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Social Neuroscience Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/psns20

Empathy, ToM, and self–other differentiation: An fMRI study of internal states a

b

a

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Renate L. E. P. Reniers , Birgit A. Völlm , Rebecca Elliott & Rhiannon Corcoran a

Neuroscience and Psychiatry Unit, University of Manchester, Manchester, UK

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Section of Forensic Mental Health, University of Nottingham, Nottingham, UK

c

Division of Psychiatry, University of Nottingham, Nottingham, UK Published online: 03 Dec 2013.

To cite this article: Renate L. E. P. Reniers, Birgit A. Völlm, Rebecca Elliott & Rhiannon Corcoran (2014) Empathy, ToM, and self–other differentiation: An fMRI study of internal states, Social Neuroscience, 9:1, 50-62, DOI: 10.1080/17470919.2013.861360 To link to this article: http://dx.doi.org/10.1080/17470919.2013.861360

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SOCIAL NEUROSCIENCE, 2014 Vol. 9, No. 1, 50–62, http://dx.doi.org/10.1080/17470919.2013.861360

Empathy, ToM, and self–other differentiation: An fMRI study of internal states Renate L. E. P. Reniers1, Birgit A. Völlm2, Rebecca Elliott1, and Rhiannon Corcoran3 1

Neuroscience and Psychiatry Unit, University of Manchester, Manchester, UK Section of Forensic Mental Health, University of Nottingham, Nottingham, UK 3 Division of Psychiatry, University of Nottingham, Nottingham, UK

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This study used functional magnetic resonance imaging to examine the neural substrates of empathy, Theory of Mind (ToM), and self–other differentiation involved in the adaptive understanding of people’s internal states. Three conditions were distinguished in both sad and neutral (no obvious emotion) contexts. The empathy condition involved imagining what another person is feeling while the more cognitively loaded ToM condition involved imagining what would make another person feel better. The self-reference condition required participants to imagine how they would feel in someone else’s situation. Areas previously implicated in empathy, ToM, and self–other differentiation were identified within the different conditions, regardless of emotional context. Specifically, the frontal and temporal poles responded more strongly for ToM than for empathy. The self-reference condition was associated with stronger dorsolateral prefrontal response than the empathy condition, while the reverse comparison revealed a stronger role for right frontal pole. Activations in frontal pole and orbitofrontal cortex were shared between the three conditions. Contrasts of parameter estimates demonstrated modulation by emotional context. The findings of common and differential patterns of responding observed in prefrontal and temporal regions suggest that within the social cognition network empathy, ToM and self–other differentiation have distinct roles that are responsive to context.

Keywords: Empathy; Theory of Mind; Self–other differentiation; fMRI.

Human social behavior is largely based on the interpretation of the actions of others, enabling a high degree of adaptability in the social world. This adaptability has been built upon abilities such as empathy and Theory of Mind (ToM) (Frith & Blakemore, 2003; Rankin, Kramer, & Miller, 2005; Völlm et al., 2006). Empathy encompasses our ability to be sensitive to and vicariously experience other people’s feelings and to create working models of emotional states (Reniers, Corcoran, Drake, Shryane, & Völlm, 2011). ToM refers to our

ability to represent other people’s mental states such as beliefs, knowledge, and intentions (Shamay-Tsoory, Tomer, Berger, & Aharon-Peretz, 2003). These mechanisms help us to understand and predict the social world, and facilitate pro-social behavior (Baron-Cohen, Richler, Bisarya, Gurunathan, & Wheelwright, 2003; Vreeke & van der Mark, 2003). Our ability to integrate our representations of other people’s beliefs and intentions with our beliefs about their feelings within specific contexts, while

Correspondence should be addressed to: Renate L. E. P. Reniers, Neuroscience and Psychiatry Unit, University of Manchester, Manchester, UK. E-mail: [email protected] The authors would like to thank the Magnetic Resonance Imaging Facility of the University of Manchester for funding the scans and their assistance in fMRI acquisition, Dr. Shane McKie for his assistance with data analyses and the Neuroscience & Psychiatry Unit for funding the participant reimbursement. The authors report no conflict of interest. Present address for Renate L. E. P. Reniers: School of Psychology, University of Birmingham, Birmingham, UK; Rhiannon Corcoran: Institute of Psychology Health and Society, University of Liverpool, Liverpool, UK.

© 2013 Taylor & Francis

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simultaneously inhibiting our own perspective, leads to an understanding of these people’s internal states (Leiberg & Anders, 2006). Our ability to monitor and manipulate cognitive and emotional processes prevents confusion between ourselves and others (Decety & Jackson, 2006; Decety & Sommerville, 2003) and helps us to regulate feelings of personal distress and anxiety (Decety & Jackson, 2006). The concepts of empathy and ToM are closely related. Some authors (e.g., Blair, 2005) equate cognitive empathy to ToM, defining it as the representation of the internal mental state of another individual. However, we suggest that although cognitive empathy is likely to rely on many of the same underlying abilities that facilitate ToM, cognitive empathy involves the attribution of emotions as opposed to cognitions and this may dissociate the two constructs at psychological and neural levels (Reniers et al., 2011). Consistent with this view, evidence shows that empathy and ToM engage common as well as distinct neuronal networks. Research on empathy (Damasio, Tranel, & Damasio, 1990; Eslinger, 1998; Hynes, Baird, & Grafton, 2006; Shamay-Tsoory et al., 2003; Shamay-Tsoory, Tomer, & Aharon-Peretz, 2005; Shamay-Tsoory, Tomer, Goldsher, Berger, & AharonPeretz, 2004; Völlm et al., 2006), suggests involvement of orbitofrontal, dorsolateral, and (ventro)medial prefrontal regions. The more cognitive components of empathy have been linked to medial prefrontal cortex, temporal poles, temporoparietal junction, occipitotemporal cortices, thalamus, and cerebellum, while affective components are linked to orbitofrontal cortex, paracingulate, anterior and posterior cingulate cortex, amygdala, premotor cortex, and insula (Rankin et al., 2005; Shamay-Tsoory et al., 2005; Völlm et al., 2006). Studies on ToM have consistently implicated frontal pole, anterior medial prefrontal cortex, temporal poles, and temporoparietal junction (Brunet, Sarfati, HardyBayle, & Decety, 2000; Frith & Frith, 1999; Frith & Frith, 2003; Gallagher & Frith, 2003; Saxe & Kanwisher, 2003; Saxe & Powell, 2006; Sommer et al., 2007; Van der Meer, Groenewold, Nolen, Pijnenborg, & Aleman, 2011; Völlm et al., 2006). These findings highlight overlap in the neural correlates of empathy and ToM but at the same time emphasize the distinct socio-cognitive features and underlying neurobiological mechanisms. Empathy and ToM consider other people’s feelings and mental states but rely on processes such as selfreflection and personal experiences to correctly identify these feelings and mental states in their social contexts. These processes of self-reflection help to identify the appropriate response to the person’s situation as well as identification of one’s own corresponding emotional

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state (Reniers et al., 2011). While evaluating externally and internally generated emotional and cognitive information, it is important that we maintain the distinction between our own internal states and those of others to prevent confusion or misattribution of emotions that may result in feelings of distress and anxiety. This process of self–other differentiation is thought to depend on frontal pole, superior frontal gyrus, somatosensory cortex, precuneus, and inferior parietal cortex (Decety & Sommerville, 2003; Ruby & Decety, 2001, 2004). The frontal pole, superior frontal gyrus, posterior cingulate, superior temporal sulcus, temporal pole, precuneus, and inferior parietal cortex seem to be specifically involved in third-person perspective taking, while somatosensory cortex, postcentral gyrus, and inferior parietal cortex are reportedly more involved with the first-person perspective (Ruby & Decety, 2001, 2003, 2004). Völlm et al. (2006) conducted the first functional magnetic resonance imaging (fMRI) study examining the neural correlates of empathy and ToM in a single study, thereby allowing direct comparison of associated areas of signal change. The authors concluded that empathy and ToM both rely on networks associated with making inferences about internal states of others but that empathic responding requires the additional recruitment of networks involved in emotional processing. The current study aimed to further advance our understanding of the neural substrates of empathy, ToM, and self–other differentiation involved in the understanding of people’s internal states. The paradigm chosen relies on the adoption of distinct perspectives that allow the separation of information that, when integrated, models the full appreciation of internal states characteristic of human social interaction. The first of the three conditions used was designed to explore predominant empathic responses toward another person and was called the “Empathy” condition. When asked to imagine what another person is feeling it is believed that we put ourselves in the other person’s shoes to consider emotional and situational cues from their perspective and reach a level of understanding of this person’s feelings. This enables us to build up a working model of the person’s emotional state (Reniers et al., 2011). The second condition, labeled the “ToM” condition, was designed to increase demands on higher order reasoning skills by asking the participant to decide what could be done to make another person feel better. This condition uses the working model of the person’s emotional state (established in the empathy condition) to formulate a context appropriate action. This approach was chosen because of the extra layer of cognitive processing that is required in comparison to considering what another person is feeling. This condition thus

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involves a degree of empathic processing, but additionally it involves careful consideration of a person’s intentions and beliefs, key elements of ToM. The third condition, the “Self-reference” condition, focuses on the distinction between self and other. This involves comparing the established working model of the other’s feelings (established in the empathy condition) to how one considers one would feel in this situation. The recognition of another person’s emotion elicits an emotional response to this person’s feelings and, using selfreflection and insight, leads to identification of one’s own feelings (Reniers et al., 2011). Visual and situational cues are used to represent the other person’s cognitive and emotional state. Crucial in this is the realization that these states are part of the other person’s subjective experience (Decety, 2011). By shifting the representational stance, one’s own likely cognitive and emotional state can be shaped (Reniers et al., 2011). It is likely that such simulations draw on self-referential processes and invoke past experiences of similar situations. Strong empathic experiences have typically been associated with events in negative contexts such as the loss of a loved one or the sight of a person in distress. It has also been suggested that events with negative valence have a greater and more lasting impact upon us than events with positive valence (Baumeister, Bratslavsky, & Finkenauer, 2001; Rozin & Royzman, 2001; Vaish, Grossmann, & Woodward, 2008). This highlights the importance of emotional valence in the context of socio-cognitive processes. All conditions were therefore performed in sad and neutral (no obvious emotion) emotional contexts to investigate whether negative emotional valence modulates blood oxygenation level dependent (BOLD) response within and across conditions. To our notion, this study is the first to contrast specifically sad feelings with neutral (no overt) emotions in a comparison of empathy and ToM-related processes involved in the inference of other people’s internal states. We hypothesized that social cognitive activations would be enhanced in the sad condition, due to the greater emotional salience of the stimuli. Our analyses focused on activations within areas most consistently associated with social cognition: frontal pole, medial and dorsolateral prefrontal cortex, orbitofrontal cortex, anterior cingulate, temporal poles, and temporoparietal junction. These areas were hypothesized to show differential activations for the three conditions. Based on prior work (see, e.g., Abu-Akel & Shamay-Tsoory, 2011; Shamay-Tsoory, 2011; Völlm et al., 2006), increased activations in orbitofrontal cortex and anterior cingulate were predicted for the empathy condition compared to the ToM and self-reference conditions. We anticipated that the higher order context-dependent reasoning required in the ToM condition

would, in comparison to the empathy condition, be associated with increased activations in medial prefrontal cortex, temporal poles, and temporoparietal junction (see, e.g., Frith & Frith, 2003; Gallagher & Frith, 2003; Saxe & Powell, 2006). We anticipated increased BOLD response in anterior cingulate (Phan, Wager, Taylor, & Liberzon, 2002) and frontal pole (Gilbert et al., 2006) in the self-reference condition, compared to the empathy condition, because of its likely relationship with personal experiences. Differential activations in the frontal pole, and medial and dorsolateral prefrontal cortex (see, e.g., Decety & Sommerville, 2003; Ruby & Decety, 2004; Schmitz, Kawahara-Baccus, & Johnson, 2004) were predicted for comparisons between the conditions mediating others’ versus own emotions (empathy versus self-reference). Activations specifically associated with sad context were predicted in the anterior cingulate, lateral orbitofrontal cortex, and medial prefrontal cortex (Phan et al., 2002; Seitz et al., 2008). We also explored the interaction between emotion and condition, and predicted strongest enhancement of response by sad context for the self-reference condition in association with the recollection of emotional personal experiences. Autobiographical recall is required for inferring internal states (Corcoran, 2000; Concoran & Frith, 2003; Gallagher & Frith, 2003) and while emotions enhance memory consolidation (Canli, Zhao, Brewer, Gabrieli, & Cahill, 2000; Hamann, Ely, Grafton, & Kilts, 1999), they may be particularly intense in the case of personal events (Salas, Radovic, & Turnbull, 2012). Although prior literature suggests plausible ROIs, as detailed above, these ROIs are not always consistent across studies, with considerable variation in both which regions respond, and where the peak of activation in larger regions is located. We therefore adopted a whole brain analysis strategy, as recommended by Lieberman and Cunningham (2009), and detailed below.

METHODS & MATERIALS Participants Participants were 15 right-handed healthy volunteers, aged between 18 and 40 years. As gender differences for social cognition have been reported (Baron-Cohen & Wheelwright, 2004; Reniers et al., 2011; Russell, Tchanturia, Rahman, & Schmidt, 2007), we restricted our sample to males. Further exclusion criteria were: non-fluent English, an estimated IQ below 85, selfreported treatment for any psychiatric illness within the last year, consumption of more than 20 units of alcohol per week, history of serious head injury (more

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EMPATHY, TOM, SELF–OTHER DIFFERENTIATION

than 5 minutes loss of consciousness or overnight hospital stay), serious medical or neurological conditions, claustrophobia, and other contraindications for fMRI. Participants were screened for Axis I psychiatric disorders using the M.I.N.I. (Sheehan et al., 1998) and the IQ was estimated using the Quick QT (Ammons & Ammons, 1962). The average IQ of participants was 105 (SD = 8, range 93–120). All participants had been in education for a minimum of 13 years. The mean age of the group was 27 (SD = 5, range 21–40) and all indicated a country of origin in Europe, with 12 specifying the United Kingdom. All participants scored in the average range for males on the Questionnaire of Cognitive and Affective Empathy (Reniers et al., 2011). Participants gave informed consent and were reimbursed for their time and effort. Ethical approval was granted by the North Manchester Research Ethics Committee.

Scanning task The scanning tasks required participants to view sad and neutral (no obvious emotion) pictures. Pictures were taken from the International Affective Picture System (IAPS) (Lang, Bradley, & Cuthbert, 1997) and sourced from the internet. The findings of a pilot study (n = 24) asking people to rate the feelings of the main character for levels of sadness, happiness, and fearfulness (“How happy/sad/frightened?”) on a 5-point Likert scale ranging from “Not happy/sad/ frightened at all” (score = 1) to “Extremely happy/ sad/frightened” (score = 5) determined which images were selected for the imaging study. The pictures selected for the sad category received highest ratings on sadness (Mdn = 3.90) and lowest ratings on happiness and fearfulness (Mdn = 1.42 and Mdn = 2.33, respectively). Neutral pictures were rated low on all three selection criteria (sadness Mdn = 1.81; happiness Mdn = 2.48; fearfulness Mdn = 1.50). Compared to the neutral pictures, the sad images were scored significantly lower on happiness (z = –2.13, p < .05, with an effect size (Field, 2005; Rosenthal, 1991) of r = .37) and significantly higher on sadness (z = –2.20, p < .05, r = .36) and fearfulness (z = –2.37, p < .05, r = .40). Three tasks were performed during scanning with the same pictures being evaluated in each condition. In the empathy condition participants imagined what the main character in the picture was feeling. In the ToM condition participants imagined what would make the main character in the picture feel better. In the self-reference condition participants imagined how they would feel if they were the main character in the picture. After scanning, participants described what

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they had imagined during the scanning task for a selection of pictures. This suggested compliance with the requirements of the task conditions. The task comprised a block design, with eighteen blocks in total and each type of block repeated three times (i.e., three each of empathy-sad, empathy-neutral, ToM-sad, ToM-neutral, self-reference-sad, self-reference-neutral). Each block consisted of six trials of either sad or neutral pictures. Equal numbers of male and female characters were seen across conditions. Each picture appeared once in each condition. Conditions and trials were pseudo-randomized. Each block was preceded by the instructions for that block which stayed on the screen for 10 seconds. The pictures were presented for 5 seconds and separated by a fixation cross that appeared for 500 milliseconds. Participants did not respond overtly during the scanning conditions but, to maintain focus, they were asked to press a button when the fixation cross appeared on the screen. Figure 1 shows a schematic representation of a trial. The total task duration was 11.5 minutes.

Data acquisition Functional magnetic resonance (fMRI) images were acquired using a 3 Tesla Philips Achieva (Philips Medical Systems, Eindhoven, the Netherlands) scanner. T2*-weighted volumes were acquired using a singleshot echo-planar (EPI) pulse sequence. Each volume comprised 34 axial slices of 3-mm thickness with a slice gap of 0.5 mm (TR = 2 seconds, TE = 35 milliseconds, in-plane resolution of 2.5 × 2.5 mm). A T1weighted structural scan was also acquired for each subject for co-registration and to exclude any structural abnormality. No abnormalities were reported.

Data analysis The imaging data were processed using Statistical Parametric Mapping (SPM5, Friston, The Welcome Department of Cognitive Neurology, London, UK) with a random effects model (http://www.fil.ion.ucl. ac.uk/spm). Individual scans were realigned using the middle scan as a reference, movement corrected using ArtRepair if movement > 2 degrees, normalized into “standard space” (Talairach & Tournoux, 1988) using MNI templates (Montreal Neurological Institute) and smoothed with a 7 × 7 × 10 mm Gaussian kernel. Statistical analysis of the imaging data was carried out using the general linear model with a delayed boxcar waveform to model BOLD signal changes to the sad relative to the neutral condition. At the first

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Figure 1. Schematic representation of an empathy trial. The trial presents an example of a sad stimulus in the empathy condition.

level, goodness-of-fit (beta) values for each contrast resulted in a contrast map for each individual. At the second level, the statistical parametric maps from each individual were combined in random effects analyses. The main effect of condition and the interaction with sad emotional context were examined using ANOVA within which we considered comparisons between empathy versus ToM and empathy versus self-reference. Note, we did not consider a direct comparison between ToM and self-reference to be theoretically meaningful, as it would involve a twofold comparison of self versus other as well as “feeling” versus “feeling better”. Therefore, we did not directly compare these conditions. To produce an acceptable balance between Type I and II error rates, statistical significance for prehypothesized areas was based on a combined intensity and cluster-size threshold (Lieberman & Cunningham, 2009). Spatial extent threshold was determined by 1,000,000 Monte Carlo simulations conducted using AphaSim (AFNI; Cox, 1996), which yielded a cluster extent of 23 voxels at a voxel-wise threshold of p < .001. This joint voxel-wise and cluster-size threshold corresponds to a false-positive discovery rate of 5% across the whole brain. For non-hypothesized areas, peak activations in clusters of a minimum of 23 contiguous voxels are reported if they met the criterion of p < .05 whole brain FDR corrected.

RESULTS Main effect of emotional context Neural responses to neutral pictures were subtracted from those to sad pictures across all conditions to reveal areas of increased signal associated with a sad emotional context (Table 1). Significant activations were

found in the posterior cingulate, temporal pole, fusiform gyrus, lingual gyrus, and middle occipital gyrus.

Effect of sad emotional context on each condition To investigate the effect of emotional context on each condition, pairwise contrasts of sad versus neutral for each condition were explored (Table 1). For the empathy condition, sad context was associated with increased signal change in the anterior medial frontal cortex, ventrolateral prefrontal cortex, posterior cingulate and cingulate gyrus, temporal pole, temporoparietal junction, bilateral cuneus, lingual gyrus, middle occipital gyrus, and the cerebellum. For the ToM condition, sad context was associated with significant responses in the temporal pole, temporoparietal junction, (pre)cuneus, and the lingual gyrus. For the self-reference condition, sad context was associated with significant response in the fusiform gyrus.

Main effects of condition To investigate the main effect of condition, brain activations across sad and neutral conditions were contrasted for (1) empathy and ToM and (2) empathy and self-reference (Table 2). Empathy > ToM revealed no areas of significant signal change in hypothesized areas. ToM > empathy was associated with significant activations in bilateral frontal pole and left temporal pole (Figure 2). For empathy > self-reference, significant signal changes were found in the right frontal pole (Figure 3a).

R L R L R R

24 30 31 38 38 39

R L R R R R R L L L R

R

45

7 17 18 17 37 18 17 18 19

L

Left/right

9

BA

^ ^

^ 2040^

^

52 44

Cluster size

y

z

11 −9 −2 −8 4

18 −92 42 −59 13 −83 −35 −83 −37 −80

10 −47 38 −45 14 −18

x

Talairach coordinates

5.23 5.04

4.86 5.65

5.12

3.39 3.44

^ ^

^ 1570^ ^

^

^

81

65

117 49

108

32

Z-score Cluster size

39 19

10 −13 −3 −48

4.74 4.40

−22 −76 −11 22 −76 −11

5.59

5.59

3.66

3.76

3.51 3.37

3.79

3.10

4.31 5.80 4.07

4

5

10

ToM TS–TN

^ 1159^

59 42 ^

32

Z-score Cluster size

−8 −2 −2

20 −78 15 −86 −45 −73

20 −89

−10 −90

48 −75

13 −28

15

27

z

23

48

−3 57

y

x

Talairach coordinates

−45

Empathy ES–EN

Notes: ^ Cluster breakdown. E = Empathy condition, T = ToM condition, SR = Self-reference condition, S = sad, N = neutral, BA = Brodmann area.

Middle occipital gyrus Declive

Fusiform gyrus Lingual gyrus

Precuneus Cuneus

Temporoparietal junction

Anterior medial frontal cortex Ventrolateral prefrontal cortex Cingulate gyrus Posterior cingulate Temporal pole

Region

Main effect (ES + TS + SRS) – (EN + TN + SRN)

TABLE 1 Main effect of emotional context on each condition

20 15

52 10 −13

45

x

z

−78 −86

−41 −50 −92

−5 −2

19 38 5

16 −24

y

Talairach coordinates

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4.07 5.89

3.11 3.72 4.93

3.26

355

Z-score Cluster size

y

z

43 −62 −12

x

Talairach coordinates

Self-reference SRS–SRN

4.80

Z-score

EMPATHY, TOM, SELF–OTHER DIFFERENTIATION 55

RENIERS ET AL.

3.43 3.53 35 44

Shared activations across conditions

3.76 88

−43 11 −33

43 3.21 3.38 20 8 82 39

−3 62 13 52

Z-score z y x Cluster size y z Z-score x

L R L R L Dorsolateral prefrontal cortex Temporal pole

Frontal pole

10 10 9 9 21

Cluster size Left/right BA Region

Notes: E = Empathy condition, T = ToM condition, SR = Self-reference condition, S = sad, N = neutral, BA = Brodmann area.

23 62 13

3.20

Z-score z y x Cluster size

Talairach coordinates Talairach coordinates Talairach coordinates

Empathy > Self-reference (ES + EN)–(SRS + SRN) ToM > Empathy (TS + TN)–(ES + EN) Empathy > ToM (ES + EN)–(TS + TN)

TABLE 2 Main effect of condition

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Self-reference > empathy revealed significantly stronger activations in the bilateral dorsolateral prefrontal cortex (Figure 3b + c).

−25 34 31 23 36 34

z y x Cluster size

Talairach coordinates

Self-reference > Empathy (SRS + SRN)–(ES + EN)

Z-score

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Conjunction analyses were conducted to reveal areas of activation shared across conditions. The empathy, ToM, and self-reference conditions in both sad and neutral contexts commonly activated the left frontal pole ([0 57 13], z = 4.16), and a cluster in the middle occipital gyrus ([47 –68 3], z = Inf) extending into parahippocampal gyrus, cuneus, fusiform gyrus, culmen, and declive. When the conjunction for just the sad context was examined, activations were again reported in the frontal pole ([0 57 17], z = 4.87), and bilateral middle occipital gyrus ([–45 –77 7], z = 6.89; [50 –68 3], z > 7) extending into thalamus, parahippocampal gyrus, superior temporal gyrus, (pre) cuneus, fusiform gyrus, culmen, and uncus. Additional activations were found in the left orbitofrontal cortex ([–30 35 –18], z = 4.48) and fusiform gyrus ([–40 –52 –15], z = 5.89).

Modulation of condition by sad emotional context This was explored by looking at the interaction terms of the ANOVA. Empathy > ToM (sad > neutral) revealed no areas of significant signal change in hypothesized areas. ToM > empathy (sad > neutral) revealed stronger activation clusters for the ToM condition in the right dorsolateral prefrontal cortex ([38 31 31], z = 3.37). Response in this region was higher in the empathy condition (neutral) than in the other three conditions. Empathy > self-reference (sad > neutral) resulted in significant signal changes in the anterior medial prefrontal cortex ([8 47 1], z = 3.76). In this region, contrasts of parameter estimates suggest that sad context had opposite effects to the empathy and selfreference conditions (increasing and decreasing response, respectively). Self-reference > empathy (sad > neutral) revealed no areas of significant signal change in the hypothesized areas.

DISCUSSION This study investigated the neural substrates of empathy, ToM, and self–other differentiation involved in the adaptive understanding of people’s internal states. It uniquely allowed for direct comparison of empathy,

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Figure 2. ToM compared to empathy regardless of emotional context. Bilateral frontal pole (a + b) and left temporal pole (c) activity associated with the ToM compared to empathy condition. Crosshairs at (–3 62 20), (13 52 8), and (–43 11–33). Plotted bars from left to right: ToM neutral context, empathy neutral context, ToM sad context, and empathy sad context.

Figure 3. Comparison of self-reference and empathy regardless of emotional context. Right frontal pole (a) activity associated with the empathy compared to self-reference condition regardless of emotional context. Bilateral dorsolateral prefrontal cortex (b + c) activity associated with the self-reference compared to empathy condition regardless of emotional context. Crosshairs at (23 62 13), (–25 34 31), and (23 36 34). Plotted bars from left to right: empathy neutral context, self-reference neutral context, empathy sad context, and self-reference sad context.

ToM, and self–other differentiation processes under subtly different contexts to advance our understanding of the neural substrates associated with these processes. As predicted, areas previously implicated in empathy, ToM, and self–other differentiation were identified for the different conditions, regardless of emotional context. Specifically, the context-dependent reasoning requirements of the ToM condition gave rise to activation in frontal and temporal poles over and above that seen in these areas in relation to the empathy condition. The self-reference condition was associated with stronger dorsolateral prefrontal response than the empathy condition, while the reverse comparison revealed a stronger role for right frontal pole. Activations in frontal pole and orbitofrontal cortex were shared between conditions.

Contrasts of parameter estimates demonstrated that the conditions were modulated by emotional context such that the right dorsolateral prefrontal cortex was most responsive for empathy under neutral context in ToM compared to empathy. In the empathy versus self-reference comparison, sad context enhanced anterior medial prefrontal responses to empathy.

Sad emotional context Activations specifically associated with sad context were found in medial prefrontal cortex, but not in lateral orbitofrontal cortex and anterior cingulate as was predicted. These activations were only observed for the empathy condition but not the ToM and self-

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reference conditions. Increased activity in the medial prefrontal cortex was observed in the empathy condition when sad context was compared to neutral context and in the interaction between empathy and self-reference in a sad versus neutral context. Increased activity in the medial prefrontal cortex has previously been associated with emotion processing (Krämer, Mohammadi, Donamayor, Samii, & Munte, 2010; Phan et al., 2002), including inferring other people’s emotions (Hynes et al., 2006) and judging their emotional state (Farrow et al., 2001), and with reflecting upon one’s own emotions (Gusnard, Akbudak, Shulman, & Raichle, 2001; Lane et al., 1997). Functions of this region have thus been associated with attending to others’ as well as our own mental states (Frith & Frith, 2003), consistent with our findings of involvement in empathy and self-referential perspective taking. Traditionally, the right temporoparietal junction has been implicated in the attribution of beliefs to other people (Mitchell, 2008; Saxe & Kanwisher, 2003; Saxe & Powell, 2006; Saxe & Wexler, 2005). In addition, studies on empathy (e.g., Hynes et al., 2006) report increased activity in the right temporoparietal regions for inferring others’ emotions. We found that sad context enhanced response in right temporoparietal junction for both empathy and ToM. This suggests the importance of this region in both empathy and ToM when the context is emotionally salient. Recent research has pointed out that, in addition to involvement in the attribution of beliefs and emotions to other people, the right temporoparietal junction may subserve a process of attention reorienting that is not specific to social contexts (Mitchell, 2008; Young, Dodell-Feder, & Saxe, 2010). Attention reorientation to clues elsewhere in the scene is likely to aid the generation of an internal working model required in the empathy condition. We reported involvement of a more anterior region of right temporoparietal junction in the empathy condition (sad > neutral) compared to the ToM condition (sad > neutral). A direct comparison (ToM > empathy) resulted in just below threshold activation in the more posterior region of right temporoparietal junction. We may have highlighted an important functional segregation within the temporoparietal junction here and suggest that the relatively posterior region may be selective for considering the beliefs of other people (Mitchell, 2008; Young et al., 2010) while the more anterior part may subserve a different process, like attention reorientation (Mitchell, 2008). It is possible to speculate that attention reorientation is one of the mechanisms that people with autism use to infer the inner experiences of others as for people with autism all emotional

displays are ambiguous and so they may need to gather information from elsewhere to disambiguate emotional situations. Thus, in our paradigm the empathy condition may be challenging our information processing systems in the same way as emotional stimuli in general challenge the information processing systems of those with autism.

Empathy > ToM No areas of significant signal increase were found for Empathy > ToM, regardless of emotion, nor in the interaction with sad emotional context. At first glance, this finding appears inconsistent with Völlm et al. (2006) who suggested that, like ToM, empathy relies on networks associated with making inferences about mental states of others but with additional recruitment of networks involved in emotional processing. However, the ToM condition in the current study built upon the empathic working model that was developed to support the empathy condition by asking participants what would make the main character in the picture feel better. This explicit consideration of the representation of the other’s feelings will have recruited emotional regions equivalent to those involved in the empathy condition. Our “ToM” condition therefore involved both empathic processing and more cognitive appraisal, and can thus be conceptualized as involving both ToM and empathy.

ToM > Empathy The frontal pole is reliably recruited when internally generated information requires evaluation (Christoff & Gabrieli, 2000; Christoff, Ream, Geddes, & Gabrieli, 2003) and several studies have reported activation of this region when participants overtly put themselves in the shoes of others (Decety & Sommerville, 2003). We observed response in two regions of frontal pole (a dorsomedial region and a more ventral region on the right) when ToM was contrasted with empathy, irrespective of emotional context. Activation of a more lateral part of right frontal pole was observed when empathy was compared to self-reference, irrespective of emotional context. The finding of a response in right frontal pole for both ToM > empathy and empathy > self-reference highlights an important role for this region in social cognition and, more particularly, the internal consideration and evaluation of others’ and our own feelings at different layers of complexity/sophistication (Christoff et al., 2003). In addition, our findings

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support suggestions of functional segregation within the frontal pole. The medial region of the frontal pole has been linked to mentalizing (Gilbert et al., 2006) and this is consistent with the extra context-dependent reasoning required in our ToM condition. Deciding what would make a person feel better also includes a future component, consistent with suggestions of involvement of this region in future thinking (Burgess, Simons, Dumontheil, & Gilbert, 2005). Evidence points to specific involvement of the more lateral part of the frontal pole in episodic memory retrieval (Gilbert et al., 2006) and inhibiting the selfperspective when taking another’s perspective (Ruby & Decety, 2001). The latter evidence is consistent with our finding of increased BOLD response in this region for empathy > self-reference, irrespective of emotion. It seems that the process of evaluating selfgenerated information is not restricted solely to contexts of high emotional valence. It has been argued that the anterior cingulate may signal the dorsolateral prefrontal cortex when high-level control is required (Gilbert & Burgess, 2008). This is reflected in involvement of right dorsolateral prefrontal cortex in the cognitive aspects of understanding mental states (Kalbe et al., 2010) and may explain our finding of increased signal changes in right dorsolateral prefrontal cortex associated with the neutral empathy condition when the interaction between ToM and empathy in sad versus neutral context was explored. Left temporal pole activity was observed in the overall sad versus neutral comparison and in the sad versus neutral contrast in the empathy condition. Left temporal pole activity was also observed when ToM was compared to empathy, irrespective of emotional context. This pattern of response in left temporal pole reflected activity associated with ToM, irrespective of emotional context, but also activity associated with empathy in sad context. It has been suggested that we draw on our past experiences to infer the internal states of others (Corcoran, 2000; Corcoran & Frith, 2003; Gallagher & Frith, 2003). The current findings are consistent with conjectures proposing that the left temporal pole is recruited when wider semantic and emotional information needs to be gathered from past experience (Frith & Frith, 2003) and with its association with autobiographical recall (Fink et al., 1996; Gallagher & Frith, 2003; Leiberg & Anders, 2006; Olson, Plotzker, & Ezzyat, 2007; Ruby & Decety, 2004).

Other’s versus own emotions Differential activations in frontal pole, and medial and dorsolateral prefrontal cortex were predicted and

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observed for the contrasts mediating others’ versus own emotions. Although not traditionally labeled a self–other distinction region (Decety & Sommerville, 2003; Ruby & Decety, 2001, 2003, 2004), the dorsolateral prefrontal cortex was bilaterally recruited when self-reference was compared to empathy, irrespective of emotional context. While the rostral area of frontal pole is recruited when internally generated information needs evaluating, the dorsolateral prefrontal cortex becomes activated when externally generated information is being evaluated (Christoff et al., 2003; Christoff & Gabrieli, 2000). This evaluation process facilitates new ways of behaving and approaching unfamiliar situations (Gilbert & Burgess, 2008). Our data suggests that this process may be most important under first-person perspective conditions where we imagine ourselves in someone else’s situation.

Shared activations across conditions Activations in frontal pole and orbitofrontal cortex were shared between conditions. Activation in frontal pole was reported regardless of emotional context while orbitofrontal activation was specifically related to conditions with sad emotional context. While these activations provide evidence for a shared social cognitive underpinning, together with the differential activations reported between the conditions, they also provide support for the suggestion that within a common social cognition network, distinct social processes may be uniquely presented.

Limitations One limitation of this study is the absence of a lowlevel task that did not concern internal states. Adding a condition in which participants are instructed to think about aspects of the stimuli irrelevant to the emotional task (e.g., gender), may provide valuable information on the areas involved in empathy, ToM, and self–other differentiation more generally. Furthermore, empathy is not something we experience just in negative contexts and therefore, future research should include the effect of a positive context. The pictures used in this study varied in terms of their emotional ambiguity meaning that it was not always easy to simulate around the uncertain nature of the scenarios. This was particularly the case in the ToM-neutral context condition that required participants to infer what would make another person feel better when, in fact, it was unclear how the person was

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feeling in the first instance (providing no clear working model upon which to build context-dependent reasoning). It furthermore needs mentioning that there were more pictures depicting people in groups in sad context than in neutral context and the enhanced interpersonal nature of the stimuli can therefore not be fully ruled out as an alternative explanation for the increased activations found in sad compared to neutral contexts. The ToM condition did not directly query the intentions or beliefs of the main character but instead asked what would make the main character feel better. While processing this question does rely strongly on ToM skills, it may also have necessitated the development of a more sophisticated working model of cognitive empathy. This may have contributed to the lack of differential activation reported for the Empathy >ToM comparison. Future studies could further examine the dissociable mechanisms underlying ToM versus high-level cognitive empathy. Employment of techniques that are more sensitive in teasing out fine distinctions between activations in commonly recruited regions, such as multi-voxel pattern analysis, will be important tools to further advance our knowledge in this field.

Clinical implications While the findings of this study go some way to explaining empathy, ToM, and self–other differentiation processes in relation to their functional anatomy, they may also have important implications for sociocognitive remediation in different clinical groups. Our findings have demonstrated that asking a participant to perform essentially the same task in different ways by giving him/her slightly different instructions results in distinct activations in a variety of brain regions. Focusing on a specific method of emotional information processing to arrive at an empathic or ToM judgment could prove useful in the treatment of personality disorders for example. More explicitly, if psychological treatments can provide a method of inducing empathic judgments that distinguishes between self and other’s emotions, this would prove particularly useful when a dysfunctional internal model of the self is implicated in the clinical disorder (Morrison, 2004).

Conclusion General agreement is emerging that empathy, ToM, and self–other differentiation are mediated by a

complex neural network in which prefrontal and temporal structures play an important role but where different kinds of processing are related to different areas and strengths of activation. Importantly, this study differed from previous studies because direct comparison between empathy, ToM, and self–other differentiation processes under subtly different contexts was possible. The results of the current study, combined with those of previous neuroimaging studies, suggest that integrated cognitive activity involving shared representations, emotional processing and regulation, self–other differentiation and integration of past experiences leads to adequate ToM and an appropriate empathic experience. Future research consisting of more detailed neuropsychological and behavioral testing in large groups of healthy volunteers and patients, together with imaging studies focusing on the mechanisms of empathy, ToM and self–other differentiation will provide a more comprehensive picture of the functional anatomy of these sociocognitive processes in their various guises. Original manuscript received 5 February 2013 Revised manuscript accepted 28 October 2013 First published online 2 December 2013

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