 |
 Previous Article | Next Article 
The Journal of Neuroscience, October 1, 2000, 20(19):7438-7445
Expectation of Pain Enhances Responses to Nonpainful
Somatosensory Stimulation in the Anterior Cingulate Cortex and Parietal
Operculum/Posterior Insula: an Event-Related Functional Magnetic
Resonance Imaging Study
Nobukatsu
Sawamoto1,
Manabu
Honda1, 3,
Tomohisa
Okada2, 3,
Takashi
Hanakawa1,
Masutaro
Kanda1,
Hidenao
Fukuyama1,
Junji
Konishi2, and
Hiroshi
Shibasaki1
Departments of 1 Brain Pathophysiology, Human Brain
Research Center and 2 Nuclear Medicine, Kyoto University
Graduate School of Medicine, Kyoto, 606-8507 Japan, and
3 Laboratory of Cerebral Integration, National Institute
for Physiological Sciences, Okazaki, 444-8585 Japan
 |
ABSTRACT |
Although behavioral studies suggest that pain distress may alter
the perception of somatic stimulation, neural correlates underlying
such alteration remain to be clarified. The present study was aimed to
test the hypothesis that expectation of pain might amplify brain
responses to somatosensory stimulation in the anterior cingulate cortex
(ACC) and the region including parietal operculum and posterior insula
(PO/PI), both of which may play roles in regulating pain-dependent
behavior. We compared brain responses with and subjective evaluation of
physically identical nonpainful warm stimuli between two
psychologically different contexts: one linked with pain expectation by
presenting the nonpainful stimuli randomly intermixed with painful
stimuli and the other without. By applying the event-related functional
magnetic resonance imaging technique, brain responses to the
stimuli were assessed with respect to signal changes and activated
volume, setting regions of interest on activated clusters in ACC and
bilateral PO/PI defined by painful stimuli. As a result, the uncertain
expectation of painful stimulus enhanced transient brain responses to
nonpainful stimulus in ACC and PO/PI. The enhanced responses were
revealed as a higher intensity of signal change in ACC and larger
volume of activated voxels in PO/PI. Behavioral measurements
demonstrated that expectation of painful stimulus amplified perceived
unpleasantness of innocuous stimulus. From these findings, it is
suggested that ACC and PO/PI are involved in modulation of affective
aspect of sensory perception by the uncertain expectation of painful stimulus.
Key words:
uncertain expectation of pain; innocuous stimulus; anterior cingulate cortex; parietal operculum; posterior insula; event-related functional magnetic resonance imaging
| |
INTRODUCTION |
Because pain is characterized as an
unpleasant and subjective experience (Merskey, 1986 ), its perception
can be influenced by the psychophysical state of individuals (Cornwall
and Donderi, 1988; Miyazaki et al., 1994; Rainville et al., 1997).
Conversely, pain and associated distress can affect the biological
state of individuals.
The effect of pain on an individual's state has been assessed from
various viewpoints. Pain, and even just anxiety related to pain, were
shown to cause diverse changes in the endocrine, immune, and other
organ systems (Cousins, 1993; Herman and Cullinan, 1997). Functions of
the CNS can also be modulated by personal experience of pain.
Unpredictable shooting pain in neuralgia may induce severe distress
even during the period without actual pain (Henderson, 1967). Severe
pain can cause behavioral modulation, including increased sensitivity
to external stimuli (Cousins, 1993). Pain distress often leads the
sufferer to complain about nonspecific physical symptoms (McCracken et
al., 1998). As the mechanism underlying the behavioral modulation by
pain distress, the amplification of somatic sensation has been proposed
(Barsky and Borus, 1999). However, neural correlates of the
pain-induced CNS modulation remain to be clarified.
The anterior cingulate cortex (ACC) and the regions including the
parietal operculum and posterior insula (PO/PI) have been proposed as
important cortical loci for pain perception based on human neuroimaging
studies (Talbot et al., 1991; Casey et al., 1994, 1996; Coghill et al.,
1994; Derbyshire et al., 1997; Xu et al., 1997; Becerra et al., 1999)
and electrophysiological studies (Lenz et al., 1998a,b). The PO/PI is
assumed to include the second somatosensory area (SII) (Penfield and
Rasmussen, 1950; Penfield and Jasper, 1954). Single cell recordings
have shown involvement of ACC and PO/PI not only in pain processing
(Robinson and Burton, 1980; Sikes and Vogt, 1992) but also in mediating
the diverse responses that can accompany pain (Dong et al., 1994;
Koyama et al., 1998). Lesion of ACC or PO/PI can modify the emotional
and behavioral reaction to pain, without impairing the ability to localize a painful stimulus (Foltz and White, 1968; Berthier et al.,
1988). These findings suggest a role of ACC and PO/PI in regulating the
pain-dependent behavior.
This study was aimed to test the hypothesis that psychological distress
related to pain might modulate neural responses to nonpainful
somatosensory stimulation. On the basis of previous studies as
discussed above, we focused on the responses in ACC and PO/PI among the
multiple brain regions associated with pain processing. By applying the
event-related functional magnetic resonance imaging (fMRI) technique,
brain responses to and subjective evaluation of physically identical
warm stimuli were compared between two psychologically different
contexts. In one session, nonpainful warm stimuli were randomly
intermixed with painful stimuli simulating unpredictable shooting pain
like neuralgia. In the other session, only nonpainful stimuli were
delivered. By comparing the responses with the nonpainful warm stimuli
linked with and without expectation of painful stimulus, we explored the neural substrates involved in modulation of affective aspect of
sensory perception by expectation of painful stimulus.
| |
MATERIALS AND METHODS |
Subjects
Ten healthy male volunteers (aged 19-24 years, mean of 21.7 years) participated in this study. All were right-handed, and none had
a previous history of any neurological or psychiatric disorders.
Subjects had refrained from smoking and from consumption of alcohol or
caffeine for a period of 24 hr before the study. The protocol was
approved by the Committee of Medical Ethics, Graduate School of
Medicine and Faculty of Medicine, Kyoto University, and each subject
gave written informed consent before the study.
Stimulus and rating of subjective sensation
We used a custom-made CO2 laser stimulator
that delivered thermal stimuli (Nippon Infrared Industries Co. Ltd.,
Kawasaki, Japan). The subjective sensation elicited by the stimulator
was variable from warm to pain by adjusting the output power. The stimulus of 60 msec duration was applied to the dorsum of the right
hand. The diameter of the irradiation beam was adjusted to ~6 mm. To
avoid habituation and sensitization, the stimulus spot was moved for
every stimulus within the dorsum of the right hand. Detailed
information on the CO2 laser stimuli was
described previously (Miyazaki et al., 1994; Kanda et al., 1996a,b,
2000; Xu et al., 1997).
Before the imaging sessions, the output power corresponding to the pain
threshold was determined individually by exposing the subject to
stimuli of various intensity arranged in three increasing and
decreasing series. The pain threshold was defined as the lowest
stimulus intensity required for the subject to report a sensation as
"just barely painful." Then, the subjects were asked to rate
stimulus intensity and unpleasantness separately between 0 and 100 (Talbot et al., 1991; Casey et al., 1994, 1996; Derbyshire et al.,
1997; Rainville et al., 1997; Svensson et al., 1997). In this scale, 0 indicated "no sensation" or "not at all unpleasant," and 100 indicated "the most intense pain imaginable" or "the most
unpleasant feeling imaginable" for the intensity or unpleasantness,
respectively. The intensity score of 70 was anchored to pain threshold.
To explain the difference between intensity and unpleasantness to the
subjects, standard instructions used by Price et al. (1989) were given
as follows. "We are interested in two aspects of sensory experience.
One is the intensity, that is, how strong the stimulus is felt. The
other is unpleasantness, or how disturbing the stimulus is for you. The
distinction between these two aspects of sensory experience might be
made clearer if you think of listening to a sound, such as a radio. As
the volume of the sound increases, I can ask you how loud it sounds, or
how unpleasant it is to you. The intensity of the stimulus is like
loudness, and the unpleasantness of the stimulus depends not only on
intensity but also on other factors that may affect you. These are
scales for measuring each of these two aspects of sensory experience.
Although some sensory experiences may be equally intense and
unpleasant, we would like you to judge these two aspects of your
sensation independently." All subjects were trained to be able to
rate sensation properly before the imaging sessions.
Experimental conditions
Each subject was examined by CO2 laser
stimulation with two different intensities that were set to either
50-60% [nonpainful warm stimulus (NPS)] or 160-200% [painful
stimulus (PS)] of the output power for each individual's pain
threshold. These two radiant heat pulses generated by the
CO2 laser stimulator were delivered in two
psychologically different contexts that corresponded to two imaging
sessions; one session was "uncertain," and the other was
"certain." In the "uncertain context" session, 20 NPS and PS
were presented in a randomized order, thus 40 stimuli in total. Subjects were told that two different stimuli, PS or NPS, would be
given in a randomized order, but they were uncertain about which
stimulus would be presented next. In the "certain context" session,
only 20 NPS were delivered, and subjects were told beforehand that the
PS would not be given in that particular session. Thus, the stimuli
were categorized into three different conditions: PS in uncertain
context (PS), NPS in uncertain context (NPS-u), and NPS in certain
context (NPS-c).
PS may induce some changes on the stimulated part of skin, which can
modulate the perception of NPS at that site (Duclaux and Kenshalo,
1980). To avoid such effects, the dorsal surface of the hand was
divided into three areas, and each area was stimulated only in one
particular condition. The location for the three conditions was
randomized among the subjects. The order of uncertain and certain
sessions was also random. Note that NPS-u and NPS-c were physically identical.
At 35.1 sec after the beginning of each imaging trial that lasted 61.1 sec, a single stimulus was delivered. Subjects were told that the
single stimulus would be presented within a fixed interval from the
start of each trial. Thus, the subjects could predict the timing of the
stimulus presentation in all the conditions but not the stimulus type
in the uncertain condition. They were asked to remain silent and
immobile during each trial and were required to report the ratings of
each stimulus intensity and unpleasantness soon after each trial had
ended. There was ~30 sec interval between successive trials to allow
subjects to report the scores and to prepare for the next trial,
resulting in the long interstimulus interval of ~90 sec. The long
prestimulus and poststimulus phases were used to obtain stable
baseline, as well as to accurately evaluate the transient signal
increase evoked by the stimulus. The long interstimulus interval was
also useful to minimize the habituation effects and effectively induce
anticipatory response.
Image acquisition
MRI scans were conducted using a whole-body 1.5 tesla scanner
(Horizon; General Electric Medical Systems, Milwaukee, WI). Functional
images were obtained with a T2* sensitive, single-shot, echo-planar
pulse sequence with the following parameters: repetition time (TR) = 1300 msec; echo time (TE) = 43 msec; flip angle (FA) = 60°; imaging matrix = 64 × 64; field of view = 22 × 22 cm; slice thickness = 5 mm; and slice gap = 1 mm. Eleven slices covering the ACC and PO/PI were acquired in an axial
orientation. One imaging trial consisted of 47 functional scans (i.e.,
61.1 sec). Subjects lay supine on an MRI scanner with their head
immobilized by a forehead strap. Before the functional scans, a
structural MRI of the whole brain was acquired using three-dimensional
fast spoiled gradient-recalled at steady-state images (TR = 10.8 msec, TE = 1.8 msec, inversion time = 300 msec, FA = 15°, imaging matrix = 256 × 256, field of view = 22 × 22 cm, slice thickness = 1.5 mm, no slice gap, and 124 slices). Partial structural T1 weighted images corresponding to
the area covered by echo-planar functional images were also obtained
(TR = 600 msec, TE = 17 msec, FA = 30°, and imaging
matrix = 256 × 256).
Data analysis
Image processing and statistical analysis. Image
processing and statistical analysis were performed using SPM96 software
(Wellcome Department of Cognitive Neurology, London, UK) with in-house
modifications. Calculations and matrix manipulations were performed
using Matlab (Mathworks, Natick, MA) on a Sun Sparc Ultra 2 workstation
(Sun Microsystems, Mountain View, CA). The initial 12 scans (i.e., 15.6 sec) in each trial were excluded from the analysis because of the
nonequilibrium state of magnetization, yielding 35 scans (i.e., 45.5 sec) to be analyzed in each trial. Of those 35 scans, the initial 15 scans corresponded to the prestimulus phase, the 16th scan to the
stimulus phase, and the last 19 scans to the poststimulus phase. The
effect of head motion was corrected by realigning all images to the
first image using a least sum of squares method with three-dimensional
sinc interpolation (Friston et al., 1994). The activity in each
voxel was linearly scaled with respect to the global activity. Data
were smoothed in a spatial domain with a Gaussian filter (full width at
half maximum = 5.16 mm) to improve the signal-to-noise ratio.
The three different stimulus conditions (i.e., PS, NPS-u, and NPS-c)
were analyzed separately using a general linear model (Friston et al.,
1995a). Statistical analysis of fMRI time series data were conducted on
an individual subject basis as described previously (Toma et al.,
1999). To model the prestimulus, stimulus, and poststimulus phases,
three boxcar functions were prepared. For each function, the value
"1" was given for the phase of interest and "0" for the
remaining phases. In the boxcar function for the stimulus phase, one
scan time-locked to the stimulus was assigned to 1. Each boxcar
function was convolved with a Gaussian-shaped hemodynamic response
function (delay, 5 sec; dispersion, 8 sec) (Friston et al., 1995b).
Systematic difference across conditions was modeled as a confounding
effect. The general linear model calculated a weighting coefficient for
each regressor. We calculated t deviates at each voxel by
using a linear contrast of [ 1, 2, 1] for [prestimulus, stimulus,
poststimulus] phases to focus on a transient signal change associated
with the stimulus. After transforming the t value into Z
scores with the unit normal distribution, the two-step analysis was conducted.
First step: analysis of anatomical location of activation.
SPM {Z} maps consisting of the voxels with Z > 3.09 were
created. Then, the correction for multiple comparisons was conducted by referring to the probabilistic behavior of Gaussian random fields. The
threshold adopted was p < 0.05. For the sake of
convenience, the term "activation" in this study refers to the
transient signal increases disclosed by the above analyses. In all
subjects, PS produced activation clusters in the medial frontal lobe,
consistent with ACC, and in the bilateral regions adjacent to the
lateral sulcus, corresponding to PO/PI (Table
1). Similar activation was observed in
nine subjects in NPS-u and seven subjects in NPS-c. To compare the
location of activated areas among the subjects, SPM {Z} was
transformed into the standardized Talairach space (Talairach and
Tournoux, 1988) by applying the parameters obtained from the anatomical
normalization of the whole-brain structural images after coregistering
them with the mean functional images. Talairach coordinates of the
activated voxels with maximum Z score were statistically compared among
the three conditions using multivariate ANOVA (MANOVA). The
analysis was conducted using the data from six subjects who showed
significant activation in both ACC and bilateral PO/PI under all
conditions. Note that the anatomically normalized data were used only
for this purpose.
View this table:
[in this window]
[in a new window]
|
Table 1.
Mean coordinates of the statistical peak of activation in
ACC and left and right PO/PI under PS, NPS-u, and NPS-c conditions
(mean ± SD)
|
|
Second step: ROI setting and comparison of NPS-u and NPS-c.
To compare brain responses in the NPS-u and NPS-c conditions, the
activation clusters identified in ACC and bilateral PO/PI under the PS
condition in the first-step analysis were used as regions of interest
(ROIs) in each individual subject (Fig.
1). Although pain and nonpainful warm
sensations are mediated by different populations of sensory receptors
in the skin and by different peripheral neuronal mechanisms, these two
could evoke responses in the similar areas of the CNS, at least at the
macroscopic level detected by the neuroimaging techniques (Becerra et
al., 1999). In addition, because CO2 laser
stimulus might induce thermal change on the skin during and after the
radiation pulse, it appears reasonable to assume that spatial and
temporal distribution of the change induced by the strong laser
stimulus would include the skin volume in which the maximum temperature
is below pain threshold but still enough to activate warmth receptors
(Haimi-Cohen et al., 1983). Cerebral evoked potentials to painful laser
stimulation seemed to include activation of warmth receptors (Towell et
al., 1996). Taking these findings into account, the ROI determined by
the PS were equally applied for the NPS-u and NPS-c. Note that the ROIs
were determined independent of the activation by the NPS-u and NPS-c.
View larger version (40K):
[in this window]
[in a new window]
|
Figure 1.
Schematic representation of the ROI setting in a
representative individual subject. First, activated clusters under the
painful stimulus (PS) condition were identified, and
those clusters on the ACC and bilateral PO/PI served as ROIs, which
were then applied to the images of nonpainful warm stimulus in
uncertain condition (NPS-u) and nonpainful warm stimulus
in certain condition (NPS-c) in the same subject.
Black areas indicate the actual activation in each
condition, and gray areas represent ROIs identical to
the activation in the PS condition. Note that ROIs are the same brain
areas for NPS-u and NPS-c and are determined independently of these two
conditions in each subject.
|
|
Brain activities in NPS-u and NPS-c were assessed with respect to both
signal change and activated volume. For comparing signal change, first,
the time course data of each voxel within ROI were averaged across 20 trials. Then, the time course data of each individual subject were
averaged over voxels within ROI. We performed two kinds of signal
change analyses regarding selection of voxels; in one analysis, all
voxels within ROI were selected, whereas, in the other analysis, only
the voxels above the predetermined threshold (i.e., Z > 3.09) in
each condition were chosen. Note that the correction for multiple
comparisons was not adopted for this purpose, partly because previous
studies suggested the roles of ACC and PO/PI in regulating
pain-dependent behavior (Foltz and White, 1968; Berthier et al., 1988;
Dong et al., 1994; Koyama et al., 1998). In addition, a broader
criterion is appropriate to avoid false negative in selecting the data
for further analysis (i.e., comparison of NPS-u and NPS-c). As shown in
Figure 2, the averaged time course data
revealed a gradual signal increase, even before the stimulus
presentation. Thus, the regression line was calculated using the
data of the prestimulus phase. The intercept of the regression line
at time 0 (i.e., stimulus onset) was defined as the baseline signal
intensity from which the signal change relating to the experimental
condition was divided into two components: prestimulus effect and
stimulus effect. The prestimulus effect was evaluated as the signal
intensity at the time of the first analyzed scan within each condition
estimated from the regression line, and the stimulus effect was
assessed as the peak signal intensity after the stimulus onset. Both
effects were represented by the percent signal change with respect to
the baseline signal intensity (percent difference). Note that the
prestimulus effects were negative values because the baseline was
defined as the intensity at the time of the stimulus. The differences
in prestimulus effects and stimulus effects between NPS-u and NPS-c
conditions were statistically examined using paired t tests.
Signal change analysis of activated voxels in the right PO/PI was
conducted using data from nine subjects because of the lack of
activation at the site in one subject. In the analyses of other ROIs,
data from all subjects (i.e., 10 subjects) were used.
View larger version (24K):
[in this window]
[in a new window]
|
Figure 2.
Schematic representation of the method used for
evaluating the time course data of individual subjects. A regression
line was calculated using the data during prestimulus phase under each
condition for each subject. The intercept of the regression line at the
time of the stimulus presentation served as the baseline signal
intensity from which the signal change relating to the stimulus was
divided into stimulus effect and prestimulus effect. The stimulus
effect was assessed as the peak signal intensity, and the prestimulus
effect was assessed as the signal intensity at the time of the first
analyzed scan estimated from the regression line. Both effects were
represented by the percent signal change with respect to the baseline
(percent difference).
|
|
For comparing activated volume, the number of voxels above the
threshold (i.e., Z > 3.09) in each condition was computed within each ROI and divided by the ROI voxel number. This can be interpreted as the ratio of activated volume in each condition with respect to
those in the PS condition. A paired t test was used to
compare activated volumes between NPS-u and NPS-c conditions.
| |
RESULTS |
Stimulus intensity and subjective rating scores
All subjects identified PS as a clearly painful stimulus and NPS
as a stimulus below the pain threshold. PS was described as a distinct
pricking sensation followed by a short-lasting burning aftersensation.
NPS caused warm or very faint pricking sensation. The output power for
the pain threshold, PS, and NPS was 5.2 ± 0.9 (mean ± SD),
9.2 ± 1.3, and 2.9 ± 0.6 W, respectively.
In the subjective evaluation of intensity, PS was rated most intense,
whereas NPS-u and NPS-c did not show significant differences from each
other (Wilcoxon signed rank test; p = 0.31) (Fig.
3). Subjective intensity scores were
82 ± 7 (mean ± SD) for PS, 33 ± 7 for NPS-u, and
32 ± 8 for NPS-c conditions.
View larger version (21K):
[in this window]
[in a new window]
|
Figure 3.
Subjective evaluation of nonpainful warm stimulus
in uncertain condition (NPS-u) and nonpainful warm stimulus in certain
condition (NPS-c). Scores of individual subjects and mean scores across
all subjects are shown. Diagonal line indicates equal
scores for NPS-u and NPS-c conditions. Subjects rated intensity and
unpleasantness of each stimulus separately. The unpleasantness score of
NPS-u was significantly higher than that of NPS-c, whereas the
intensity scores did not show a significant difference between the two
conditions. Statistical analysis was conducted with Wilcoxon signed
rank tests.
|
|
Subjective unpleasantness was dependent on the conditions. The highest
score was obtained for PS. More importantly, NPS-u was reported to be
more unpleasant than NPS-c (Wilcoxon signed rank test;
p < 0.01) (Fig. 3). Unpleasantness scores were 69 ± 15 for PS, 24 ± 12 for NPS-u, and 17 ± 12 for NPS-c. The
observation of positive unpleasantness scores in response to completely
nonpainful stimulus seems reasonable, because the unpleasantness was
not necessarily associated with pain depending on the instruction (Price et al., 1989; Svensson et al., 1997).
The unpleasantness scores of all the subjects were actually below 70 in
NPS-u and NPS-c conditions, although they could have varied as much as
100 points. The grand averaged unpleasantness scores were smaller than
the intensity scores. Therefore, it is reasonable to conclude that the
present finding is not attributable to an artifact introduced by
the different scaling range of the scores.
Activated areas in each condition
PS evoked activation in the medial frontal lobe (i.e., ACC) and
the regions adjacent to the lateral sulcus (i.e., PO/PI) in all
subjects. Figure 4A indicates brain
responses of a representative subject superimposed on his own
anatomical MRI. The activated clusters in the PS condition served as
the ROI for ACC and bilateral PO/PI for each individual subject.
Volumes of activated clusters were 5.67 ± 3.95 ml (mean ± SD) in ACC, 7.76 ± 4.23 ml in the left PO/PI, and 10.27 ± 6.51 ml in the right PO/PI.
View larger version (41K):
[in this window]
[in a new window]
|
Figure 4.
Activated areas for PS, NPS-u, and NPS-c
conditions (A) and averaged time course data of
activated cluster in ACC for each condition (B),
obtained from a single subject. A, Activated areas,
which showed significant transient signal increase time-locked to the
stimulus, are superimposed on the subject's own structural MRI.
Activation is seen in ACC, bilateral PO/PI, anterior insula, and other
areas. The activated areas look similar in PS, NPS-u, and NPS-c
conditions. The right side of the brain is shown on the left
side of the image. Brighter color represents a
higher statistical significance. B, Averaged signals
across 20 trials at the activated cluster in ACC are shown for PS,
NPS-u, and NPS-c conditions. The vertical dotted
line indicates the time of the stimulus presentation. Transient
signal increase after the stimulus (stimulus effect) and gradual signal
increase before the stimulus (prestimulus effect) are observed. The
stimulus effect is highest in PS and higher in NPS-u compared with
NPS-c condition.
|
|
NPS-u and NPS-c produced brain activation in regions similar to those
by PS, as shown in Figure 4A. In both conditions, the activity in ACC and bilateral PO/PI was observed in almost all subjects
(nine subjects in NPS-u and seven subjects in NPS-c) (Table 1). MANOVA
indicated no significant difference in the location of the peak
activation among PS, NPS-u, and NPS-c in ACC (Wilks' lambda = 0.78; p = 0.75), left PO/PI (Wilks' lambda = 0.69; p = 0.52), or right PO/PI (Wilks' lambda = 0.72; p = 0.60). The Talairach coordinates of
activated areas by PS and NPS were consistent with the previous studies
(Talbot et al., 1991; Coghill et al., 1994; Xu et al., 1997; Becerra et
al., 1999). Activation by PS, NPS-u, and NPS-c was also observed in
other multiple brain areas including, the anterior insula, thalamus,
and prefrontal and premotor cortices.
Averaged time course data of the activated cluster on ACC in a
representative subject are shown in Figure 4B. As
expected, the stimulus effect of PS was higher than NPS conditions.
More importantly, the stimulus effect of NPS-u was greater than that of
NPS-c. Time course data of individual subjects revealed that the
latencies of peak signal response to each stimulus were shorter than
7.8 sec after the stimulus presentation.
Comparison of activation between NPS-u and NPS-c
NPS-u and NPS-c were compared using the voxels within the ROIs.
Figure 5 represents the time course data
of all voxels within each ROI averaged across all subjects, comparing
PS, NPS-u, and NPS-c conditions. A gradual signal increase before the
stimulus (prestimulus effect) and a transient signal change after the
stimulus (stimulus effect) were observed in all ROIs under all
conditions.
View larger version (20K):
[in this window]
[in a new window]
|
Figure 5.
Averaged time course data of all voxels within
each ROI. Signal changes in ACC and left and right PO/PI under each of
the PS, NPS-u, and NPS-c conditions were averaged across all subjects.
The vertical dotted line indicates the time of the
stimulus presentation. Transient signal increase after the stimulus
(stimulus effect) and gradual signal increase before the stimulus
(prestimulus effect) are observed in all ROIs under all conditions. In
all ROIs, the stimulus effects are highest in PS and higher in NPS-u
compared with NPS-c condition.
|
|
Results of signal change analyses are presented in Figure
6, A and B, and
Table 2. The prestimulus effects showed
no significant differences between NPS-u and NPS-c in any of the three
ROIs, in either all voxels or selected voxels comparisons (i.e., Z > 3.09). In ACC and bilateral PO/PI, the stimulus effects of all voxels in NPS-u were significantly higher than those in NPS-c. Regarding the selected voxels within ROI, the stimulus effect was
higher in NPS-u than in NPS-c only in ACC, whereas the effects of the
two conditions were not different in bilateral PO/PI. Results of
activated volume analyses (i.e., Z > 3.09) are shown in Figure 6C and Table 2. In bilateral PO/PI, the activated volumes in the NPS-u condition were significantly greater than those in NPS-c. In
contrast, in ACC, the volume showed a larger tendency in NPS-u than
NPS-c, but the difference did not reach statistical significance. In
summary, higher intensity of signal change after the stimulus in ACC
and larger volume of activated volume in PO/PI were
consistently shown, which suggests enhanced brain responses
in NPS-u compared with NPS-c. The relationship between the increase of
signal intensity and activation volume might be interpreted by the
models of Baker et al. (1999) in which fMRI signal comprises a Gaussian
distribution.
View larger version (30K):
[in this window]
[in a new window]
|
Figure 6.
Comparison of NPS-u with NPS-c conditions. Each
dot represents individual subject data. Diagonal
line indicates equal responses in NPS-u and NPS-c conditions.
The two conditions are compared with respect to signal change and
activated volume setting ROI on ACC and bilateral PO/PI. For signal
change comparison, the time course data of each subject are averaged
over voxels within ROI: in one analysis averaged over all voxels
(A) and in the other analysis averaged over
selected voxels in each condition (i.e., Z > 3.09)
(B). Transient signal changes after the stimulus
(stimulus effect; see Fig. 2) are shown. For comparing activated
volume, the number of activated voxels above the threshold (i.e.,
Z > 3.09) in each condition was computed within each ROI and
divided by the ROI voxel number (C). As for the
signal change of all voxels (A), stimulus effect
averaged over all voxels within ROI revealed significantly larger
change in NPS-u than NPS-c condition in ACC and left and right PO/PI.
As for the signal change of selected voxels (B),
stimulus effect averaged over the selected voxels within ROI revealed
significantly larger change in NPS-u than in NPS-c condition in ACC. In
contrast, the response in bilateral PO/PI was not different between the
two conditions. In regards to the activated volume
(C), the proportions of the activated volume in
NPS-u were significantly larger than NPS-c in bilateral PO/PI. In
contrast, the difference in ACC did not reach statistical significance.
In summary, higher intensity of signal change after the stimulus in ACC
and larger volume of activated voxels in bilateral PO/PI are
consistently observed, which suggests enhanced brain responses in NPS-u
compared with NPS-c. Statistical analyses were conducted using paired
t tests.
|
|
| |
DISCUSSION |
The present fMRI study showed that, in normal human subjects, the
uncertain expectation of painful stimulation enhanced the transient
brain responses to nonpainful warm stimulation in the ACC and PO/PI. In
the behavioral measurements, the expectation of painful stimulation
amplified perceived unpleasantness of even innocuous stimulation,
whereas it did not influence the perceived intensity. From these
findings, ACC and PO/PI are considered to be involved in modulation of
affective aspect of sensory perception by the uncertain expectation of
painful stimulus.
In pain studies using persistent or trains of painful stimuli, it has
been hypothesized that pain distress might enhance the stimulus-evoked
neural responses (Coghill et al., 1994). This hypothesis was tested in
the present study by comparing the responses to nonpainful warm stimuli
linked with and without pain expectation. To link the warm stimulus
with pain expectation, we randomly presented nonpainful stimuli
intermixed with painful stimuli. This kind of paradigm design can be
effectively analyzed by event-related procedures (Rosen et al., 1998).
The procedure also enabled us to assess how subjects felt the stimulus
on a trial-by-trial basis. In addition, within-trial responses were
chronologically separated into two components: the response before the
stimulus (prestimulus effect) and the response after the stimulus
(stimulus effect). Comparison of fMRI responses to nonpainful warm
stimuli between the two psychologically different contexts showed that
only the stimulus effect, but not the prestimulus effect, was
significantly enhanced by the uncertain expectation of painful
stimulus. Thus, the enhancement may not be caused just by the induced
psychological state but by the interaction of the psychological state
with the sensory processes.
The response to somatic stimuli in the CNS can be exaggerated in
patients suffering from pain (Dahl et al., 1992; Flor et al., 1997).
However, this enhancement may be associated with complex features of
pain, which could be affected by tissue injury, psychological aspects,
and other factors. Among these effects, the peripheral responses
related to pain were unlikely to cause the enhancement in the present
study. Pain may induce some changes on the skin, which can modulate
somatic sensation (Duclaux and Kenshalo, 1980). To avoid such effects,
three different areas were prepared for painful stimulus, nonpainful
stimulus with pain expectation, and nonpainful stimulus without pain
expectation, and the locations of these areas were randomized among the
subjects. Therefore, psychological distress related to pain could have
been the main cause of the enhanced cortical activity.
Anticipation of pain with uncertainty would play a substantial role in
psychological modulation. In a previous behavioral study, uncertain
pain was shown to increase unpleasantness and to result in less pain
tolerance compared with certain pain (Staub et al., 1971). The present
findings may support the behavioral study, although we investigated the
response to nonpainful stimulus instead of painful stimulus. In
contrast, uncertainty about sensory stimuli, regardless of their
properties, modulates brain responses and evokes potentials of positive
deflection at 300 msec after the stimulus (i.e., P300) that are
recorded from widespread brain areas (Sutton et al., 1965; McCarthy et
al., 1997). This nonspecific uncertainty effect should also be
considered as a component of the modulatory factors.
Selective attention to the stimulus modulates the activity of early
sensory processing areas (Frith and Dolan, 1997; Mima et al., 1998).
Although the present findings did not contradict those previous
studies, it is unlikely that the psychological modulation documented in
the present study would be exactly the same as the effect of selective
attention itself, because subjects had to attend to and evaluate the
stimulus regardless of the presence or absence of pain anticipation.
The sensations of pain and cold are mediated by parallel ascending
sensory channels that interact with each other, and these interactions
can influence brain responses to thermal stimulus (Craig and Bushnell,
1994; Craig et al., 1996). Although cold and warm sensations are
mediated by separate populations of receptors and by different neural
mechanisms (Darian-Smith, 1984), the interaction between the systems
that mediate pain and warmth might also have affected brain responses
to warm stimuli adopted in the present study (Duncan et al., 1998).
Role of ACC in modulation of affective aspect of sensory perception
by pain expectation
ACC is an important area for processing sensory information
related to pain (Devinsky et al., 1995). The fact that neural responses
to pain in ACC have almost no localizing information suggests its role
in affective coding (Sikes and Vogt, 1992). Neuronal recordings and
neuroimaging studies suggest that ACC is involved in mediating the
affective components associated not only with painful stimulation but
also with attention and anticipation of upcoming painful stimulation
(Koyama et al., 1998; Hsieh et al., 1999; Hutchison et al., 1999;
Ploghaus et al., 1999). These neural properties are consistent with the
present findings that expectation of pain modulates ACC responses. The
present findings may also agree with clinical observations of pain in
patients treated by limbic surgery. Those patients, who are too
precipitously reactive to their environment and showed augmented pain
symptoms, appeared to be relieved by cingulotomy and no longer suffer
from those symptoms after cingulotomy, although they recognize chronic pain as it had been (Foltz and White, 1968). This observation suggests
an important role of ACC in regulating pain-dependent behavior.
On the other hand, in the present study, the ACC response to innocuous
stimulus also increased in association with the enhancement of the
unpleasantness. The parallel relationship between pain unpleasantness
and the ACC responses was elucidated in a positron emission tomography
study (Rainville et al., 1997). These findings of Rainville et al.
suggested the significant involvement of ACC in the affective component
of pain. The present study may extend their view and implicate the
involvement of ACC in processing negative affect associated with
somatic stimulation independent of pain sensation. Rainville et al.
(1997) demonstrated a significantly increased signal change and
activation volume in ACC in relation to increased unpleasantness.
Although the fMRI signal of ACC significantly increased in the present
study, the increase in activated volume in ACC did not reach
statistical significance. The difference might be attributable to the
low spatial resolution of positron emission tomography or intersubject
spatial averaging of images for group analysis, which was not used in
the present study (Sadato et al., 1997)
Overlapping activation and constant anticipatory responses of ACC
provoked by noxious and innocuous stimulation even without pain
anticipation may reflect nonspecific function, such as general arousal
effect (Vogt and Sikes, 2000). The activation could be associated with a broad role of ACC in modulating behavioral reactions to external stimuli (Devinsky et al., 1995).
Role of PO/PI in modulation of affective aspect of sensory
perception by pain expectation
Neuronal recordings from monkey PO/PI have identified nociceptive
neurons in the SII, neighboring area 7b, and posterior insula (Robinson
and Burton, 1980). The response characteristics of nociceptive neurons
in SII and area 7b suggest an involvement of those neurons in learning
and attention to events that produce pain (Dong et al., 1994; Treede et
al., 1999). Anatomical evidence suggests that the route from the
parietal operculum to posterior insula may act as a principal neural
relay for conveying somatosensory information into the limbic system
and thus provide a means for interrelating the painful events with
relevant affective states (Mesulam and Mufson, 1982). Moreover, the
lesion in PO/PI may produce a clinical syndrome called asymbolia for
pain in which patients recognize pain but lack appropriate affective
responses to painful stimulation (Berthier et al., 1988). The evidence
may concur with the present findings implicating functional modulation of PO/PI by expectation of pain. A subdivision of the somatosensory areas around the operculum was proposed (Krubitzer et al., 1986; Mima
et al., 1997). The greater volume of activation caused by expectation
of pain might be associated with multiple sensory representation within
the operculum.
In summary, the neuroimaging method in the present study had advantages
for assessing the functional neuroanatomy of pain distress. The
event-related experimental design allowed us to use random-order
presentation of different stimuli, to assess subjective evaluation of
the stimuli on a trial-by-trial basis, and to analyze transient brain
responses. The present findings suggest that the ACC and PO/PI are
involved in modulation of affective aspect of sensory perception by the
uncertain expectation of painful stimulus. Interpreting these findings
in the light of psychological and biological meaning of pain, the
modulation might be considered as an adaptive response to pain as a
warning signal. However, when pain is excessively severe or prolonged,
the response may lead to deleterious effects. Understanding this aspect
of pain from a viewpoint of symptomatic treatment may contribute to the control of the complex nature of pain experiences.
| |
FOOTNOTES |
Received March 6, 2000; revised June 27, 2000; accepted July 17, 2000.
This work was supported in part by Grants-in-Aid for Scientific
Research on Priority areas (C) 12210012 from the Japan Ministry of
Education, Sciences, Sports, and Culture, Research for the Future
Program JSPS-RFTF97L00201 from Japan Society for the Promotion Science,
and a General Research grant for Aging and Health "Analysis of aged
brain function with neuroimaging" from the Japan Ministry of Health
and Welfare. We thank S. Nishizawa for technical support.
Correspondence should be addressed to Dr. Hiroshi Shibasaki, Department
of Brain Pathophysiology, Human Brain Research Center, Kyoto University
Graduate School of Medicine, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto,
606-8507 Japan. E-mail: shib{at}kuhp.kyoto-u.ac.jp.
| |
REFERENCES |
-
Baker JT,
Donoghue JP,
Sanes JN
(1999)
Gaze direction modulates finger movement activation patterns in human cerebral cortex.
J Neurosci
19:10044-10052[Abstract/Free Full Text].
-
Barsky AJ,
Borus JF
(1999)
Functional somatic syndromes.
Ann Intern Med
130:910-921[Abstract/Free Full Text].
-
Becerra LR,
Breiter HC,
Stojanovic M,
Fishman S,
Edwards A,
Comite AR,
Gonzalez RG,
Borsook D
(1999)
Human brain activation under controlled thermal stimulation and habituation to noxious heat: an fMRI study.
Magn Reson Med
41:1044-1057[Web of Science][Medline].
-
Berthier M,
Starkstein S,
Leiguarda R
(1988)
Asymbolia for pain: a sensory-limbic disconnection syndrome.
Ann Neurol
24:41-49[Web of Science][Medline].
-
Casey KL,
Minoshima S,
Berger KL,
Koeppe RA,
Morrow TJ,
Frey KA
(1994)
Positron emission tomographic analysis of cerebral structures activated specifically by repetitive noxious heat stimuli.
J Neurophysiol
71:802-807[Abstract/Free Full Text].
-
Casey KL,
Minoshima S,
Morrow TJ,
Koeppe RA
(1996)
Comparison of human cerebral activation pattern during cutaneous warmth, heat pain, and deep cold pain.
J Neurophysiol
76:571-581[Abstract/Free Full Text].
-
Coghill RC,
Talbot JD,
Evans AC,
Meyer E,
Gjedde A,
Bushnell MC,
Duncan GH
(1994)
Distributed processing of pain and vibration by the human brain.
J Neurosci
14:4095-4108[Abstract].
-
Cornwall A,
Donderi DC
(1988)
The effect of experimentally induced anxiety on the experience of pressure pain.
Pain
35:105-113[Web of Science][Medline].
-
Cousins M
(1993)
Acute and postoperative pain.
In: Textbook of pain (Wall PD,
Melzack R,
eds), pp 357-385. Edinburgh: Churchill Livingstone.
-
Craig AD,
Bushnell MC
(1994)
The thermal grill illusion: unmasking the burn of cold pain.
Science
265:252-255[Abstract/Free Full Text].
-
Craig AD,
Reiman EM,
Evans A,
Bushnell MC
(1996)
Functional imaging of an illusion of pain.
Nature
384:258-260[Medline].
-
Dahl JB,
Erichsen CJ,
Fuglsang-Frederiksen A,
Kehlet H
(1992)
Pain sensation and nociceptive reflex excitability in surgical patients and human volunteers.
Br J Anaesth
69:117-121[Abstract/Free Full Text].
-
Darian-Smith I
(1984)
Thermal sensibility.
In: Handbook of physiology, Sec 1, The nervous system, Vol III, Sensory processes, Pt 2 (Darian-Smith I,
ed), pp 879-913. Bethesda, MD: American Physiological Society.
-
Derbyshire SW,
Derbyshire SW,
Jones AK,
Gyulai F,
Clark S,
Townsend D,
Firestone LL
(1997)
Pain processing during three levels of noxious stimulation produces differential patterns of central activity.
Pain
73:431-445[Web of Science][Medline].
-
Devinsky O,
Morrell MJ,
Vogt BA
(1995)
Contributions of anterior cingulate cortex to behaviour.
Brain
118:279-306[Abstract/Free Full Text].
-
Dong WK,
Chudler EH,
Sugiyama K,
Roberts VJ,
Hayashi T
(1994)
Somatosensory, multisensory, and task-related neurons in cortical area 7b (PF) of unanesthetized monkeys.
J Neurophysiol
72:542-564[Abstract/Free Full Text].
-
Duclaux R,
Kenshalo Sr DR
(1980)
Response characteristics of cutaneous warm receptors in the monkey.
J Neurophysiol
43:1-15[Free Full Text].
-
Duncan GH,
Kupers RC,
Marchand S,
Villemure JG,
Gybels JM,
Bushnell MC
(1998)
Stimulation of human thalamus for pain relief: possible modulatory circuits revealed by positron emission tomography.
J Neurophysiol
80:3326-3330[Abstract/Free Full Text].
-
Flor H,
Braun C,
Elbert T,
Birbaumer N
(1997)
Extensive reorganization of primary somatosensory cortex in chronic back pain patients.
Neurosci Lett
224:5-8[Web of Science][Medline].
-
Foltz EL,
White LE
(1968)
The role of rostral cingulumotomy in "pain" relief.
Int J Neurol
6:353-373[Medline].
-
Friston KJ,
Jezzard P,
Turner R
(1994)
Analysis of functional MRI time-series.
Hum Brain Mapp
1:153-171.
-
Friston KJ,
Holmes AP,
Worsley KJ,
Poline JB,
Frith C,
Frackowiak RS
(1995a)
Statistical parametric maps in functional imaging: a general linear approach.
Hum Brain Mapp
2:189-210.
-
Friston KJ,
Holmes AP,
Poline JB,
Grasby PJ,
Williams SC,
Frackowiak RS,
Turner R
(1995b)
Analysis of fMRI time-series revisited.
NeuroImage
2:45-53[Web of Science][Medline].
-
Frith C,
Dolan RJ
(1997)
Brain mechanisms associated with top-down processes in perception.
Philos Trans R Soc Lond B Biol Sci
352:1221-1230[Abstract/Free Full Text].
-
Haimi-Cohen R,
Cohen A,
Carmon A
(1983)
A model for the temperature distribution in skin noxiously stimulated by a brief pulse of CO2 laser radiation.
J Neurosci Methods
8:127-137[Web of Science][Medline].
-
Henderson WR
(1967)
Trigeminal neuralgia: the pain and its treatment.
Br Med J
1:7-15.
-
Herman JP,
Cullinan WE
(1997)
Neurocircuitry of stress: central control of the hypothalamo-pituitary-adrenocortical axis.
Trends Neurosci
20:78-84[Web of Science][Medline].
-
Hsieh JC,
Stone-Elander S,
Ingvar M
(1999)
Anticipatory coping of pain expressed in the human anterior cingulate cortex: a positron emission tomography study.
Neurosci Lett
262:61-64[Web of Science][Medline].
-
Hutchison WD,
Davis KD,
Lozano AM,
Tasker RR,
Dostrovsky JO
(1999)
Pain-related neurons in the human cingulate cortex.
Nat Neurosci
2:403-405[Web of Science][Medline].
-
Kanda M,
Fujiwara N,
Xu X,
Shindo K,
Nagamine T,
Ikeda A,
Shibasaki H
(1996a)
Pain-related and cognitive components of somatosensory evoked potentials following CO2 laser stimulation in man.
Electroencephalogr Clin Neurophysiol
100:105-114[Medline].
-
Kanda M,
Mima T,
Xu X,
Fujiwara N,
Shindo K,
Nagamine T,
Ikeda A,
Shibasaki H
(1996b)
Pain-related somatosensory evoked potentials can quantitatively evaluate hypalgesia in Wallenberg's syndrome.
Acta Neurol Scand
94:131-136[Web of Science][Medline].
-
Kanda M,
Nagamine T,
Ikeda A,
Ohara S,
Kunieda T,
Fujiwara N,
Yazawa S,
Sawamoto N,
Matumoto R,
Taki W,
Shibasaki H
(2000)
Primary somatosensory cortex is actively involved in pain processing in human.
Brain Res
853:282-289[Web of Science][Medline].
-
Koyama T,
Tanaka YZ,
Mikami A
(1998)
Nociceptive neurons in the macaque anterior cingulate activate during anticipation of pain.
NeuroReport
9:2663-2667[Web of Science][Medline].
-
Krubitzer LA,
Sesma MA,
Kaas JH
(1986)
Microelectrode maps, myeloarchitecture, and cortical connections of three somatotopically organized representations of the body surface in the parietal cortex of squirrels.
J Comp Neurol
250:403-430[Web of Science][Medline].
-
Lenz FA,
Rios M,
Zirh A,
Chau D,
Krauss G,
Lesser RP
(1998a)
Painful stimuli evoke potentials recorded over the human anterior cingulate gyrus.
J Neurophysiol
79:2231-2234[Abstract/Free Full Text].
-
Lenz FA,
Rios M,
Chau D,
Krauss GL,
Zirh TA,
Lesser RP
(1998b)
Painful stimuli evoke potentials recorded from the parasylvian cortex in humans.
J Neurophysiol
80:2077-2088[Abstract/Free Full Text].
-
McCarthy G,
Luby M,
Gore J,
Goldman-Rakic P
(1997)
Infrequent events transiently activate human prefrontal and parietal cortex as measured by functional MRI.
J Neurophysiol
77:1630-1634[Abstract/Free Full Text].
-
McCracken LM,
Faber SD,
Janeck AS
(1998)
Pain-related anxiety predicts non-specific physical complaints in persons with chronic pain.
Behav Res Ther
36:621-630[Web of Science][Medline].
-
Merskey H
(1986)
Classification of chronic pain. Descriptions of chronic pain syndromes and definitions of pain terms. Prepared by the International Association for the Study of Pain, Subcommittee on Taxonomy.
Pain [Suppl]
3:S1-S226[Medline].
-
Mesulam MM,
Mufson EJ
(1982)
Insula of the old world monkey. III. Efferent cortical output and comments on function.
J Comp Neurol
212:38-52[Web of Science][Medline].
-
Mima T,
Ikeda A,
Nagamine T,
Yazawa S,
Kunieda T,
Mikuni N,
Taki W,
Kimura J,
Shibasaki H
(1997)
Human second somatosensory area: subdural and magnetoencephalographic recording of somatosensory evoked responses.
J Neurol Neurosurg Psychiatry
63:501-505[Abstract/Free Full Text].
-
Mima T,
Nagamine T,
Nakamura K,
Shibasaki H
(1998)
Attention modulates both primary and second somatosensory cortical activities in humans: a magnetoencephalographic study.
J Neurophysiol
80:2215-2221[Abstract/Free Full Text].
-
Miyazaki M,
Shibasaki H,
Kanda M,
Xu X,
Shindo K,
Honda M,
Ikeda A,
Nagamine T,
Kaji R,
Kimura J
(1994)
Generator mechanism of pain-related evoked potentials following CO2 laser stimulation of the hand: scalp topography and effect of predictive warning signal.
J Clin Neurophysiol
11:242-254[Web of Science][Medline].
-
Penfield W,
Jasper H
(1954)
Functional localization in the cerebral cortex.
In: Epilepsy and the functional anatomy of the human brain, pp 41-155 Boston: Little Brown.
-
Penfield W,
Rasmussen T
(1950)
Secondary sensory and motor representation.
In: The cerebral cortex of man, pp 109-134 New York: Macmillan.
-
Ploghaus A,
Tracey I,
Gati JS,
Clare S,
Menon RS,
Matthews PM,
Rawlins JN
(1999)
Dissociating pain from its anticipation in the human brain.
Science
284:1979-1981[Abstract/Free Full Text].
-
Price DD,
McHaffie JG,
Larson MA
(1989)
Spatial summation of heat-induced pain: influence of stimulus area and spatial separation of stimuli on perceived pain sensation intensity and unpleasantness.
J Neurophysiol
62:1270-1279[Abstract/Free Full Text].
-
Rainville P,
Duncan GH,
Price DD,
Carrier B,
Bushnell MC
(1997)
Pain affect encoded in human anterior cingulate but not somatosensory cortex.
Science
277:968-971[Abstract/Free Full Text].
-
Robinson CJ,
Burton H
(1980)
Somatic submodality distribution within the second somatosensory (SII), 7b, retroinsular, postauditory, and granular insular cortical areas of M. fascicularis.
J Comp Neurol
192:93-108[Web of Science][Medline].
-
Rosen BR,
Buckner RL,
Dale AM
(1998)
Event-related functional MRI: past, present, and future.
Proc Natl Acad Sci USA
95:773-780[Abstract/Free Full Text].
-
Sadato N,
Ibanez V,
Campbell G,
Deiber MP,
Le Bihan D,
Hallett M
(1997)
Frequency-dependent changes of regional cerebral blood flow during finger movements: functional MRI compared to PET.
J Cereb Blood Flow Metab
17:670-679[Web of Science][Medline].
-
Sikes RW,
Vogt BA
(1992)
Nociceptive neurons in area 24 of rabbit cingulate cortex.
J Neurophysiol
68:1720-1732[Abstract/Free Full Text].
-
Staub E,
Tursky B,
Schwartz GE
(1971)
Self-control and predictability: their effects on reactions to aversive stimulation.
J Pers Soc Psychol
18:157-162[Web of Science][Medline].
-
Sutton S,
Braren M,
Zubin J,
John ER
(1965)
Evoked-potential correlates of stimulus uncertainty.
Science
150:1187-1188[Abstract/Free Full Text].
-
Svensson P,
Beydoun A,
Morrow TJ,
Casey KL
(1997)
Human intramuscular and cutaneous pain: psychophysical comparisons.
Exp Brain Res
114:390-392[Web of Science][Medline].
-
Talairach J,
Tournoux P
(1988)
In: Co-planar stereotaxic atlas of the human brain. New York: Thieme.
-
Talbot JD,
Marrett S,
Evans AC,
Meyer E,
Bushnell MC,
Duncan GH
(1991)
Multiple representations of pain in human cerebral cortex.
Science
251:1355-1358[Abstract/Free Full Text].
-
Toma K,
Honda M,
Hanakawa T,
Okada T,
Fukuyama H,
Ikeda A,
Nishizawa S,
Konishi J,
Shibasaki H
(1999)
Activities of the primary and supplementary motor areas increase in preparation and execution of voluntary muscle relaxation: an event- related fMRI study.
J Neurosci
19:3527-3534[Abstract/Free Full Text].
-
Towell AD,
Purves AM,
Boyd SG
(1996)
CO2 laser activation of nociceptive and non-nociceptive thermal afferents from hairy and glabrous skin.
Pain
66:79-86[Web of Science][Medline].
-
Treede RD,
Kenshalo DR,
Gracely RH,
Jones AK
(1999)
The cortical representation of pain.
Pain
79:105-111[Web of Science][Medline].
-
Vogt BA,
Sikes RW
(2000)
The medial pain system, cingulate cortex, and parallel processing of nociceptive information.
Prog Brain Res
122:223-235[Web of Science][Medline].
-
Xu X,
Fukuyama H,
Yazawa S,
Mima T,
Hanakawa T,
Magata Y,
Kanda M,
Fujiwara N,
Shindo K,
Nagamine T,
Shibasaki H
(1997)
Functional localization of pain perception in the human brain studied by PET.
NeuroReport
8:555-559[Web of Science][Medline].
Copyright © 2000 Society for Neuroscience 0270-6474/00/20197438-08$05.00/0
This article has been cited by other articles:
|
|
|
|
 
C. L. Masten, N. I. Eisenberger, L. A. Borofsky, J. H. Pfeifer, K. McNealy, J. C. Mazziotta, and M. Dapretto
Neural correlates of social exclusion during adolescence: understanding the distress of peer rejection
Soc Cogn Affect Neurosci,
June 1, 2009;
4(2):
143 - 157.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Kong, R. L. Gollub, G. Polich, I. Kirsch, P. LaViolette, M. Vangel, B. Rosen, and T. J. Kaptchuk
A Functional Magnetic Resonance Imaging Study on the Neural Mechanisms of Hyperalgesic Nocebo Effect
J. Neurosci.,
December 3, 2008;
28(49):
13354 - 13362.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. N. Ochsner, J. Zaki, J. Hanelin, D. H. Ludlow, K. Knierim, T. Ramachandran, G. H. Glover, and S. C. Mackey
Your pain or mine? Common and distinct neural systems supporting the perception of pain in self and other
Soc Cogn Affect Neurosci,
June 1, 2008;
3(2):
144 - 160.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. Benuzzi, F. Lui, D. Duzzi, P. F. Nichelli, and C. A. Porro
Does It Look Painful or Disgusting? Ask Your Parietal and Cingulate Cortex
J. Neurosci.,
January 23, 2008;
28(4):
923 - 931.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. M. Berman, B. D. Naliboff, B. Suyenobu, J. S. Labus, J. Stains, G. Ohning, L. Kilpatrick, J. A. Bueller, K. Ruby, J. Jarcho, et al.
Reduced Brainstem Inhibition during Anticipated Pelvic Visceral Pain Correlates with Enhanced Brain Response to the Visceral Stimulus in Women with Irritable Bowel Syndrome
J. Neurosci.,
January 9, 2008;
28(2):
349 - 359.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. Benoliel, J. Epstein, E. Eliav, R. Jurevic, and S. Elad
Orofacial Pain in Cancer: Part I--Mechanisms
Journal of Dental Research,
June 1, 2007;
86(6):
491 - 505.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. A. Seminowicz and K. D. Davis
Interactions of Pain Intensity and Cognitive Load: The Brain Stays on Task
Cereb Cortex,
June 1, 2007;
17(6):
1412 - 1422.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. Benedetti, M. Amanzio, S. Vighetti, and G. Asteggiano
The Biochemical and Neuroendocrine Bases of the Hyperalgesic Nocebo Effect.
J. Neurosci.,
November 15, 2006;
26(46):
12014 - 12022.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. Qiu, Y. Noguchi, M. Honda, H. Nakata, Y. Tamura, S. Tanaka, N. Sadato, X. Wang, K. Inui, and R. Kakigi
Brain Processing of the Signals Ascending Through Unmyelinated C Fibers in Humans: An Event-Related Functional Magnetic Resonance Imaging Study
Cereb Cortex,
September 1, 2006;
16(9):
1289 - 1295.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. R. Keltner, A. Furst, C. Fan, R. Redfern, B. Inglis, and H. L. Fields
Isolating the modulatory effect of expectation on pain transmission: a functional magnetic resonance imaging study.
J. Neurosci.,
April 19, 2006;
26(16):
4437 - 4443.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. L. Malin and J. L. McGaugh
Differential involvement of the hippocampus, anterior cingulate cortex, and basolateral amygdala in memory for context and footshock
PNAS,
February 7, 2006;
103(6):
1959 - 1963.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. B. Eickhoff, K. Amunts, H. Mohlberg, and K. Zilles
The Human Parietal Operculum. II. Stereotaxic Maps and Correlation with Functional Imaging Results
Cereb Cortex,
February 1, 2006;
16(2):
268 - 279.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Kurata, K. R. Thulborn, and L. L. Firestone
The Cross-Modal Interaction Between Pain-Related and Saccade-Related Cerebral Activation: A Preliminary Study by Event-Related Functional Magnetic Resonance Imaging
Anesth. Analg.,
August 1, 2005;
101(2):
449 - 456.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. P. Paulus, S. F. Tapert, and M. A. Schuckit
Neural Activation Patterns of Methamphetamine-Dependent Subjects During Decision Making Predict Relapse
Arch Gen Psychiatry,
July 1, 2005;
62(7):
761 - 768.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Schreckenberger, T. Siessmeier, A. Viertmann, C. Landvogt, H. -G. Buchholz, R. Rolke, R. -D. Treede, P. Bartenstein, and F. Birklein
The unpleasantness of tonic pain is encoded by the insular cortex
Neurology,
April 12, 2005;
64(7):
1175 - 1183.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. A. Moulton, M. L. Keaser, R. P. Gullapalli, and J. D. Greenspan
Regional Intensive and Temporal Patterns of Functional MRI Activation Distinguishing Noxious and Innocuous Contact Heat
J Neurophysiol,
April 1, 2005;
93(4):
2183 - 2193.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C H Wilder-Smith, D Schindler, K Lovblad, S M Redmond, and A Nirkko
Brain functional magnetic resonance imaging of rectal pain and activation of endogenous inhibitory mechanisms in irritable bowel syndrome patient subgroups and healthy controls
Gut,
November 1, 2004;
53(11):
1595 - 1601.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. H. Gracely, M. E. Geisser, T. Giesecke, M. A. B. Grant, F. Petzke, D. A. Williams, and D. J. Clauw
Pain catastrophizing and neural responses to pain among persons with fibromyalgia
Brain,
April 1, 2004;
127(4):
835 - 843.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Maihofner, H. O. Handwerker, B. Neundorfer, and F. Birklein
Patterns of cortical reorganization in complex regional pain syndrome
Neurology,
December 23, 2003;
61(12):
1707 - 1715.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. J. Bair, R. L. Robinson, W. Katon, and K. Kroenke
Depression and Pain Comorbidity: A Literature Review
Arch Intern Med,
November 10, 2003;
163(20):
2433 - 2445.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. I. Eisenberger, M. D. Lieberman, and K. D. Williams
Does Rejection Hurt? An fMRI Study of Social Exclusion
Science,
October 10, 2003;
302(5643):
290 - 292.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. A. Porro
Functional Imaging and Pain: Behavior, Perception, and Modulation
Neuroscientist,
October 1, 2003;
9(5):
354 - 369.
[Abstract]
[PDF]
|
|
|
|
|
|
|
J. Lorenz, S. Minoshima, and K. L. Casey
Keeping pain out of mind: the role of the dorsolateral prefrontal cortex in pain modulation
Brain,
May 1, 2003;
126(5):
1079 - 1091.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Frot and F. Mauguiere
Dual representation of pain in the operculo-insular cortex in humans
Brain,
February 1, 2003;
126(2):
438 - 450.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G.D. Iannetti, A. Truini, A. Romaniello, F. Galeotti, C. Rizzo, M. Manfredi, and G. Cruccu
Evidence of a Specific Spinal Pathway for the Sense of Warmth in Humans
J Neurophysiol,
January 1, 2003;
89(1):
562 - 570.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. M. Smith, J. H. Freeman Jr, D. Nicholson, and M. Gabriel
Limbic Thalamic Lesions, Appetitively Motivated Discrimination Learning, and Training-Induced Neuronal Activity in Rabbits
J. Neurosci.,
September 15, 2002;
22(18):
8212 - 8221.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Bornhovd, M. Quante, V. Glauche, B. Bromm, C. Weiller, and C. Buchel
Painful stimuli evoke different stimulus-response functions in the amygdala, prefrontal, insula and somatosensory cortex: a single-trial fMRI study
Brain,
June 1, 2002;
125(6):
1326 - 1336.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. A. Porro, P. Baraldi, G. Pagnoni, M. Serafini, P. Facchin, M. Maieron, and P. Nichelli
Does Anticipation of Pain Affect Cortical Nociceptive Systems?
J. Neurosci.,
April 15, 2002;
22(8):
3206 - 3214.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Ostrowsky, M. Magnin, P. Ryvlin, J. Isnard, M. Guenot, and F. Mauguiere
Representation of Pain and Somatic Sensation in the Human Insula: a Study of Responses to Direct Electrical Cortical Stimulation
Cereb Cortex,
April 1, 2002;
12(4):
376 - 385.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Buchel, K. Bornhovd, M. Quante, V. Glauche, B. Bromm, and C. Weiller
Dissociable Neural Responses Related to Pain Intensity, Stimulus Intensity, and Stimulus Awareness within the Anterior Cingulate Cortex: A Parametric Single-Trial Laser Functional Magnetic Resonance Imaging Study
J. Neurosci.,
February 1, 2002;
22(3):
970 - 976.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Ploghaus, C. Narain, C. F. Beckmann, S. Clare, S. Bantick, R. Wise, P. M. Matthews, J. N. P. Rawlins, and I. Tracey
Exacerbation of Pain by Anxiety Is Associated with Activity in a Hippocampal Network
J. Neurosci.,
December 15, 2001;
21(24):
9896 - 9903.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
TOP
ABSTRACT
INTRODUCTION
Anxiety
