Neurobiology of Aging 35 (2014) 827e836

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Aging is associated with changes in the neural circuits underlying empathy Yao-Chu Chen a, Cheng-Chiang Chen a, b, Jean Decety d, Yawei Cheng a, c, * a

Institute of Neuroscience and Brain Research Center, National Yang-Ming University, Taipei, Taiwan Department of Neurology, Cathay General Hospital, Hsinchu, Taiwan c Department of Rehabilitation, National Yang-Ming University Hospital, Yilan, Taiwan d Department of Psychology and Department of Psychiatry and Behavioral Neuroscience, The University of Chicago, Chicago, IL, USA b

a r t i c l e i n f o

a b s t r a c t

Article history: Received 3 August 2012 Received in revised form 26 September 2013 Accepted 16 October 2013 Available online 18 October 2013

Although the neurodevelopment of empathy from childhood to adolescence has been documented, no study has yet examined it across a life span aging perspective. Sixty-five healthy participants from 3 age groups (young, middle-aged, old) underwent functional magnetic resonance imaging while presented with visual stimuli depicting body parts being injured, either accidentally by oneself or intentionally by another, thus isolating pain and agency as 2 variables of interest. Older adults reported less dispositional emotional empathy as assessed by the interpersonal reactivity index, and their unpleasantness ratings were more sensitive to intentional harm. The response in anterior insula and anterior mid-cingulate cortex to others’ pain, indicative of emotional empathy, showed an age-related decline, whereas the response in medial prefrontal cortex and posterior superior temporal sulcus to perceived agency did not change with age. Dynamic causal modeling demonstrated that their effective connectivity remained stable. The pattern of hemodynamic response was not related to regional gray matter volume loss. These findings suggest that the neural response associated with emotional empathy lessened with age, whereas the response to perceived agency is preserved. Ó 2014 Elsevier Inc. All rights reserved.

Keywords: Aging Empathy Agency Functional MRI Dynamic causal modeling Effective connectivity Gray matter volume

1. Introduction Empathetic responding, which implies a shared interpersonal experience, is implicated in many aspects of social cognition, notably prosocial behavior, morality, and the regulation of aggression (Decety, 2010; Eisenberg and Eggum, 2009). Many behavioral studies have investigated the development of empathy during childhood (e.g., Bandstra et al., 2011; Roth-Hanania et al., 2011; Vaish and Warneken, 2012; Zahn-Waxler et al., 1992), and a few have begun to examine neuro-developmental changes using functional neuroimaging methods (Decety and Michalska, 2010; Decety et al., 2008, 2012). Much less is known about the developmental changes in empathy over the life span. To the best of our knowledge, no study has yet examined the neuro-hemodynamic response underlying empathy in elderly adults in comparison with younger adults. Such studies are critical to advance our understanding of typical aging

Yao-Chu Chen and Cheng-Chiang Chen equally contributed to the study. * Corresponding author at: Institute of Neuroscience, National Yang-Ming University, No. 155, St. Linong, Sec. 2, Beitou, Taipei, Taiwan 112, R.O.C. Tel.: þ886 2 28267912; fax: þ886 2 28204903. E-mail address: [email protected] (Y. Cheng). 0197-4580/$ e see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.neurobiolaging.2013.10.080

processes, and can provide insight into neurodegenerative conditions associated with socioemotional deficits (Gleichgerrcht et al., 2011; Lough et al., 2006). Empathy is a construct that has been defined in multiple ways using various criteria (Batson, 2009). While empathy is often viewed as feelings of concern for another, it is important to note that empathy is a multidimensional construct composed of dissociable neurocognitive components that include sensorimotor resonance, emotional, and cognitive components. Emotional empathy involves the capacity to either share or becomes affectively aroused by others’ emotions, commonly referred to as emotion contagion or empathic arousal. Cognitive empathy operates similarly to the construct of theory of mind and perspective-taking, that is the ability to explain, predict, and interpret behavior by attributing mental states such as desires, beliefs, intentions, and emotions to oneself and to others (Decety and Svetlova, 2012). The neural mechanisms underlying the emotional component of empathy have been well studied in adults particularly with regards to the perception of pain and distress in others. Numerous neuroimaging studies have demonstrated the reliable activation of a neural network involved in pain processing,

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including the anterior mid-cingulate cortex (aMCC), anterior insular cortex (AIC), supplementary motor area (SMA), and periaqueductal gray area. Activation of this network has been reported in response to facial expressions of pain, body parts being injured, imagining the pain of others, or simply anticipating harm to someone (Botvinick et al., 2005; Chen et al., 2012; Cheng et al., 2007, 2010; Decety and Porges, 2011; Decety et al., 2010; Jackson et al., 2005, 2006; Lamm et al., 2007; Singer et al., 2004). Of particular importance, the involvement of the AIC is nearly ubiquitous in studies of pain empathy (Gu et al., 2010). The aMCC, a region that implements a domain-general process integral to negative affect, pain, and cognitive control, is activated by anticipation of pain and instrumental escape from pain (Shackman et al., 2011). The cognitive component of empathy partially overlaps with the construct of affective theory of mind, which accounts for the intersubjective awareness that other individuals’, internal subjective states may be similar or different from our own (ShamayTsoory, 2009). The ability to conceptualize and reflect on our own and other’s emotions, to appreciate that these can differ, is central to socioemotional competence. Functional neuroimaging studies have identified a circumscribed neural network reliably underpinning the understanding of mental states, linking the medial prefrontal cortex (mPFC), posterior superior temporal sulcus and/or temporoparietal junction (pSTS/TPJ), and temporal poles and/or amygdala (Brunet et al., 2000; Choudhury et al., 2009; Vollm et al., 2006). Particularly, the mPFC has been reported to preserve the cortical thickness in the elderly individuals (Salat et al., 2004). When engaging in the self-referencing and mentalizing tasks, older adults and younger counterparts could elicit comparable activations in the mPFC and pSTS and/or TPJ (Castelli et al., 2010; Gutchess et al., 2007). Evidence about age-related changes in empathy from selfreported questionnaires and performance-based tasks is mixed. Driven by large samples consisting of individuals in their teens or early 20s through later adulthood (i.e., the 70s or 80s), some studies suggest age-related stability in empathy (Diehl et al., 1996; Eysenck et al., 1985), whereas other studies point to a pattern of negative age differences in empathy (Grühn et al., 2008; Helson et al., 2002; Phillips et al., 2002; Schieman and van Gundy, 2000). When dichotomizing the cognitive and emotional components of empathy, the findings are also inconclusive. One study found that older adults regulate their emotions more effectively than younger counterparts (Gross et al., 1997), whereas another reported reduced cognitive empathy in late adulthood (Bailey and Henry, 2008; Bailey et al., 2008). Furthermore, based exclusively on emotion recognition tasks, a growing body of evidence reports an age-related decline (Ruffman et al., 2008 for a meta-analysis). Importantly, contextual factors, such as the age-relevance of the emotion-elicitor (Charles and Piazza, 2007), seem to moderate age differences in empathic accuracy and emotional congruence (Richter and Kunzmann, 2011). The ability to perceive others in pain is an empathetic capacity with great evolutionary significance. When individuals perceive others in physical pain, agency plays an important role in whether the action resulting in the pain is perceived as intentional or accidental (Akitsuki and Decety, 2009; Decety et al., 2008). Specifically, whether harm was caused intentionally or not, influences self-reported pain (Gray and Wegner, 2008) and neural responses (Decety et al., 2012). The perception of agency is a critical aspect in social understanding (Decety and Grèzes, 2006; Decety and Sommerville, 2003). Accordingly, we chose to use 2 categories of empathy-eliciting stimuli, depicting an individual in pain caused either accidentally by oneself or intentionally by another, with a well-validated functional magnetic

resonance imaging (fMRI) paradigm in participants aged between 20 and 80 years to examine the aging trajectories underpinning emotional empathy and perceived agency. According to previous fMRI studies (Akitsuki and Decety, 2009; Decety et al., 2009), the AIC and aMCC involvement in response to perceiving others’ pain primarily reflects emotional empathy, whereas the mPFC and pSTS and/or TPJ activation represents the neural computation involved in the perception of agency. It was hypothesized that, if aging affects emotional empathy, the hemodynamic response and effective connectivity between AIC and aMCC elicited by the perception of pain in others would change with age. On the other hand, if decline in understanding agency were associated with aging, then elderly individuals would demonstrate different hemodynamic activity and effective connectivity to perceived agency as compared with younger counterparts. Furthermore, given the fact that gray matter volume loss appears to be a linear function of age throughout adult life (Good et al., 2001), we conducted voxel-based morphometry (VBM) and examined the extent to which changes in BOLD responses for emotional empathy and agency perception would be driven by regional gray matter volume loss. 2. Methods 2.1. Participants The study enrolled 3 groups of right-handed, ethnic Chinese participants from the community: (1) 22 young participants (11 males, aged from 20 to 35 years); (2) 22 middle-aged participants (11 males, 40e55 years); and (3) 21 older participants (11 males, 65e80 years). All participants were screened to ensure they had no history of neurologic damage or color-blindness. The older participants were further screened for medication use, recent surgical procedures, and psychiatric illness. Subjects were excluded from participation if they reported taking blood pressure medications or had previous surgical procedures in the head and/or neck area. All participants gave written informed consent for the study, which was approved by the local Ethic Committee (Yang-Ming University Hospital), and conducted in accordance with the Declaration of Helsinki. 2.2. General procedures Before fMRI scanning, each participant underwent assessment on the Chinese version of Cognitive Abilities Screening Instrument (CASI C-2.0) (Lin et al., 2002) and filled in a self-reported dispositional measure of empathy (the interpersonal reactivity index [IRI]). After scanning, participants were requested to evaluate the pain intensity and unpleasantness of the stimuli (Dyad Pain and Solo Pain) that they had seen in the scanner, on a 6-point scale with the computerized Facial Pain Scale-Revised (Bieri et al., 1990). 2.3. Visual stimuli A total of 48 stimuli consisting of animations (2.2 s) depicting body parts (hands and feet) in pain or no pain were presented to participants, who were requested to passively view these scenarios. Two categories of stimuli were included (Akitsuki and Decety, 2009; Decety and Michalska, 2010; Decety et al., 2008) for behavioral and fMRI validation (Fig. 1). One category referred to accidental harm, including: (1) Solo Pain (SP): 1 person is in a painful situation that was accidentally caused; and (2) Solo No-pain (SN): 1 person is involved in a non-painful situation. Another category was intentional harm, which included (1) Dyad Pain (DP): 1 person is in a painful situation, intentionally caused by

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Fig. 1. Examples of the visual stimuli used in the empathy task. The two categories of stimuli include accidental harm (Solo Pain [SP], Solo No-pain [SN]) and intentional harm (Dyad Pain [DP], Dyad No-pain [DN]). Abbreviations: DN, Dyad No-pain; DP, Dyad Pain; SN, Solo No-pain; SP, Solo Pain.

another individual; and (2) Dyad No-pain (DN): 2 individuals are present and moving, but there is no pain in their interaction. No faces were shown in the stimuli. Perceiving others’ pain ([SP þ DP]  [SN þ DN]) was the pain effect, reflecting emotional empathy. Perceiving social context ([DP þ DN]  [SP þ SN]) was the agency effect in relation with social understanding. 2.4. Functional magnetic resonance imaging data acquisition, imaging processing, and statistical analysis Structural and functional magnetic resonance imaging data were acquired using a Siemens 3 tesla magnetic resonance imaging scanner (Magnetom Trio-Tim, Siemens Medical Solutions, Erlangen, German) equipped with a high-resolution 12-channel head array coil. Image processing was carried out using SPM8 (Statistical Parametric Mapping 8, Wellcome Department of Imaging Neuroscience, London, UK). Please refer to Supplementary Data for details. Subjects went through 1 structural and 2 functional scans. The functional scanning consisted of 2 sessions: 1 with the checkerboard pattern reversal stimulation and another with the empathyeliciting stimuli (SP, SN, DP, DN). The checkerboard pattern reversal stimulation served as a control to ensure that the hemodynamic change to basic visual stimuli across age groups would not confound the response to empathy-eliciting stimuli. 2.5. Region of interest (ROI) definition and analysis Three ROIs were defined for the checkerboard stimuli, including superior, middle, and inferior occipital cortex. Eight ROIs

were defined for the empathy stimuli, including AIC, posterior insular cortex (PIC), aMCC, pSTS, mPFC, superior frontal gyrus (SFG), inferior frontal gyrus, and dorsolateral prefrontal cortex (dlPFC) individually for each subject, based on the anatomic coordinates from previous fMRI studies of empathy for pain (Lamm et al., 2011 for a meta-analysis). See Supplementary Table S1 for further information, including the ROI coordinates. 2.6. Dynamic causal modeling (DCM) Connectivity analyses were carried out with the DCM toolbox in SPM8. Functional imaging data were modeled at the first level for each subject. The general linear model for DCM consisted of 3 regressors: (1) visual: all conditions with visual inputs; (2) pain: all visual input depicting painful situations; and (3) agency: painful situations intentionally caused by another individual. Drawing from the results of previous investigations (Lamm et al., 2011) and anatomic projections, dlPFC, mPFC, AIC, and aMCC were subsequently designated as the volumes of interest (see Supplementary methods for details). The initial driving input was designated from V1 to aMCC because visual stimuli were used. The modulatory effect of pain was designated between AIC and aMCC. The modulatory effect of perceived agency was designated from aMCC to either mPFC or dlPFC (Shackman et al., 2011). The existence of 2 directions between aMCC and mPFC and between aMCC and dlPFC, respectively, resulted in yielding a total of 4 combinations. A group Bayesian model selection was carried out with random effects of standard procedures (Penny et al., 2010) to determine the best fitted model within all 4 possible

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3. Results

effect, perceiving social context ([DP þ DN]  [SP þ SN]), found activations in the mPFC, pSTS, posterior cingulate cortex, and fusiform gyrus. The interaction ([DP DN]  [SP  SN]) was not significant. In addition, there was no sex-related activation associated with the pain and agency contrasts and no significant interaction between sex and age. A direct voxel-by-voxel comparison did not find any difference across 3 age groups in the occipital cortex (p > 0.5) in response to the checkerboard stimuli. For the empathy-eliciting stimuli, activation in the right AIC (F[2, 62] ¼ 7.33, p < 0.001, h2 ¼ 0.19) and in the PIC (F[2, 62] ¼ 3.69, p < 0.05, h2 ¼ 0.11) showed an interaction between pain and age. There was no interaction of agency by age. Post hoc analysis found that, for the right AIC, the pain effect was present in the young (p < 0.001) and middle-aged (p < 0.01) groups, but not in the old group (p > 0.05). For PIC, there was the pain effect in the middle-aged only (p < 0.01).

3.1. Behavior performance

3.3. Correlations with age and subjective evaluation of the stimuli

Table 1 lists the demographic data and clinical variables. The older adults were not suffering from dementia, as indicated by higher CASI C-2.0 scores (96.5  3.1) on the diagnosis of dementia (Lin et al., 2002). A 1-way analysis of variance revealed that older adults reported the lowest dispositional empathy (IRI) (p < 0.05) except on the perspective-taking subscale (p > 0.05). For the subjective ratings of unpleasantness and pain intensity, a 2-way mixed analysis of variance indicated an effect of perceived agency (Dyad Pain vs. Solo Pain: F [1, 62] ¼ 5.75, p < 0.05; F [1, 62] ¼ 15.54, p < 0.001) and an interaction of agency by age (F [2, 62] ¼ 3.27, p < 0.05; F [2, 62] ¼ 3.94, p < 0.05). The age itself had no effect on ratings of unpleasantness. Post hoc tests revealed that older adults had higher ratings for Dyad Pain relative to Solo Pain (pain intensity: p < 0.001; unpleasantness: p < 0.01), whereas their younger and middle-aged counterparts demonstrated no difference. In addition, there was no gender difference for subjective ratings (p > 0.05; p > 0.05).

For the pain effect ([SP þ DP]  [SN þ DN]), there were age-related negative correlations in the right AIC (r ¼ 0.37, t63 ¼ 3.20, p < 0.01) and aMCC (r ¼ 0.31, t63 ¼ 2.54, p < 0.05) across all age groups (Fig. 3). However, no quadratic relationship was found in either ROI. The agency effect ([DP þ DN]  [SP þ SN]) was not correlated with age. Interestingly, when perceiving someone intentionally hurt by another individual (Dyad Pain), the young and old groups showed a double dissociation between neural correlates and subjective ratings. Solo pain had no such dissociation. When viewing Dyad Pain, young adults’ ratings of unpleasantness positively predicted activation in the pSTS (r ¼ 0.45, p < 0.05), but not the aMCC response (r ¼ 0.12) (Fig. 4). Fisher z transformation suggested that pSTS had a significantly stronger correlation than aMCC (z ¼ 1.87, p < 0.05). In contrast, within older adults, unpleasantness ratings were associated with the aMCC response (r ¼ 0.57, p < 0.01), but not the pSTS response (r ¼ 0.09). Fisher transformation confirmed that the correlation was significantly stronger for aMCC than pSTS in older adults (z ¼ 1.67, p < 0.05).

combinations. After DCM had been estimated, we extracted the parameter representing the modulatory effect of pain and agency (the “B” parameter) from the best fitting model. A statistical threshold of p < 0.05 (Bonferroni-correction) was used for connectivity analyses. 2.7. Voxel-based morphometry Individual T1 weighted images were implemented into SPM8 for VBM analysis. Standard procedures included image segmentation, deformation estimation, and generation of spatially normalized, and smoothed Jacobian scaled gray matter images, and fitting a general linear model for statistical analysis (Supplementary Data).

3.2. Neuroimaging results With age as a covariate of no interest, whole brain analysis for the pain effect, perceiving others’ pain ([SP þ DP]  [SN þ DN]) was associated with significant signals in the aMCC, AIC, supplementary motor area, and somatosensory cortex (Fig. 2). The agency Table 1 Demographic and clinical variables of the participants Demographics and scales

Age Education CASI C-2.0 IRI PT FS EC PD Pain intensities Solo Dyad Unpleasantness Solo Dyad

Young

Middle-aged

Old

(N ¼ 22)

(N ¼ 22)

(N ¼ 21)

p

M

SD

M

SD

M

SD

23.4 16.1 99.4

2.5 0.9 1.0

43.7 15.6 99.6

3.1 2.7 0.7

69.4 12.4 96.5

4.4 4.8 3.1

0.05) (Fig. 6). In addition, gray matter volume changes were

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Fig. 2. Hemodynamic responses to the perception of others’ pain. (A) Whole brain analysis for the pain effect ([SP þ DP]  [SN þ DN]), reflecting emotional empathy, shows a significant signal increase in the anterior insular cortex (AIC), anterior mid-cingulate cortex (aMCC), and supplementary motor area (SMA). (B) A direct voxel-by-voxel comparison: the pain effect in the right AIC is mainly driven by young (*** p < 0.001) and middle-aged groups (** p < 0.01), rather than older adults (p > 0.05). Activation in the inferior occipital cortex (IOC) does not differ across age groups. Abbreviations: AIC, anterior insular cortex; aMCC, anterior mid-cingulate cortex; IOC, inferior occipital cortex; SMA, supplementary motor area.

not correlated with hemodynamic responses to others’ pain (AIC: r ¼ 0.09; aMCC: r ¼ 0.12) and to perceived agency (pSTS: r ¼ 0.16; SFG: r ¼ 0.12). 4. Discussion The present study examined whether aging has an impact on the neural mechanisms involved in empathy. We tackled this issue with self-reported dispositional empathy (IRI) and subjective pain ratings, and functional and structural neuroimaging data across 3 age groups. Results showed that older participants reported less dispositional empathy (except on the perspective-

taking subscale), but rated unpleasantness higher for the scenarios that depicted the pain intentionally caused by another person (Dyad Pain). The impact of aging on the neural correlates of emotional empathy and agency perception was dissociated. The neural response to emotional empathy, as indicated by the hemodynamic response in the AIC and aMCC in response to others’ pain ([SP þ DP]  [SNþ DN]), showed an age-related decline. The neural response to perceived agency ([DP þ DN]  [SP þ SN]), as indicated by the hemodynamic activity in the mPFC and pSTS, did not change with age. The association between hemodynamic responses and unpleasantness ratings shifted from pSTS in younger counterparts to aMCC in older adults when

Fig. 3. Age-related changes in the hemodynamic response to empathy-eliciting stimuli. Age has a negative effect in the anterior insular cortex (AIC) when perceiving others in pain (r ¼ 0.37, p < 0.01). Abbreviation: AIC, anterior insular cortex.

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Fig. 4. Double dissociation between the hemodynamic response and the subjective pain ratings in older and younger participants. When young adults viewed stimuli depicting someone intentionally hurt by another (Dyad Pain), ratings of unpleasantness are positively correlated with the response in the pSTS (r ¼ 0.45, p < 0.05), but not the anterior midcingulate cortex (aMCC) response (r ¼ 0.12, p ¼ 0.59). In contrast, in older adults, ratings of unpleasantness are associated with the response in the aMCC (r ¼ 0.57, p < 0.01), but not the posterior superior temporal sulcus (pSTS) response (r ¼ 0.09, p ¼ 0.69). Abbreviations: aMCC, anterior mid-cingulate cortex; pSTS, posterior superior temporal sulcus.

viewing scenarios depicting intentional harm (Dyad Pain). Dynamic causal modeling demonstrated that the effective connectivity of AIC to aMCC and aMCC to mPFC responsible for other’s pain and perceived agency, respectively, remained stable across age groups. Importantly, the changes in the pattern of hemodynamic response were not related to regional gray matter volume loss. These findings suggest that aging is associated with uncoupling between emotional empathy and agency understanding, as reflected by an age-related decline in the hemodynamic response to the perception of pain in others but by preservation in the response to perceived agency. Previous neuroimaging studies of episodic memory (e.g., Hazlett et al., 1998; Madden et al., 1999), working memory (e.g., Reuter-Lorenz et al., 2000; Rypma and D’Esposito, 2000), attention (e.g., Anderson et al., 2000; Johannsen et al., 1997), and executive function (Smith et al., 2001) suggest that older adults tend to activate more brain regions than their younger counterparts, coinciding with the hemispheric asymmetry reduction in older adults model, which suggests that older adults attempt to compensate for cortical networks that have become less efficient with advanced age (Cabeza, 2002). The passive viewing paradigm of pain empathy that we used did not detect the recruitment of additional cortical regions. In addition, the occipital activation elicited by checkerboard visual stimuli did not differ among age

groups (young vs. middle-aged vs. old). In accordance with previous similar fMRI studies (Akitsuki and Decety, 2009; Lamm et al., 2011), the whole brain analysis with age as a covariate of no interest showed reliable involvement of regions that belong to the pain matrix and the processing of agency understanding. Given the fact that aging can influence the cerebral vasculature by altering neuro-vascular coupling (Riecker et al., 2003), these findings indicate that vascular variability is unlikely a confounding factor in the observed age-dependent activation in response to empathy-eliciting stimuli. Alternatively, attentional bias to emotional stimuli in aging adults (Mather and Carstensen, 2003) could potentially contribute to the observed age-related reduction in the AIC response. Consistent with previous neuroimaging studies across the adult life span (Grady et al., 2006; Marcus et al., 2007), the inclusion of 3 age groups (young vs. middle-aged vs. old) across a large age range (20e80 years) helps delineate the aging processes on the neural circuitry underlying empathy. This study along with a cross-sectional fMRI study with 50 participants aged from 7 to 40 years old using a similar paradigm (Decety and Michalska, 2010) contributes to the understanding of the neurocognitive mechanisms mediating empathy from a life span developmental and aging perspective. In this cross-sectional study, individuals in the first half of life showed an age-related gain in the AIC activity

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Fig. 5. Effective connectivity across 3 age groups. The upper diagram shows that perceiving others’ pain and agency exert the modulatory effect on the connection from anterior insular cortex (AIC) to anterior mid-cingulate cortex (aMCC) and from the aMCC to mPFC, respectively. Neither the pain effect modulating the connection from AIC to aMCC, (F[2, 57] ¼ 1.24, p ¼ 0.30) nor the agency effect modulating the connection from aMCC to medial prefrontal cortex (mPFC) (F[2, 57] ¼ 0.57, p ¼ 0.57) are correlated with age. Abbreviations: AIC, anterior insular cortex; aMCC, anterior mid-cingulate cortex; mPFC, medial prefrontal cortex.

when perceiving others’ pain but an age-related decrease in the subjective pain ratings and PIC activity. In the second half of life, neither subjective ratings nor hemodynamic responses had any age-related gain. Instead, an age-related decrease was found in the AIC hemodynamic response, a region that plays a key role in emotional awareness, and a critical hub to integrate salient stimuli and events with visceral and autonomic information (Menon and Uddin, 2010). Interestingly, in the present study, older adults reported less dispositional empathy but scored higher on ratings of unpleasantness in response to Dyad Pain versus Solo Pain. Behavioral, anatomic, and neuroimaging evidences support that emotion processing is relatively well preserved in healthy older adults despite changes in other cognitive domains (for a review, see Reuter-Lorenz and Lustig, 2005). For instance, compared with young adults, older adults are just as likely to understand emotional stimuli (Keightley et al., 2006; LaBar et al., 2000; Mather and Knight, 2006), and report intense emotional experience (Levine and Bluck, 1997). Additionally, older adults have greater emotional regulation to view emotional stimuli (Carstensen et al., 2011; Gross et al., 1997). Specifically, while watching film clips depicting an empathy-inducing episode, older adults expressed greater sympathy and performed better in

empathic accuracy tasks than their younger counterparts (Richter and Kunzmann, 2011). Our results showed that scores on the perspective-taking subscale of IRI did not change with age, supporting the hypothesis that the ability to understand others’ feeling without being emotionally distressed may contribute to well-being in the elderly individuals (Gross et al., 1997), but challenging the model that cognitive empathy is adversely affected as a consequence of normal aging (Bailey and Henry, 2008; Bailey et al., 2008). Recent neuroimaging studies of emotional processing have provided contradictory results. Some studies have found reduced activity in the amygdala during the perception of negative stimuli (Gunning-Dixon et al., 2003; Iidaka et al., 2001; Mather et al., 2004). Alternatively, others have proposed increased functional connectivity between the amygdala and ventral anterior cingulate cortex (reflecting enhanced emotional regulation) and decreased connectivity with posterior brain regions (reflecting decreased perceptual processing) when older adults made valence ratings for emotional pictures (St Jacques et al., 2010). In our study, the AIC and aMCC activity in response to the perception of empathy-eliciting stimuli indicates that emotional empathy is diminished in older adults. Alternatively, the mPFC and pSTS activity along with the effective connectivity between

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Fig. 6. Gray matter volume across 3 age groups. Total gray matter volume (TGM) has no significant difference across age groups (p > 0.05). The age group (young vs. middle-aged vs. old) is significant for the regional gray volume (GM) volume in the inferior frontal gyrus (IFG) (*** p < 0.001), anterior mid-cingulate cortex (aMCC) (** p < 0.01), anterior insular cortex (AIC) (*** p < 0.001) and posterior insular cortex (PIC) (*** p < 0.001), but not in the superior frontal gyrus (SFG) (p > 0.05). Abbreviations: AIC, anterior insular cortex; aMCC, anterior mid-cingulate cortex; GM, gray volume; IFG, inferior frontal gyrus; PIC, posterior insular cortex; SFG, superior frontal gyrus; TGM, total gray matter volume.

aMCC and mPFC indicates that the neural correlates of perceived agency do not change with age. Interestingly, the association between hemodynamic changes and unpleasantness ratings in response to Dyad Pain shifted from pSTS in younger counterparts into aMCC in older adults. The present findings indicate that older adults rely on different cortical networks to process empathy-eliciting stimuli compared with their younger counterparts. With age, the neural underpinning for affective sharing tends to be diminished while the neural response associated with agency understanding is preserved. In accordance with the previous findings (Good et al., 2001; Resnick et al., 2003; Walhovd et al., 2005), regional gray matter volumes were found to decline with advanced age. Theoretically, the aging brain exhibits an assortment of micro- and macroscopic changes that ultimately result in some degree of cognitive and functional decline. However, few aging studies have investigated gray matter changes in relation to functional brain changes. Fluid-intelligence skills, such as working memory, are believed to be largely mediated by frontal-subcortical structures (Kausler, 1991; West, 1996) and appear particularly susceptible to agerelated anatomic changes (Haug and Eggers, 1991; Tisserand et al., 2002). One recent aging study reported that the hemodynamic activation responsible for the working memory task was more correlated with white matter integrity than gray matter volume of the frontal lobe (Schulze et al., 2011). Also, we did not find that the hemodynamic response to the perception of others’ pain and agency is in association with the volume loss of regional gray matter.

5. Conclusion Recruiting younger, middle-aged, and older adults, this multimodal study combined subjective evaluation and structural and functional imaging to elucidate the relationship between gray matter, brain activity, and empathy associated with healthy aging. Notably, the present study adds to previous developmental findings (Decety and Michalska, 2010) in demonstrating the neurocognitive trajectories of empathy over the life span (7e80 years). The comprehensive life span approach can identify the links between brain and behavior in development, including both linear and nonlinear changes (Grady, 2012). Given the fact that empathy arguably serves adaptive social functions at any period during the life span, and especially in adulthood as individuals become increasingly responsible for themselves and for the wellbeing of others (e.g., own children, aging parents) (Richter and Kunzmann, 2011), the present findings contribute to a better understanding of multidirectional age differences in empathy. Disclosure statement The authors certify that they have no actual or potential conflicts of interest regarding the research reported in this article. Acknowledgements This study was sponsored by National Science Council (NSC 992314-B-010-037-MY3; NSC 100-2628-H-010-001-MY3), National

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