NeuroImage 19 (2003) 655– 664
www.elsevier.com/locate/ynimg
Pain modulates cerebral activity during cognitive performance
Florence Rémy,* Uta N. Frankenstein, Adina Mincic,
Boguslaw Tomanek, and Patrick W. Stroman
MR Technology, Institute for Biodiagnostics, National Research Council, Winnipeg, Manitoba, Canada
Received 20 September 2002; revised 4 February 2003; accepted 14 February 2003
Abstract
The present study investigates how pain modulates brain activity during the performance of a semantic cognitive task. Based on previous
observations, we hypothesized that a simultaneous painful stimulus will induce an activation increase in brain regions engaged in the
cognitive task. High-field BOLD-fMRI experiments were conducted on 12 young healthy subjects, using a 2 ⫻ 2 factorial design. Painful
stimuli were induced by thermal hot stimulation (46 – 49°C) on the palmar surface of the hand, using a contact thermode. Cognitive tasks
consisted of either word generation (category fluency) or word repetition. Brain activity owing to the semantic tasks in the group was highly
consistent with previous neuroimaging studies. When the painful stimulus was added to the cognitive task, activity in brain regions involved
in semantic cognition, such as Broca’s area, was increased (P ⬍ 0.01). Pain also modulated activity in brain areas not directly engaged in
cognition. A positive modulation effect was observed in the midcingulate and the dorsomedial prefrontal cortex (P ⬍ 0.05). A negative
modulation effect was observed in perigenual cingulate cortex, insula, and medial thalamus (P ⬍ 0.05).
© 2003 Elsevier Science (USA). All rights reserved.
Keywords: Pain; Cognition; Attention; fMRI, Human; Brain
Introduction
It is a common experience that the feeling of pain, such
as a headache for example, makes the performance of a
specific cognitive task more difficult and influences the
successful completion of the task. It has been observed that
chronic pain patients perform significantly poorer than
healthy controls in different neuropsychological tests involving attention, psychomotor speed, or working memory
(Sjogren et al., 2000). As well, incapacity to think or concentrate was reported by patients with severe symptoms of
migraine (Caro et al., 1998). The neural mechanisms underlying the influence of pain on cognition are not well
known. Thus it is the aim of the present experiment to
investigate how the administration of a noxious stimulus
* Corresponding author. Institute for Biodiagnostics, National Research Council, 435 Ellice Avenue, Winnipeg, Manitoba, R3B 1Y6,
Canada. Fax: ⫹1-204-984-7036.
E-mail address: [email protected] (F. Rémy).
modulates cognition-related activity, in a group of young
healthy subjects.
Cognitive demands influence the perceived intensity of
painful stimuli. Neuroimaging studies of pain have used
various attention-demanding cognitive tasks as distractors
from painful stimuli to investigate the modulatory role of
attention on the perception of pain (Petrovic et al., 2000;
Peyron et al., 1999; Bantick et al., 2002; Brooks et al.,
2002). Using a verbal attention task as a distractor from the
cold pressor test, our group has observed a modulation of
activity in distinct anterior cingulate gyrus (ACG) subregions involved in the processing of painful and cognitive
stimuli (Frankenstein et al., 2001). Reversing the focus, we
also compared the brain activation patterns involved in the
verbal attention task in the presence and absence of a painful stimulus. Interestingly, we observed an increase of activity in the ACG (Brodmann area (BA) 32⬘/24⬘ in reference
to Vogt et al. (1995)), Broca’s area (BA44/45), ipsilateral
insula, dorsolateral prefrontal cortex, posterior cingulate
gyrus, and parietal cortex, when pain was added (Rémy et
al., 2001). These results obtained with a simple subtraction
1053-8119/03/$ – see front matter © 2003 Elsevier Science (USA). All rights reserved.
doi:10.1016/S1053-8119(03)00146-0
656
F. Rémy et al. / NeuroImage 19 (2003) 655– 664
Fig. 1. Thermal stimulation profiles. Painful temperatures (between 46 and 49°C) were determined for each subject to obtain a moderately painful sensation.
Temperature differences between rest and active epochs were 8°C in every stimulation, with a ramp time of 1 s. Semantic tasks were synchronized with the
thermal profiles.
contrast suggested an increase of activity in the brain regions involved in the verbal attention task when a pain task
was superimposed. Based on this observation, the influence
of pain on cognition-related activity was further investigated in the present blood oxygen level-dependent functional magnetic resonance imaging (BOLD-fMRI) study,
using a more appropriate experimental design for this purpose. Our first objective was to replicate previous findings
for patterns of activity during verbal attention and pain tasks
(Baker et al., 1997; Frankenstein et al., 2001). Our second
and main objective was to investigate positive and negative
pain interactions with cognition-related activity. Based on
our previous findings (Rémy et al., 2001), we hypothesized
that a simultaneous painful stimulus results in greater activity in brain regions involved in the cognitive task.
Materials and methods
periods were repeated four times, resulting in a total stimulation length of 1 min 45 s in each session.
Thermal stimulation
Nonpainful warm (39°C) and moderately painful hot
(46 – 49°C) stimuli were induced using a peltier thermode
(Medoc TSA-II) with a 3 ⫻ 3-cm2 flat probe on the
palmar surface of the left hand. Prior to fMRI experiments, individual heat pain thresholds were determined
to select a temperature profile acceptable to the subject.
This practice run started with a 47°C heat stimulus and
the temperature was either increased or decreased to
obtain a moderately painful stimulation. Precisely, the
stimulation runs consisted of alternate 9-s warm (38 –
41°C) and 13-s hot (46 – 49°C) periods (ascendant/descendant ramp time 1 s; see Fig. 1). No practice run was
conducted for the nonpainful warm stimulation, which
consisted of the same block design of alternate 9-s rest
(31°C) and 13-s warm (39°C) periods (Fig. 1).
Subjects
Twelve healthy volunteers (mean age, 24.2 ⫾ 3.4 years,
6 women, predominantly right-handed (10/12)) were recruited from the general population. Studies were performed at the Saint-Boniface General Hospital MRI facility
in Winnipeg, Canada. Approval for this experiment was
obtained from the National Research Council’s Human Research Ethics Board. Subjects gave written informed consent and were free of exclusion criteria for MRI.
Tasks
Subjects underwent four different functional imaging
sessions and were asked to remain still during the scanning
time. To avoid habituation effects in the group, tasks were
presented in random order, although painful and nonpainful
conditions were always alternated. All tasks consisted of
alternate 9-s rest and 15-s stimulation periods. Stimulation
Cognitive tasks
Semantic tasks were presented through goggles inserted
in the head coil (Avotec system with Neuroscan STIM
software) and were synchronized with the thermal stimulation (Fig. 1). In every session, subjects were asked to always
focus on the semantic task while the warm and painful hot
stimuli were ongoing. The semantic tasks consisted of either
word repetition (a word, for example “apple,” was presented
for 15 s and subjects were asked to repeat this word in their
mind, without articulation) or word generation (a category,
for example “fruits” or “actors,” was presented for 15 s and
subjects were asked to generate as many words in this
category as possible without articulation). During rest periods, a small cross at the center of the visual display was
shown, and subjects were instructed not to think about
anything in particular. For each semantic condition (repetition or generation), two separate tasks were programmed
with different words and categories, so that each subject
F. Rémy et al. / NeuroImage 19 (2003) 655– 664
could perform the same type of semantic task successively
during both warm and painful hot stimulations.
The four different imaging sessions combining semantic
and thermal stimulations were as follows:
1. Nonpainful warm stimulus and word repetition task
(WR);
2. Nonpainful warm stimulus and word generation task
(WG);
3. Painful hot stimulus and word repetition task (PR);
4. Painful hot stimulus and word generation task (PG).
After each imaging session, subjects were asked to rate
the pain sensation from 0 (no pain) to 10 (worst pain
imaginable) and the unpleasantness from 0 (not unpleasant
at all) to 10 (most unpleasant sensation imaginable). As
well, subjects were asked to rate the difficulty of the semantic task from 0 (not difficult at all) to 10 (most difficult task
imaginable).
Imaging protocol
Functional MRI experiments were conducted on a 3-T
head-only system (IMRIS, Winnipeg, Canada) with asymmetric gradient coils (Magnex, UK) and a quadrature head
coil built in-house. Sixteen 5-mm thick contiguous axialoblique slices were acquired parallel to the AC–PC line
(anterior/posterior commissure, Talairach and Tournoux,
1988) and allowed for whole-brain EPI (though inferior
occipital cortex and cerebellum were out of the acquisition
volume). Thirty-seven single-shot gradient-echo EPI volumes were acquired (TR/TE ⫽ 3000/30 ms, flip angle ⫽
60°, 64 ⫻ 64 matrix, 20-cm FOV) for each functional
imaging session.
Data analysis
Image preprocessing and statistical analysis were performed using Statistical Parametric Mapping 99 (SPM99)
software (Friston et al., 1994). In every time series, the first
two scans were discarded prior to preprocessing, resulting in
35 volumes in each series. Then, for each subject and each
session, all EPI volumes were realigned to the first volume
to correct for movement of the head during time-series
acquisitions. To allow for group analysis, realigned images
were spatially normalized to the Montreal Neurological
Institute (MNI) EPI brain template using affine and nonlinear transformations. During normalization, all scans were
resampled to 2 ⫻ 2 ⫻ 2-mm3 voxels using sinc interpolation. Finally, all images were spatially smoothed using an
8-mm full-width-at-half-maximum isotropic Gaussian kernel, to improve signal-to-noise ratio and to account for
residual intersubject differences.
Statistical analysis was performed on a voxel-by-voxel
basis using a general linear model approach (Friston et al.,
1995). First, a within-subject analysis was performed with
identical models across subjects (balanced design). For
657
model estimation, individual data were temporally
smoothed using a convolution with the hemodynamic response function. A temporal high-pass filter (cutoff 48 s)
was applied as well to remove low-frequency confounding
effects, such as cardiac and respiratory artifacts. Proportional scaling was applied to adjust for global signal
changes in each time series. For each individual, the four
different sessions (WR, WG, PR, and PG) were all included
in the same design matrix. Each session was identically
modeled using a boxcar convolved with the hemodynamic
response function.
Our experimental design allowed for a 2 ⫻ 2 factorial
analysis (Friston et al., 1996), the two factors being cognitive (semantic) and sensory states. The main effects of the
semantic and pain stimuli were evaluated using the contrasts
((WG ⫹ PG) ⫺ (WR ⫹ PR)) and ((PR ⫹ PG) ⫺ (WR ⫹
WG)) respectively. Also, the main effect of pain was
masked by the main effect of the semantic task to investigate common areas of activity. Modulation effects were
evaluated through the contrasts ((PG ⫺ PR) ⫺ (WG ⫺
WR)) and ((WG ⫺ WR) ⫺ (PG ⫺ PR)), to look at positive
and negative interactions of pain on cognition, respectively.
A group analysis was performed using a random-effects
procedure (Holmes and Friston, 1998). This procedure takes
into account both random effects (within and between subjects components of variance) and fixed effects (activation
owing to a particular task) to provide a better generalization
to a population effect. For each of the different contrasts of
interest defined above, one contrast image per subject was
entered into a one-sample t test across the 12 subjects. The
resulting SPM maps show the t statistics in every voxel for
the group and for each effect of interest. As well, a correlation analysis was performed to investigate the main effect
of pain contrast as a function of the pain intensity, evaluated
by the average pain ratings during PR and PG conditions for
each subject. We report all activations observed at a threshold of P ⬍ 0.01 (uncorrected) for main effects and at P ⬍
0.05 for modulation effects, masked analysis, and correlation analysis. We report as well P values corrected for
multiple comparisons at the cluster level. When an a priori
hypothesis existed about well-defined coordinates of functional activity, small-volume corrections (SVCs; Worsley et
al., 1996) were performed on SPMs, and SV-corrected P
values are reported. In all cases, the volume used to perform
SVCs was a 20 ⫻ 20 ⫻ 20-mm3 box (approximately 10
resels).
Results
Behavioural results
Pain ratings were reduced during the PG condition when
compared to the PR condition. Average rating of pain intensity was 6.5 ⫾ 1.5 during the PR task and 6.1 ⫾ 1.4
during the PG task. This reduction was significant at P ⬍
658
F. Rémy et al. / NeuroImage 19 (2003) 655– 664
0.026 (paired t test on ratings). Also, the average rating of
pain was 1.2 during the WR task and 1.2 during the WG
task. Average unpleasantness rating was the same during the
PR and PG tasks (6.2 for both conditions) and was 1.2 and
1 during the WR and WG tasks, respectively.
During semantic repetition, average ratings of task difficulty were 0.1 ⫾ 0.3 for the WR condition and 1.4 ⫾ 1.6
for the PR condition. During semantic generation, task difficulty was rated 1.6 ⫾ 1.5 for the WG condition and 2.7 ⫾
2.0 for the PG condition. The difference in difficulty ratings
between nonpainful and painful conditions was less significant during semantic generation (P ⫽ 0.075) than during
semantic repetition (P ⬍ 0.017).
fMRI results
Brain areas showing significant activations in the group
(P ⬍ 0.05 corrected for the whole brain or after SVC) for
the different contrasts investigated (main and modulation
effects) are listed in Table 1, with coordinates and T values
of local peaks as well as cluster sizes and corrected P
values. Some of these activated regions are also shown on
statistical parametric maps in Fig. 2, with the adjusted fMRI
signal change in each condition.
Main effect of semantic task
The main effect of the semantic task shows regions
significantly increased during word generation compared to
word repetition. In reference to Fig. 2, activity was observed
in the occipital cortex (mainly on the left side, x ⫽ ⫺8 or
⫺4 mm), superior frontal cortex (BA8, x ⫽ ⫺4 mm) extending to midcingulate (BA32⬘, bilateral, x ⫽ ⫺8 or ⫺4
mm), left Broca’s area (BA45, z ⫽ ⫹ 24 mm), left insular
and orbitofrontal cortices (z ⫽ ⫺4 mm), and the thalamus
bilaterally (x ⫽ ⫺8 mm). In addition, the left premotor area
(supplementary motor area, SMA), auditory association
area (BA22, bilateral), left parietal cortex (BA40), and left
lenticular nucleus were activated (not listed in the table). An
SVC was performed to correct BA32⬘ activation using coordinates observed in our previous study during a verbal
attention task (Frankenstein et al., 2001; local peak at (12,
30, 28)).
Main effect of pain
This contrast shows regions significantly increased during heat pain conditions compared to warm conditions.
Activity was observed in the bilateral dorsolateral prefrontal
cortex (DLPFC, BA9), Broca’s area (z ⫽ ⫹24 mm), occipital cortex (x ⫽ ⫺4 mm), and the midcingulate (BA24⬘ at x
⫽ ⫺4 mm and BA32⬘ at x ⫽ ⫺8 mm). In addition, activity
was observed in the lateral orbitofrontal cortices bilaterally
(left BA47, z ⫽ ⫺4 mm), precuneus (BA7), premotor area
bilaterally, left insula (ipsilateral to the thermal stimulation,
z ⫽ ⫺4 mm), posterior cingulate gyrus, right thalamus, and
the right parietal cortex (not listed in Table 1). Midcingulate
BA24⬘ activation was corrected using an ACG local peak
(⫺6, 20, 30) reported in our previous study during distraction from cold pain (Frankenstein et al., 2001).
Main effect of pain masked by main effect of semantic
The masked analysis allows investigation of brain regions that are part of the semantic network and show increased activity when the painful task is superimposed. In
decreasing order of significance, clusters were observed in
the left anterior insula, left DLPFC (BA9), left occipital
cortex (BA19 extending to BA18), left Broca’s area (BA45
extending to BA44), left SMA (BA4/6), midcingulate (medial BA32⬘), right thalamus, and posterior cingulate gyrus
(BA31).
Positive modulation of pain on semantic
This modulation contrast shows brain regions where simultaneous painful stimulation induces a greater difference
of activity between word generation and repetition. A positive modulation was observed in the left premotor area
(BA4/6, z ⫽ ⫹24 mm), left and medial parietal cortex, left
occipital cortex, dorsomedial prefrontal cortex (three separate clusters in medial BA9, left and right BA10, x ⫽ 0 and
⫹8 mm), right midcingulate (BA24⬘, x ⫽ ⫹8mm), and the
periaqueductal gray (x ⫽ 0 and ⫹8 mm). In addition,
activity was observed in the somatosensory cortex bilaterally (z ⫽ ⫹24 mm), lenticular nucleus bilaterally, thalamus
bilaterally, posterior cingulate gyrus (x ⫽ 0 mm), right
occipital cortex, right SMA, and right parietal cortex (not
listed in Table 1). Dorsomedial prefrontal activation was
corrected using contralateral coordinates (8, 60, 4) reported
by Porro et al. (2002) during painful somatosensory stimulation. Periaqueductal gray activity was corrected using
coordinates (⫺3, ⫺28, ⫺6) reported by Hsieh et al. (1995).
BA24⬘ activity was corrected using a small volume around
coordinates (8, 10, 32), contralateral to the painful stimulation. This voxel was reported in our previous study as an
ACG local peak during attention to a painful cold stimulus
(Frankenstein et al., 2001).
Negative modulation of pain on semantic
This contrast shows brain regions where simultaneous
painful stimulation induces a smaller difference of activity
between word generation and repetition. A negative modulation was observed in the left anterior insula (ipsilateral, z
⫽ ⫺12 to ⫹4 mm) extending to left orbitofrontal cortex (z
⫽ ⫺4 to ⫹4 mm) and the perigenual ACG (BA24/32, x ⫽
0 mm). Activity was also observed in the right middle and
left posterior insula (z ⫽ ⫺4 mm), right temporal cortex (z
⫽ ⫺4 mm), superior frontal cortex (x ⫽ ⫹8 mm), medial
thalamus (x ⫽ 0 mm), and left DLPFC (not listed in Table
1). The left insular and perigenual activations were corrected using small volumes around coordinates (⫺36, 16, 4)
and (⫺6, 40, 6), respectively, as reported by Porro et al.
(2002), who observed that activity in these areas was related
to individual pain intensity profiles.
F. Rémy et al. / NeuroImage 19 (2003) 655– 664
659
Table 1
Foci of significant fMRI signal increases during the main and modulation effects of semantic and pain tasks
Cluster
size
Local activation peaks
Coordinates (mm)
x
y
T
value
Corrected
P value
14
8
16
52
40
40
18
20
4
24
0
⫺12
⫺2
9.55
6.64
6.18
8.98
7.27
6.60
8.59
5.90
4.22
6.05
5.19
4.85
3.31
0.000
42
40
26
26
22
30
30
8.52
7.73
4.86
6.14
4.84
4.61
5.08
0.004
7.01
4.91
3.59
5.60
5.49
4.78
4.97
3.84
3.32
3.26
0.019
0.999
1.000
1.000
1.000
0.042
0.006
0.048
0.034
4.85
4.61
3.45
2.52
0.447
0.039
1.000
0.039
z
SV-corrected
P value
Main effect of semantic task
704
540
693
47
263
Occipital cortex (BA18)
BA17
BA18
Frontal oculomotor (BA8)
Midcingulate (BA32⬘)
BA32⬘
Broca’s area (BA45)
DLPFC (BA46)
BA45
Midcingulate (BA32⬘)
Insula
Lateral orbitofrontal cortex (BA47)
BA47
⫺18
⫺2
⫺6
⫺2
4
⫺12
⫺46
⫺50
⫺48
10
⫺34
⫺38
⫺32
⫺82
⫺72
⫺92
22
22
20
22
38
18
30
16
20
32
0.000
0.000
0.981
0.004
0.009
Main effect of pain task
261
207
26
DLPFC (BA9)
BA9
Broca’s area (BA44)
Occipital cortex (BA18)
BA18
BA19
Midcingulate (BA24⬘)
⫺30
⫺40
⫺60
⫺14
⫺6
⫺24
⫺6
4
16
12
⫺74
⫺72
⫺78
8
0.016
1.000
0.010
Positive Modulation effect of pain on semantic
751
2042
216
258
57
62
Premotor area (BA4/6)
Parietal cortex (BA40)
BA40
Precuneus (BA7)
Occipital cortex (BA19)
BA19
DMPFC (BA9)
DMPFC (BA10)
Midcingulate (BA24⬘)
Periaqueductal gray
⫺50
⫺52
⫺54
⫺14
⫺14
4
2
8
12
4
⫺6
⫺30
⫺34
⫺76
⫺84
⫺68
60
62
4
⫺28
20
42
30
46
40
30
22
2
34
⫺6
0.000
Negative modulation effect of pain on semantic
352
39
Anterior insula
Lateral orbitofrontal cortex (BA47)
Anterior insula
Perigenual ACG (BA24/32)
⫺40
⫺32
⫺32
⫺4
22
44
24
46
6
⫺6
8
6
Note. Cluster size in voxels, anatomical location, MNI coordinates (x, y, z), T values of local peaks, and P values corrected for the whole brain and after
SVC, for both main and modulation effects. Main effects were thresholded at P ⬍ 0.01 and modulation effects were thresholded at P ⬍ 0.05 (uncorrected
for multiple comparisons). The table displays only activations reaching significance (whole-brain corrected P ⬍ 0.05 at the cluster level or SV corrected P
⬍ 0.05 at the voxel level). Coordinates used for small-volume corrections on P values are reported in the text (Results section). X represents the left–right
axis from midline (negative ⫽ left), Y represents the front– back axis (negative ⫽ posterior to the anterior commissure), and Z represents the up– down axis
(negative ⫽ ventral to the AC–PC line).
Discussion
The results obtained in this experiment confirmed our
hypothesis that when performing a cognitive task, the presentation of a painful stimulus results in greater activity in
brain regions involved in this cognitive task. Modulation
effects of pain on semantic activity were observed in several
brain regions. The discussion will largely concentrate on the
cerebral activity specific to the pain conditions and on the
positive and negative modulation effects of pain on cognitive activity.
Activity owing to the semantic task
Activity in midcingulate (bilateral BA32⬘), Broca’s area,
left SMA, left anterior insula/lateral orbitofrontal cortex,
660
F. Rémy et al. / NeuroImage 19 (2003) 655– 664
F. Rémy et al. / NeuroImage 19 (2003) 655– 664
left occipital cortex, left superior frontal cortex, and left
thalamus was observed in the main effect of the semantic
task. Predominance of prefrontal activity in the left hemisphere is consistent with results reported during semantic
retrieval tasks (Cabeza and Nyberg, 2000). Using an auditory word generation versus repetition task, Baker et al.
(1997) reported activity in BA32⬘, BA44, insula, SMA, and
thalamus, which is highly consistent with our results. Also,
the left occipital cortex has been shown to be preferentially
involved in visual language tasks (Shulman et al., 1997).
When compared to our previous results in a nonvisual
verbal attention task (Frankenstein et al., 2001), BA32⬘
activity is smaller and located more superior in the present
study. This may be due to the different design used, as a
word repetition task was subtracted from semantic word
generation. Indeed, word generation versus word repetition
has been shown to result in superior BA32⬘ activity (Petersen et al., 1988; Baker et al., 1997; Drevets and Raichle,
1998).
Activity owing to pain
As observed in the main effect of pain and in the masked
analysis of both main effects, activity in brain areas involved in the semantic task was increased when pain was
experienced. An overlap between semantic and pain contrasts was observed in midcingulate (BA32⬘), Broca’s area
(BA45), left insula/BA47, occipital cortex, right thalamus,
and left premotor area. Therefore, activity in all areas involved in the semantic task (except superior frontal BA8)
was increased in painful conditions when compared to nonpainful ones. Activity in the ACG and Broca’s area will be
discussed in particular.
Painful conditions (PR and PG) resulted in a small-extent
increase of activity in BA32⬘ and in an increase of activity
in BA24⬘ when compared to warm conditions (WR and
WG).
BA32⬘ is part of the semantic network, and the increase
in this region overlaps with semantic activity. Peyron et al.
(1999) have reported BA32⬘ as being part of a “selective
attention” network during thermal stimulation. In the
present study, it could therefore reflect an increasing attentional effort to perform the semantic tasks during pain.
The increased activity in left BA24⬘ is more difficult to
interpret. Pain-related neurons have been evidenced using
electrophysiological recordings precisely in this ACG sub-
661
region (Hutchison et al., 1999). A similar ACG response
specific to pain has been reported in several neuroimaging
studies (Davis et al., 1997; Derbyshire et al., 1998b; Peyron
et al., 1999; Petrovic et al., 2000; Frankenstein et al., 2001;
Bantick et al., 2002; Brooks et al., 2002). Peyron et al.
(1999) have suggested that BA24⬘ activity is “enhanced
under conditions of divided attention,” which may also be
the case in our experiment.
In our study, the BA24⬘ cluster was located on the left
side of ACG, ipsilateral to the thermal stimulation, which is
in contradiction with results reported in the studies referenced above. However, pain studies looking at individuals
have demonstrated a strong intersubject variability in terms
of ACG activity laterality during heat pain (Vogt et al.,
1996; Derbyshire et al., 1998b; Hutchison et al., 1999;
Kwan et al., 2000). This suggests that arbitrary grouping of
individuals might possibly induce laterality differences in
different groups of subjects and could explain the disparity
between our results and those reported by others.
An increase of activity owing to pain was also observed
in Broca’s area. Broca’s area is involved in semantic generation tasks (Cabeza and Nyberg, 2000) and does not
belong to the pain matrix. Activity in this region was greater
during pain conditions and was furthermore moderately
correlated with pain ratings (cluster extent, 64 voxels, local
peak at (⫺56, 16, 22), T ⫽ 3.01). This suggests that, when
focusing on a cognitive task, there is a general response to
pain, manifested in a global increase of activity in brain
regions specific to the cognitive task. This may be due to the
increasing difficulty of focussing on and performing the
cognitive task, as suggested by the increased difficulty ratings during pain conditions. Our results regarding Broca’s
area activity can be compared with observations made by
Ghatan et al. (1998). This group has observed increased
activity in parietal cortex during an arithmetic task when an
auditory irrelevant-speech task was superimposed and has
interpreted this increase as a “facilitation of task-relevant
processing.” Similarly, in our experiment, the noxious stimulus could be considered as a disturbing interference, resulting in an increase of semantic-relevant activity. Baker et
al. (1997) have used a word generation versus repetition
task to study the interaction between mood and cognitive
function and have reported that the network engaged by
word generation was extensively attenuated in depressed
mood when compared to neutral mood. A depressed mood
may result in loss of motivation to perform the cognitive
Fig. 2. Statistical parametric maps (SPMs) of group results for main (top) and modulation (bottom) effects. The SPMs are superimposed on sagittal and axial
slices of a standard T1-weighted MNI image provided by SPM99. X or Z coordinates for each slice are indicated on the left-hand top corner of each image.
Axial slices are displayed according to neurological convention (left is left). Main effects of the semantic task (red-yellow color scale) and of the pain task
(blue-purple color scale) are thresholded at P ⬍ 0.01 uncorrected. Positive (red-white color scale) and negative (blue-green color scale) modulation effects
are thresholded at P ⬍ 0.05 uncorrected. No extent threshold was used. The right-hand section of the figure shows the adjusted fMRI signal changes (arbitrary
units) in each condition for local maxima in regions of interest, as identified in Table 1. The graphs point to the corresponding brain activations on the images.
The signal change is relative to the image mean intensity for each time point (i.e., after proportional scaling). Error bars show the standard error of the mean
in the group of 12 subjects. Significant signal differences between conditions are indicated with an asterisk (P ⬍ 0.05, paired t test). WR, warm stimulus and
word repetition; WG, warm stimulus and word generation; PR, painful stimulus and word repetition; PG, painful stimulus and word generation.
662
F. Rémy et al. / NeuroImage 19 (2003) 655– 664
task, whereas pain, in healthy subjects, may result in more
effort to focus on the task.
It should be noted that the cognitive task used in this
study was not rated as very challenging (average difficulty
rating was around 2.2 for word generation tasks) and that a
more demanding cognitive task may lead to a different
response in the cognitive brain regions when a noxious
stimulus is simultaneously presented. This is the focus of an
ongoing study by our group.
Modulation effects of pain on semantic activity
A positive modulation shows brain areas that are more
active when semantic and pain tasks are presented together
than would be predicted by the addition of the responses to
semantic and pain tasks alone. A negative modulation reveals reduced activity when pain and semantic tasks are
presented together. Modulation effects were observed in
ACG, DMPFC, and insula.
In the ACG, a positive modulation was observed in right
midcingulate BA24⬘ and a negative modulation was observed in medial perigenual cingulate BA24/32. Positive
modulation in BA24⬘ was found significant after SVC using
coordinates reported during the cold pressor test (Frankenstein et al., 2001) and was located contralateral to the
painful stimulus. Figure 2 shows that this region was activated during the PG condition only. Negative modulation in
the perigenual region was found significant after SVC using
coordinates reported by Porro et al. (2002). Figure 2 shows
that this region was activated during the PR condition only.
Drevets and Raichle (1998) and Derbyshire et al. (1998b)
reported blood flow increases in perigenual cortex during
specific emotion-related tasks and decreases during performance of attention-demanding cognitive tasks, which is
consistent with the negative modulation in this brain region
observed in our study. Drevets and Raichle (1998) also
reported reciprocal blood flow changes between ventral and
caudal ACG, which is observed in our study during PR and
PG conditions (Fig. 2).
The present results in the caudal and rostral ACG can
also be compared to the interaction effects reported by
Bantick et al. (2002). This group has looked at positive and
negative interactions between cognitive and heat pain conditions. They used a Stroop interference task as an attentiondemanding task and a Stroop neutral task as a baseline.
Their study revealed a positive interaction in perigenual
ACG and a negative interaction in bilateral midcingulate,
which is consistent with the reciprocal blood flow suppression between rostral and caudal ACG suggested by Drevets
and Raichle (1998). The observations by Bantick et al.
(2002) in midcingulate are also consistent with those reported by Rainville et al. (1997), who observed that midcingulate activity increases with the perceived unpleasantness
of the stimulus. In our study, modulation effects observed in
caudal and rostral ACG were opposite when compared to
the effects reported by Bantick et al. (2002) in the same
regions. It should be noted that, in our study, unpleasantness
ratings were not reduced in the PG versus PR conditions,
and pain ratings were significantly but only slightly reduced. This could possibly account for the absence of a
midcingulate activity decrease in the (PG ⫺ PR) contrast.
Also, our experimental design and data analysis were different from those used by Bantick et al. (2002). In particular, Bantick et al. did not include a warm condition (sensory
baseline), and this may influence our different observations
in ACG activity. Peyron et al. (1999) and Petrovic et al.
(2000) did not observe any significant ACG activation when
subtracting a nonpainful thermal condition from a painful
one. In the study by Frankenstein et al. (2001), no thermal
baseline was subtracted and ACG activity was observed
during the cold pressor test. Therefore, in the current study,
the subtraction of a warm condition from a painful one, as
well as the different type of cognitive task used (word
generation versus Stroop task), may have induced different
activity patterns in caudal and rostral ACG from those
observed by Bantick et al. (2002).
A positive modulation effect was observed in the dorsomedial prefrontal cortex (DMPFC, three clusters in BA9
and BA10). No activity in the DMPFC was observed in
main effects of both semantic and pain, showing that
DMPFC activity was neither “semantic-” nor “pain - specific,” but resulted from an interaction between semantic
and pain tasks. The decreased activity in DMPFC in the
(WG - WR) simple effect (Fig. 2) has also been observed by
other groups (Baker et al., 1997; Shulman et al., 1997;
Drevets and Raichle, 1998; Petrovic et al., 2000). Petrovic
et al. (2000) suggested a functional inhibition of task-irrelevant processing. During pain, the trend is reversed, as the
PG condition results in more activity than the PR condition.
Interestingly, this area has been reported to be engaged in an
analgesic response mechanism during the placebo effect
(Petrovic et al., 2002). The DMPFC has also been implicated in the anticipation of pain (Ploghaus et al., 1999;
Porro et al., 2002). There are also cortical projections from
DMPFC to the periaqueductal gray (PAG, Hardy and Leichnetz, 1981), where a positive modulation was observed in
the present study. PAG is involved in traumatic pain (Hsieh
et al., 1995) and in mediating analgesia (Fields and Basbaum, 1999; Tracey et al., 2002). Therefore, the positive
interaction in both DMPFC and PAG suggests their potential involvement in analgesia, when semantic and pain tasks
are presented together.
A negative modulation effect was observed in bilateral
insula. Left (ipsilateral) anterior insula as well as left orbitofrontal BA47 were also significantly involved in the
main effects of the semantic and pain tasks. The anterior
insula activates during noxious versus nonnoxious stimulation (Casey et al., 1996; Derbyshire et al., 1998a; Coghill et
al., 1999) and has been shown to correlate with the subjective evaluation of thermal stimuli (Craig et al., 2000).
Bantick et al. (2002) and Brooks et al. (2002) reported
similar negative interactions in insula during distraction
F. Rémy et al. / NeuroImage 19 (2003) 655– 664
from pain. Insular cortex (together with the cingulate gyrus)
receives projections from the medial pain system, particularly the medial thalamic nuclei (Vogt et al., 1987). Interestingly, we observed a negative modulation in medial thalamus, which was also reported by Bantick et al. (2002).
The insular cortex and thalamus, along with the cingulate
gyrus, belong to the limbic system and are thought to be
involved in the evaluation of affective aspects of pain (Ingvar, 1999). The negative modulation observed in our study
suggests that, to perform an attention-demanding cognitive
task while experiencing pain, activity in the medial pain
system is reduced. This may result in the lowered perception
of pain in the PG condition when compared to the PR
condition. In regard to the negative modulation and pain
ratings, similar observations were made by Bantick et al.
(2002). Also, as the medial pain system is classically related
to the affective-motivational component of pain (Treede et
al., 1999), our results reinforce the observations made by
Drevets and Raichle (1998), who reported blood flow decreases in areas required in emotional processing, during the
performance of higher level cognitive tasks.
Conclusion
In the present study, the cerebral activity pattern induced
by a semantic cognitive task is modified when pain is
experienced. Consistent with our hypothesis, we report a
global increase of activity in brain regions engaged in the
cognitive task. We also observed pain modulation effects on
cognition. A positive modulation was found in the midcingulate and in brain areas classically associated with analgesia during pain, such as the DMPFC and PAG. A negative
modulation was found in brain areas involved in affect, such
as the insula, perigenual ACG, and medial thalamus. Future
work needs to assess the effect of pain on more complex
cognitive tasks to determine whether the difficulty of the
task influences brain activation patterns. As well, the same
type of experiment in chronic pain patients may help to
understand how these patients cope with pain in their everyday lives.
Acknowledgments
We thank Dr. Valerie Strevens and Barbara Duke from
the Human Studies Department at the NRC for the recruitment of our subjects. We also thank Rudy Sebastian, Dr.
Mihaela Onu, and Dara Morden for helping with experiments.
References
Baker, S.C., Frith, C.D., Dolan, R.J., 1997. The interaction between mood
and cognitive function studied with PET. Psychol. Med. 27, 565–578.
663
Bantick, S.J., Wise, R.G., Ploghaus, A., Clare, S., Smith, S.M., Tracey, I.,
2002. Imaging how attention modulates pain in humans using functional MRI. Brain 125, 310 –319.
Brooks, J.C.W., Nurmikko, T.J., Bimson, W.E., Singh, K.D., Roberts, N.,
2002. FMRI of thermal pain: effects of stimulus laterality and attention.
NeuroImage 15, 293–301.
Cabeza, R., Nyberg, L., 2000. Imaging cognition II: an empirical review of
275 PET and fMRI studies. J. Cogn. Neurosci. 12 (1), 1– 47.
Caro, G., Caro, J.J., O’Brien, J.A., Anton, S., Jackson, J., 1998. Migraine
therapy: development and testing of a patient preference questionnaire.
Headache 38 (8), 602– 607.
Casey, K.L., Minoshima, S., Morrow, T.J., Koeppe, R.A., 1996. Comparison of human cerebral activation patterns during cutaneous warmth,
heat pain, and deep cold pain. J. Neurophysiol. 76 (1), 571–581.
Coghill, R.C., Sang, C.N., Maisog, J.M., Iadarola, M.J., 1999. Pain intensity processing within the human brain: a bilateral, distributed mechanism. J. Neurophysiol. 82, 1934 –1943.
Craig, A.D., Chen, K., Bandy, D., Reiman, E.M., 2000. Thermosensory
activation of insular cortex. Nat. Neurosci. 3 (2), 184 –190.
Davis, K.D., Taylor, S.J., Crawley, A.P., Wood, M.L., Mikulis, D.J., 1997.
Functional MRI of pain- and attention-related activations in the human
cingulate cortex. J. Neurophysiol. 77, 3370 –3380.
Derbyshire, S.W.G., Jones, A.K.P., 1998a. Cerebral responses to a continual tonic pain stimulus measured using positron emission tomography.
Pain 76, 127–135.
Derbyshire, S.W.G., Vogt, B.A., Jones, A.K.P., 1998b. Pain and Stroop
interference tasks activate separate processing modules in anterior
cingulate cortex. Exp. Brain Res. 118, 52– 60.
Drevets, W.C., Raichle, M.E., 1998. Reciprocal suppression of regional
cerebral blood flow during emotional versus higher cognitive processes: implications for interactions between emotion and cognition.
Cogn. Emotion 12 (3), 353–385.
Fields, H.L., Basbaum, A.I., 1999. Central nervous system mechanisms of
pain modulation, in: Wall, P.D., Melzack, R. (Eds.), Textbook of Pain,
Churchill Livingstone, London, pp. 309 –329.
Frankenstein, U.N., Richter, W., McIntyre, M.C., Rémy, F., 2001. Distraction modulates anterior cingulate gyrus activations during the cold
pressor test. NeuroImage 14, 827– 836.
Friston, K.J., Holmes, A.P., Worsley, K.J., Poline, J.P., Frith, C.D., Frackowiak, R.S., 1995. Statistical parametric maps in functional imaging: a
general linear approach. Hum. Brain Map. 2, 189 –210.
Friston, K.J., Jezzard, P., Turner, R., 1994. Analysis of functional MRI
time-series. Hum. Brain Map. 1, 153–171.
Friston, K.J., Price, C.J., Fletcher, P., Moore, C., Frackowiak, R.S.J.,
Dolan, R.J., 1996. The trouble with cognitive subtraction. NeuroImage
4, 97–104.
Ghatan, P.H., Hsieh, J.C., Petersson, K.M., Stone-Elander, S., Ingvar, M.,
1998. Coexistence of attention-based facilitation and inhibition in the
human cortex. NeuroImage 7, 23–29.
Hardy, S.G.P., Leichnetz, G.R., 1981. Cortical projections to the periaqueductal gray in the monkey: a retrograde and orthograde horseradish
peroxidase study. Neurosci. Lett. 22, 97–101.
Holmes, A.P., Friston, K.J., 1998. Generalisability, random effects and
population inference. NeuroImage 7, S754.
Hsieh, J.C., Stahle-Backdahl, M., Hagermark, O., Stone-Elander, S.,
Rosenquist, G., Ingvar, M., 1995. Traumatic nociceptive pain activates
the hypothalamus and the periaqueductal gray: a positron emission
tomography study. Pain 64, 303–314.
Hutchison, W.D., Davis, K.D., Lozano, A.M., Tasker, R.R., Dostrovsky,
J.O., 1999. Pain-related neurons in the human cingulate cortex. Nat.
Neurosci. 2 (5), 403– 405.
Ingvar, M., 1999. Pain and functional imaging. Phil. Trans. R. Soc. Lond.
B354, 1347–1358.
Kwan, C.L., Crawley, A.P., Mikulis, D.J., Davis, K.D., 2000. An fMRI
study of the anterior cingulate cortex and surrounding medial wall
activations evoked by noxious cutaneous heat and cold stimuli. Pain 85,
359 –374.
664
F. Rémy et al. / NeuroImage 19 (2003) 655– 664
Petersen, S.E., Fox, P.T., Posner, M.I., Mintun, M., Raichle, M.E., 1988.
Positron emission tomographic studies of the cortical anatomy of single-word processing. Nature 331, 585–589.
Petrovic, P., Kalso, E., Petersson, K.M., Ingvar, M., 2002. Placebo and
opioid analgesia—imaging a shared neuronal network. Science 295,
1737–1740.
Petrovic, P., Petersson, K.M., Ghatan, P.H., Stone-Elander, S., Ingvar, M.,
2000. Pain-related cerebral activation is altered by a distracting cognitive task. Pain 85, 19 –30.
Peyron, R., Garcia-Larrea, L., Grégoire, M.C., Costes, N., Convers, P.,
Lavenne, F., Mauguiére, F., Michel, D., Laurent, B., 1999. Haemodynamic brain responses to acute pain in humans: sensory and attentional
networks. Brain 122, 1765–1779.
Ploghaus, A., Tracey, I., Gati, J.S., Clare, S., Menon, R.S., Matthews, P.M.,
Rawlins, J.N.P., 1999. Dissociating pain from its anticipation in the
human brain. Science 284, 1979 –1981.
Porro, C.A., Baraldi, P., Pagnoni, G., Serafini, M., Facchin, P., Maieron,
M., Nichelli, P., 2002. Does anticipation of pain affect cortical nociceptive systems? J. Neurosci. 22 (8), 3206 –3214.
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.
Rémy, F., Frankenstein, U.N., Richter, W., 2001. Pain modulates brain
activity in a semantic attention task. NeuroImage 13 (6), S349.
Shulman, G.L., Corbetta, M., Buckner, R.L., Raichle, M.E., Fiez, J.A.,
Miezin, F.M., Petersen, S.E., 1997. Top-down modulation of early
sensory cortex. Cereb. Cortex 7, 193–206.
Sjogren, P., Thomsen, A.B., Olsen, A.K., 2000. Impaired neuropsychological performance in chronic malignant pain patients receiving longterm oral opioid therapy. J. Pain Symptom Manage. 19 (2), 100 –108.
Talairach, J., Tournoux, P., 1988. Co-planar Stereotaxic Atlas of the
Human Brain. Thieme, New York.
Tracey, I., Ploghaus, A., Gati, J.S., Clare, S., Smith, S., Menon, R.S.,
Matthews, P.M., 2002. Imaging attentional modulation of pain in the
periaqueductal gray in humans. J. Neurosci. 22 (7), 2748 –2752.
Treede, R.D., Kenshalo, D.R., Gracely, R.H., Jones, A.K.P., 1999. The
cortical representation of pain. Pain 79, 105–111.
Vogt, B.A., Derbyshire, S., Jones, A.K.P., 1996. Pain processing in four
regions of human cingulate cortex localized with co-registered PET and
MR imaging. Eur. J. Neurosci. 8, 1461–1473.
Vogt, B.A., Nimchimsky, E.A., Vogt, L.J., Hof, P.R., 1995. Human cingulate cortex: surface features, flat maps, and cytoarchitecture.
J. Comp. Neurol. 359, 490 –506.
Vogt, B.A., Pandya, D.N., Rosene, D.L., 1987. Cingulate cortex of the
rhesus monkey. I. Cytoarchitecture and thalamic afferents. J. Comp.
Neurol. 262, 256 –270.
Worsley, K.J., Marrett, S., Neelin, P., Vandal, A.C., Friston, K.J., Evans,
A.C., 1996. A unified statistical approach for determining significant
signals in images of cerebral activation. Hum. Brain Map. 4, 58 –73.