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Neuropsychologia 46 (2008) 160–173

Temporal dynamic of neural mechanisms involved in empathyfor pain: An event-related brain potential study

Yan Fan a,b, Shihui Han a,b,∗a Department of Psychology, Peking University, Beijing 100871, PR China

b Functional Imaging Center, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, PR China

Received 25 May 2007; received in revised form 28 July 2007; accepted 30 July 2007Available online 6 August 2007

bstract

Previous neuroimaging studies have identified a neural circuit that is involved in empathy for pain. However, the temporal dynamics of neuralctivities underlying empathic processes remains poorly understood. This was investigated in the current study by recording event-related brainotentials (ERPs) from healthy adults who were presented with pictures or cartoons of hands that were in painful or neutral situations. Subjectserformed a pain judgment task that required attention to pain cues in the stimuli or a counting task that withdrew their attention from these cues.he ERP results showed early differentiation between painful and neutral stimuli over the frontal lobe at 140 ms after sensory stimulation. A long-

atency empathic response was observed after 380 ms over the central–parietal regions and was more salient over the left than right hemispheres.

he early and late empathic responses were, respectively, modulated by contextual reality of stimuli and by top-down attention to the pain cues.oreover, the mean ERP amplitudes at 140–180 ms were correlated with subjective reports of the degree of perceived pain of others and of

elf-unpleasantness. The ERP results support a model of empathy for pain consisting of early emotional sharing and late cognitive evaluation.2007 Elsevier Ltd. All rights reserved.

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eywords: Empathy; ERP; Pain; Attention; Contextual reality

. Introduction

Successful social interactions require the capacity to under-tand emotional and sensory experience of other individuals.n addition, appropriate social communications and behaviourseed vicarious experiencing of emotions congruent with those ofthers while being aware of the distinction between the self andthers (Decety & Jackson, 2004; Decety & Lamm, 2006). Thisbility, referred to as empathy, has epistemological significanceecause it provides direct estimate of other’s possible behavioursnd the knowledge about potential properties of environmentsDe Vignemont & Singer, 2006).

A traditional approach to the understanding of psychology

f empathy relies on subjective ratings of empathic emotionBatson, 1987) and self-report questionnaires that measurempathy as a trait (Bryant, 1987; Davis, 1996). While this

∗ Corresponding author at: Department of Psychology, Peking University, 5iheyuan Road, Beijing 100871, PR China. Tel.: +86 10 6275 9138;

ax: +86 10 6276 1081.E-mail address: shan@pku.edu.cn (S. Han).

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028-3932/$ – see front matter © 2007 Elsevier Ltd. All rights reserved.oi:10.1016/j.neuropsychologia.2007.07.023

pproach helps to comprehend subjective emotional reaction tothers’ feeling, the results of these studies could be influencedy intention of self-presentation and social desirability. Earlyesearchers tried to obtain physiological measures of empathicesponses by recording heart rate or galvanic skin responseCraig & Lowery, 1969; Orr & Lanzetta, 1980) and electromyo-raphy (EMG) (Lanzetta & Englis, 1989; Vaughan & Lanzetta,980). However, the subjective reports and physiological mea-ures manifest the final outcome of neural responses to emotionsf other individuals but tell little about the cognitive and neuralrocesses of empathy.

Recent studies used functional magnetic resonance imagingfMRI) to explore the neural substrates of empathy-related pro-esses by manipulating representation of others’ affective statend provided evidence that certain brain areas are engaged inhared representation of one’s own and others’ emotional states.or example, observing disgust faces and feeling disgust one-

elf activated the same sites in the anterior insula and anterioringulate cortex (ACC) (Wicker et al., 2003), which were alsoctivated when participants viewed faces with painful expressionBotvinick et al., 2005). Moreover, insula and ACC activities

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Y. Fan, S. Han / Neurops

nduced by painful faces were correlated with subjects’ esti-ates of intensity of observed pain whereas magnitudes of the

nsula and left inferior frontal activities correlated with subjects’elf-rated empathy (Saarela et al., 2007). Perception of paintimulation applied to hands or feet also generated increasednsula and ACC activation that was correlated with subjec-ive estimation of pain intensity (Jackson, Meltzoff, & Decety,005; Jackson, Brunet, Meltzoff, & Decety, 2006; Morrison,loyd, di Pellegrino, & Roberts, 2004). Empathy-related neu-

al activity has also been investigated in conditions simulatingeal social contexts. Singer et al. (2004) scanned female vol-nteers who either experienced painful stimuli themselves oratched symbols indicating application of painful stimuli to

heir partners. The authors found that both noxious stimulipplied to the subjects and perception of symbols indicatinghe partners’ pain resulted in activation in the insular and ACC.ecause ACC is involved in coding the affective dimension ofain such as subjectively perceived unpleasantness (Rainville,uncan, Price, Carrier, & Bushnell, 1997), Singer et al. (2004)roposed that empathizing with pain is mediated by activa-ion of re-representations of the affective dimension of pain.he sensorimotor cortex can be also involved in empathic

esponses because the amplitudes of motor-evoked potentialsnduced by transcranial magnetic stimulation (TMS) over the

otor cortex were reduced when subjects observed others’ handseing pricked relative to when observing objects such as aomato being pricked (Avenanti, Bueti, Galati, & Aglioti, 2005;venanti, Paluello, Bufalari, & Aglioti, 2006). Viewing videolips of painful stimuli delivered to others increased the ampli-udes of somatosensory-evoked potentials elicited by nonpainfullectrical stimulation to the observers’ wrist (Bufalari, Aprile,venanti, di Russo, & Aglioti, in press). These findings sup-ort the existence of a shared neural network for one’s ownmotional or sensory experience and the observation of others’imilar states.

Researchers have tried to understand empathy as a processith which an observer perceives others’ emotional states andenerates a similar mental state in the self. Such approachecomposes the process of empathy into components that are

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Fig. 1. Illustration of the stimulus displays used in the current stud

gia 46 (2008) 160–173 161

utomatically elicited by mere perception of others’ emotionaltates (i.e., bottom-up process) and that depend upon top-downontrolled processes. Preston and de Waal (2002) suggest thatnvoluntarily triggered processes such as emotion contagion ormitation play a key role in understanding and sharing others’motion. This view is supported by the neuroimaging findingshat a shared neural network is engaged in perception of oth-rs’ emotional states and in generation of one’s own emotionalxperience (Botvinick et al., 2005; Jackson et al., 2005; Saarelat al., 2007; Singer et al., 2004). It has also been suggestedhat empathy is based on an unconscious and automatic simula-ion of the subjectivity of others through the function of mirroreurons (Gallese & Goldman, 1998). In agreement with this,euroimaging studies observed empathy-related neural activi-ies in association with others’ pain regardless the relationshipetween an observer and the one being observed (e.g., lovednes in Singer et al., 2004 or strangers in Botvinick et al., 2005).oreover, the sensorimotor activity linked to empathic process-

ng was not influenced by instructions that emphasized either therst- or third-person perspective (Avenanti et al., 2006), suggest-

ng that the sensorimotor component of empathy for pain mayccur independent of task demands. These findings suggest thatmpathy may involve an automatic process that result in affectiveharing.

However, top-down controlled processes may also affectmpathic responses profoundly. Goubert et al. (2005) suggesthat prior personal experiences and shared knowledge lead toeadily elicited empathic responses when perceiving someonelse in similar situations. In line with this, it has been shownhat social relations and social contexts modulate physiologi-al measures of empathy. For example, while EMG inducedy displays of distress were of larger amplitudes than those toisplays of pleasure, such differential responses were greaterhen subjects expected cooperation than when expected com-etition with the one being observed (Lanzetta & Englis, 1989).

inger et al. (2006) found that insula activity related to empathyas modulated by evaluation of others’ social behaviours, beingreater to confederates who played fairly than unfairly. Simon,raig, Miltner, and Rainville (2006) also observed that ACC

y. The cartoons were transformed from the picture stimuli.

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nd amygdala activations induced by facial expressions of painere greatly reduced when subjects performed pain irrelevant

ask (e.g., gender judgment).More recently, Gu and Han (2007) found that attention to

ain cues in the stimuli modulate the neural activities linkedo empathy. They designed two tasks to manipulate top-downttention to pain cues in the stimuli in which hands were inainful or neutral situations (see Fig. 1), i.e., rating the intensityf pain felt by a model that required focused attention to theain cues or counting the number of hands in the stimuli thatrew attention away from others’ feeling. Gu and Han foundhat, relative to counting neutral stimuli, rating pain intensityf painful pictures induced increased activation in part of theain matrix including ACC/paracingulate, insula, and the leftiddle frontal gyrus. However, these neural activities were evi-

ent in the pain judgment task but not in the counting task,ndicating that empathic responses strongly depended upon top-own attention to the emotional cues. In addition, they foundhat empathy-related neural activities were also modulated byhe contextual reality of stimuli. By transforming the painfulictures into cartoons so as to degenerate the realism of stimuli,u and Han (2007) found that, relative to rating pain intensity ofainful pictures, rating pain intensity of painful cartoons failedo activate the insula and produced weaker ACC activity.

These findings suggest that the neural correlates of empathyre strongly modulated by social relations between individu-ls, by the voluntary effort to understand others’ emotion, andy the prior knowledge of contextual reality of stimuli. Prestonnd de Waal (2002) proposed that early on, automatic processesause the state of individuals who experience an emotional stateo elicit a similar or relevant state in the observers. Top-downontrolled processes may then inhibit or facilitate this vicar-ous emotional state. Decety and Lamm (2006) suggest thatmpathy involves both emotion sharing (bottom-up informationrocessing) and executive control to regulate this experiencetop-down information processing), underpinned by specificnd interacting neural systems. However, it is unclear at whichtage of empathic processing the top-down controlled mech-nisms (e.g., attention and evaluation of social relations andehaviours) are involved in modulation of empathic response.e Vignemont and Singer (2006) suggest two models to account

or the modulation of vicarious affective responses towards oth-rs’ emotion. The late appraisal model proposes that empathicesponses are automatically activated by the perception of emo-ional cues while contextual information is processed in parallelo as to be involved to modulate the empathic responses at aater stage. The early appraisal model, however, suggests thatmotional cues are first evaluated in a context of external andnternal information. The outcome of the contextual appraisalrocesses determines whether empathic responses take place at aater stage. Nevertheless, previous research failed to distinguishetween these two models because blood oxygen dependentBOLD) signals recorded in fMRI studies have a low temporal

esolution.

The current study investigated several issues regarding theognitive and neural mechanisms underlying empathy for pain.irst, we investigated the temporal dynamics of neural mecha-

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ogia 46 (2008) 160–173

isms underlying empathy for pain by recording event-relatedrain potentials (ERPs) elicited by pictures of hands in painful oreutral situations (Fig. 1). Empathic responses to pain of otherndividuals were indexed by the difference between ERPs toainful and neutral stimuli, similar to that in previous fMRItudies (Gu & Han, 2007; Jackson et al., 2005). Of particularnterest were the temporal features of the ERP differentiationetween painful and neutral stimuli.

Secondly, we studied whether and how empathic responsesre modulated by top-down attention to pain cues. Similar tour previous fMRI study (Gu & Han, 2007), we manipulatedttention to pain cues by asking subjects to judge pain intensityupposedly felt by the model or to count the number of hands inhe stimuli. The effects of task demands on empathic responseselp to distinguish between the automatic and top-down con-rolled process of empathy for pain. Specifically, the automaticrocess is indexed by the responses that are not influencedy task demands, whereas the top-down controlled process iseflected in the responses that depend upon task manipulations.lthough the responses in ACC and insula were observed in

he pain judgment task but not in the counting task (Gu &an, 2007), such fMRI results do not necessarily mean that

ll empathic neural responses depend upon task demands or thathere are no automatic empathic responses. It is possible thatOLD signals with low temporal resolution, particularly in the

tudies using box-car design (Gu & Han, 2007; Jackson et al.,005, 2006; Singer et al., 2004), mainly reflect sustained neuralctivity related to empathy and are not efficacious to reveal auto-atic empathic neural responses that are essentially transient

nd occur early and rapidly. The slow sustain empathic neu-al responses revealed by fMRI studies may conceal the rapidransient empathic neural responses.

Third, we investigated to what degree the automatic and con-rolled processes of empathy for pain are modulated by priornowledge of contextual reality of stimuli. We recently foundhat, although the knowledge of contextual reality of stimuli

odulated empathic neural responses, this effect was differentrom that produced by top-down attention (Gu & Han, 2007).articularly, empathy-related insula activity to painful cartoonsas eliminated and ACC activity was weakened when perceiv-

ng pain in cartoons compared with that in pictures. However, theight frontal activity was not influenced by the contextual real-ty of stimuli. As mentioned above, if brain areas such as ACCnd insula underpin the automatic “affective sharing” processJackson et al., 2005, 2006; Singer et al., 2004; Wicker et al.,003), it may be hypothesized, on the ground of Gu and Han’sbservation, that the prior knowledge of contextual reality oftimuli should modulate early automatic processes of empathyor pain. To assess this hypothesis, we compared neural activ-ties differentiating painful versus neutral pictures and painfulersus neutral cartoons, similar to our previous fMRI researchGu & Han, 2007). We expected weaker neural responses relatedo empathy for pain shown in cartoons than in pictures.

Finally, we explored ERP correlates of subjective feel-ng about others in pain and subjective feeling of one’s ownnpleasantness. While previous fMRI studies showed correla-ion between ACC/insula activity and subjective ratings of pain

ychologia 46 (2008) 160–173 163

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f other individuals (Jackson et al., 2005; Saarela et al., 2007)nd between ACC/insula activity and individual differences inmpathy as measured with empathic concern scale (Singer etl., 2004), we know little about the relationship between elec-rophysiological activity and subjective feeling of empathy forain. Specifically, it is unknown whether the automatic or con-rolled process of empathy for pain is more closely related withubjective feeling of others’ pain and self-unpleasantness.

. Methods

.1. Subjects

Thirty-one healthy undergraduate and graduate students (16 males and 15emales) from Peking University participated in the study as paid volunteers.ive of the subjects (3 males and 2 females) were excluded from data analysisecause of excessive artifacts during EEG recording. The behavioural and EEGata were reported from 26 subjects (13 males, 13 females, aged between 18 and5 years, mean age ± S.D. = 20.96 ± 1.87). All subjects had no neurological orsychiatric history. All were right-handed, had normal or corrected-to-normalision, and were not color blind. Informed consent was obtained from eachubject before the study. This study was approved by a local ethic committee athe Department of Psychology, Peking University.

.2. Stimuli and procedure

Visual stimuli consisted of 40 digital color pictures showing one hand or twoands in painful and neutral situations, similar to those in our previous fMRItudy (Gu & Han, 2007). The pictures were shot from the first-person perspec-ive and described accidents that may happen in everyday life, as illustrated inig. 1. Painful pictures included situations such as a hand trapped in a door orut by scissors. Twenty pictures showed hands in painful situation (1 hand in 8ainful pictures and two hands in 12 painful pictures). The left and right handas, respectively, involved in the painful situations in half of the painful stimuli.ach painful picture was matched with a neutral picture that showed one or twoands in situations that, although similar in contexts, did not imply any pain. Theictures were transformed into a set of cartoons using “filter → artistic → posterdge” tool of the software “Photoshop”. Thus the cartoons were similar to the pic-ure stimuli in presentation of painful and neutral situations but lacked the colorsnd textures that were necessary for representation of visual reality. The stimuliere presented in the center of a grey (128 cd/m2) background of a 21-inch coloronitor. Each stimulus was 7 cm × 5.5 cm (width × height), subtending a visual

ngle of 4◦ × 3.15◦ at a viewing distance of 100 cm.Each subject participated in 16 blocks of trials that varied in stimuli and tasks.

n each four blocks of trials, subjects (1) judged pain versus no-pain for handsn painful and neutral pictures; (2) counted the number of hands in painful andeutral pictures; (3) judged pain versus no-pain for hands in painful and neutralartoons; or (4) counted the number of hands in painful and neutral cartoons.ach block started with the presentation of instructions for 3 s, which defined the

ask (i.e., pain judgment or counting the number of hands) for each block. Thereere 80 trails in each block. On each trial the stimulus display was presented for00 ms at the center of the screen, which was followed by a fixation cross with auration varying randomly between 800 and 1600 ms. The stimuli in each blockf trials and the four tasks were presented in a random order for each subject.ubject responded to each stimulus by a button pressing using the left or right

ndex finger.

.3. ERP data recording and analysis

The electroencephalogram (EEG) was continuously recorded from 62 scalp

lectrodes that were mounted on an elastic cap in accordance to the extended0–20 system (see Fig. 2), with the addition of two mastoid electrodes. Thelectrode at the right mastoid was used as reference. The electrode impedanceas kept less than 5 kohms. Eye blinks and vertical eye movements were mon-

tored with electrodes located above and below the left eye. The horizontal

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ig. 2. The diagram of 62-channel scalp montage used in the present study.ND, the ground electrode.

lectro-oculogram was recorded from electrodes placed 1.5 cm lateral to theeft and right external canthi. The EEG was amplified (band pass 0.1–100 Hz)nd digitized at a sampling rate of 250 Hz. The ERPs in each condition wereveraged separately off-line with an epoch beginning 200 ms before stimulusnset and continuing for 1200 ms. Trials contaminated by eye blinks, eye move-ents, or muscle potentials exceeding ±50 �V at any electrode were excluded

rom the average. 8.89% of the trials were excluded due to artifacts (pictures:ain judgment = 9.0%; counting = 9.3%; cartoons: pain judgment = 8.5%; count-ng = 8.8%).

ERPs at each electrode were re-referenced to the algebraically computedverage of the left and right mastoids before further analysis. The baselineor ERP measurements was the mean voltage of a 200 ms prestimulus inter-al and the latency was measured relative to the stimulus onset. Mean voltagef ERPs were obtained (a) at 20-ms intervals starting at 80 ms after stimu-us onset and continuing until 380 ms post-stimulus and (b) at 40-ms intervalsrom 380 to 820 ms post-stimulus. Statistical analysis was conducted at elec-rodes selected from the frontal (Fz, FCz, F3–F4, FC3–FC4), central (Cz, CPz,3–C4, CP3–CP4), parietal (Pz, P3–P4), temporal (T7–T8, TP7–TP8, P7–P8),ccipito-temporal (POz, Oz, PO3–PO4, PO7–PO8) regions.

Reaction times (RTs) and response accuracies were subjected to a repeatedeasure analysis of variance (ANOVA) with Pain (painful vs. neutral stimuli),ask (pain judgment vs. counting the number of hands), Stimulus Reality (pictures. cartoon) as within-subject independent variables. The mean ERP amplitudesere subjected to ANOVAs with the factors being Pain, Task, Stimulus Real-

ty, Hemisphere (electrodes over the left or right hemisphere) as within-subjectndependent variables. Because the ANOVAs of the ERP data showed similaresults at anterior and posterior electrodes, we only reported the statistical resultst electrodes C3–C4 and PO7–PO8.

.4. Measurement of subjective reports

After the EEG recording session, subjects were asked to evaluate the inten-ity of pain supposedly felt by the model in the stimuli. Subjects were alsosked to evaluate their own unpleasantness when they observed the painful stim-

li. The evaluations were measured using a 6-point scale (1 = no pain, 6 = veryuch painful, or 1 = no unpleasantness, 6 = very much unpleasant) with the Faceain Scale-Revised (FPS-R) adapted from the Faces Pain Scale (Bieri, Reeve,hampion, Addicoat, & Ziegler, 1990), which contained six photocopied faces

howing neutral to extremely painful expression.

164 Y. Fan, S. Han / Neuropsychologia 46 (2008) 160–173

Table 1Mean RTs (ms) and response accuracy (%) (standard deviation) in each stimulus condition

Picture Cartoon

Pain judgment Hands counting Pain judgment Hands counting

RTsPainful 609.05 (51.56) 469.83 (40.04) 596.13 (43.52) 463.17 (38.66)Neutral 613.52 (58.33) 466.33 (38.06) 604.21 (49.57) 461.55 (37.37)

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. Results

.1. Behavioural performance

The mean RTs and response accuracies in each conditionre shown in Table 1. ANOVAs of RTs showed significantain effects of Task (F(1,25) = 307.12, p < 0.001) and Stimu-

us Reality (F(1,25) = 10.42, p < 0.01). RTs were longer in theain judgment task than in the counting task. Subjects respondedlower to picture than to cartoon stimuli. The ANOVAs per-ormed on response accuracies showed significant main effectf Pain (F(1,25) = 13.02, p < 0.01), Task (F(1,25) = 157.39,< 0.001), and Stimulus Reality (F(1,25) = 74.32, p < 0.001).esponse accuracy was higher to the neutral than painful stimuli,igher in the counting than pain judgment tasks, and higher toartoon than to picture stimuli. There was a reliable interactionf Pain × Task (F(1,25) = 9.07, p < 0.01), suggesting the differ-nce in response accuracy between painful and neutral stimulias larger in the pain judgment task than in the counting task.

.2. Electrophysiological data

Grand-averaged ERPs to pictures and cartoons were com-uted separately for each stimulus condition and are illustratedn Figs. 3 and 4. Stimuli in all conditions evoked a negative com-onent between 90 and 130 ms (N110) over the frontal–centralrea. The N110 was followed by a positive deflection between40 and 200 ms (P180) over the central area and a negativeave peaking between 200 and 280 ms (N240) over the frontal

egion. There was another negative deflection peaking at 340 msN340) over the frontal area followed by a long-latency positiv-ty between 360 and 800 ms (P3) with the maximum amplitudever the parietal area. ERPs over the occipito-temporal area wereharacterized with a positivity wave between 80 and 140 msP1), a negative wave between 140 and 200 ms (N170), and aositive wave between 200 and 450 ms (P320). A long-latencyegative deflection was also observed over the occipito-temporallectrodes. The voltage topographies in Figs. 3 and 4 show thecalp distribution of each ERP component.

.2.1. ERPs to picture stimuli

.2.1.1. Automatic versus controlled processes of empathy.NOVAs of the mean ERP amplitudes recorded at the

rontal–central electrodes showed a significant main effect ofain at 140–200 ms (F(1,25) = 14.832, p < 0.01), 200–280 ms

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F(1,25) = 16.457, p < 0.001), 280–360 ms (F(1,25) = 15.095,< 0.001), and 360–660 ms (F(1,25) = 30.384, p < 0.001). Rel-tive to the neutral stimuli, painful stimuli elicited a positivehift of the ERPs in these time windows. The main effect ofask was significant at 100–280 ms over the frontal–central areaF(1,25) = 15.061, p < 0.001), suggesting that the pain judgmentask induced a positive shift in this time window relative to theounting task. There was also a significant main effect of Taskt 460–820 ms over the frontal–central area (F(1,25) = 116.442,< 0.001), because the P3 was of larger amplitude in the pain

udgment task than that in the counting task.To examine whether the effects of Pain were modulated by

he tasks, we analyzed the interaction of Pain × Task. Thereas a reliable interaction of Pain × Task at 380–500 ms over the

rontal–central area (F(1,25) = 6.604, p < 0.05), suggesting thathe painful stimuli elicited larger amplitudes at the ascendinghase of the P3 component than the neutral stimuli when subjectserformed the pain judgment task (F(1,25) = 29.846, p < 0.001)ut not when they performed the counting task (380–460 ms,(1,25) = 3.257, p > 0.05).

The ERPs recorded at the occipito-temporal electrodeshowed a significant main effect of Pain between 420 and60 ms (F(1,25) = 9.408, p < 0.01), due to the fact that the painfultimuli elicited larger amplitudes of the descending phase ofhe P320 relative to the neutral stimuli. There was a signif-cant main effect of Task over the occipito-temporal area at0–320 ms (F(1,25) = 18.383, p < 0.001) and at 460–780 msF(1,24) = 73.497, p < 0.001), suggesting that pain judgmentlicited a positive shift at 80–320 ms relative to the countingask, whereas the counting task evoked a larger long-latencyegativity at 460–780 ms.

Significant interactions of Pain × Task were observed overhe occipito-temporal area at 220–300 ms (F(1,24) = 5.378,< 0.05) and 420–580 ms (F(1,24) = 6.691, p < 0.05), suggest-

ng stronger modulation of the P320 amplitudes by the painudgment than the counting task. Post-hoc analysis confirmedhat the pain judgment task elicited larger amplitude at thescending phase of the P320 associated with the neural stim-li than with the painful stimuli (220–300 ms, F(1,25) = 7.432,< 0.05) whereas a reverse pattern was observed in the descend-

ng phase of the P320 (420–580 ms, F(1,25) = 14.377, p < 0.01).

owever, there was no significant difference between painful

nd neutral stimuli in the counting task in these two timeindows (220–300 ms, F(1,25) = 0.077, p > 0.5; 420–540 ms,(1,25) = 0.296, p > 0.5).

Y. Fan, S. Han / Neuropsychologia 46 (2008) 160–173 165

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ig. 3. (a) ERPs to picture stimuli in each stimulus condition. ERPs to the painfuloltage topographies illustrate the scalp distribution of each ERP component. (bRPs to neutral stimuli from those to painful stimuli between 500 and 590 ms.

.2.1.2. Hemispheric difference. A reliable main effect ofemisphere was observed at 80–140 ms (F(1,25) = 7.886,< 0.01), 220–360 ms (F(1,25) = 8.518, p < 0.01), and60–820 ms (F(1,25) = 6.530, p < 0.05) at the frontal–centrallectrodes, suggesting that the N110, N240 and N340 were ofarger amplitudes over the right than left hemispheres, and theescending phase of the P3 showed larger amplitudes over theeft than right hemispheres.

There was a highly significant interaction of Pain × Hemis-

here at 380–700 ms (F(1,25) = 25.726, p < 0.001) at therontal–central–parietal area, suggesting larger difference in P3mplitude between the painful and neutral stimuli over the lefthan the right hemispheres. Separate analysis showed that, over

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eutral pictures recorded at F3–4, C3–4, P3–P4, and PO7–8 were illustrated. Theent source density calculated from the difference wave obtained by subtracting

he left hemisphere, there was a reliable main effect of Pain at80–700 ms (F(1,25) = 50.853, p < 0.001), because the painfultimuli elicited a larger P3 relative to the neutral stimuli. How-ver, over the right hemisphere, the main effect of Pain wasignificant at 380–540 ms (F(1,25) = 12.200, p < 0.01) but not at40–700 ms (F(1,25) = 0.551, p > 0.5). These results suggest aonger differentiation between painful and neutral stimuli overhe left than right hemispheres.

The ANOVAs also showed a reliable interaction of

ask × Hemisphere at 200–380 ms (F(1,25) = 19.610, p < 0.001)ver the frontal–central–parietal area, indicating larger dif-erence in the N240 and N340 amplitudes between the painudgment and the counting task over the left than right hemi-

166 Y. Fan, S. Han / Neuropsychologia 46 (2008) 160–173

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ig. 4. ERPs to cartoons in each stimulus condition. ERPs to the painful andoltage topographies illustrate the scalp distribution of each ERP component.

pheres. Separate analysis confirmed a reliable main effect ofask over the left hemisphere at 200–360 ms (F(1,25) = 11.469,< 0.01) because the pain judgment task induced a positive shiftf the ERPs relative to the counting task. In contrast, the mainffect of Task was significant at 200–260 ms (F(1,25) = 29.385,< 0.001) but not at 260–380 ms (F(1,25) = 0.350, p > 0.5) over

he right hemisphere, suggesting a longer duration of the leftemispheric dominance in pain judgments.

Furthermore, ANOVAs showed a reliable interaction ofain × Task × Hemisphere at 420–780 ms (F(1,25) = 32.895,< 0.001) over the frontal–central–parietal area. Separatenalysis showed that there was a reliable interaction ofain × Hemisphere at 420–780 ms in the pain judgment

ask (F(1,25) = 34.566, p < 0.001). Further separate analysishowed that, in the pain judgment task, there was a sig-ificant main effect of Pain over the left hemisphere at

20–700 ms (F(1,25) = 37.814, p < 0.001), whereas such painffect was evident only at 420–500 ms over the right hemi-phere (F(1,25) = 4.195, p < 0.05). In contrast, the interactionf Pain × Hemisphere was not significant in the counting task

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al cartoons recorded at F3–4, C3–4, P3–P4, and PO7–8 were illustrated. The

F(1,25) = 0.853, p > 0.5), although the main effect of Pain wasignificant at 460–660 ms (F(1,25) = 7.852, p < 0.01).

There was also a reliable interaction of Task × Hemisphere at80–580 ms over the occipito-temporal area (F(1,25) = 13.032,< 0.01), due to a larger effect of task over the right

han left hemispheres. Separate analysis confirmed a mainffect of Task at 420–580 ms over the right hemisphereF(1,25) = 22.056, p < 0.001) and at 460–580 ms over the leftemisphere (F(1,25) = 61.939, p < 0.001), suggesting that bothffects of pain cues in the stimuli and task demands were morealient over the left than right frontal–central–parietal areas.uch hemispheric asymmetry in the processing of empathy forain was evident only when subjects performed the pain judg-ent task, suggesting that task demands for pain judgment is

ecessary for the left hemispheric dominance in empatheticrocessing of pain.

.2.2. ERPs to cartoon stimuli

.2.2.1. Automatic versus controlled processes of empathy.he ANOVAs of the mean ERP amplitudes to cartoons

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howed a main effect of Pain over the frontal–centralrea at 220–280 ms (F(1,25) = 6.475, p < 0.05), 280–360 msF(1,25) = 9.894, p < 0.01) and 360–620 ms (F(1,25) = 28.382,< 0.001), reflecting the fact that, relative to the neutral stim-li, the painful stimuli elicited a positive shift of the ERPs inhese time windows. The main effect of Task was significantver the frontal–central area at 180–260 ms (F(1,25) = 15.163,< 0.001) and 460–820 ms (F(1,25) = 75.401, p < 0.001), sug-esting that the pain judgment task induced a positive shift at80–260 ms relative to the counting task, and the P3 was ofarger amplitude in the pain judgment task than in the countingask.

There was a reliable interaction of Pain × Task over therontal–central area between 320 ms and 540 ms (F(1,25) =0.528, p < 0.01). Separate analysis confirmed that the painfultimuli elicited a larger P3 component than neutral stimuli in theain judgment task (F(1,25) = 31.404, p < 0.001) but not in theounting task between 380 and 540 ms (F(1,25) = 2.703, p > 0.1).

Over the occipito-temporal area, the main effect of Pain

as observed at 160–300 ms (F(1,25) = 15.822, p < 0.001) and80–620 ms (F(1,25) = 22.524, p < 0.001), indicating that theainful stimuli evoked a positive shift relative to the neu-ral stimuli in these time windows. There was also a main

2Ns6

Fig. 5. Comparison between the early ERP pain

gia 46 (2008) 160–173 167

ffect of Task over the occipito-temporal area at 120–260 msF(1,25) = 26.975, p < 0.001), 280–340 ms (F(1,25) = 5.609,< 0.05), and 420–780 ms (F(1,25) = 54.291, p < 0.001) because

he pain judgment task elicited a positive shift in these timeindows relative to the counting task.Moreover, a significant interaction of Pain × Task was

bserved over the occipito-temporal area at 220–260 msF(1,25) = 12.129, p < 0.01) and 380–580 ms (F(1,25) = 22.889,< 0.001). Separate analysis revealed that the painful stimulivoked a smaller amplitude at the ascending phase of P320 thanhe neutral stimuli in the pain judgment task (F(1,25) = 34.974,< 0.001) but not in the counting task (F(1,25) = 2.664, p > 0.1).owever, the painful stimuli evoked a larger amplitude at theescending phase of P320 than the neutral stimuli in the painudgment task (F(1,25) = 31.030, p < 0.001) but not in the count-ng task (F(1,25) = 0.629, p > 0.5).

.2.2.2. Hemispheric difference. There was a significant mainffect of Hemisphere over the frontal–central–parietal area at

20–360 ms (F(1,25) = 6.343, p < 0.05), because the N240 and340 were of larger amplitude over the right than the left hemi-

pheres. The main effect of Hemisphere was also observed at60–820 ms (F(1,25) = 8.463, p < 0.01) suggesting larger ampli-

effects induced by pictures and cartoons.

168 Y. Fan, S. Han / Neuropsychol

Table 2Mean FPS-R scores (standard deviation) under each condition

Painful stimuli Neutral stimuli(other’s pain)

Other’s pain Self-unpleasantness

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ude of the descending phase of the P3 over the right than theeft hemispheres.

There was a reliable interaction of Pain × Hemisphere overhe frontal–central–parietal area between 380 and 740 msF(1,25) = 21.955, p < 0.001), suggesting a greater pain effectver the left than right hemispheres. Separate analysis indicatehat the painful stimuli induced a larger P3 than the neutraltimuli over the left hemisphere (380–660 ms, F(1,25) = 39.017,< 0.001) but not over the right hemisphere (500–660 ms,(1,25) = 1.998, p > 0.1). There was also a reliable interactionf Task × Hemisphere over frontal–central area at 140–420 msF(1,25) = 13.903, p < 0.01) and 580–820 ms (F(1,25) = 11.995,< 0.01), suggesting a larger task effect over the left than the

ight hemispheres. The task of pain judgment elicited a pos-tive shift relative to the counting task in both time windowsver the left hemisphere (F(1,25) = 21.175, p < 0.001). How-ver, the effect of Task was significant only at 180–260 msnd 580–820 ms over the right hemisphere (F(1,25) = 22.672,< 0.001).

.2.3. Effects of stimulus realityTo confirm whether stimulus reality influenced the automatic

nd controlled process of empathy for pain, we examined thenteraction of Pain × Stimulus Reality and found significantnteraction at 200–240 ms (F(1,25) = 4.394, p < 0.05) over therontal–central area. There was a significant main effect of Painn this time windows for pictures (F(1,25) = 16.457, p < 0.001)ut not for cartoons (F(1,25) = 1.839, p > 0.1). This indicates thathe automatic process of empathy for pain was evident only foricture stimuli at this time window. Fig. 5 illustrates the differ-nce in the early automatic process of empathy for pain betweenictures and cartoons. A reliable interaction of Task × Stimuluseality was found at 120–160 ms over the frontal–central area

F(1,25) = 5.559, p < 0.05), because the effect of Task in this timeindow was significant for pictures (F(1,25) = 10.272, p < 0.01)ut not for cartoons (F(1,25) = 0.572, p > 0.5), suggesting that theask modulate early frontal–central activity only when subjectserceived picture stimuli.

.2.4. Subjective reports and their correlation with neuralctivity

The mean scores and standard deviation of subjective reportsf the degree of perceived pain and self-unpleasantness arehown in Table 2. The scores of pain intensity were subject to

NOVAs with Pain (painful vs. neutral) and Stimulus Reality

picture vs. cartoon) as main effect. There was only a significantain effect of Pain (F(1,25) = 565.51, p < 0.001), suggesting

igher scores for painful than neutral stimuli. Paired-sample t-

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ogia 46 (2008) 160–173

est confirmed that there was no significant difference betweenhe scores related to other’s pain and self-unpleasantness (pic-ures: t(25) = 0.545, p > 0.5; cartoons: t(25) = 0.503, p > 0.5).

oreover, the scores of rating others’ pain did not differ betweenictures and cartoons (t(25) = 0.782, p > 0.1), nor did the scoresf rating self-unpleasantness (t(25) = 0.618, p > 0.5). We alsoalculated the correlation between the scores of other’s pain andelf-unpleasantness and found a significant correlation betweenhe two scores both when watching painful pictures (r = 0.688,< 0.001) and cartoons (r = 0.498, p < 0.01).

To investigate whether the electrophysiological activitylicited by the painful stimuli was correlated with subjectivevaluation of other’s pain and the self-unpleasantness, we cal-ulated the correlation between the mean amplitudes of ERPslicited by painful stimuli in each time window and the FPS-Rcores, as illustrated in Fig. 6. When subjects performed the painudgment task, the mean ERP amplitudes at 140–180 ms relatedo the painful pictures was significantly correlated with both thecore of other’s pain (r(1,25) = −0.485, p < 0.05) and the score ofelf-unpleasantness (r(1,25) = −0.464, p < 0.05). However, theean ERP amplitudes evoked by painful cartoons at 140–200 ms

uring the pain judgment task was significantly correlated withhe score of other’s pain (r(1,25) = −0.641, p < 0.001) but notith the score of self-unpleasantness (r(1,25) = −0.152, p > 0.1).o reliable correlation between the rating score and ERP ampli-

udes was observed in the counting task for both pictures andartoons.

. Discussion

The present study utilized ERPs to investigate temporalynamics of neural activity underlying empathy for pain. OurRP data analysis focused on when neural activities started toifferentiate between perception of painful and neutral stimulind whether such differential activity was modulated by taskemands so as to identify the automatic and controlled compo-ents of empathy-related activity. We also tested the hypothesishat empathic neural responses are modulated by contextualeality of stimuli using cartoons to manipulate stimulus realism.

.1. Sustained neural activity underlying the pain judgmentask

The mean response accuracy was high for both pain judg-ent and counting tasks, although the former was lower than

he latter. Consistent with the results of response accuracy, sub-ects responded slower in the pain judgment task than in theounting task, suggesting that pain judgment took more time forvaluation of the pain cues in the stimuli relative to the countingask. The ERPs differentiating the pain judgment and countingasks reflected sustained neural activity associated with the taskemand. The early task effect occurred at 120 ms as indexed bypositive shift at 120–280 ms over the anterior frontal–central

lectrodes induced by the pain judgment relative to the count-ng task. The pain judgment task was also characterized witharger P3 amplitudes over the posterior parietal area. Most ofhe previous fMRI studies of empathy for pain compared neu-

Y. Fan, S. Han / Neuropsychologia 46 (2008) 160–173 169

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al activities elicited by observations of painful and nonpainfultimulation applied to others (Botvinick et al., 2005; Gu & Han,007; Jackson et al., 2005, 2006; Morrison et al., 2004; Singert al., 2004) and found evidence for the involvement of a neuraletwork including the insula, ACC, and thalamus in empathicrocesses for pain. The observed activations in these neuraltructures were related per se to both perception of painful stim-lation and the task of pain judgment or evaluation. Gu and Han2007) examined the stimulus-independent neural correlates ofain judgment by comparing pain judgment of painful stimulind hand-number counting of painful stimuli. Because the visualtimuli (both visual features and emotional cues) were identicaln both conditions, the brain activations observed in the con-rast between the two tasks (e.g., bilateral ACC/Paracingulate,he right insula and inferior frontal gyrus, right putamen, andight middle frontal gyrus) mainly manifest the neural activitynderlying the pain judgment task itself. However, activation ofhese brain areas was also observed in the contrast between painudgment of painful stimuli and hand-number counting of non-ainful stimuli. These results indicate that the neural networkdentified in the fMRI studies possibly mediates both the cogni-ive processes and emotional responses related to empathy forain. Our ERP results complement the fMRI findings by provid-ng evidence that the neural activities related to pain-judgmentan be divided into an early component over the frontal–central

rea and a late component over the parietal area. The ERP volt-ge topographies suggests that the early and late components ofhe activities associated with pain-judgment may arise from dis-inct brain areas, i.e., the early response possibly with an anterior

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s for other’s pain and the FPS-R scores for self-unpleasantness.

rontal source whereas the late response possibly with a posteriorarietal source. In addition, our ERP data demonstrated largerifference in neural activities at 200–380 ms between the painudgment and counting tasks over the left than right hemispheres,uggesting a left hemispheric dominance in pain judgment in thisime window.

The effects of pain-judgment task were observed over theccipito-temporal area as well. A positive shift was evidentt 80–320 ms over the occipito-temporal electrodes to the painudgment task compared with the counting task. The ERP com-onents in this time window included early visual activities suchs the P1 that showed maximum amplitudes over bilateral occip-tal areas. Because the P1 component evoked by visual stimulirises from the lateral extrastriate cortex (Hillyard & Anllo-ento, 1998; Mangun, Buonocore, Girelli, & Jha, 1998), it maye assumed that paying attention to the pain cues in the stimuli,s required by the pain judgment task, may result in modula-ion of the early visual activities. This is consistent with theMRI results that, relative to neutral pictures or faces, emotionalictures or facial expressions enhanced activity in the occipitalortex (Lang et al., 1998; Sato, Kochiyama, Yoshikawa, Naito,

Matsumura, 2004). Our ERP results also showed a significantask effect in a late time window of 380–580 ms at posteriorlectrodes. However, unlike the hemispheric asymmetric effectver the frontal–central area, the neural activity distinguishing

ain judgment from hand-number counting was greater at theight than left occipital electrodes, suggesting different func-ional roles of the hemisphere asymmetry between the anteriornd posterior brain areas in pain judgment.

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.2. Automatic versus controlled processes of empathy forain

A main purpose of the current ERP study was to isolate theutomatic process from the controlled process of empathy forain under the assumption that the automatic empathic responsesay not be modulated by task demands whereas the top-down

ontrolled empathic processes depend greatly upon task require-ents. Our ERP results showed a salient pain effect in a long

ime window from 140 to 660 ms, i.e., painful stimuli elicitedpositive shift of the ERP waves relative to the neutral stim-

li. This long-duration pain effect could be demarcated into anarly and a late stage in terms of remarkable differences in theollowing aspects.

First, the early pain effect at 140–380 ms was not influencedy task demands. The positive shift at 140–380 ms induced byhe painful pictures relative to the neutral stimuli was evident inoth the pain judgment and counting tasks. The late pain effectt 380–500 ms, however, was prominent in the pain judgmentask but was greatly reduced in the counting task. It appearshat the long-latency pain effect was weakened or eliminatedhen subjects’ attention was withdrawn from the pain cues in

he stimuli. Secondly, the ERP components that mediated thearly pain effect, such as the N110 and N240, had maximummplitudes over the anterior frontal region, as illustrated by thecalp voltage topographies in Figs. 3 and 4. The long-latencyRP component bearing the late pain effect (P3) showed largestmplitudes over the posterior parietal area. The early and lateain effects were different not only in temporal features but in thecalp distribution as well. Third, the early ERP differentiationetween painful and neutral stimuli did not differ between thelectrodes over the left and right hemispheres. In contrast, theong-latency ERP differentiation between painful and neutraltimuli in the pain judgment task was stronger at central/parietallectrodes over the left than right hemispheres. Finally, the meanmplitudes of the short-latency ERP components that mediatedhe early pain effect were correlated with the subjective reportsf both other’s pain and self-unpleasantness. The long-latencyRP components, however, did not show such correlations withubjective reports.

These ERP results are of great significance for understand-ng the cognitive and neural mechanisms of empathy for pain.lthough it has been proposed that the process of empathy cane divided into a bottom-up and a top-down controlled processDecety & Lamm, 2006; Goubert et al., 2005), previous fMRIesults could not dissociate the two processes because of theow temporal resolution of BOLD signals and lack of properask manipulations (Botvinick et al., 2005; Jackson et al., 2005,006; Saarela et al., 2007; Singer et al., 2004). Although weecently showed fMRI evidence that neural activities related tompathy for pain in the insula and ACC were weakened whenarticipants’ attention was withdrawn from the pain cues inhe stimuli (Gu & Han, 2007), such modulation of sustained

ctivity observed in an fMRI block-design mainly reflected theffect of task demands and could conceal the transient automaticmpathic responses. Our ERP results provide the first piece ofvidence for the dissociation between the automatic and con-

maep

ogia 46 (2008) 160–173

rolled processes of empathy for pain, indicating that the tworocesses are different in time course, scalp distribution, andunctional significance. The automatic component of empathicesponses took place early (as early as 140 ms after sensory stim-lation) over the anterior frontal area whereas the controlledomponent of empathic responses occurred late over the pos-erior parietal region. The controlled process was also differentrom the automatic process in that the left hemisphere dominatedhe right one in the judgment of others’ pain.

The correlation analysis of subjective feelings and the ERPmplitudes has significant implications for the distinct func-ional roles of the early automatic and late controlled processesf empathy for pain. Because the early pain effect at 140–180 msas independent of task demands and negatively correlatedith subjective report of intensity of perceived pain, we pro-osed that the early automatic empathic responses, rather thanhe late controlled empathic responses, underlie the emotionalomponents of empathizing. Similar correlation between neu-al activities and subjective feelings of others’ pain has beeneported in fMRI studies. For example, researcher reported pos-tive correlation between ACC activity and subjective intensityf pain rating (Jackson et al., 2005) or between ACC activitynd subjective report of distress arising from social exclusionEisenberger, Lieberman, & Williams, 2003) but negative cor-elation between the activity in the right ventral prefrontal cortexnd the degree of distress after social exclusion (Eisenberger etl., 2003). Such results support the proposal that the right ven-ral prefrontal activity is engaged in regulation or inhibition ofegative affect. Because the pattern of correlation shown in ourRP results is similar to the right ventral prefrontal activity, itay be suggested that the amplitudes of the early ERP compo-

ents, which reflected the pain effect, also manifest the effectf emotional regulation during the empathic process of others’ain. This, however, needs to be confirmed in future research.ore interestingly, we found that the early ERP amplitudes in

he same time window correlated with both subjective ratings ofelf-unpleasantness and subjective feeling of others’ pain. Theseesults lend support to the existence of a mechanism of emo-ional sharing in empathy for pain, i.e., the neural representationf others’ pain can be automatically activated by perception ofthers in pain and at the same time stimulate one’s own similarffective responses. While the previous fMRI findings show evi-ence that neural substrates underlying pain experience partiallyverlap with those for the empathic experience (Botvinick et al.,005; Gu & Han, 2007; Jackson et al., 2005, 2006; Saarela et al.,007; Singer et al., 2004), our ERP results indicate that perceiv-ng others’ pain also overlaps with the production of ones’ ownmotional responses in the time course. Therefore, ‘emotionalharing’ during empathy for pain is mediated by both overlappedeural structures and overlapped time course of the processingtream.

The late controlled process indexed by the modulation ofhe P3 component strongly depended upon the task require-

ents. The P3 with largest amplitudes over the posterior parietalrea has been suggested to reflect the process of stimulusvaluation and classification that is, to a cetain degree, inde-endent of response selection and execution (Duncan-Johnson,

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981; Duncan-Johnson & Kopell, 1981; McCarthy & Donchin,981). The P3 component with largest amplitudes over therontal–central area, however, is associated with the evalua-ion of novel stimuli for subsequent behavioural action (seeriedman, Cycowicz, & Gaeta, 2001 for review). On the basisf these functional roles of the P3 component, we suggest thathe enlarged P3 to painful relative to neutral stimuli observedn the pain judgment task may reflect two differences betweenhe processes of painful and neutral stimuli. First, although bothainful and neutral stimuli were targets for judgments, morextensive evaluation could be applied to the painful stimuliecause painful stimuli are more important than neutral stimulior survival. Second, the novelty of painful stimuli was higherhan that of the neutral stimuli from the evolutional point ofiew, although the probability of painful and neutral stimulias equivalent in the current study. Thus the painful stimuli

ould capture attention and induce further evaluation of stimu-us novelty. Because the activity in the ACC, insula, and middlerontal cortex showed a similar pattern of modulation by taskequirements, being present in the pain judgment task but elim-nated in the counting task (Gu & Han, 2007), it is likely thathe late controlled process of empathy for pain observed in ourRP results derived at least partially from these brain struc-

ures. However, as ACC activity also correlated with subjectiveeeling of others’ pain (Jackson et al., 2005), it is possible thathe brain structures such as ACC underlies both the emotionalnd cognitive components of empathic processes of pain. Theeft hemispheric dominance for the late controlled processes ofmpathy is consistent with the recent fMRI findings that the leftCC, left inferior frontal cortex, and left postcentral sulcus arengaged in perception of others painful expression (Saarela et al.,007). However, these results are incongruent with a recent brainesion study that reported correlation between loss of empathynd lesions of the right hemisphere (Rankin et al., 2006). Theesults of the patient study mainly reflected the behavioural out-ome of brain lesions related to empathy rather than the cognitiveechanisms.The visual activity over the occipital area did not differenti-

te the painful and neutral stimuli until 240 ms after sensorytimulation, suggesting similar extent of the early sensory-erceptual processing of the painful and neutral stimuli. Inddition, although the neutral stimuli elicited larger amplitude athe rising phase of the P320 relative to the painful stimuli in theain judgment task, this effect was opposite to that observed overhe frontal electrodes. These results indicate that it is unlikelyhat the early pain effect observed over the frontal arose fromhe difference in visual features between painful and neutraltimuli.

Taken together, our ERP results provide electrophysiologicalvidence for the existence of both an automatic process andcontrolled process of empathy for pain. The early automatic

rocess, which was independent of the task demands, encodedhe emotional content of the stimuli and underlay subjective

eeling of both others’ pain and self-unpleasantness. The lateontrolled process was characterized by the enlarged P3 to paintimuli, reflecting enhanced evaluation and appraisal of stimulihowing others in pain.

absm

gia 46 (2008) 160–173 171

.3. Contextual reality of stimuli and empathic responses

To investigate how contextual reality of stimuli affected pain-elated empathic responses, we presented subjects with cartoonsransformed from the picture stimuli, similar to our previousMRI research (Gu & Han, 2007). We found that empathicesponses to the painful cartoons were different from those tohe painful pictures in several aspects. First, although the painfulartoons elicited a positive shift of the neural activities over therontal–central electrodes, similar to the effect observed on theainful pictures, this effect on cartoons started later (220 msfter stimulus onset) than that observed for the picture stim-li (140 ms after stimulus onset). As discussed above, the earlyain effect was not modulated by task demands and reflected thearly automatic component of empathic processes underlyingmotional sharing. Therefore, the difference between empathicesponses to the painful pictures and painful cartoons indicatehat the contextual reality of stimuli weakened or postponed thearly empathic processes of pain over the frontal–central area.econdly, the ERP amplitudes evoked by painful cartoons at40–200 ms were correlated with the ratings of other’s pain,ossibly reflecting the effect of emotional regulation on neu-al activity, similar to that observed for pictures. However, theRP amplitudes evoked by painful cartoons were not correlatedith the scores of self-unpleasantness. This is different from

he results of the painful pictures in that the ERP amplitudes inhis time window to the painful pictures correlated with both theubjective feeling of others’ pain and self-unpleasantness. Third,hile the ERP amplitudes at an early time window (120–160 ms)

licited by picture stimuli was modulated by task demands,ask modulations of ERPs to cartoons started at a later time180–260 ms).

The late controlled process of empathy was similar for painfulartoons and painful pictures in that the painful cartoons elicitedarger P3 amplitudes than neutral cartoons during the pain judg-

ent task. Moreover, this late empathic responses were morealient over the left than right hemispheres and were eliminatedhen participants performed the counting task, similar to thatbserved with picture stimuli. These ERP results suggest thatontextual reality of stimuli produced little influence on the lateognitive component of empathy for pain.

Several prior studies have employed cartoons to study thenfluence of contextual reality of stimuli on neural substratesnderlying the processes of emotional and mental states of oth-rs. For instance, Perani et al. (2000) reported that perceptionf real hand actions activated a visual spatial network includinghe posterior parietal cortex whereas virtual-reality hand actionsctivated the occipital cortex. Han, Jiang, Humphreys, Zhou,nd Cai (2005) found that, while watching movie clips depict-ng social interactions between humans automatically inducedncreased activity in the brain area mediating theory-of-mindbility (e.g., the medial prefrontal cortex), watching cartoonlips describing similar situations failed to activate this brain

rea. Instead, cartoons activated the posterior parietal corticesilaterally. As cartoons are different from movie clips in pre-entation of a virtual reality, the findings provide evidence forodulation of neural substrates of the perception of others’ men-

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al states by contextual reality of stimuli. However, a recent fMRItudy using cartoons depicting emotional social contexts foundmpathy-related activity in ACC, paracingulate, and the amyg-ala (Vollm et al., 2006). Gu and Han (2007) observed increasedctivation in the ACC/paracingulate induced by painful cartoons,imilar to those observed in the studies using painful pictures ofody parts (Jackson et al., 2005, 2006) or faces (Botvinick et al.,005; Saarela et al., 2007). However, painful cartoons failed toctivate the insula and induced weaker ACC activation relativeo painful pictures. Because it has been supposed that the ACCnd insula underlies the affective component of empathy for painSinger et al., 2004), Gu and Han’s fMRI results indicate thatack of contextual reality of stimuli may reduced the affectivempathic responses.

As discussed above, the early ERP pain effect observed inhe current work possibly mediated the affective componentf empathy for pain such as emotional sharing. Thus our ERPesults are in agreement with the implications of the fMRI find-ngs because the early rather than the late pain effects inducedy painful cartoons were decreased relative to those relatedo painful pictures. Furthermore, the results of correlationnalysis indicate that the early neural activity evoked by painfulartoons contributed to the subjective ratings of pain intensityf others although the contextual reality of stimuli was reduced.evertheless, unlike the results of painful pictures, the earlyeural activity evoked by painful cartoons did not correlateith subjective feelings of self-unpleasantness when watchingainful cartoons. This result has two implications, i.e., thearly responses could be related to pain intensity judgmentather than to an emotional response from the observer whentimulus reality was destroyed and subjective feelings ofthers’ pain could be dissociated from subjective feelings ofelf-unpleasantness. The modulation of empathic responsesy manipulation of contextual reality of stimuli was differentrom that by manipulation of task demands. Task demandshanged greatly the late controlled process whereas contextualeality of stimuli modulated the early affective component ofmpathy.

.4. Conclusion

We found ERP evidence for an early empathic response overhe frontal–central cortex that was independent of task demandsut was modulated by the contextual reality of stimuli. The mag-itude of the early neural activity was correlated with subjectiveeelings of both others’ pain and self-unpleasantness, providingvidence for the functional role of the early empathic responsen emotional sharing. We also found ERP evidence for a latempathic response over the central–parietal area that was mod-lated by task demands but independent of the contextual realityf stimuli. Given the frontal–central focus of the early ERPomponents and the correlation between the early ERP compo-ents and subjective feelings, it may be speculated that the early

mpathic ERP effect may arise from the brain areas such as ACCnd insula that underlie the affective component of empathy forain (Singer et al., 2004; Jackson et al., 2005). The cingulatend supplementary motor cortex might be engaged in the late

C

ogia 46 (2008) 160–173

mpathic response as suggested by the results of current sourceensity analysis.

The ERP findings provide important implications for theodels to account for the modulation of our vicarious affective

esponses towards others’ emotion. According to De Vignemontnd Singer (2006), while being confronted with an emotionalontext, the brain processes contextual information before orfter the perception of emotional cues in the context. This inurn leads to modulations of empathic responses at either anarly or later stage. Our ERP results indicate that modulationsf empathy for pain may occur at both the early and late stagesf empathic responses. The early modulation by contextual real-ty led to enhancement or weakening of subjective feelings ofelf-unpleasantness induced by perception of others in pain butid not to influence subjective ratings of pain intensity of otherndividuals. The late modulation by task demands altered theognitive evaluation of others’ pain. While previous fMRI stud-es suggest that empathic responses in the insula and ACC were

odulated by the affective link between the empathizer and theerson in pain (Singer et al., 2006) and by self-other differenti-tion and cognitive appraisal (Lamm, Batson, & Decety, 2007),he current ERP results demarcated the temporal course of modu-ation of empathic responses by contextual reality and top-downttention, both enhancing the previous fMRI results and fininghe temporal neural mechanisms underlying empathy for pain.

cknowledgements

This work was supported by National Natural Science Foun-ation of China (Projects 30630025, 30225026, and 30328016).e thank Xiaosi Gu for helping to prepare the stimuli and pro-

edure of this study.

eferences

venanti, A., Bueti, D., Galati, G., & Aglioti, S. M. (2005). Transcranial mag-netic stimulation highlights the sensorimotor side of empathy for pain.Nature Neuroscience, 8, 955–960.

venanti, A., Paluello, I. M., Bufalari, I., & Aglioti, S. M. (2006). Stimulus-driven modulation of motor-evoked potentials during observation of others’pain. Neuroimage, 32, 316–324.

atson, C. D. (1987). Physiological indices of empathy. In N. Eisenberg &J. Strayer (Eds.), Empathy and its development (pp. 356–360). New York:Cambridge University Press.

ieri, D., Reeve, R. A., Champion, G. D., Addicoat, L., & Ziegler, J. B. (1990).The face pain scale for the self-assessment of the severity of pain experiencedby children: Development, initial validation, and preliminary investigationfor ratio scale properties. Pain, 41, 139–150.

otvinick, M., Jha, A. P., Bylsma, L. M., Fabian, S. A., Solomon, P. E., &Prkachin, K. M. (2005). Viewing facial expressions of pain engages corticalareas involved in the direct experience of pain. Neuroimage, 25, 312–319.

ryant, B. K. (1987). Critique of comparable questionnaire methods in useto assess empathy in children and adults. In N. Eisenberg & J. Strayer(Eds.), Empathy and its development (pp. 361–373). New York: CambridgeUniversity Press.

ufalari, I., Aprile, T., Avenanti, A., di Russo, F., & Aglioti, S. M. (in press).

Empathy for pain and touch in the human somatosensory cortex. CerebralCortex.

raig, K. D., & Lowery, H. J. (1969). Heart-rate components of conditionedvicarious autonomic responses. Journal of Personality and Social Psychol-ogy, 11, 381–387.

ycholo

D

D

D

D

D

D

E

F

G

G

G

G

H

H

J

J

L

L

L

M

M

M

O

P

P

R

R

S

S

S

S

S

V

V

mind and empathy: A functional magnetic resonance imaging study in a

Y. Fan, S. Han / Neurops

avis, M. H. (1996). Empathy: A social psychological approach. Boulder:Westview Press.

e Vignemont, F., & Singer, T. (2006). The empathic brain: How, when andwhy? Trends in Cognitive Science, 10, 435–441.

ecety, J., & Jackson, P. L. (2004). The functional architecture of human empa-thy. Behavioral and Cognitive Neuroscience Review, 3, 71–100.

ecety, J., & Lamm, C. (2006). Human empathy through the lens of socialneuroscience. Scientific World Journal, 6, 1146–1163.

uncan-Johnson, C. C. (1981). P300 latency: A new metric of informationprocessing. Psychophysiology, 18, 207–215.

uncan-Johnson, C. C., & Kopell, B. S. (1981). The stroop effect: Brain poten-tials localize the source of interference. Science, 214, 938–940.

isenberger, N. I., Lieberman, M. D., & Williams, K. D. (2003). Does rejectionhurt? An fMRI study of social exclusion. Science, 302, 290–292.

riedman, D., Cycowicz, Y. M., & Gaeta, H. (2001). The novelty P3: Anevent-related brain potential (ERP) sign of the brain’s evaluation of novelty.Neuroscience and Biobehavioral Review, 25, 355–373.

allese, V. (2001). The “shared manifold” hypothesis: From mirror neurons toempathy. Journal of Consciousness Studies, 8, 33–50.

allese, V., & Goldman, A. (1998). Mirror neurons and the simulation theoryof mind-reading. Trends in Cognitive Science, 2, 493–501.

oubert, L., Craig, K. D., Vervoort, T., Morley, S., Sullivan, M. J. L., Williams,A. C., de, C., Cano, A., & 7 Crombez, G. (2005). Facing others in pain: Theeffects of empathy. Pain, 118, 285–288.

u, X., & Han, S. (2007). Attention and reality constraints on the neutralprocesses of empathy for pain. Neuroimage, 36, 256–267.

an, S., Jiang, Y., Humphreys, G. W., Zhou, T., & Cai, P. (2005). Distinct neuralsubstrates for the perception of real and virtual visual worlds. Neuroimage,24, 928–935.

illyard, S. A., & Anllo-Vento, L. (1998). Event-related brain potentials in thestudy of visual selective attention. Proceedings of the National Academy ofSciences, USA, 95, 781–787.

ackson, P. L., Meltzoff, A. N., & Decety, J. (2005). How do we perceive thepain of others? A window into the neural processes involved in empathy.Neuroimage, 24, 771–779.

ackson, P. L., Brunet, E., Meltzoff, A. N., & Decety, J. (2006). Empathy exam-ined through the neural mechanisms involved in imagining how I feel versushow you feel pain. Neuropsychologia, 44, 752–761.

amm, C., Batson, C. D., & Decety, J. (2007). The neural substrate of humanempathy: Effects of perspective-taking and cognitive appraisal. Journal ofCognitive Neuroscience, 19, 42–58.

ang, P. J., Bradley, M. M., Fitzsimmons, J. R., Cuthbert, B. N., Scott, J. D.,

Moulder, B., & Nangia, V. (1998). Emotional arousal and activation of thevisual cortex: An fMRI analysis. Psychophysiology, 35, 199–210.

anzetta, J. T., & Englis, B. G. (1989). Expectations of cooperation and compe-tition and their effects on observers’ vicarious emotional responses. Journalof Personality and Social Psychology, 56, 543–554.

W

gia 46 (2008) 160–173 173

angun, G. R., Buonocore, M. H., Girelli, M., & Jha, A. P. (1998). ERP andfMRI measures of visual spatial selective attention. Human Brain Mapping,6, 383–389.

cCarthy, G., & Donchin, E. (1981). A metric for thought: A comparison ofP300 latency and reaction time. Science, 211, 77–80.

orrison, I., Lloyd, D., di Pellegrino, G., & Roberts, N. (2004). Vicariousresponses to pain in anterior cingulate cortex: Is empathy a multisensoryissue? Cognitive, Affective & Behavioral Neuroscience, 4, 270–278.

rr, S. P., & Lanzetta, J. T. (1980). Facial expressions of emotion as conditionedstimuli for human autonomic responses. Journal of Personality and SocialPsychology, 38, 278–282.

erani, D., Fazio, F., Borghese, N. A., Tettamanti, M., Ferrari, S., Decety, J., &Gilardi, M. C. (2000). Different brain correlates for watching real and virtualhand actions. Neuroimage, 14, 749–758.

reston, S. D., & de Waal, F. B. M. (2002). Empathy: Its ultimate and proximatebases. Behavioral and Brain Sciences, 25, 1–72.

ainville, P., Duncan, G. H., Price, D. D., Carrier, B., & Bushnell, C. (1997). Painaffect encoded in human anterior cingulate but not somatosensory cortex.Science, 277, 968–971.

ankin, K. P., Gorno-Tempini, M. L., Allison, S. C., Stanley, C. M., Glenn, S.,Weiner, M. W., & Miller, B. L. (2006). Structural anatomy of empathy inneurodegenerative disease. Brain, 129, 2945–2956.

aarela, M. V., Hlushchuk, Y., Williams, A. C. de C., Schurmann, M., Kalso,E., & Hari, R. (2007). The compassionate brain: Humans detect intensity ofpain from another’s face. Cerebral Cortex, 17, 230–237.

ato, W., Kochiyama, T., Yoshikawa, S., Naito, E., & Matsumura, M. (2004).Enhanced neural activity in response to dynamic facial expressions of emo-tion: An fMRI study. Cognitive Brain Research, 20, 81–91.

imon, D., Craig, K. D., Miltner, W. H. R., & Rainville, P. (2006). Brainresponses to dynamic facial expressions of pain. Pain, 126, 309–318.

inger, T., Seymour, B., O’Doherty, J., Kaube, H., Dolan, R. J., & Frith, C. D.(2004). Empathy for pain involves the affective but not sensory componentsof pain. Science, 303, 1157–1162.

inger, T., Seymour, B., O’Doherty, J. P., Stephan, K. E., Dolan, R. J., & Frith,C. D. (2006). Empathic neural responses are modulated by the perceivedfairness of others. Nature, 439, 466–469.

aughan, K. B., & Lanzetta, J. T. (1980). Vicarious instigation and conditioningof facial expressive and autonomic responses to a model’s expressive displayof pain. Journal of Personality and Social Psychology, 38, 909–923.

ollm, B. A., Taylor, A. N. W., Richardson, P., Corcoran, R., Stirling, J., McKie,S., Deakin, J. F. W., & Elliott, R. (2006). Neuronal correlates of theory of

nonverbal task. Neuroimage, 29, 90–98.icker, B., Keysers, C., Plailly, J., Royet, J. –P., Gallese, V., & Rizzolatti, G.

(2003). Both of us disgusted in my insula: The common neural basis ofseeing and feeling disgust. Neuron, 40, 655–664.