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Copyright 2004 Psychonomic Society, Inc. 270
Cognitive, Affective, & Behavioral Neuroscience
2004, 4 (2), 270-278
When once compassion is stirred within me by another’s
pain, then his weal and woe go straight to my heart, exactly
in the same way, if not always to the same degree, as oth-
erwise I feel only my own. Consequently the difference be-
tween myself and him is no longer an absolute one.
—Arthur Schopenhauer,
On the Basis of Morality (1841)
The sensation one gets upon watching another person
get hurt has probably happened to all of us: It is some-
thing that makes us recoil, cringe, wince, say “ouch!” or
experience feelings otherwise associated with pain, even
if we are sitting snugly in an armchair at a safe remove
from any harm. Although familiar to most people, this
variety of experience is not easily described in empirical
terms and is usually called empathy or sympathy in every-
day language. Here we refer to the sensations that arise
with regard to the perceived physical pain of others as
vicarious pain. Vicarious pain may be a crucial predicate
for more sophisticated forms of empathy, such as helping
and offering comfort, and perhaps even for such complex
cognitive processes as moral reasoning. When one reacts
to another person’s predicament as if one were in that po-
sition oneself, processes are taking place in the brain that
may facilitate an immediate grasp of that person’s emo-
tional state.
However, thinkers pondering the nature of empathy
have noticed a tangled problem at its core, which has
been referred to as the paradox of sympathy (Wispé,
1991). The paradox is this: If all that is available to us is
third-person information about someone else’s situation
or emotional state, how can that produce what we readily
identify as a similar first-person subjective state within
ourselves? Put in other terms, this paradox can be broken
down into two related questions. The first is a question
of mechanism; that is, how does the brain accomplish
this? The second is a motivational question, having to do
with the behavioral relevance to an observer of another
person’s distress: We may understand what is happening,
but what makes us care about it?
Recently, neuroscience has begun to reveal mecha-
nisms that could throw light upon the first of these ques-
tions and thus provide insight into the second. Several
neuroimaging studies have supported the view that an
immediate, subjective interpretation of another person’s
particular emotional state is accompanied by the activa-
tion of regions directly involved in the production of that
emotion (Carr, Iacoboni, Dubeau, Mazziotta, & Lenzi,
The authors thank Paul Downing, John Parkinson, Francis McGlone,
Justin Williams, and two anonymous reviewers for valuable comments.
We also thank Phillipa Walker, Sarah Wilson, Arshad Zaman, and the radi-
ographers at the Walton Centre for Neurology, Liverpool.Correspondence
concerning this article should be addressed to I. Morrison, Centre for
Cognitive Neuroscience, School of Psychology, University of Wales,
Bangor, Gwynedd LL57 2AS, U.K. (e-mail: pspc46@bangor.ac.uk).
Vicarious responses to pain in anterior cingulate
cortex: Is empathy a multisensory issue?
INDIA MORRISON
University of Wales, Bangor, Wales
DONNA LLOYD
University of Liverpool, Liverpool, England
GIUSEPPE
DI PELLEGRINO
University of Urbino, Urbino, Italy
and
NEIL ROBERTS
University of Liverpool, Liverpool, England
Results obtained with functional magnetic resonance imaging show that both feeling a moderately
painful pinprick stimulus to the fingertips and witnessing another person’s hand undergo similar stim-
ulation are associated with common activity in a pain-related area in the right dorsal anterior cingulate
cortex (ACC). Common activity in response to noxious tactile and visual stimulation was restricted to
the right inferior Brodmann’s area 24b. These results suggest a shared neural substrate for felt and seen
pain for aversive ecological events happening to strangers and in the absence of overt symbolic cues.
In contrast to ACC 24b, the primary somatosensory cortex showed significant activations in response
to both noxious and innocuous tactile, but not visual, stimuli. The different response patterns in the
two areas are consistent with the ACC’s role in coding the motivational-affective dimension of pain,
which is associated with the preparation of behavioral responses to aversive events.
VICARIOUS RESPONSES TO PAIN IN ACC 271
2003; Decety & Chaminade, 2003; Phillips et al., 1997;
Wicker et al., 2003). This perspective is bolstered by a
growing body of research indicating that the observation
of others’ actions engages circuits involved in the prepa-
ration and planning of self-generated motor actions
(di Pellegrino, Fadiga, Fogassi, Gallese, & Rizzolatti,
1992; Hari et al., 1998; Iacoboni et al., 1999; Rizzolatti,
Fadiga, Fogassi, & Gallese, 1999; Rizzolatti, Fadiga,
Gallese, & Fogassi, 1996). The existence of such action-
perception mechanisms has provided the foundation for a
recent model of empathy which integrates emotional, be-
havioral, and cognitive aspects of interpersonal phenom-
ena (Preston & de Waal, 2002).
A similar unifying basis has so far been little investi-
gated with respect to the mechanisms of pain process-
ing. A notable exception is a recent functional magnetic
resonance imaging (fMRI) study showing that affective
pain-related areas such as the dorsal anterior cingulate
cortex (ACC) and anterior insula can be activated by a
visual signal indicating that a loved one will receive a
painful electric shock (Singer et al., 2004). In this study,
each female participant viewed her own hand alongside
that of her established romantic partner as electrode shocks
were delivered to one or the other at either low or high
levels of stimulation. Visual cues projected onto a screen
indicated to the participant whether the shock would occur
to herself or to her partner, as well as whether the stim-
ulation would be low (not painful) or high (painful). This
study demonstrated that affect-related regions of a pain
network can be engaged in situations in which there is an
imminent and ongoing threat of pain both to oneself and
to a loved one.
More specific indications come from earlier single-cell
data of pain-related processing in human neurological pa-
tients (Hutchison, Davis, Lozano, Tasker, & Dostrovsky,
1999). This study investigated pain-related responses in
the ACC in 11 individuals undergoing cingulotomy
surgery for the treatment of obsessive–compulsive disor-
der or severe depression. Using microelectrodes, Hutchi-
son et al. recorded from the ACC as several types of
painful stimuli were applied to the patients’ hands (painful
heat, painful cold, and mechanical pinpricks from a sharp
probe). They found stimulus-specific pain responses in
area 24b of the dorsal ACC (24b′ of Vogt, Nimchinsky,
Vogt, & Hof, 1995), including cells that discharged pref-
erentially to the pinprick stimulus. One of these cells re-
sponded to the pinprick whether it was administered to the
patient’s own hand or to that of the experimenter. This par-
ticular cell appears to have been sensitive not only to pain-
related input originating from the hand, but also to visual
input carrying information about another person’s hand.
Evidence surrounding vicarious pain mechanisms
from neurological case studies is quite scant, but one un-
usual case that may have bearing on the pathological rep-
resentation of others’ pain was reported anecdotally in a
letter (Bradshaw & Mattingley, 2001). A deceased pa-
tient’s widow described to the authors an unusual symp-
tom of her husband’s allodynia (a condition in which
non-noxious touch is painful). When she herself would
experience a sudden minor injury such as knocking her
hand against a table, he would become very agitated,
claiming that it hurt him to witness such accidents. Un-
fortunately, no CT scans exist of the extent of the dam-
age in the man’s brain or the areas affected. It is possible
only to speculate about what might have caused his
symptoms, but perhaps the damage altering the repre-
sentation of his own sensations had a corresponding im-
pact upon his representation of others’ sensations as
well. However, a combined positron emission tomogra-
phy (PET) and fMRI investigation of another allodynia
patient, in whom symptoms persisted despite a bifocal
infarct in both the primary somatosensory cortex (SI)
and the right ACC, suggests that any possible cortical
substrates of allodynia are complex and not isolable to a
single circumscribed region in the ACC or elsewhere
(Peyron, Garcia-Larrea, et al., 2000).
Taken together, the available neuroimaging and neuro-
physiological evidence raises the possibility that merely
observing another person in a painful situation can give
rise to a pain-related response in the ACC. In the present
study, we used f MRI to test the hypothesis that painful
stimulation increases bloodflow in ACC 24b of normal
individuals, not only during the firsthand experience of
an ecologically relevant mechanical stimulus (pinprick),
but also during the observation of another individual un-
dergoing similar stimulation. Such a common neural
substrate for felt and vicarious pain would address the
question of mechanism posed by the “paradox of sym-
pathy” mentioned above.
Other studies have shown a dissociation between the
sensory-discriminative and motivational-affective dimen-
sions of pain processing. In the sensory-discriminative di-
mension, the SI encodes sensory components of a painful
stimulus, such as the bodily location and intensity of the
stimulus; in the motivational-affective dimension, the
ACC contributes to evaluation, subjective discomfort,
and response preparation in the context of painful or
aversive stimuli (Craig, 2003; Devinsky, Morrell, & Vogt,
1995; Melzack, 1999; Rainville, Carrier, Hofbauer, Bush-
nell, & Duncan, 1999; Sewards & Sewards, 2002). To de-
termine whether a similar dissociation held in our own
study, blood flow responses to noxious and innocuous
tactile and visual stimuli were compared in right ACC
24b, and in a region of interest (ROI) on the postcentral
gyrus corresponding to SI area 3b/1 contralateral to the
stimulated hand. Differences in response patterns to sen-
sory aspects (e.g., tactile) and motivational aspects (e.g.,
noxiousness) between the SI and the ACC would rein-
force the distinctive roles for these areas in sensory-dis-
criminative and motivational-affective dimensions of
pain processing, respectively.
METHOD
Participants and Experimental Design
Functional MRI (1.5 T; 24 slices; 5 mm thickness; TR ⫽ 3 sec)
was used to compare the responses of 14 healthy participants (9 fe-
male, 5 male; mean age 23 years; 9 right-handed, 5 left-handed) as
they experienced unpleasant pricks to the fingertips and as they
272 MORRISON, LLOYD,
DI PELLEGRINO, AND ROBERTS
viewed video clips of others being similarly pricked. Data were also
collected for control conditions involving innocuous touch pre-
sented in both the tactile and visual modalities. The stimulus for the
experienced pain condition was a mildly painful prick to the mid-
dle finger of the left hand using a nonferromagnetic sharp probe
(~1 Hz/15 sec). During scanning, the hand was placed palm-up in
a relaxed position, out of the participant’s sight. The tactile control
stimulus was a cotton bud (Q-tip) similarly pressed onto the fingertip.
For the observed pain condition, a video featuring a model’s left
hand being pricked on the finger with a hypodermic needle was dis-
played. The video featured the needle coming into contact with the
hand and excluded the model’s face. The visual control video was
identical except for the substitution of a cotton bud for the needle.
Placement of the sharp probe in a plasticine-filled syringe increased
the visual resemblance between it and the hypodermic needle in the
video. The participants were familiarized with the sharp probe prior
to scanning, but during scanning they could neither see their hands
nor the stimulus being applied. The videos were projected onto a
screen at the participants’ feet as they looked into a mirror.
All visual stimuli were presented on a laptop computer using Pre-
sentation software (Version 0.70, www.neurobs.com). The ob-
served pain and visual control stimuli were presented in a trial iden-
tical in design to the tactile run. The observed and experienced pain
experimental runs were conducted separately. Each run consisted of
five blocks of 15-sec presentations of both the painful and neutral
stimuli interspersed with 15 sec of baseline rest, giving a total scan
time of approximately 5 min. For every condition, there was a total
of five stimulus presentations. After scanning, participants were
asked to rate the unpleasantness of both the experienced and the ob-
served stimuli, respectively, on a scale of 1 to 5, ranging from not
at all unpleasant to extremely unpleasant.
Analysis
Analysis was carried out using FEAT (fMRI Expert Analysis Tool)
Version 5.00, part of the FMRIB software library (FSL—Oxford
Centre for Functional Magnetic Resonance Imaging of the Brain;
www.fmrib.ox.ac.uk/fsl). The following prestatistics processing
was applied: motion correction using MCFLIRT (Jenkinson, Ban-
nister, Brady, & Smith, 2002); nonbrain removal using BET (Smith,
2002); spatial smoothing using a Gaussian kernel of FWHM 5 mm;
mean-based intensity normalization of all volumes by the same fac-
tor; and highpass temporal filtering (Gaussian-weighted LSF straight-
line fitting, with
σ
⫽ 30.0 sec). Time-series statistical analysis was
carried out using FILM (FMRIB’s Improved Linear Model) with
local autocorrelation correction (Woolrich, Ripley, Brady, & Smith,
2001). Z (Gaussianized T/F) statistic images were thresholded
using clusters determined by Z ⬎ 1.8 and a (corrected) cluster sig-
nificance threshold of p ⫽ .05 (Forman et al., 1995; Friston, Wors-
ley, Frackowiak, Mazziotta, & Evans, 1994; Worsley, Evans, Mar-
rett, & Neelin, 1992). Registration to high-resolution and/or standard
images was carried out using FLIRT (FMRIB’s Linear Image Reg-
istration Tool; Jenkinson & Smith, 2001; Jenkinson et al., 2002).
RESULTS
Whole Brain Contrasts
Feeling the sharp probe elicited significant activations
in cortical areas consistently implicated in imaging in-
vestigations of pain (Table 1; Peyron, Laurent, & Garcia-
Larrea, 2000). Peak clusters in group-averaged data fell
in the left insula, the contralateral primary and secondary
(SII) somatosensory cortices, and the left (ipsilateral)
cerebellum. Significant peaks in these areas and the right
(contralateral) medial thalamus remained after subtrac-
tion of the tactile control eliminated the signal resulting
from stimulation of non-nociceptive tactile receptors.
The main effect of pain observation revealed activity in
the anterofrontal and medial frontal regions including
the cingulate gyrus, whereas the neutral visual stimulus
failed to produce activations above the threshold level. A
conjunction analysis showing common areas of signifi-
cant activation between the main effects of pain experi-
ence and observation compared to a resting baseline re-
vealed a significant cluster in the right inferior ACC area
24b (x ⫽ 6 mm, y ⫽ 0 mm, z ⫽ 32 mm) common to the
two conditions, reflecting shared activity correlated with
both feeling and seeing the noxious stimulus (Figure 1).
ROI Analyses
Anterior cingulate area 24b
. The anatomical defini-
tion of the ROI was based on Talairach coordinates re-
ported in Hutchison et al.’s (1999) previous single-unit
study, which also encompasses the site of overlap between
the experience and observation conditions in our study
(x ⫽ 3–5 mm, y ⫽ 3–13 mm, z ⫽ 26–36 mm) (Figure 1A).
This region corresponds to the right dorsal Brodmann’s
area (BA) 24, area 24b′ of Vogt et al. (1995). Within this
region, the average percent signal change was signifi-
cantly greater ( p ⬍ .001) for the pain conditions than for
the control conditions, irrespective of whether the stim-
ulus was felt or seen (Figure 1B).
Primary somatosensory 3b/1
. An ROI in the right
(contralateral) SI was defined by the coordinates of the
most significant cluster in the main effect for the innocu-
ous tactile stimulus (x ⫽ 64, y ⫽⫺16, z ⫽ 28) (not
shown in Table 1). This activation fell on a region of
postcentral gyrus most likely corresponding to the hand
Table 1
Foci of Pain-Related Activation
During Experience and Observation
Coordinates of
Peak Activation Max
Brain Regions (x,y,z, in mm) Z Scores
Main Effect of Experienced Pain (Pain–Rest)
Right inferior parietal lobule 70, ⫺24, 26 5.18
Left insula ⫺46, ⫺6, 0 5.05
Right parietal postcentral gyrus 62, ⫺16, 38 4.80
Left cerebellum ⫺18, ⫺56, ⫺30 5.18
Pain Compared With Neutral Stimulus (Pain–Neutral)
Right parietal postcentral gyrus 62, ⫺16, 22 5.13
ACC/pre-SMA 0, ⫺8, 58 5.12
Left parietal postcentral gyrus ⫺58, ⫺24, 14 4.77
Right frontal precentral gyrus 32, ⫺20, 58 4.81
Right medial thalamus 16, ⫺14, 2 4.80
Main Effect of Observed Pain (Pain–Rest)
Right ACC 2, 42, 16 4.72
Right medial frontal gyrus 6, 52, 2 4.40
Left ACC ⫺8, ⫺2, 32 4.09
Left superior frontal gyrus ⫺12, 34, 50 3.94
Conjunction Analysis
[(Pain Experience–Rest) ⫹ (Pain Observation–Rest)]
Right ACC 6, 0, 32 4.40
Note—All values p ⬍ .05, corrected.
VICARIOUS RESPONSES TO PAIN IN ACC 273
area 3b/1. This showed significant activations to both
noxious and innocuous tactile stimuli but not to visual
stimuli ( p ⬍ .001) (Figure 2). The difference between
the tactile activations in the SI was not significant ( p ⫽
.60).
Comparison of ACC and SI ROIs
. The SI ROI
showed a significantly greater response to the innocuous
tactile stimulus than did the ACC ROI ( p ⬍ .001). In
contrast, the noxious visual stimulus elicited a greater
response in the ACC than in the SI ( p ⬍ .001). Mean
percent signal changes for the innocuous visual stimulus
were at or below baseline for both the ACC and the SI
(Figure 2). The response to the sharp probe in the SI was
significantly greater than the tactile pain-related re-
sponse in the ACC ( p ⬍ .001), although both activations
were significant in the higher level group analysis ( p ⫽
.05, corrected).
Unpleasantness Ratings
Ratings were collected from 13 of the 14 participants
after scanning. The participants consistently rated the
observed unpleasantness (how unpleasant did it look?)
higher than the experienced unpleasantness (how un-
pleasant did it feel?) of the visual and tactile conditions,
respectively. On a scale of 1–5, ranging from not at all
unpleasant to extremely unpleasant, the mean score for
feeling the sharp probe was 2.15; for seeing the pinprick
video, it was 3.15. This difference was not significant
( p ⫽ .10).
DISCUSSION
These findings corroborate single-unit evidence
(Hutchison et al., 1999) and point to a unique role for the
right ACC 24b in vicarious pain. Our results are also
consistent with other studies demonstrating the partici-
pation of the dorsal ACC in either experienced and ob-
served pain, or both (Jackson, Meltzoff, & Decety, 2004;
Singer et al., 2004), and with neuroimaging results impli-
cating the ACC in the appraisal of one’s own and others’
distress (Eisenberger, Lieberman, & Williams, 2003;
Peyron, Laurent, & Garcia-Larrea, 2000; Singer et al.,
2004). Furthermore, a comparison of mean percent signal
changes in the right ACC and SI ROIs showed significant
differences between responses to the innocuous tactile
stimuli and noxious visual stimuli. The ACC modulation
corresponded to noxious aspects of the stimuli, regardless
of whether they were presented in the tactile or visual
modality, whereas the SI responses corresponded to tac-
tile but not visual elements of the stimuli, regardless of
noxiousness.
A Common Neural Substrate for
Felt and Seen Pain
The main result of this study was a focal overlap of ac-
tivity in a pain-related area of the ACC, the right area 24b
(24b′ of Vogt et al., 1995), suggesting a common neural
substrate for felt and seen pain. Such shared activity pro-
vides a potential mechanism for the rapid subjective ap-
praisal, in pain-related terms, of tissue-damaging events
happening to others. It may also serve as a springboard
for further neuroscientific study of the phenomenon of
vicarious pain, as well as of more sophisticated processes
or outcomes of empathy which may rely on such a mech-
anism. These results affirm previous neurophysiological
and neuroimaging observations that nociceptive pro-
cessing in the ACC, and area 24 in particular, can utilize
visual information in its encoding of pain (Hutchison et al.,
1999; Jackson et al., 2004; Singer et al., 2004).
The participants’ own hands were not visible to them,
and they were instructed to close their eyes during the
“felt pain” condition. This allowed a dissociation be-
A
B
0.2
0.15
0.1
0.05
0
–0.05
Mean % signal change
Feeling
pain
Feeling
control
Seeing
pain
Seeing
control
Figure 1. Activation in the ACC in response to sharp probe
stimulation delivered in the tactile and visual modalities. (A) Sag-
ittal slice showing the common activation between the main effects
of feeling the sharp probe versus seeing it applied to someone else
(x,y,z ⴝ 6,0,32). Group functional data are superimposed upon a
T1-weighted normalized anatomical image for 14 participants.
Dashed line indicates the region of interest defined by the single-
unit recording site reported in Hutchison et al. (1999). AC ⴝ an-
terior commissure, PC ⴝ posterior commissure. (B) Signal mod-
ulation in a region of interest in ACC 24b defined by the
coordinate range reported in Hutchison et al. (x ⴝ 3–5 mm, y ⴝ
2–4 mm, z ⴝ 32 mm). Mean percent signal change was signifi-
cantly greater in the pain conditions than in the control condi-
tions (see Results).
274 MORRISON, LLOYD,
DI PELLEGRINO, AND ROBERTS
tween nociceptive/tactile and visual perception of the
painful stimuli and an analysis of the differential contri-
butions of each modality. This dissociation makes it pos-
sible to confirm that ACC 24b is capable of integrating
pain-related information independently of visual informa-
tion about one’s own hand in the firsthand experience of
pain, rather than being a predominantly visually guided
area.
The experiment differs from a recent neuroimaging
study of empathy (Singer et al., 2004) in several crucial
respects. Most notably, the participants were given no
overt or arbitrary cue indicating the painful stimulation
of the other person, but observed the needle coming di-
rectly into contact with the fingertip, distending the skin.
Also, the models whose hands were featured in the videos
were unknown to the participants, implying that vicari-
ous pain effects do not depend on a longstanding rela-
tionship with the other person. A sharp, needlelike probe
rather than an electrode was used as a painful stimulus.
Although electrode stimulation more effectively elicits
activation of nociceptive pathways, the needle stimulus
was used here partly to recreate as well as possible the
conditions of Hutchison et al.’s (1999) study and partly
to maintain ecological validity in the stimulus videos.
It is conceivable that a function of visually cued re-
sponses in area 24b is to apprehend potential threats,
whether it is oneself or someone else who stands to be
hurt. Areas of the ACC that represent pain affect are also
active in anticipation of painful stimuli (Hsieh, Stone-
Elander, & Ingvar, 1999; Koyama, Tanaka, & Mikami,
1998; Porro, Cettolo, Francescato, & Baraldi, 2003), in-
cluding stimulus-specific anticipatory discharge of neu-
rons in area 24b (Hutchison et al., 1999). The relation-
ship between anticipation and empathy in visually cued
pain representations in the ACC may thus be a very close
one, both functionally and subjectively. As such, it may
even be fruitful to regard the representation of others’
pain as a special case of anticipation.
Previous studies have shown the dorsal ACC to be im-
plicated in attention and arousal (Downar, Crawley,
A
B
0.95
0.75
0.55
0.35
0.15
0
–0.05
–0.25
–0.45
Mean % signal changeMean % signal change
Noxious
tactile
Innocuous
tactile
Noxious
visual
Innocuous
visual
Noxious
tactile
Innocuous
tactile
Noxious
visual
Innocuous
visual
0.95
0.75
0.55
0.35
0.15
0
–0.05
–0.25
–0.45
Right SI
Right ACC
Figure 2. Differential responses in somatosensory and anterior cingulate cortices to nox-
ious and innocuous tactile and visual stimuli. (A) Preferential modulation within cluster in
right primary somatosensory hand area (x,y,z ⴝ 64,ⴚ16,28) to tactile noxious and innocu-
ous stimuli. (B) Preferential modulation within cluster of right anterior cingulate cortex
(x,y,z ⴝ 3,4,32) to noxious tactile and visual stimuli. Clusters are sample clusters represent-
ing activation within regions of interest. SI image: (innocuous tactile ⴚ rest); ACC image:
(noxious tactile ⴚ rest) ⴙ (noxious visual ⴚ rest).
VICARIOUS RESPONSES TO PAIN IN ACC 275
Mikulis, & Davis, 2002), especially when related to re-
sponse preparation (Milham, Banich, Claus, & Cohen,
2003). However, peak activations in studies of attention
and emotional arousal tend to fall more anteriorly and
superiorly than does the focus in this study, as, for exam-
ple, in BA 32 or the more rostral portions of BA 24/25
(Keightley et al., 2003; Yamasaki, LaBar, & McCarthy,
2002), which are larger in spatial extent and do not re-
spond to painful stimulation (Davis, Taylor, Crawley,
Wood, & Mikulis, 1997). In our study, common activa-
tion in the ACC was restricted to 24b and did not extend
into these other areas.
Vicarious Pain as a Motivational-Affective
Representation
We interpreted the profile of modulation in ACC 24b
as indicative of a motivational, rather than a sensory, role
in vicarious pain. Various studies have implicated the
ACC in motivation (Bush, Lu, & Posner, 2000; Bush et al.,
2002; Devinsky et al., 1995; Hadland, Rushworth,
Gaffan, & Passingham, 2003a), emotion and social be-
havior (Bush et al., 2000; Eisenberger et al., 2003; Had-
land, Rushworth, Gaffan, & Passingham, 2003b), and re-
sponse selection (Hadland et al., 2003a; Paus, Petrides,
Evans, & Meyer, 1993; Rushworth, Hadland, & Pass-
ingham, 2003; Walton, Bannerman, Alterescu, & Rush-
worth, 2003). Motivational aspects of pain are those that
pertain to desires, urges, or impulses to avoid or termi-
nate a painful experience (Craig, 2003; Sewards & Se-
wards, 2002).
Motivational-affective processing is associated primar-
ily with nociceptive pathways ascending from the dorsal
horn of the spinal cord through the medial thalamic nuclei,
which send projections to the ACC (Craig, 2003; Devin-
sky et al., 1995; Peyron, Laurent, & Garcia-Larrea, 2000;
Vogt & Sikes, 2000). In the ACC, nociceptive neurons are
interspersed among cells that code for the aversive value
of the stimulus (Koyama, Kato, Tanaka, & Mikami, 2001;
Porro et al., 2003). Projections from the anterior cingu-
late of area 24b reach supplementary motor, premotor,
cingulate motor, and primary motor cortices, influenc-
ing the selection of skeletomotor responses to painful
stimuli (Devinsky et al., 1995; Matelli, Luppino, & Riz-
zolatti, 1991; Vogt et al., 1995). Nociceptive fields in the
ACC are thus taken to represent a motivational aspect of
somatic pain, contributing to the mobilization and exe-
cution of volitional movements of aversion (Schnitzler
& Ploner, 2000; Sewards & Sewards, 2002). The results
of the present study support this view, especially in light
of the premotor activations alongside the ACC when pain
experience was compared to the neutral tactile stimulus.
The motivational-affective dimension of pain pro-
cessing is to a large extent functionally distinct from the
sensory-discriminative dimension, which concerns so-
matotopic localization, intensity coding, discrimination
of the type of painful sensation (e.g., burning, aching,
stinging), and temporal characteristics such as its onset
and offset (Hofbauer, Rainville, Duncan, & Bushnell,
2001; Ploner, Freund, & Schnitzler, 1999; Rainville,
2002; Rainville et al., 1999; Rainville, Duncan, Price,
Carrier, & Bushnell, 1997). The sensory-discriminative
dimension is associated with nociceptive pathways as-
cending through the lateral thalamic nuclei and projecting
to somatosensory cortices, including hand areas 3b and
1 (Kenshalo, Iwata, Sholas, & Thomas, 2000; Schnitzler,
Seitz, & Freund, 2000; Timmermann et al., 2001).
A relevant case study (Ploner et al., 1999) reports a
patient with selective damage to the right postcentral
gyrus and parietal operculum, the hand area of the SI and
SII. When stimulated with a laser on the skin of the
hands and feet, the patient was unable to localize a painful
stimulus on the left hand but appeared to have intact mo-
tivational processing. He identified the painful sensation
as “something he wanted to avoid,” although he could
not discriminate its sensory characteristics (Ploner et al.,
1999). Conversely, stimulation of the anterior cingulate
cortex in humans produces reports of unspecific motiva-
tions or urges, and feelings of “wanting or planning to do
something” (Bancaud & Talairach, 1992). Damage to the
ACC, a cortical target for medial fiber projections, can
alter pain perception without impairing localization, yet
microstimulation does not produce feelings of pain (Davis,
Hutchison, Lozano, & Dostrovsky, 1994; Hutchison
et al., 1999).
To investigate any similar dimensional dissociation in
our data, we compared mean percent signal changes in
right ACC 24b with those in a region of the postcentral
gyrus corresponding to primary somatosensory hand area
3b/1. Areas 3b and 1 are directly adjacent (Gelnar, Krauss,
Szeverenyi, & Apkarian, 1998; Powell & Mountcastle,
1959), and both are associated with the discrimination of
passive tactile stimulation on the skin surface (Burton,
MacLeod, Videen, & Raichle, 1997; Kaas & Collins,
2001; McGlone et al., 2002), as well as cutaneous repre-
sentation of the digits of the contralateral hand (Blanken-
burg, Ruben, Meyer, Schwiemann, & Villringer, 2003;
Francis et al., 2000; Gelnar et al., 1998; Ringler, Greiner,
Kohlloeffel, Handwerker, & Forster, 2003). The SI ROI
was defined on the basis of its significant response to the
innocuous tactile stimulus under the assumption that acti-
vation here reflects a localized sensory response to stim-
ulation of the contralateral hand.
The SI showed higher responses to both noxious and
innocuous tactile stimuli, but not to visual stimuli, when
compared to a resting baseline. The ACC showed a pat-
tern of response that was higher to noxious stimuli re-
gardless of sensory modality, but not to innocuous tactile
or visual stimuli (Figure 2). These differences suggest
that the vicarious pain effect observed in right ACC 24b
was more closely associated with the motivational than
the sensory properties of the stimulus. They are also in
accordance with other pain empathy studies in which a
somatosensory contribution to vicarious pain was lack-
ing (Jackson et al., 2004; Singer et al., 2004).
276 MORRISON, LLOYD,
DI PELLEGRINO, AND ROBERTS
“Visuo-Nociceptive” Selectivity in the ACC:
Analogy With Premotor Mirror Neurons
This study demonstrates that the mere observation of
a sharp object approaching a hand, making contact with
it and distending the skin, is sufficient to engage a spe-
cific pain-related area in the ACC. The dorsal ACC re-
ceives indirect projections from superior temporal areas
associated with higher level, semantic visual processing
(Vogt & Pandya, 1987), a region also important in asso-
ciative and multisensory processing of information from
different sensory modalities (Calvert, Campbell, & Bram-
mer, 2000; Calvert, Hansen, Iversen, & Brammer, 2001;
Hikosaka, 1997).
Pain-related areas in the ACC have extensive output
connections to premotor and motor areas, as noted above.
In this respect, ACC 24b has several formal similarities
to the properties of mirror neurons discovered in areas of
macaque monkey premotor and parietal cortex (di Pelle-
grino et al., 1992; Rizzolatti et al., 1996), prompting an
analogy between the functional organization of action
recognition and that of the motivational-affective encod-
ing of aversive third-person events.
Neural populations in macaque premotor F5 and pari-
etal PF transform visual shape- and space-related object
information into a motor-specific vocabulary of poten-
tial actions (Rizzolatti & Luppino, 2001). These trans-
formations are based on object features or other relevant
cues, or, in the case of mirror neurons, upon the observa-
tion of others. Whereas in these fronto-parietal circuits,
perception–action transformations are processed in
kinesthetic–pragmatic terms, medial frontal circuits in-
cluding the anterior cingulate area 24b may code analo-
gous transformations in terms of affective and motiva-
tional significance. Whether neurons in ACC 24b can be
considered “affective mirror neurons” remains to be
seen, but the results of this study illustrate the strong
possibility that a “mirror neuron principle” is not limited
to kinesthetic action–perception circuits (Gallese, 2001,
2003), but may be at work in affective-motivational cir-
cuits as well.
SUMMARY AND CONCLUSIONS
A fundamental question about empathy concerns the
neural correlates of our ability to understand the emo-
tional states of others in immediate terms. To address
this issue, fMRI was used to measure brain activation in
normal participants while they either underwent moder-
ately painful pinpricks to the fingertips or viewed a video
of another person experiencing a similar stimulus. Both
being pricked and observing another person being pricked
was associated with focal activation of right inferior ACC
24b (24b′ of Vogt et al., 1995). Differences in the coding
of noxious and tactile properties between the ACC and
the SI support a dissociation between the motivational-
affective and sensory-discriminative dimensions of pain
processing.
The organizational feature that enables the processing
of visual information about painful events that befall
others, even when they pose no immediate threat to the
observer, admits an analogy with mirror neurons in the
premotor cortex. Taken together, these results encroach
on the age-old “paradox of sympathy” by providing a
mechanism connecting observed painful events to an
egocentric emotional and motivational network. Perhaps,
although we cannot directly detect another person’s tis-
sue damage, we can still feel the suffering it causes.
REFERENCES
Bancaud, J., & Talairach, J. (1992). Clinical semiology of frontal
lobe seizures. Advances in Neurology, 57, 3-58.
Blankenburg, F., Ruben, J., Meyer, R., Schwiemann, J., & Vill-
ringer, A. (2003). Evidence for a rostral-to-caudal somatotopic or-
ganization in human primary somatosensory cortex with mirror-
reversal in areas 3b and 1. Cerebral Cortex, 13, 987-993.
Bradshaw, J. L., & Mattingley, J. B. (2001). Allodynia: A sensory
analogue of motor mirror neurons in a hyperaesthetic patient reporting
instantaneous discomfort to another’s perceived sudden minor injury?
Journal of Neurology, Neurosurgery, & Psychiatry, 70, 135-136.
Burton, H., MacLeod, A. M., Videen, T. O., & Raichle, M. E.
(1997). Multiple foci in parietal and frontal cortex activated by rubbing
embossed grating patterns across fingerpads: A positron emission to-
mography study in humans. Cerebral Cortex, 7, 3-17.
Bush, G., Luu, P., & Posner, M. I. (2000). Cognitive and emotional in-
fluences in anterior cingulate cortex. Trends in Cognitive Sciences, 4,
215-222.
Bush, G., Vogt, B. A., Holmes, J., Dale, A. M., Greve, D., Jenike,
M. A., & Rosen, B. R. (2002). Dorsal anterior cingulate cortex: A
role in reward-based decision making. Proceedings of the National
Academy of Sciences, 99, 523-528.
Calvert, G. A., Campbell, R., & Brammer, M. J. (2000). Evidence
from functional magnetic resonance imaging of crossmodal binding
in the human heteromodal cortex. Current Biology, 10, 649-657.
Calvert, G. A., Hansen, P. C., Iversen, S. D., & Brammer, M. J.
(2001). Detection of audio-visual integration sites in humans by ap-
plication of electrophysiological criteria to the BOLD effect. Neuro-
Image, 14, 427-438.
Carr, L., Iacoboni, M., Dubeau, M. C., Mazziotta, J. C., & Lenzi,
G. L. (2003). Neural mechanisms of empathy in humans: A relay
from neural systems for imitation to limbic areas. Proceedings of the
National Academy of Sciences, 100, 5497-5502.
Craig, A. D. (2003). Interoception: The sense of the physiological con-
dition of the body. Current Opinion in Neurobiology, 13, 500-505.
Davis, K. D., Hutchison, W. D., Lozano, A. M., & Dostrovsky, J. O.
(1994). Altered pain and temperature perception following cingulo-
tomy and capsulotomy in a patient with schizoaffective disorder.
Pain, 59, 189-199.
Davis, K. D., Taylor, S. J., Crawley, A. P., Wood, M. L., & Mikulis,
D. J. (1997). Functional MRI of pain- and attention-related activa-
tions in the human cingulate cortex. Journal of Neurophysiology, 77,
3370-3380.
Decety, J., & Chaminade, T. (2003). Neural correlates of feeling sym-
pathy. Neuropsychologia, 41, 127-138.
Devinsky, O., Morrell, M. J., & Vogt, B. A. (1995). Contributions of
anterior cingulate cortex to behavior. Brain, 118
, 279-306.
di Pellegrino, G., Fadiga, L., Fogassi, L., Gallese, V., & Rizzo-
latti, G. (1992). Understanding motor events: A neurophysiological
study. Experimental Brain Research, 91, 176-180.
Downar, J., Crawley, A. P., Mikulis, D. J., & Davis, K. D. (2002). A
cortical network sensitive to stimulus salience in a neutral behavioral
context across multiple sensory modalities. Journal of Neurophysi-
ology, 87, 615-620.
Eisenberger, N. I., Lieberman, M. D., & Williams, K. D. (2003).
VICARIOUS RESPONSES TO PAIN IN ACC 277
Does rejection hurt? An f MRI study of social exclusion. Science,
302, 290-292.
Forman, S. D., Cohen, J. D., Fitzgerald, M., Eddy, W. F., Mintun,
M. A., & Noll, D. C. (1995). Improved assessment of significant ac-
tivation in functional magnetic resonance imaging (f MRI): Use of a
cluster-size threshold. Magnetic Resonance in Medicine, 33, 636-647.
Francis, S. T., Kelly, E. F., Bowtell, R., Dunseath, W. J., Folger,
S. E., & McGlone, F. (2000). f MRI of the responses to vibratory
stimulation of digit tips. NeuroImage, 11, 188-202.
Friston, K. J., Worsley, K. J., Frackowiak, R. S. J., Mazziotta, J.,
& Evans, A. C. (1994). Assessing the significance of focal activa-
tions using their spatial extent. Human Brain Mapping, 1, 214-220.
Gallese, V. (2001). The shared manifold hypothesis: From mirror neu-
rons to empathy. Journal of Consciousness Studies, 8, 33-50.
Gallese, V. (2003). The manifold nature of interpersonal relations: The
quest for a common mechanism. Philosophical Transactions of the
Royal Society of London: Series B, 358, 517-528.
Gelnar, P. A., Krauss, B. R., Szeverenyi, N. M., & Apkarian, A. V.
(1998). Fingertip representation in the human somatosensory cortex:
An fMRI study. NeuroImage, 7, 261-283.
Hadland, K. A., Rushworth, M. F. S., Gaffan, D., & Passingham,
R. E. (2003a). The anterior cingulate and reward-guided selection of
actions. Journal of Neurophysiology, 89, 1161-1164.
Hadland, K. A., Rushworth, M. F. S., Gaffan, D., & Passingham,
R. E. (2003b). The effect of cingulate lesions on social behavior and
emotion. Neuropsychologia, 41, 919-931.
Hari, R., Forss, N., Avikainen, S., Kirveskari, E., Salenius, S., &
Rizzolatti, G. (1998). Activation of human primary motor cortex
during action observation: A neuromagnetic study. Proceedings of
the National Academy of Sciences, 95, 15061-15065.
Hikosaka, K. (1997). Responsiveness of neurons in the posterior in-
ferotemporal cortex to visual patterns in the macaque monkey. Be-
havioural Brain Research, 89, 275-283.
Hofbauer, R. K., Rainville, P., Duncan, G. H., & Bushnell, M. C.
(2001). Cortical representation of the sensory dimension of pain.
Journal of Neurophysiology, 86, 402-411.
Hsieh, J.-C., Stone-Elander, S., & Ingvar, M. (1999). Anticipatory
coping of pain expressed in the human anterior cingulate cortex: A
positron emission tomography study. Neuroscience Letters, 262, 61-64.
Hutchison, W. D., Davis, K. D., Lozano, A. M., Tasker, R. R., &
Dostrovsky, J. O. (1999). Pain-related neurons in the human cingu-
late cortex. Nature Neuroscience,
2, 403-405.
Iacoboni, M., Woods, R. P., Brass, M., Bekkering, H., Mazziotta,
J. C., & Rizzolatti, G. (1999). Cortical mechanisms of human im-
itation. Science, 286, 2526-2528.
Jackson, P. L., Meltzoff, A. N., & Decety, J. (2004, April). Perceiv-
ing others in painful situations activates the affective pain neural net-
work. Paper presented at the annual meeting of the Cognitive Neuro-
science Society, San Francisco.
Jenkinson, M., Bannister, P., Brady, M., & Smith, S. (2002). Im-
proved optimization for the robust and accurate linear registration
and motion correction of brain images. NeuroImage, 17, 825-841.
Kaas, J. H., & Collins, C. E. (2001). The organization of sensory cor-
tex. Current Opinion in Neurobiology, 11, 498-504.
Keightley, M. L., Winocur, G., Graham, S. J., Mayberg, H. S.,
Hevenor, S. J., & Grady, C. L. (2003). An fMRI study investigat-
ing cognitive modulation of brain regions associated with emotional
processing of visual stimuli. Neuropsychologia, 41, 585-596.
Kenshalo, D. R., Iwata, K., Sholas, M., & Thomas, D. A. (2000).
Response properties and organization of nociceptive neurons in area 1
monkey primary somatosensory cortex. Journal of Neurophysiology,
84, 719-729.
Koyama, T., Kato, K., Tanaka, Y. Z., & Mikami, A. (2001). Anterior
cingulate activity during pain-avoidance and reward tasks in mon-
keys. Neuroscience Research, 39, 421-430.
Koyama, T., Tanaka, Y. Z., & Mikami, A. (1998). Nociceptive neu-
rons in the macaque anterior cingulate activate during anticipation of
pain. NeuroReport, 9, 2663-2667.
Matelli, M., Luppino, G., & Rizzolatti, G. (1991). Architecture of
superior and mesial area 6 and the adjacent cingulate cortex in the
macaque monkey. Journal of Comparative Neurology, 311, 445-462.
McGlone, F., Kelly, E. F., Trulsson, M., Francis, S. T., Westling, G.,
& Bowtell, R. (2002). Functional neuroimaging studies of human
somatosensory cortex. Behavioural Brain Research, 135, 147-158.
Melzack, R. (1999). From the gate to the neuromatrix. Pain, 6(Suppl.),
S121-S126.
Milham, M. P., Banich, M. T., Claus, E. D., & Cohen, N. J. (2003).
Practice-related effects demonstrate complementary roles of anterior
cingulate and prefrontal cortices in attentional control. NeuroImage,
18, 483-493.
Paus, T., Petrides, M., Evans, A. C., & Meyer, E. (1993). Role of the
human anterior cingulate cortex in the control of oculomotor, man-
ual, and speech responses: A positron emission tomography study.
Journal of Neurophysiology, 70, 453-469.
Peyron, R., Garcia-Larrea, L., Gregoire, M. C., Convers, P.,
Richard, A., Lavenne, F., Barral, F. G., Mauguiere, F., Michel, D.,
& Laurent, B. (2000). Parietal and cingulate processes in central pain.
A combined positron emission tomography (PET) and functional mag-
netic resonance imaging (fMRI) study of an unusual case. Pain, 84
, 77-
87.
Peyron, R., Laurent, B., & Garcia-Larrea, L. (2000). Functional
imaging of brain responses to pain: A review and meta-analysis
(2000). Clinical Neurophysiology, 30, 263-288.
Phillips, M. L., Young, A. W., Senior, C., Brammer, M., Andrews, C.,
Calder, A. J., Bullmore, E. T., Perrett, D. I., Rowland, D.,
Williams, S. C. R., Gray, J. A., & David, A. S. (1997). A specific
neural substrate for perceiving facial expressions of disgust. Nature,
389, 495-498.
Ploner, M., Freund, H. J., & Schnitzler, A. (1999). Pain affect without
pain sensation in a patient with a postcentral lesion. Pain, 81, 211-214.
Porro, C. A., Cettolo, V., Francescato, M. P., & Baraldi, P. (2003).
Functional activity mapping of the mesial hemispheric wall during
anticipation of pain. NeuroImage, 19, 1738-1747.
Powell, T. P. S., & Mountcastle, V. B. (1959). The cytoarchitecture
of the postcentral gyrus of the monkey Macaca mulatta. Bulletin of
Johns Hopkins Hospital, 105, 108-131.
Preston, S. D., & de Waal, F. B. M. (2002). Empathy: Its ultimate and
proximate bases. Behavioral & Brain Science, 25, 1-20.
Rainville, P. (2002). Brain mechanisms of pain affect and pain mod-
ulation. Current Opinion in Neurobiology, 12, 195-204.
Rainville, P., Carrier, B., Hofbauer, R. K., Bushnell, M. C., &
Duncan, G. H. (1999). Dissociation of sensory and affective dimen-
sions of pain using hypnotic modulation. Pain, 82, 159-171.
Rainville, P., Duncan, G. H., Price, D. D., Carrier, B., & Bushnell,
M. C. (1997). Pain affect encoded in human anterior cingulate but not
somatosensory cortex. Science, 277, 968-971.
Ringler, R., Greiner, M., Kohlloeffel, L., Handwerker, H. O.,
Forster, C. (2003). BOLD effects in different areas of the cerebral
cortex during painful mechanical stimulation. Pain, 105, 445-453.
Rizzolatti, G., Fadiga, L., Fogassi, L., & Gallese, V. (1999). Reso-
nance behaviors and mirror neurons. Archives Italiennes de Biologie,
137, 85-100.
Rizzolatti, G., Fadiga, L., Gallese, V., & Fogassi, L. (1996). Pre-
motor cortex and the recognition of motor actions. Cognitive Brain
Research, 3, 131-141.
Rizzolatti, G., & Luppino, G. (2001). The cortical motor system.
Neuron, 31, 889-901.
Rushworth, M. F. S., Hadland, K. A., & Passingham, R. E. (2003).
The effect of cingulate cortex lesions on task switching and working
memory. Journal of Cognitive Neuroscience, 15, 338-353.
Schnitzler, A., & Ploner, M. (2000). Neurophysiology and func-
tional neuroanatomy of pain perception. Journal of Clinical Neuro-
physiology, 17, 592-603.
Schnitzler, A., Seitz, R. J., & Freund, H.-J. (2000). The somato-
sensory system. In A. W. Toga & J. C. Mazziotta (Eds.), Brain map-
ping: The systems (pp. 291-329). San Diego: Academic Press.
Sewards, T. V., & Sewards, M. A. (2002). The medial pain system:
Neural representations of the motivational aspect of pain. Brain Re-
search Bulletin, 59, 163-180.
Singer, T., Seymour, B., O’Doherty, J., Kaube, H., Dolan, R. J., &
Frith, C. D. (2004). Empathy for pain involves the affective but not
sensory components of pain. Science, 303, 1157-1162.
Smith, S. M. (2002). Fast robust automated brain extraction. Human
Brain Mapping, 17, 143-155.
278 MORRISON, LLOYD,
DI PELLEGRINO, AND ROBERTS
Timmermann, L., Ploner, M., Haucke, K., Schmitz, F., Baltissen, R.,
& Schnitzler, A. (2001). Differential coding of pain intensity in the
human primary and secondary somatosensory cortex. Journal of
Neurophysiology, 86, 1499-1503.
Vogt, B. A., Nimchinsky, E. A., Vogt, L. J., & Hof, P. R. (1995).
Human cingulate cortex: Surface features, flat maps, and cytoarchi-
tecture. Journal of Comparative Neurology, 359, 490-506.
Vogt, B. A., & Pandya, D. N. (1987). Cingulate cortex of the rhesus
monkey: II. Cortical afferents. Journal of Comparative Neurology,
262, 271-289.
Vogt, B. A., & Sikes, R. W. (2000). The medial pain system, cingulate
cortex, and parallel processing of nociceptive information. Progress
in Brain Research, 122, 223-235.
Walton, M. E., Bannerman, D. M., Alterescu, K., & Rushworth,
M. F. (2003). Functional specialization within medial frontal cortex
of the anterior cingulate for evaluating effort-related decisions. Jour-
nal of Neuroscience, 23, 6475-6479.
Wicker, B., Keysers, C., Plailly, J., Royet, J. P., Gallese, V., & Riz-
zolatti, G. (2003). Both of us disgusted in my insula: The common
neural basis of seeing and feeling disgust. Neuron, 40, 655-664.
Wispé, L. (1991). The psychology of sympathy. New York: Plenum.
Woolrich, M. W., Ripley, B. D., Brady, M., & Smith, S. M. (2001).
Temporal autocorrelation in univariate linear modeling of f MRI data.
NeuroImage, 14, 1370-1386.
Worsley, K. J., Evans, A. C., Marrett, S., & Neelin, P. (1992). A
three-dimensional statistical analysis for CBF activation studies in
human brain. Journal of Cerebral Blood Flow Metabolism, 12, 900-
918.
Yamasaki, H., LaBar, K. S., & McCarthy, G. (2002). Dissociable pre-
frontal brain systems for attention and emotion. Proceedings of the
National Academy of Sciences, 99, 11447-11451.
(Manuscript received October 16, 2003;
revision accepted for publication May 4, 2004.)
