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J Neurophysiol
88: 464 – 474, 2002; 10.1152/jn.00999.2001.
Differentiating Noxious- and Innocuous-Related Activation of Human
Somatosensory Cortices Using Temporal Analysis of fMRI
JEN-I CHEN,1 BRIAN HA,2 M. CATHERINE BUSHNELL,3– 6 BRUCE PIKE,4,7 AND GARY H. DUNCAN3,4,8
Department of Neurology and Neurosurgery, Faculty of Graduate Studies & Research, McGill University, Montreal, Quebec
H3A 2B4; 2Department of Physiology, Faculty of Graduate Studies & Research, McGill University, Montreal, Quebec H3G 1Y6;
3
Centre de recherche en sciences neurologiques, Université de Montréal, Montreal, Quebec H3C 3J7; 4Department of Neurology
and Neurosurgery, and 5Department of Anesthesiology, Faculty of Medicine, and 6Faculty of Dentistry, McGill University,
Montreal, Quebec H3G 1Y6; 7McConnell Brain Imaging Centre, Montreal Neurological Institute, Montreal, Quebec H3A 2B4;
and 8Département de stomatologie, Faculté de médicine dentaire, Université de Montréal, Montreal, Quebec H3C 3J7, Canada
1
Chen, Jen-I, Brian Ha, M. Catherine Bushnell, Bruce Pike, and
Gary H. Duncan. Differentiating noxious- and innocuous-related activation of human somatosensory cortices using temporal analysis of
fMRI. J Neurophysiol 88: 464 – 474, 2002; 10.1152/jn.00999.2001. The
role of the somatosensory cortices (SI and SII) in pain perception has long
been in dispute. Human imaging studies demonstrate activation of SI and
SII associated with painful stimuli, but results have been variable, and the
functional relevance of any such activation is uncertain. The present study
addresses this issue by testing whether the time course of somatosensory
activation, evoked by painful heat and nonpainful tactile stimuli, is
sufficient to discriminate temporal differences that characterize the perception of these stimulus modalities. Four normal subjects each participated in three functional magnetic resonance imaging (fMRI) sessions, in
which painful (noxious heat 45– 46°C) and nonpainful test stimuli (brushing at 2 Hz) were applied repeatedly (9-s stimulus duration) to the left leg
in separate experiments. Activation maps were generated comparing
painful to neutral heat (35°C) and nonpainful brushing to rest. Directed
searches were performed in SI and SII for sites reliably activated by
noxious heat and brush stimuli, and stimulus-dependent regions of interest (ROI) were then constructed for each subject. The time course, per
stimulus cycle, was extracted from these ROIs and compared across
subjects, stimulus modalities, and cortical regions. Both innocuous brushing and noxious heat produced significant activation within contralateral
SI and SII. The time course of brush-evoked responses revealed a
consistent single peak of activity, approximately 10 s after the onset of the
stimulus, which rapidly diminished upon stimulus withdrawal. In contrast, the response to heat pain in both SI and SII was characterized by a
double-peaked time course in which the maximum response (the 2nd
peak) was consistently observed ⬃17 s after the onset of the stimulus (8
s following termination of the stimulus). This prolonged period of activation paralleled the perception of increasing pain intensity that persists
even after stimulus offset. On the other hand, the temporal profile of the
initial minor peak in pain-related activation closely matched that of the
brush-evoked activity, suggesting a possible relationship to tactile components of the thermal stimulation procedure. These data indicate that
both SI and SII cortices are involved in the processing of nociceptive
information and are consistent with a role for these structures in the
perception of temporal aspects of pain intensity.
Address for reprint requests: G. H. Duncan, Centre de recherche en sciences
neurologiques, C.P. 6128, Succursale Centre-Ville, Université de Montréal,
Montréal, Québec H3C 3J7 Canada (E-mail: [email protected]).
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INTRODUCTION
Despite extensive research efforts, the role of the somatosensory cortex (SI and SII) in human pain processing remains
largely unclear and controversial. Historically, clinical observations of focal brain lesions and electrical stimulation of the
cortex suggested that cortical involvement in pain perception
was minimal or absent and indicated, instead, a predominant
role for thalamic and subcortical contributions to the experience of pain (Head and Holmes 1911; Penfield and Boldrey
1937). More recently, however, neurophysiological studies
have documented that SI and SII receive noxious and innocuous cutaneous input from somatosensory thalamus (Friedman
and Murray 1986; Gingold et al. 1991; Kenshalo et al. 1980;
Rausell and Jones 1991; Shi and Apkarian 1995) and contain
neurons that code spatial, temporal, and intensive aspects of
innocuous and noxious somatosensory stimuli (Chudler et al.
1990; Dong et al. 1994; Kenshalo and Isenesee 1983; Kenshalo
et al. 1988, 2000). These experimental data provide a possible
neural substrate for the processing of cutaneous information
within SI and SII; however, the scarcity of nociceptive neurons
within these areas has led to questions concerning their functional significance in pain perception.
Adding to this controversy have been the inconsistent results
observed in different human brain imaging experiments. Although activation of SII by noxious stimuli has been consistently reported in both positron-emission tomography (PET)
and functional magnetic resonance imaging (fMRI) studies
(e.g., Peyron et al. 2000), involvement of SI in the processing
of nociceptive information has been less obvious. Imaging
studies over the past decade have confirmed, at most, that SI
activation is a variable finding when human subjects are presented painful stimuli (Bushnell et al. 1999).
Even if activation of somatosensory cortices is observed
during the presentation of painful stimuli, the functional significance of this activation for the perception of pain remains in
question. Although some studies have demonstrated that cognitive manipulation of pain perception is paralleled by changes
in the activation of SI (Carrier et al. 1998; Hofbauer et al.
1998), other reports suggest that these pain-related changes in
SI activation may also have an important function in modulat-
0022-3077/02 $5.00 Copyright © 2002 The American Physiological Society
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Received 7 December 2001; accepted in final form 7 March 2002
TEMPORAL ANALYSIS OF PAIN-RELATED ACTIVATION
METHODS
Subjects
Six normal volunteers (4 males, 2 females, ages 23– 47) participated in the imaging study; however, data from two subjects were
excluded due to the presence of motion artifacts. Eight normal volunteers (6 males, 2 females, ages 21–52, including 2 from the imaging
study) participated in psychophysical experiments that incorporated
stimuli identical to those presented in the scanning sessions. All
subjects were instructed in the basic design of the experiment and
were fully aware of the duration and intensity of pain. The study was
approved by the Montreal Neurological Institute and Hospital (MNI)
Research Ethics Committee, and written informed consent was obtained from each subject prior to each study session.
tral warm stimuli served as a control for tactile and cognitive aspects
of the phasic stimulation paradigm.
MECHANICAL. Mechanical stimulation was presented to the same
site used for heat stimulation and consisted of light manual brushing
at 2 Hz, using a 2-cm wide soft artist’s paint brush moving back and
forth in a proximal-distal orientation, over a 10-cm region of the skin.
The brush stimuli were also presented during the preliminary session
during which subjects practiced rating the intensity of stimulation
using a similar five-point scale, where 0 represented no sensation and
5 represented very intense, but nonpainful sensation. During imaging
sessions, the brush stimuli were presented in separate scanning runs,
without thermal stimulation; periods of stimulation and rest (interstimulus intervals) were identical to those used in the thermal stimulation experiments.
Experimental protocol
Each subject participated in three imaging sessions conducted on
different days. Before being placed in the scanner, subjects were
instructed to attend to the stimuli, to keep their eyes closed, and to
refrain as much as possible from moving throughout the imaging
session. After being placed in a comfortable position, the head was
immobilized with padded ear-muffs, a foam headrest, and a plastic bar
across the bridge of the nose; an additional bite bar was used in two
subjects. Each imaging session consisted of five to eight functional
scanning runs and one high-resolution anatomical scan. During the
scanning, thermal and tactile stimuli were applied to the left calf on
separate runs. Imaging sessions always started with tactile runs followed by thermal runs to avoid the possible effect of sensitization
induced by the noxious stimuli. Thermal runs consisted of 10 cycles
of rest, painful heat, rest, and neutral heat stimulation, with each
condition lasting 3 complete full-brain scans, ⬃10 s (Fig. 1A). Tactile
runs contained 20 cycles of brushing and rest, each with the same
duration as that used during the thermal runs (Fig. 1B). Auditory
signals, generated by the scanner at the beginning of each full-brain
scan sequence, were used to cue the manual presentation of both
thermal and brush stimuli, thus synchronizing stimuli with data acquisition.
To assess the consistency of stimulation and to control for possible
stimulus sensitization and/or habituation, subjects were instructed,
following each run, to rate the intensity of the stimuli as perceived at
the beginning and at the end of the run, in the manner described
previously. Subjects were also asked to rate any discomfort arising
from sources other than the stimulus. All ratings were given nonverbally, using the fingers of one hand, to minimize head movement.
Separate psychophysical experiments, following the same stimulus
Stimuli
Thermal stimulation consisted of noxious (45– 46°C) and
neutral (35–36°C) stimuli applied to the inner left calf via contact
thermodes (9-cm2 aluminum blocks connected to recirculating water
baths under thermostatic control). These temperatures were chosen
prior to imaging experiments during a preliminary session in which
subjects were acclimated to the thermal stimuli and trained to rate the
perceived pain intensity using a five-point verbal scale (“0” ⫽ no
sensation of pain; “5” ⫽ the most intense pain sensation that the
subject would tolerate). For each subject, the temperature of the
noxious heat stimulus was determined as that which produced a
moderate but tolerable level of pain (a rating of 4 out of 5 on the pain
intensity scale). The temperature of the neutral stimulus was chosen as
that which produced a sensation of innocuous warmth. During imaging sessions, the thermal stimuli (noxious heat and neutral warmth)
were applied in an alternating cyclic fashion (described below) within
the same scanning run. Each of the two thermodes was maintained at
a constant preset temperature (by means of the circulating water
baths) and applied to the skin during stimulation periods and withdrawn during the interstimulus interval. The presentation of the neu-
THERMAL.
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FIG. 1. Stimulation paradigm. Each study session consisted of 5– 8 functional scanning runs. Thermal runs (A) consisted of 10 cycles of rest, painful
heat, rest, and neutral heat stimulation delivered manually via a 9-cm2 contact
thermode. Tactile runs (B) contained 20 cycles of brushing and rest. Each
stimulus condition was presented for ⬃10 s during which 3 brain scans were
acquired.
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ing tactile activity rather than specifically encoding perceptual
features of pain perception (Apkarian et al. 1992, 1994; Backonja et al. 1991; Tommerdahl et al. 1996; see also Stohler et al.
2001 for the influence of muscle pain on touch perception).
Considering the substantial overlap in activity evoked by noxious and innocuous stimuli within both SI and SII (Coghill et
al. 1994; Gelnar et al. 1999), these regions may, indeed, be
involved in both perception and modulation of both painful and
nonpainful somatosensory sensations. The present study uses
fMRI to address the hypothesized role of somatosensory cortices in pain perception by comparing the time course of
cortical activity evoked by innocuous brush and noxious heat
stimuli with the temporal features of touch perception and pain
perception that are associated with those respective stimuli.
Implicit within this hypothesis is the assumption that the distinctive, time-dependent changes in the conscious perception
of heat pain (and innocuous touch) must be mirrored by similar
changes in the dynamic response of neuronal activity observed
within those cerebral structures that participate in this process.
While negative findings might be difficult to interpret (and
could simply reflect a lack of sensitivity in the recording
technique, fMRI), a positive temporal relationship between
cerebral activity and conscious perception would lend strong
support to the hypothesized role of the somatosensory cortices
in the appreciation of pain sensation. A subset of these data has
been previously reported in abstract form (Chen et al. 1999).
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J.-I. CHEN, B. HA, M.C. BUSHNELL, B. PIKE, AND G. H. DUNCAN
paradigms used in fMRI, were also performed by two of the subjects
who participated in the imaging sessions and by six other healthy
volunteers of similar age and gender. During these psychophysical
experiments, subjects gave continuous ratings throughout the stimulus
period using a mechanical visual analogue scale (VAS), sampled at 10
Hz, which allowed instantaneous changes in the ratings according to
the changing perception of the stimulation.
Data acquisition
Data analysis
Functional data were motion corrected and low-pass filtered with a 6-mm FWHM Gaussian kernel in
order to increase the signal-to-noise ratio. Activation maps, comparing painful heat to neutral heat conditions and tactile to rest conditions, were generated using fMRISTAT-MULTISTAT software developed at the MNI. This analysis yields t-statistics based on a linear
model using random field theory, correlated errors, and Bonferroni
correction; data are also corrected for temporal correlation, artifactual
drift, and random effects. We have recently described the procedures
in detail (Worsley et al. 2002; technical support available at http://
www.math.mcgill.ca/keith/fmristat).
In brief, the design matrix for the linear model is based on a
regressor defined by the external stimulus events convolved with a
prespecified hemodynamic response function. To circumvent a biased
selection of regions of interest based on presumed differences in the
time course of activation, we purposefully avoided using a customized
regressor for each stimulus type, choosing instead to define all stimulus events simply in terms of the onset and duration of contact with
the skin. The analysis fits the linear model to a single run of fMRI data
allowing for spatially varying autocorrelated errors. Statistical output
from different runs during a session are then combined using a type of
random effects analysis. Thresholds for peak and cluster size detection
are set using random field theory (Cao 1999; Worsley et al. 1996).
The three initial scans in each run were excluded from analysis
since these scans do not achieve a steady-state of magnetization. All
images were resampled into stereotaxic space using an automated
registration method based on a multiscale, three-dimensional crosscorrelation with the average of 305 normal MR scans registered into
Talairach space (Collins et al. 1994). Functional and anatomical data
were then merged to locate regions of globally significant activation.
STATISTICAL ACTIVATION MAP.
CONSTRUCTION OF REGIONS OF INTEREST (ROIs) AND EXTRACTION
OF TIME-COURSE INFORMATION. For each subject, the central sulcus
and Sylvian fissure were identified relative to other easily recognizable cortical landmarks, i.e., the superior frontal sulcus, the precentral
sulcus, and the ascending marginal branch of the cingulate sulcus
(Kido et al. 1980; Sobel et al. 1993). Then, directed searches were
performed on identified somatosensory regions reliably activated by
the brush and noxious heat stimuli. For each subject, the session
showing the strongest activation by these two stimulus modalities was
chosen for further comparison of their temporal components. ROIs
were thus defined for the two stimulus modalities in each subject as
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RESULTS
Psychophysical results
FUNCTIONAL SCANNING ESTIMATES. During the fMRI sessions,
all subjects rated noxious heat stimuli as painful (mean rating
4.1 ⫾ 0.1 out of 5.0 on the pain scale) and innocuous tactile
stimuli (light mechanical brushing) as moderately intense but
nonpainful (mean rating 2.0 ⫾ 0.5 out of 5 on the nonpain
scale). In addition, no significant differences were found between the ratings of pain experienced at the beginning and at
the end of scanning runs (P ⫽ 0.12, paired t-test).
Figure 2 illustrates perceptual ratings
evoked by noxious heat and innocuous brush stimuli obtained
in a separate psychophysical experiment following the same
stimulus paradigm as that used for fMR scanning. During the
noxious heat condition, the temporal profile describing the
perception of pain intensity (Fig. 2A, black line) was characterized by a delayed peak response, in which the perceived pain
intensity gradually increased over time, exceeding the duration
of the stimulation period, and finally reaching its maximum
approximately 12 s after the onset of the stimulus. By contrast,
during the brush condition, the subjects’ perception of innocuous mechanical stimulation quickly reached its maximum
response and remained at this level throughout the stimulation
period (Fig. 2B, black line). Statistical comparison of these
continuous ratings confirmed that perceived intensity of the
heat pain stimulus is significantly delayed compared with that
recorded for the brush stimulus (paired t-test, 2-tailed comparison of peak responses relative to stimulus onset: heat pain
intensity ⫽ 11.86 s, brush intensity ⫽ 6.45 s, t ⫽ 6.87, P ⬍
0.001).
CONTINUOUS RATINGS.
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Imaging was performed in the McConnell Brain Imaging Center at
the Montreal Neurological Institute using a 1.5 Tesla Siemens Vision
scanner with a standard head coil. BOLD fMRI images were obtained
using a T2*-weighted gradient echo (GE) echo planar imaging (EPI)
sequence (TR ⫽ 3.36 s, TE ⫽ 51 ms, flip angle ⫽ 90°, FOV ⫽ 300
mm, matrix ⫽ 128 ⫻ 128). Images were taken in 120 whole-brain
volumes (or “frames”) per run (3.36 s/frame, ⬃7 min/run) with 10 –13
contiguous axial slices of 7-mm thickness parallel to the AC-PC line
(in-plane resolution 2.3 ⫻ 2.3 mm), covering the brain from the vertex
to the base of the thalamus. High-resolution T1-weighted anatomical
scans (3-dimensional gradient recalled echo, TR ⫽ 22 ms, TE ⫽ 10
ms, flip angle ⫽ 30°, 1-mm isotropic sampling) were acquired for all
scanning sessions.
the cluster of significant voxels surrounding the highest peak of
stimulus-related activation within the SI and SII search areas. In
general, the inclusion criterion for the ROI was conservatively defined
as the global threshold t-value, as calculated for each individual
subject (i.e., the minimum t-value, approximately 4.7, associated with
a significance of P ⫽ 0.05 for a global search of the entire brain
volume, defined as 1,000 cm3). In 3 of the 16 cases (4 subjects, 2
stimulus modalities, contralateral SI and SII), in which stimulusrelated activation did not meet the strict global search threshold, ROIs
were determined based on the appropriate threshold for a directed
search (i.e., a minimum t-value, approximately 1.7, associated with a
significance of P ⫽ 0.05 for a directed search of the target region).
Subsequently, the original raw data (i.e., unanalyzed) from functional
runs of like modality were averaged for individual subjects. The time
course of activation was then extracted from these averaged functional
runs by using the corresponding ROI as a selection mask. These data
were further averaged, within the mean experimental run, to examine
the time course of activation per stimulus cycle.
In summary, statistical contrasts, comparing painful heat to neutral
heat conditions and tactile brushing to rest conditions, were used to
identify significant stimulus-related activation in the somatosensory
cortices. Results of these statistical contrasts were then used to determine, for each subject, individual ROIs for the two conditions (noxious heat and innocuous brush). And finally, the individualized ROIs
were used as spatial masks to extract temporal information from the
original, unfiltered fMRI data sets. Results of this last stage of
analysis demonstrate the time-dependent changes in raw activity
levels, before, during, and after presentation of the test stimuli.
TEMPORAL ANALYSIS OF PAIN-RELATED ACTIVATION
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TABLE 1. Stereotaxic coordinates and peaks of SI pain- and
tactile-related activation
Stereotaxic Coordinates, mm
Subject
M-L
A-P
S-I
Peak T-Value*
A. Pain-related SI activation sites
1
2
3
4
8
24
12
20
⫺46
⫺38
⫺32
⫺24
74
68
66
62
6.0
4.5
7.7
9.5
B. Brush-related SI activation sites
14
22
22
24
⫺40
⫺36
⫺34
⫺38
74
72
74
72
9.6
7.4
5.9
6.7
M-L, medial-lateral relative to midline (positive ⫽ right); A-P, anteriorposterior relative to the anterior commissure (positive ⫽ anterior); S-I, superior-inferior relative to the commissural line (positive ⫽ superior). *T-value of
approximately 3.3 corresponds to a threshold of P ⫽ 0.05 for a conservatively
estimated search volume of 10 cm3 (all activation peaks fall within a 4.2-cm3
volume of the postcentral gyrus).
FIG. 2. Continuous visual analogue scale (VAS) intensity ratings. Mean
(⫾SE) intensity ratings recorded from 8 normal subjects during presentation of
noxious heat stimuli (A: 45– 46°C) and innocuous brushing stimuli (B: 2-cm
soft artist’s paint brush) to the lower leg. Arrows and the gray lines illustrate
onset and duration of stimulation, respectively.
Somatosensory activation related to noxious heat and
innocuous brush stimuli
Single-session analyses revealed significant pain- and brushrelated activation within both SI and SII in all four subjects
(Tables 1 and 2). Three of the four subjects demonstrated
pain-related activation within SI contralateral to the stimulated
body site, while one subject (subject 4) showed bilateral painrelated activation of SI (Fig. 3A). Gentle mechanical brushing
produced significant activity within contralateral SI in all subjects (Fig. 3B, Table 1B); however, this innocuous tactile
stimulation showed no indication of activating ipsilateral SI in
these subjects. All stimulus-related activation sites observed
within SI were limited to a 4.2-cm3 region approximating the
area associated with cutaneous input from the leg.
Within SII, pain-related activation (Fig. 4A) was restricted to
the contralateral side in two subjects (subjects 1 and 3) and was
bilateral in two subjects (subjects 2 and 4). Brush-related
activation within SII (Fig. 4B) was observed bilaterally in all
subjects.
Examination of pain- and brush-related activations within
contralateral somatosensory cortices showed some degree of
variability across the four subjects. Within SI, pain- and brushrelated activation sites were in close spatial proximity for two
of the four subjects (Table 1 and Fig. 3); however, the remaining two subjects (subjects 3 and 4) demonstrated heat-related
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activation 8 –14 mm displaced from that associated with their
respective brush-related activation sites. Although the mean
coordinates for SI sites of activation indicate a tendency for
heat-pain activity to be displaced medial and inferior to the
corresponding sites activated during brush stimulation, these
differences are not consistent across all subjects. Within SII,
pain- and brush-related activation sites were also in close
spatial proximity for two of the four subjects (Table 2 and Fig.
4); however, the remaining two subjects (subjects 1 and 2),
who showed up to 14-mm differences for sites activated by the
two stimulus modalities, were those who had demonstrated the
least spatial variability in SI activation. In general, activation
sites in SII for pain and brush stimulation showed no consistent
differences in spatial localization across all subjects.
TABLE 2. Stereotaxic coordinates and peaks of SII pain- and
tactile-related activation
Stereotaxic Coordinates, mm
Subject
M-L
A-P
S-I
Peak T-Value*
A. Pain-related SII activation sites
1
2
3
4
52
36
46
54
⫺26
⫺20
⫺24
⫺24
22
18
16
16
4.6
7.1
6.1
4.5
B. Brush-related SII activation sites
1
2
3
4
42
50
42
52
⫺26
⫺28
⫺22
⫺20
22
30
18
16
7.8
10.6
3.8
6.9
M-L, medial-lateral relative to midline (positive ⫽ right); A-P, anteriorposterior relative to the anterior commissure (positive ⫽ anterior); S-I, superior-inferior relative to the commissural line (positive ⫽ superior). *T-value of
approximately 3.3 corresponds to a threshold of P ⫽ 0.05 for a conservatively
estimated search volume of 10 cm3 (all activation peaks fall within a 2.2-cm3
volume defined as SII).
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1
2
3
4
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J.-I. CHEN, B. HA, M.C. BUSHNELL, B. PIKE, AND G. H. DUNCAN
FIG. 4. Pain- and brush-related SII activation. Activation sites within contralateral SII cortex were observed in all subjects in
response to noxious heat (A) and innocuous brush stimulation (B) applied to the left leg. Two subjects (subjects 2 and 4) showed
bilateral activation during noxious heat stimulation. All 4 subjects demonstrated bilateral activation of SII during brush stimulation.
Coordinates are expressed in millimeters according to the Talairach atlas (Collins et al. 1994).
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FIG. 3. Pain- and brush-related SI activation. Activation sites within contralateral SI cortex were observed in all subjects in response
to noxious heat (A) and innocuous brush stimulation (B) applied to the left leg. One subject (subject 4) showed bilateral activation during
noxious heat stimulation. All coordinates are expressed in millimeters according to the Talairach atlas (Collins et al. 1994).
TEMPORAL ANALYSIS OF PAIN-RELATED ACTIVATION
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FIG. 5. Temporal profiles of somatosensory activation per stimulus cycle. Each subject’s mean time course of activation for
noxious heat (top graphs) and innocuous brush (middle graphs) was extracted from contralateral SI and SII regions of interest
centered on significant stimulus-evoked activity as described in Tables 1 and 2. Data are normalized, expressed as % change in
signal intensity (⫾SE) relative to the prestimulation baseline, and averaged across all experimental runs in which the relevant
stimulus was presented. Time is expressed relative to stimulus onset (arrow); data recorded at each full-brain scan (3.4-s intervals)
are temporally registered at the midframe latency (scan onset ⫹ 1.7 s). The bottom graphs illustrate the mean time course of SI
and SII stimulus-related activity, averaged across the 4 subjects.
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J.-I. CHEN, B. HA, M.C. BUSHNELL, B. PIKE, AND G. H. DUNCAN
Temporal analysis of SI and SII responses
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Examination of the time course of somatosensory activation
associated with the noxious heat and innocuous brush stimuli
revealed a consistent and distinctive temporal signature for
each of these stimulus modalities. The temporal profiles extracted from the fMRI data (averaged over one experimental
session for each subject) are illustrated in Fig. 5. For activity
evoked by noxious heat stimulation, all subjects demonstrated
a maximum response approximately 15 s following stimulus
onset, as recorded in SI and in SII (Fig. 5, A and B, top graphs).
In contrast, brush-evoked activity for each subject approached
its maximum response within 5– 8 s following stimulus onset,
and generally remained at this plateau for approximately 10 s
before returning to baseline levels (Fig. 5, A and B, middle
graphs).
Temporal differences between the pain- and brush-related
responses are clearly illustrated in the bottom graphs of Fig. 5.
Statistical comparison, across all subjects, of the peak responses evoked by these two stimulus modalities in SI and in
SII confirmed a significant temporal delay in the response to
noxious heat compared with that evoked by the innocuous
brush stimuli (linear model, t(54) ⬎ 5.0, Ps ⬍ 0.001).
A smaller initial peak of activity observed during noxious
heat stimulation is evident in the mean response recorded in SII
approximately 5 s after application of the stimulus (Fig. 5B,
bottom graph). This initial response to painful heat, which
approximates temporally the onset of activity following application of the innocuous brush stimulus, is a variable feature in
the SI response pattern (Fig. 5A, top graph), but is consistently
observed in all subjects in SII (Fig. 5B, top graph). Statistical
analysis of activity levels observed during the three components of this SII double response (initial and final peaks,
separated by the relative decline in activity) reveals a highly
significant main effect (ANOVA, 4 subjects, 3 conditions; F ⫽
52.2, P ⬍ 0.001) and significant differences between each of
the three components (peak 1 vs. interpeak response: F ⫽ 5.4,
P ⫽ 0.002; interpeak response vs. peak 2: F ⫽ 12.2, P ⬍
0.001; peak 1 vs. peak 2: F ⫽ 34.1, P ⬍ 0.001).
tions evoked by these stimuli and the fMRI responses recorded
in the somatosensory cortices during the presentation of each
stimulus modality. Likewise, the 6 to 9-s difference between
the perceptual maxima associated with noxious heat and innocuous brush (Fig. 6A) closely approximates the differences
in the maximum fMRI responses to noxious heat pain and
Perceptual versus fMRI response
The sensory experiences evoked by these two stimulus modalities (noxious heat and innocuous brush) differed not only in
perceived intensity, but also in the temporal domain, as described above in the psychophysical results. Figure 6 illustrates, for the two stimulus modalities, the mean time course of
perceptual estimates recorded during the continuous-rating experiment and the mean temporal profile of fMRI responses
recorded during the comparable stimulation cycles. As described above, the maximum responses to noxious heat are
significantly delayed relative to the maximum responses associated with innocuous brush stimulation, for both the percepFIG. 6. Temporal comparison of SI activity and perceived intensity evoked by
experimental stimuli. The functional magnetic resonance imaging (fMRI)– defined
SI and SII activations evoked by noxious heat and innocuous brush (B and C)
occur ⬃3 to 5 s following the corresponding peaks of the perceptual responses (A).
This difference corresponds to the hemodynamic delay between neuronal activation and the de-oxyhaemoglobin– dependent fMRI response and is thus consistent
with a role for this activation in cortical processes underlying the perception of
these stimuli. fMRI activity is expressed as mean % change in signal intensity
(described in Fig. 5)].
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TEMPORAL ANALYSIS OF PAIN-RELATED ACTIVATION
innocuous brush observed in SI (Fig. 6B) and SII (Fig. 6C),
respectively. In addition, for each stimulus modality, the time
lag between perceptual maxima and the associated fMRI responses is consistent with the accepted hemodynamic delay
between neuronal activity and the related changes in deoxyhemoglobin detected by fMRI.
DISCUSSION
Spatial aspects of somatosensory cortex activation
In the present study, significant pain- and brush-related
activation loci were observed in somatosensory areas located
J Neurophysiol • VOL
within the postcentral gyrus (SI) and along the upper bank of
the Sylvian fissure (SII, parietal operculum). Within SI, stimulus-evoked activation was predominantly contralateral for
both pain and brush stimuli, in agreement with the majority of
previous studies using PET or fMRI imaging techniques (for
review, see Bushnell et al. 1999). Although all SI activation
sites fell within a 4.2-cm3 region of the postcentral gyrus
(spatial coordinates normalized across all subjects), the relative
positions of pain- and brush-related loci for individual subjects
were variable, ranging from partial overlap to approximately
14 mm of separation between sites activated by the two stimulus modalities. Although the mean coordinates for SI sites of
activation indicate a tendency for heat-pain activity to be
displaced medial and inferior to the corresponding sites activated during brush stimulation, these differences were not
consistent, nor significant, across all subjects.
Previous studies have not yielded a consistent view of the
possible relationship between sites of SI activation evoked by
noxious and innocuous stimuli. For example, Coghill et al.
(1994) observed a substantial overlap between the activation
sites associated with noxious heat and innocuous vibrotactile
stimulation; however, the relatively poor spatial resolution of
the PET technique may not resolve activation loci that differ by
less than the spatial smoothing required for averaging across
subject groups. Using magnetoencephalography (MEG) in human subjects, Ploner et al. (2000) described a single dipole
source of laser pain-related activation in area 1 compared with
two sources (in areas 3b and 1) evoked by innocuous electrical
stimulation of a peripheral nerve. This approach, however, was
restricted to an analysis of A␦ fiber–mediated responses and
could not assess the localization of the more slowly conducting
C-fiber responses likely to contribute to the longer duration of
pain perception described in the present study. A somewhat
conflicting result was described by Tommerdahl et al., using
intrinsic optical signal imaging of SI cortex; this study, in
anesthetized monkey, demonstrated a distinct response to noxious heat within area 3a, rather than area 1, and showed a
separate region of vibrotactile-evoked activation within areas
3b and 1 (Tommerdahl et al. 1996).
Compared with the predominantly contralateral activation
that we observed in SI, stimulus-related activity detected in SII
showed a stronger tendency to be bilateral, with all subjects
exhibiting bilateral activation by innocuous brush stimuli and
half of the subjects showing bilateral activation by the noxious
heat stimuli (a nonsignificant trend toward bilateral activation
by noxious heat was observed in one additional subject: subject
3). As seen in SI, the relative positions of pain- and brushrelated loci for individual subjects did not differ significantly,
but were variable, with a similar range of overlap or disparity.
Interestingly, the two subjects who demonstrated the most
disparity between innocuous- and noxious-related sites of activation within SII were those who showed the least spatial
variability in SI activation evoked by these stimuli. Previous
studies have likewise found little difference in the spatial
extent of SII activation evoked by innocuous tactile and noxious thermal stimuli (Coghill et al. 1994; Ploner et al. 2000);
however, the complex folding of the Sylvian fissure and the
limited spatial resolution of MEG (and PET) may not allow for
fine determination of spatial differences in activation sites. An
answer to this issue awaits high-resolution fMRI studies of a
larger number of subjects.
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The present study assessed the time course of stimulusrelated activity (BOLD-fMRI) observed in human somatosensory cortices in order to examine the possible relevance of this
activation to the human perception of pain. We hypothesized
that, if stimulus-evoked activation of SI and/or SII contributes
to the contemporaneous perception of pain intensity, then the
time course of this activation should encode, or at least differentiate, the distinct temporal features that characterize the
ongoing perceptions evoked by innocuous and noxious stimulation.
Other fMRI pain studies have examined temporal aspects of
pain-related cerebral activation, but results have been less than
definitive. Porro et al. (1998) demonstrated activation in a
number of cortical areas (including SI) that was correlated with
the perception of pain intensity measured over a period of
10 –15 min following subcutaneous injection of ascorbic acid.
However, the control group received only 20 s of innocuous
cutaneous touch stimulation, thus limiting any direct comparison between the two stimulus modalities. In addition, individual subjects received only one stimulus modality, permitting
only between-group comparisons (with a limited temporal resolution; two slices/21 s). More recently, Apkarian and colleagues (Apkarian et al. 1999) assessed cortical activity in the
middle third of the brain during vibratory and heat pain stimulation and found that activation in posterior areas of parietal
cortex were better related to temporal properties of pain perception compared with that observed in more anterior areas. In
their study, however, both vibration and pain tasks required the
subject to move his hand onto the stimulating surface, thus
confounding motor and sensory components in each task. In
addition, response variability in the thermal pain task necessitated averaging activation over all ROIs identified in the middle third of the brain, prohibiting any site-specific temporal
analyses or direct comparisons of vibratory and heat-pain responses in SI cortex.
The present fMRI study utilized a within-subject design to
directly compare activation observed during the presentation of
noxious heat and innocuous brush stimuli of the same duration.
Our results demonstrate that, although SI and SII are each
activated by both innocuous brush and noxious heat stimulation, the time course of these activations is characterized by
separate temporal signatures consistent with the time-dependent changes in perceived intensity reported by the subjects for
these two modes of stimulation. The following discussion
describes results of the current study in light of previous
investigations and the implications of these results to understanding the role of somatosensory cortices in the perception of
pain.
471
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J.-I. CHEN, B. HA, M.C. BUSHNELL, B. PIKE, AND G. H. DUNCAN
Time course of somatosensory activations
second-order nociceptive neurons (Campbell and Lamotte
1983; Lewis and Pochin 1937).
J Neurophysiol • VOL
Hemodynamic response versus perception
A comparison of perceptual and fMRI hemodynamic responses revealed a close temporal relationship between pain
perception and blood flow. This finding suggests that the
activation observed in somatosensory cortices during noxious
stimulation is related to the nociceptive component of the
stimuli, providing evidence for the involvement of SI (and SII)
in pain, as well as in innocuous tactile processing. Our results
also show that the fMRI-defined activations, evoked by the
innocuous tactile and noxious heat stimulation, followed the
peak perceptual responses by approximately 3–5 s, a time lapse
consistent with the hemodynamic delay that follows neuronal
activation in the cortex (Bandettini et al. 1995).
Functional significance of somatosensory cortices in pain
perception
The possible roles of SI and SII in pain perception have been
addressed by studies in a number of different disciplines. As
discussed above, neurophysiological studies in animals indicate that nociceptive pathways lead to the somatosensory cortices and that lesions to some of these cortical areas may alter
the animal’s ability to use noxious stimuli in discriminative
tasks (see especially Kenshalo and Willis 1991). Although
much has been learned from the rigorous experimental approach that can be used in animal studies, the relationship
between these identified nociceptive responses and the human
perception of pain remains indirect.
Early reports of human brain lesions indicated little or no
involvement of the cortex in pain perception; however, more
recent studies, incorporating detailed psychophysical assessments, have suggested a role for SI and SII in certain aspects
of pain perception. Greenspan and Winfield (1991) described a
patient with deficits in pain and tactile perception associated
with a tumor located near the most posterior portion of the
insula and parietal operculum. Following surgical removal of
the tumor, the patient’s perceptual capacities returned to normal, suggesting to the authors that SII and the posterior insular
region are essential for the normal pain and tactile perception
(Greenspan and Winfield, 1991). In a more recent report,
Ploner et al. (1999) described an unusual example of pain
deficits in a patient with an ischemic lesion of the right postcentral gyrus and parietal operculum, comprising the hand area
of SI and SII. Noxious laser stimuli, presented to the patient’s
involved left hand, evoked a “clearly unpleasant” feeling that
the patient wanted to avoid, but he could not localize the
stimulus to the hand, and denied any qualitative characteristics
like warm, hot, cold, touch, or even “pain-like.” The authors
argue that these results indicate an essential role of SI and SII
for the sensory-discriminative aspects of pain perception, and
suggest that pain affect does not require the integrity of SI and
SII (Ploner et al. 1999). While these studies lend support to the
notion of a critical role for the somatosensory cortices in pain
perception, their implications are limited by problems inherent
in human lesion data, i.e., difficulty in determining the precise
delineation of the cortical lesions, possible damage to fibers of
passage altering the function of distant regions, and the prob-
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The most prominent finding revealed by the present fMRI
time-course analysis was the extended period of activation
associated with noxious heat stimuli, compared with that of
innocuous brush stimuli (Fig. 5). These distinct temporal patterns of somatosensory cortex activity are consistent with the
temporal patterns of perceived intensity observed in the psychophysical experiment, which showed that the perception of
pain intensity increases gradually over time, reaching its maximum following stimulus offset, whereas the perception of
touch (brushing) reaches its maximum soon after the onset of
stimulation and terminates immediately following the offset of
stimulation (Fig. 2). These data suggest that somatosensory
cortex activation observed during noxious heat stimulation is
indeed related to the processing of painful heat, and not simply
to tactile input occasioned by contact of the thermode with the
skin. Such observations are similar to results shown in primate
studies using intrinsic optical imaging (Tommerdahl et al.
1996), where nociceptive neurons in area 3a of SI cortex were
found to exhibit slow temporal summation and poststimulus
response persistence after repeated cutaneous heat stimulation,
paralleling the perceptual consequences of such stimulation in
humans (Price et al. 1977).
Another temporal characteristic of somatosensory cortex
activity evoked by noxious heat stimulation was the biphasic
nature of the fMRI response. Although not robust within SI,
this double-peak response was substantial and significant in SII
across all subjects. This biphasic response is consistent with
findings reported in a recent fMRI study using a similar type of
thermal stimulus. Becerra et al. (1999) observed both early and
late responses associated with noxious heat stimulation (46°C)
during the initial two presentations of a repeated-stimulation
paradigm; however, only the late response was seen (in several
regions of the cortex, including SI and SII) during subsequent
stimulation periods. Since only a single early peak had been
observed during a neutral heat (40°C) condition, the authors
concluded that the late portion of the double response was
uniquely associated with the sensation of pain (Becerra et al.
1999).
In the present study, the early peak of activity observed in
the pain condition approximates that observed with innocuous
brushing and is thus consistent with a response to mechanical
consequences of applying the thermode. In addition, the absence of a perceptual distinction in the psychophysical results,
between “first pain” and “second pain,” would argue against
involvement of a nociceptive A␦ component in the early portion of the byphasic cortical response. However, the 9-s stimulation paradigm used in the present study was not optimized
for separating perceptual components of first- and second-pain
(see Price et al. 1977), and possible contributions of thermal
information to the early fMRI response observed in somatosensory areas during noxious heat stimulation cannot be ruled
out. Although the 3-s resolution of the present fMRI paradigm
limits identification of specific afferent contributions to cortical
activation, the first peak in the SII response may well be related
to myelinated input (conveying either touch or A␦-dependent
heat information), while the second peak may reflect a contribution by the slower C-fiber afferents, which are responsible
for temporal summation of noxious information observed in
TEMPORAL ANALYSIS OF PAIN-RELATED ACTIVATION
J Neurophysiol • VOL
ing noxious stimulation, may be related to a modulation of
touch sensation that is proportional to the perception of pain;
however, a potential role for SI nociceptive activity in the
modulation of innocuous cutaneous sensations does not rule
out or preclude a role for this structure in sensory aspects of
pain perception.
In conclusion, different lines of evidence have pointed toward a role for the somatosensory cortices in pain perception,
including a growing number of studies that have utilized functional imaging. However, inconsistent results among some of
these studies had led to controversy and suggestions that activation observed during noxious stimulation might only reflect
spatial cues or attentional factors related to innocuous aspects
of stimulation. Our data now show, in normal intact human
subjects, that activation in both SI and SII encodes a temporal
signature specific to the perceptual characteristics of both noxious thermal and innocuous tactile stimulation, thus indicating
a role for these cortical areas in processing sensory information
inherent to the perception of pain intensity. Future studies will
continue to investigate whether the processing of this “painrelated” information by the somatosensory cortices is sufficient
or even necessary for the overall, multidimensional phenomenon of pain perception.
The authors express appreciation to V. Petre of the Brain Imaging Center at
Montreal Neurological Institute, to C. Liao and Dr. K. Worsley for assistance
in data analyses, to L. TenBokum for technical support, and to A. Petersen for
editorial suggestions regarding this manuscript.
The study was supported by grants from the Medical Research Council of
Canada.
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