Proc. Natl. Acad. Sci. USA
Vol. 96, pp. 7705–7709, July 1999
This paper was presented at the National Academy of Sciences colloquium ‘‘The Neurobiology of Pain,’’ held
December 11–13, 1998, at the Arnold and Mabel Beckman Center in Irvine, CA.
Pain perception: Is there a role for primary
M. C. BUSHNELL*, G. H. DUNCAN, R. K. HOFBAUER, B. HA, J.-I. CHEN, AND B. CARRIER
McGill University and Universite ´ de Montre ´al, Montreal, Quebec, Canada H3A 1A1
implicate multiple cortical regions in the complex experience
of pain. These regions include primary and secondary so-
matosensory cortices, anterior cingulate cortex, insular cor-
tex, and regions of the frontal cortex. Nevertheless, the role of
different cortical areas in pain processing is controversial,
particularly that of primary somatosensory cortex (S1). Hu-
man brain-imaging studies do not consistently reveal pain-
related activation of S1, and older studies of cortical lesions
and cortical stimulation in humans did not uncover a clear
role of S1 in the pain experience. Whereas studies from a
number of laboratories show that S1 is activated during the
presentation of noxious stimuli as well as in association with
some pathological pain states, others do not report such
activation. Several factors may contribute to the different
results among studies. First, we have evidence demonstrating
alter pain perception, including attention and previous expe-
rience. Second, the precise somatotopic organization of S1
may lead to small focal activations, which are degraded by
sulcal anatomical variability when averaging data across
subjects. Third, the probable mixed excitatory and inhibitory
effects of nociceptive input to S1 could be disparately repre-
sented in different experimental paradigms. Finally, statisti-
cal considerations are important in interpreting negative
findings in S1. We conclude that, when these factors are taken
into account, the bulk of the evidence now strongly supports
a prominent and highly modulated role for S1 cortex in the
sensory aspects of pain, including localization and discrimi-
nation of pain intensity.
Anatomical, physiological, and lesion data
The role of primary somatosensory cortex (S1) in pain per-
ception has long been in dispute. In the early 20th century,
Head and Holmes (1) observed that patients with longstanding
cortical lesions did not show deficits in pain perception.
Similarly, Penfield and Boldrey (2), based on studies of
electrical stimulation of patients’ exposed cerebral cortices
during epilepsy surgery, concluded that pain probably has little
or no cortical representation. In more recent studies of S1
cortex in monkeys, single-cell recordings in both anesthetized
(3) and awake (4) monkeys revealed so few nociceptive
neurons that their functional significance was uncertain.
Other evidence suggests that S1 cortex may indeed play an
important role in pain perception. Despite the lack of pro-
found deficits in pain perception after widespread cortical
lesions, patients do show at least transient deficits following
reported that some patients with epileptic foci involving S1
cortex experience painful seizures. Anatomical evidence from
primates demonstrates that regions of thalamus containing
nociceptive neurons project to S1 cortex (7–9), thus providing
the possible framework necessary to support the processing of
nociceptive information within S1. Additionally, despite the
small numbers of nociceptive neurons observed in monkey S1
cortex, their responses parallel pain perception in humans (10,
11). For example, by using optical imaging and neuronal
recording techniques, Tommerdahl et al. (11) showed that
nociceptive activity in area 3a of S1 cortex exhibited slow
temporal summation and poststimulus response persistence
after repeated cutaneous heat stimulation, which parallel
bilateral ablation of S1 cortex in monkeys disrupts their ability
to discriminate intensities of noxious heat (D. R. Kenshalo, Jr.,
D. A. Thomas, and R. Dubner, unpublished observations).
Findings from human brain imaging studies have produced
inconsistent results pertaining to the role of S1 cortex in pain
perception. The first three modern brain imaging studies of
pain, published in the early 1990s, produced vastly different
results in terms of S1 cortex. By using positron emission
tomography (PET) and repeated 5-sec heat stimuli presented
to six spots on the arm, Talbot et al. (12) found a significant
activation focus in S1 cortex contralateral to the stimulated
arm. By using similar heat stimuli, but repetitively presented to
a single spot on the dorsal hand, Jones et al. (13) failed to
observe significant activation in S1 cortex. Finally, by using
single photon-emission computed tomography, Apkarian et al.
(14) found that submerging the fingers in hot water for 3
minutes led to a decrease in S1 activity.
Jones and colleagues (15, 16) postulated that the experi-
mental procedures used by Talbot et al., particularly moving
the stimulus among six spots during the scans, differentially
direct more attention to the pain stimulus than to the control
stimulus, and thus produce an attention-related modulation of
S1 cortical activity. They further postulated that the presence
or absence of pain, itself, is probably not a main determinant
of S1 activation. More recent studies support the idea that
attention can significantly modulate pain-evoked S1 activity,
but little evidence supports the premise that pain is not a major
determinant of S1 activity during painful stimulation.
brain imaging studies of pain, by using PET, single photon-
emission computed tomography, functional MRI, and magne-
toencephalographic imaging. In the various studies, pain stim-
uli include phasic and tonic heat, cold, chemical irritants,
electric shock, ischemia, visceral distension, headache, and
neuropathic pain. As can be seen in Table 1, there is little
consistency among the studies as to whether S1 is activated by
pain. Some studies involving thermal, chemical, or electrical
stimulation reveal S1 activation, whereas others using similar
stimuli do not. Several factors that may contribute to these
PNAS is available online at www.pnas.org.
Abbreviations: S1, primary somatosensory cortex; PET, positron
emission tomography; rCBF, regional cerebral blood flow.
*To whom reprint requests should be addressed. e-mail: bushnell@
differential results include (i) influences of cognitive modu-
lation in S1 activity; (ii) averaging-related degradation of the
signal because of variability of sulcal anatomy; (iii) a possible
combination of excitatory and inhibitory effects of nociceptive
input to S1; and (iv) differences in statistical analyses and
Cognitive Modulation of S1 Activity. As proposed by Jones
and colleagues (15, 16), S1 pain-related activation is highly
modulated by cognitive factors that alter pain perception,
we have shown that when the subject’s attention is directed
away from a painful stimulus, the activity of S1 cortex is
dramatically reduced (B.C., P. Rainville, T. Paus, G.H.D., and
M.C.B., unpublished observations). Fig. 1 shows the results of
this study, in which we used PET H215O bolus methods to
measure regional cerebral blood flow (rCBF) in nine subjects
while they discriminated changes in thermal intensity or au-
ditory frequency. During all scans, concurrent sequences of
tones and contact heat stimuli (pain, 46.5–48.5°C or warm,
32–38°C on the left arm) were presented. After each scan,
subjects used a 100-mm visual analogue scale to rate the
perceived level of pain associated with the thermal stimuli.
Statistical brain maps of pain-related activity, i.e., rCBF during
the pain condition minus rCBF during the nonpainful warm
thermal than in the auditory task (50.4 vs. 41.4, P ? 0.01),
indicating that pain perception was modulated by the atten-
tional demands of the discrimination tasks. Likewise, whereas
in the thermal task there was a significant pain-related rCBF
increase within S1 (t ? 4.42, P ? 0.01), there was no significant
(Fig. 1). A direct comparison of pain-related S1 activity during
the pain and auditory tasks showed that pain-evoked rCBF was
significantly larger in the thermal than in the auditory task (t ?
3.92; P ? 0.01). In this experiment, the behavioral task used to
direct attention toward the thermal stimuli involved the de-
tection of a small change in the intensity of the heat stimulus.
This task probably served to specifically direct the subjects’
attention to sensory aspects of the pain, rather than to the
unpleasantness or suffering.
Other data from our laboratory also support the idea that
attention to sensory aspects of the pain experience can alter S1
activity. By using hypnosis, we found that suggestions specif-
ically directed toward increasing or decreasing the perceived
intensity of the burning pain sensation produced by submerg-
ing a subject’s hand in painfully hot water modulated pain-
related activity in S1 (R.K.H., P. Rainville, G.H.D., and
M.C.B., unpublished observations). In contrast, suggestions
Table 1.Methods and results of brain imaging studies
Subjectn Stimulation device
Thermode 1 cm2
Thermode 2.5 cm ? 5.0
Thermode, 1 cm2
36.1, 41.3, and
Moderate heat pain
Cold pressor test
Talbot et al.
Jones et al.
Apkarian et al.
Crawford et al.
Coghill et al.
Di Piero et al.
Derbyshire et al.
Rosen et al.
Hsieh et al.
Hsieh et al.
Davis et al.
Electrical nerve stimulator
Median nerve, 50
Electric finger shock
Electric finger shock
Bars 20 and 40°C
40 and 50°C
Electric hand shock
Weiller et al. 32PET H215O Migraine patients9 NoneNo
Howland et al.
Kitamura et al.
Craig et al.
Casey et al.
Casey et al.
Hsieh et al.
Andersson et al.
Antognini et al.
Aziz et al.
Electrical nerve stimulator
Electrical nerve stimulator
DiPiero et al.
Rainville et al.
Silverman et al.
Svensson et al.
Svensson et al.
Xu et al.
Binkofski et al.
Finger, 8 Hz
40 & 50°C
Derbyshire et al.
Iadarola et al.
May et al.
Oshiro et al.
Paulson et al.
ns, not significant; SPECT, single photon-emission computed tomography; fMRI, functional MRI; MEG, magnetoencephalographic imaging.
Thermode, 254 mm2
7706 Colloquium Paper: Bushnell et al. Proc. Natl. Acad. Sci. USA 96 (1999)
directed toward changing the unpleasantness of the pain had
no effect on pain-related activity in S1, but produced instead
a robust modulation of activity in anterior cingulate cortex
directly correlated with the subjects’ perception of unpleas-
antness (ANCOVA, P ? 0.005) (17).
In these hypnosis experiments, we also found evidence that
experience with the hypnotic suggestions may have produced
least a week before participating in a PET scanning session, all
subjects received the same hypnotic induction, suggestions,
and painful stimuli that were to be used during the scanning
experiment. In subsequent PET sessions, two scans using the
painful heat and two using the nonpainful warm control
stimulus were performed before the subjects underwent hyp-
notic induction and suggestions. During these four scans, the
subjects were simply instructed to relax and attend to the
thermal stimulus—a control situation for identifying regions
that could be examined for modulation related to hypnotic
two hypnosis experiments produced similar ratings of pain
intensity and unpleasantness during these control scans, those
previously trained to attend to the intensity of the painful
stimuli showed substantially greater pain-related activity in S1
than did those who had been trained to attend to the unpleas-
Attentional modulation within S1 cortex is not restricted to
in S1, evoked by tactile stimuli, is reduced when subjects attend
to another stimulus modality (18). Similarly, neuronal record-
ings in S1 cortex of trained monkeys reveal low-threshold
neurons whose activity is enhanced by attention to the tactile
stimulus (19, 20). Despite the extensive nature of attentional
modulation of S1 activity, there is little evidence that attention
activates S1 neurons without the concurrent presence of
sensory-evoked activation. Anticipation of a painful stimulus
has been shown to produce decreases in S1 rCBF (51) rather
than increases in rCBF that would reflect excitatory neuronal
Variability of S1 Sulcal Anatomy. Both monkey and human
data indicate that nociceptive activity in S1 cortex is somato-
topically organized. Neuronal recording studies in monkeys
show a somatotopic organization for nociceptive neurons
similar to that observed for low-threshold cells (3). Similarly,
by using PET to measure rCBF and capsaicin as a specific
nociceptive stimulus, Andersson et al. (21) found distinct
activation sites related to foot and hand pain, consistent with
the known topographic organization of cutaneous receptive
fields within S1. The somatotopic organization of S1 cortex
probably results in a small focal activation evoked by a
localized pain stimulus. Such focal activation is more easily
observed with single-subject functional MRI studies than in
PET studies involving a number of subjects and data smooth-
ing. Fig. 3 shows the focal activation produced in S1 cortex of
three individual subjects when the leg was stimulated with
noxious heat (B.H., J.-I.C., B. Pike, G.H.D., and M.C.B.,
unpublished observations). The images show regions activated
during stimulation with painful heat, as compared with that
observed during nonpainful warm. Fig. 3 also shows that the
pain-related S1 activation sites, although on the posterior bank
of the central sulcus in all subjects, varied in terms of their
stereotaxic coordinates, suggesting small intersubject differ-
ences in the localization of pain-related activity. This anatom-
ical variability, although not of a large magnitude, degrades a
focal signal when data are averaged across subjects. Thus,
because of the somatotopically organized focal activation
observed in S1, the rCBF signal arising from this area may be
particularly susceptible to degradation when averaging data.
Inhibitory Effects of Noxious Stimuli in S1 activity. Tom-
of noxious heat reduced the intrinsic optical-imaging signal
evoked by low-threshold mechanical stimulation of the skin.
subtracting PET data recorded when a warm stimulus (32–38°C) was presented from those recorded when a painfully hot stimulus (46.5–48.5°C)
was presented during each attentional state. Differences in pain-related activity during the two attentional conditions are revealed (Right) by
subtracting PET data recorded during the auditory task from that recorded during the heat-discrimination task (using only painful stimulus
trials—46.5–48.5°C). PET data, averaged across nine subjects, are illustrated against an MRI from one subject. Horizontal and coronal slices
through S1 are centered at the activation peaks. Red circles surround the region of S1. Whereas there was a significant activation of S1 when subjects
attended to the painful stimulus (Left), there was no significant activation when subjects attended to the auditory stimulus (Center). However, there
was a subsignificant activation in S1 during the auditory task, as shown in the Inset. The direct comparison of pain in the two attentional conditions
(Right) shows a significant difference in pain-related S1 activity during the two attentional states.
Pain-related activity when attention is directed to the painful heat stimulus (Left) or to an auditory stimulus (Center) is revealed by
Colloquium Paper: Bushnell et al. Proc. Natl. Acad. Sci. USA 96 (1999)7707
These data are consistent with the findings of Apkarian et al.
(14), which showed a decrease in blood flow to S1 cortex in
human subjects during the presentation of a tonic heat stim-
ulus. Consonant with the idea that noxious stimulation pro-
duces inhibition of tactile sensitivity in S1 cortex are psycho-
physical data showing that the presence of pain reduces tactile
Other evidence suggests that the inhibition of S1 tactile
activity by noxious stimuli may take place at lower levels of the
neuraxis rather than through a direct inhibitory influence at
the level of S1. In awake monkeys, the spontaneous activity of
low-threshold neurons in the ventroposterior thalamus is in-
hibited by topical application of capsaicin, which specifically
excites C fibers (C.-C. Chen and M.C.B., unpublished obser-
vations). Similarly, capsaicin sometimes reduces the responses
of spinothalamic tract neurons to noxious heat stimulation
(23). Thus, when a painful stimulus is presented in a human
brain imaging study, the net effect of exciting some neurons
and inhibiting the spontaneous activity of others could have
different effects on rCBF (as measured by PET) or on venous
blood oxygenation (as measured by functional MRI), depend-
ing on such variables as timing, duration, location, and inten-
sity of the painful stimulus.
Procedural and Analytical Differences in Studies. In human
brain imaging studies, many procedural variables can influence
the resultant data. Analytical techniques are not standardized
across laboratories or across imaging methods. For example,
different approaches are used to compare stimulation condi-
tions, including subtraction and regression comparisons across
scans. Instructions to the subjects, which can influence the
cognitive state, vary among studies, as does the timing of
stimulus variables. The statistical analyses, including methods
for calculating variance and assumptions about the nature of
the data, also differ among laboratories. Although all analyses
rely on some type of statistical determination of significance,
the method of accounting for multiple comparisons varies, and
thus the criteria for identifying an activation as significant are
not uniform across studies. Finally, the power of any statistical
test is influenced by the number of subjects studied, which is
another factor that varies greatly among studies.
As with any statistical test, the interpretation of negative
results must be performed with caution. Thus, it would appear
more fruitful to identify regions that show activation across a
hypnotic training by using suggestions for modulating pain sensation
(Upper) or pain unpleasantness (Lower). Both images represent data
from control scans, in which no hypnotic suggestions were given. Each
image represents the subtraction of PET data recorded when the hand
was submerged in thermally neutral water (35°C) from data recorded
when the hand was submerged in painfully hot water (47°C). PET data
were averaged across 10 experimental sessions in the sensory study
(Upper) and, in a different group of subjects, 11 experimental sessions
in the affective study (Lower). The PET data are illustrated against the
average MRI for that subject group. Coronal slices through S1 are
centered at the activation peaks, and red circles surround the region
Changes in pain-related activity associated with previous
scanner and standard head coil. Each horizontal and coronal image
represents the anatomical and functional data from a single subject
during one session, which included a high-resolution anatomical scan
7-mm slices acquired at 3-sec intervals. Thermal stimuli were applied
to the left calf on separate runs. Thermal runs consisted of 9 s
alternating cycles of rest, painful (45–46°C), rest, and neutral (35–
36°C) stimulation by using a 9 cm2thermode. Activation maps were
generated by using Spearman’s rank order correlation, comparing
painful to neutral heat. The coronal and horizontal slices through S1
are centered at the activation peaks, and red circles surround the
region of S1.
Functional MRI data from three subjects, using a 1.5-T
7708 Colloquium Paper: Bushnell et al. Proc. Natl. Acad. Sci. USA 96 (1999)
in isolation. Despite the wide methodological and analytical
variation in human brain imaging studies of pain, there is
surprising consistency in the activation of a number of brain
regions, including anterior cingulate and insular cortices.
Although the observation of pain-related activation in S1 is
somewhat less consistent, the fact that at least half of the
human brain imaging studies have identified significant acti-
vation of this region when subjects perceive pain suggests that
S1 has a significant role in nociceptive processing.
What Is the Role of S1 in Pain Processing? Anatomical,
neurophysiological, and imaging data confirm a role of S1
cortex in pain processing. Overall, the findings support the
traditional view that S1 is primarily involved in discriminative
aspects of somatic sensation and extends this view to include
discriminative aspects of somatic stimulation that is potentially
tissue-damaging, e.g., painful. Single neurons in monkey S1
code stimulus intensity, location, and duration, and their
activity correlates with human perception. Human imaging
studies show activation of S1 by a range of noxious stimuli,
including capsaicin, which selectively activates C fibers. These
studies also confirm the somatotopic organization of S1 pain
responses, thus supporting the role of S1 in pain localization.
Other imaging data that implicate S1 in the sensory aspect of
pain perception are findings that S1 activation is modulated by
cognitive manipulations that alter perceived pain intensity but
pain intensity. Nevertheless, despite the probable role of S1 in
the encoding of the various sensory features of pain, a con-
S1 may also serve to modulate tactile perception, described by
Apkarian et al. as a ‘‘touch gate’’ (22). Thus, S1 cortex may be
involved in both perception and modulation of both painful
and nonpainful somatosensory sensations.
We wish to express our appreciation to Ms. Francine Be ´langer for
her help in preparing this manuscript and to Dr. Pierre Rainville for
his intellectual and technical contributions to these studies. Imaging
studies were performed at the Montreal Neurological Institute with
the help and expertise of the its staff. This research is supported by
operating grants from the Canadian Medical Research Council
awarded to M.C.B. and to G.H.D.
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