants had to indicate which emotion is shown by a certain person in a specific situation, thus analyzing interaction effects between body and facial expressions of the two people as well as situational parameters to identify the adequate emotional expression that was hidden behind the mask. Hence, males might rely more strongly on a perceptual-analyzing network and mentalizing abilities (cf. Hooker et al., 2008) than do females who rather recruit regions associated with emotional contagion and affective responsiveness when assessing the emotional expression of

78 another person supporting the view that men probably have a lower tendency to share their emotions with others than females. This is in line with results from Singer et al. (2006) who report stronger suppression of automatic mirror reactions in response to pain in unfair situations in males than females.

4.3. Affective responsiveness Similar to emotional perspective taking, for affective responsiveness females showed stronger activation of several regions, including the cingulate gyrus, the cerebellum, the superior frontal gyrus, and the hippocampus as well as the insula. These results partly support previous studies on mood induction (Hofer et al., 2006, 2007; Schneider et al., 1998), where female participants also exhibited stronger neural activation in general, and in particular in the cingulate cortex and the cerebellum compared to males (Hofer et al., 2006). The (ventral) anterior cingulate cortex has been shown to be involved in a wide range of competencies and in particular anterior cingulate activation has been observed during mood induction paradigms (e.g., Habel et al., 2005; Schneider et al., 1998) as well as during emotional tasks with cognitive demand (e.g., Phan et al., 2002) and processing of the self (Kircher et al., 2002). This applies to our affective responsiveness task, where emotional situations are imagined, generating an emotion. Here, cognitive processes as well as emotional memory may play a substantial role to truly experience the emotion. Besides its association with various motor functions and even speech perception and production (e.g., Ackermann et al., 2007 for review), the cerebellum is also known to be involved in emotion processing (Schmahmann, 2000), emotional modulation of cognitive processing (Simpson et al., 2000), and mood induction (Hofer et al., 2006, 2007). We observed cerebellar activation during affective responsiveness, in particular in the female subjects, however, its role in emotional behavior with its intimate efferent and afferent connections to structures of the limbic system is still unsolved and might be broader than previously assumed (Schutter and Van Honk, 2005), especially in females. Again, females relied more on emotional regions to experience the emotion, while males show a different neural strategy to emotionally respond to the stimuli, at least showing less activation in primarily emotion-related regions, supporting assumptions on the recruitment of a more cognitive route. Moreover, this processing strategy seems to function irrespective of task instructions since the affective responsiveness task was the only self-oriented task in comparison to emotional perspective taking, where we observed a similar pattern.

4.4. Empathy network Across the three tasks, females showed more activation which is in line with several studies addressing emotion processing (Hofer et al., 2006, 2007; Kempton et al., 2008; Schneider et al., 1998). However, both female and male participants exhibited bilateral amygdala activation to all presented empathy tasks. This is in accordance to previous reports of bilateral amygdala activation to various emotional expressions (e.g., Derntl et al., 2008a, 2009b; Fitzgerald et al., 2006), and studies investigating emotional experience

B. Derntl et al. (e.g., Hofer et al., 2007; Habel et al., 2005). However, we observed a significant gender difference with females exhibiting an overall stronger activation of the amygdala than males, an effect that was most pronounced for affective responsiveness. The fact that we observed amygdala activation during all empathy tasks and a significant correlation of self-report empathy and amygdala activation is in accordance with Blair’s proposal of a mediating role of the amygdala in empathy. While an intact amygdala enables empathic behavior, a lack of empathy might be due to an impaired structural and functional development of the amygdala, as has been proclaimed as a core feature of psychopathy (Blair, 2003). However, higher amygdala activation cannot be equated to higher empathy in the sense of affect sharing in females which is demonstrated by similar behavioral responses in both genders. But it may either reflect a higher attention, cognitive modulation (Pessoa et al., 2005) or greater affective reactivity to the stimulus material in females. Furthermore, in empathy, the role of the amygdala in contrast to that of the insula seems to be rather secondary which may be due to such gender differences possibly concealing a different modulatory role in males and females. Moreover, we also observed a strong trend towards a significant general task independent impact of menstrual cycle phase on amygdala activation further supporting the assumption that the hormone status during the follicular phase facilitates sensitivity and behavior in socio-emotional situations (e.g., Derntl et al., 2008a,b; Pearson and Lewis, 2005). This may be traced back to the evolutionary advantage of higher attention and responsiveness to social-emotional interactions thereby improving mating chances during times of increased fertility. Although the sample size is very small for this analysis, this effect, nearly significant, demonstrates the strong influence of sex hormones on amygdala activation. Recently, Van Wingen et al. (2009) reported that lower androgen levels are associated with lower amygdala reactivity to biologically relevant stimuli in females. Furthermore, increased reactivity of the reward system including the amygdala during the midfollicular phase suggests a critical role of estrogen, however application of progesterone has also been effective in increasing amygdala activity (Van Wingen et al., 2008). The amygdala has high concentrations of sex hormone receptors thus modulation of its activity by changes in sex hormones during the menstrual cycle is clearly indicated although further research has to follow to clarify the exact nature of this influence. Regarding the behavioral performance during scanning, no significant impact of menstrual cycle phase emerged. This lack of an effect did not surprise us since in a preceding study from our group (Derntl et al., 2008a) we also only observed a significant difference in neural response and in more cognitive demanding tasks applying more answering alternatives than just two (as used for the functional tasks here and in the previous study). Besides amygdala activation, results of the conjunction analysis showed that the inferior frontal gyri bilaterally (including BA 45), the right superior temporal gyrus, and the left middle temporal gyrus, are recruited during all tasks, thus constitute the neural network of human empathy in females and males. The inferior temporal gyrus has been shown to be part of the ventral stream of visual processing (Milner and Goodale,

Gender and empathy 1995), and in particular is involved in the processing of complex visual objects and face perception, as has been shown repeatedly (e.g., Kesler-West et al., 2001; Moser et al., 2007). In the present study, activation was extending to the middle temporal gyrus, a region which has been associated with action knowledge (Quadflieg et al., 2009), and numerous findings point to its involvement in movement perception and knowledge about action concepts (Assmus et al., 2007). Moreover, this region is also associated with the acquisition (Maguire and Frith, 2004) and the retrieval of different kinds of semantic information (Vandenberghe et al., 1996; Phillips and Niki, 2002). In our tasks, a retrieval of semantic information and the processing of complex visual objects including faces might have been necessary in order to correctly classify the emotional faces, and in particular to adequately react to the emotional scenes and sentences. Taken together, results of the conjunction analysis suggest that after a rough evaluation and processing of the social cues (apparent in activation of the inferior frontal and superior medial-frontal gyri) retrieval of semantic knowledge about the emotional experience/state of another person or oneself (middle temporal gyrus and cingulate gyrus activation) enables the attribution of emotional expressions to others and to oneself, thus constituting the basis of empathic behavior. Gender-specific conjunction analyses indicated that females consistently activated the left inferior frontal region during all empathy tasks, whereas males engaged the right middle temporal region, further supporting the assumption of different processing strategies. While females more strongly recruited the so-called ‘‘core structure of empathy’’ (cf. Shamay-Tsoory et al., 2009), the inferior frontal region, associated with emotion imitation and evaluation, males rather relied on a region known to be involved in semantic retrieval to correctly classify the items, thus indicating a rather cognitive approach. This supports previous results and our own assumptions on divergent neural processing strategies as well as sensitivity to emotional stimuli (e.g., Li et al., 2008; Schulte-Ru ¨ther et al., 2008).

4.5. Self-reported empathy As expected, females demonstrated higher self-report empathy scores compared to males as has been shown in previous studies (e.g., Rueckert and Naybar, 2008). Moreover, these scores also correlated positively with amygdala activation. Since we observed no significant gender difference in behavioral performance these results support the assumptions by Eisenberg and Lennon (1983), who suggested that gender differences may be due to demand characteristics. While women assume that it is expected to be more empathic as a female and thus are more likely to describe themselves according to this gender stereotype, men refrain from describing themselves as more emotional since this is not part of the ‘‘typical’’ male stereotype. Previous studies have consistently demonstrated that men are generally seen by others as more agentic and more competent than women, whereas women are seen as more emotionally expressive and more communal than men (e.g., Diekman and Eagly, 2000). In light of our findings of significant positive correlations between empathy scores and neural activation of emotionrelated regions, in particular amygdala activation, in

79 females, these gender stereotypes might even extend to neurobiological responses, prompting stronger activation of emotion-related areas when subjects, in particular females, assume that it is expected to act according to a certain stereotype. This clearly demonstrates the limitations and flaws of self-reports in assessing emotion processing capacities in females and males but also points to the power of stereotypes on behavior and its neural correlates (see Krendl et al., 2008). Although important, relying on selfreports only is not sufficient to characterize empathic behavior according to Dimaggio et al. (2008). Thus, behavioral tasks are advantageous here and we have previously demonstrated this benefit in a sample of schizophrenia patients (Derntl et al., 2009a).

4.6. Limitations Several methodological limitations of the study have to be considered, since we used a forced-choice answering format, thus hindering sufficient analyses of misidentifications and error patterns. Furthermore, restriction to two possible response alternatives may have decreased overall difficulty of tasks, thereby limiting the variability between groups and provoking ceiling effects. Also, our tasks are not completely comparable since two of them involve recognition of emotions in another person, while the third measures emotional processing in the self. However, this was intended, since being able to empathize also requires the different perspectives ranging from recognizing emotions in other persons to the identification and experiencing your own feelings. Furthermore, it should be noted while all of the tasks might measure single components of empathy, none of them is an actual empathy task, since none of them explicitly requires feeling with someone or the same emotion as someone else. Previous studies of our group have reported significant differences in amygdala activation during emotion recognition due to menstrual cycle phase (Derntl et al., 2008a) and we tried to address this point by measuring six females during their follicular phase and the other six during their luteal phase. Hence, we only gathered information on the day of the menstrual cycle, but did not take blood samples, allowing only a rough estimation of menstrual cycle influence. However, a more thorough investigation including blood draw and a larger sample will enable a deeper understanding of the observed gender differences and their relation to biological factors, such as actual sex hormone concentration. In particular these studies seem necessary regarding recent findings from Knickmeyer et al. (2006) who observed a significant correlation between prenatal testosterone levels and empathy-related behavior in 4-year old children.

5. Conclusion We observed significant gender differences in the neurobiological substrates underlying the processing of three separate tasks tapping the core components of empathy resulting in a similar behavioral outcome. Our results strongly support the assumption that females recruit more emotion-related regions, whereas males engage a different neural network, rather associated with cognitive evaluation, mentalizing, and behavior anticipation.

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Role of funding source Funding for this study was provided by the Interdisciplinary Centre for Clinical Research (ICCR) of the Medical Faculty RWTH Aachen University (IZKF, TVN70 to U.H.); the ICCR had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.

Conflict of interest None declared.

Acknowledgements B.D. and A.F. were supported by the Interdisciplinary Centre for Clinical Research of the Medical Faculty RWTH Aachen University (IZKF, TVN70 to U.H.) and the International Research Training Group (IRTG 1328) of the German Research Foundation (DFG). UH was further supported by the DFG (KFO 112).

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