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The Journal of Neuroscience, April 1, 2002, 22(7):2748-2752
Imaging Attentional Modulation of Pain in the Periaqueductal Gray
in Humans
Irene
Tracey1,
Alexander
Ploghaus1,
Joseph
S.
Gati2,
Stuart
Clare1,
Steve
Smith1,
Ravi S.
Menon2, and
Paul M.
Matthews1
1 Centre for Functional Magnetic Resonance Imaging of
the Brain, Department of Clinical Neurology, University of Oxford,
Oxford OX3 9DU, United Kingdom, and 2 Laboratory for
Functional Magnetic Resonance Research, John P. Robarts Research
Institute, London, Ontario N6A 5K8, Canada
 |
ABSTRACT |
Pain is an unpleasant sensory and emotional experience usually
triggered by stimulation of peripheral nerves and often associated with
actual or potential tissue damage. It is well known that pain
perception for patients and normal subjects can be modulated by
psychological factors, such as attention, stress, and arousal. Our
understanding of how this modulation occurs at a neuroanatomical level
is poor. Here we neuroanatomically defined a key area in the network of
brain regions active in response to pain that is modulated by attention
to the painful stimulus. High-resolution functional magnetic resonance
imaging was used to define brain activation to painful heat stimulation
applied to the hand of nine normal subjects within the periaqueductal
gray region. Subjects were asked to either focus on or distract
themselves from the painful stimuli, which were cued using colored
lights. During the distraction condition, subjects rated the pain
intensity as significantly lower compared with when they attended to
the stimulus. Activation in the periaqueductal gray was significantly
increased during the distraction condition, and the total increase in
activation was predictive of changes in perceived intensity. This
provides direct evidence supporting the notion that the periaqueductal gray is a site for higher cortical control of pain modulation in humans.
Key words:
pain; fMRI; PAG; attention; modulation; brainstem
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INTRODUCTION |
Control of pain in both acute and
chronic conditions is a major medical problem. Although much pain is a
consequence of stimulation of peripheral nociceptors, the CNS
plays a major role in the processing of all noxious sensations (Wall
and Melzack, 1999 ). Activation of a specific network of brain regions
is associated with the perception of pain, and candidate brain regions
processing sensory-discriminative and emotional-affective components of
pain perception are being defined (Albe-Fessard et al., 1985; Rainville
et al., 1997; Ploghaus et al., 1999, 2000; Ploner et al., 1999;
Petrovic et al., 2000; Tracey et al., 2000).
Under certain conditions, however, it is possible to block the
perception of pain despite noxious stimulation. A lack of reported pain
by soldiers during battle, despite severe injuries, and experimental observations of changes in responses to painful stimuli with changes in
psychological factors, such as arousal, attention, stress, and mood
state, demonstrate that pain perception varies with context (Melzack et
al., 1982; Gaughan and Gracely, 1989). That the relationship between
reported pain and stimulus intensity is highly variable led Head and
Holmes (1911) to postulate that the psychological state of the subject
can modulate the perception of pain. One critical element of the
psychological state that can powerfully modulate subjective responses
to noxious stimuli is attention. Decreased attention to noxious stimuli
raises the pain threshold (Miron et al., 1989), whereas perceived pain
intensity is increased when a subject's attention is directed to
painful stimuli (Bushnell et al., 1985). Indeed, distraction is used as
an adjunct in pain management (Good et al., 1999).
There is limited information, however, concerning the central
mechanisms by which attentional changes modulate pain perception (Fields and Basbaum, 1999; Petrovic et al., 2000). One potential site
for mediation of modulatory impulses from higher centers was suggested
with the description of stimulation-produced analgesia (SPA) (Reynolds,
1969; Mayer et al., 1971; Mayer and Price, 1976). SPA is produced by
electrical stimulation of discrete brain sites and produces inhibition
of reflex responses to noxious stimulation, such as tail flick in rats.
An SPA effect is also generated in humans by direct
stimulation of the periaquectual gray (PAG) (Boivie and Meyerson,
1982; Baskin et al., 1986). The PAG may therefore be a critical center
for control of peripheral nociceptive perception by descending activity
from higher cortical regions.
Here we describe functional magnetic resonance imaging (fMRI) studies
that test directly whether the PAG is part of a descending pathway for
attentional control of pain. Specifically, we tested whether activation
changes in the PAG accompany changes in attention to a painful
stimulus. To optimize the sensitivity for detection of PAG activation
by fMRI, we collected functional imaging data using a high-field (4 tesla) imaging system to enhance the relative blood oxygen
level-dependent (BOLD) contrast contribution from the parenchyma
rather than any draining veins (Gati et al., 1997). In addition, we
make use of the greater signal-to-noise available at high field to
acquire images at a higher spatial resolution than used typically for
fMRI studies and restricted our data collection to slices within the
PAG region.
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MATERIALS AND METHODS |
Subjects. Nine right-handed volunteers were studied
(six males, three females; mean ± SD age, 26 ± 2.6 years).
All subjects gave informed consent, and the study was approved both by
the Oxford Committee for Research Ethics and the University of Western Ontario Ethics Review Board. Noxious and warm thermal stimuli were
applied to the dorsum of the right hand with a 3 × 3 cm Peltier thermode, designed and built in-house. In the scanner, an adaptive procedure was used to identify two stimuli consistently described for
each subject as "painfully hot, moderate-strong pain" and "clearly warm, but not painful." Subjects were instructed which of
two of three possible light-emitting diodes (LEDs), observable from the
magnet bore (red, blue, or green), would signify onset of either
painful heat or nonpainful warm stimulation, with no delay between LED
and stimulus onset. The LEDs would remain on throughout the duration of
stimulation. Each subject received five bursts of painful heat and five
bursts of nonpainful warm stimulation, in which stimulus duration
lasted 12 sec, in a randomized manner. The assignment of LED color to
intensity of stimulation was randomized across subjects. Subjects
underwent two experiments within the same imaging session. In one
session, they were instructed to pay full attention to the painful or
warm stimulation (denoted "attending" or "A" task) and, in the
second, to try and decrease the perception of painful or warm
stimulation by not attending (i.e., think of something else) to the
stimulus (denoted "not attending" or "NA" task). All subjects
understood the instructions and cooperated, based on postexperimental
interviews. The order of the two tasks was randomized across subjects.
After the imaging data were completed and subjects were removed from
the scanner, they rated both the intensity and unpleasantness of
thermal stimulation in both conditions using an 11 point scale with
verbal descriptors. On the basis of previous work, we expected subjects
to rate the NA pain condition lower than the A pain condition;
ratings between conditions were analyzed for significance using a
one-tailed Student's t test.
Imaging. Data were acquired on a 4 tesla whole-body imaging
system (Varian, Palo Alto, CA; Siemens, Erlangen, Germany) with a
hybrid birdcage transmit-receive radio frequency coil. The
subject's head was placed into a head holder and packed with foam to
reduce motion. T1-weighted sagittal scout images were used to select seven contiguous 4 mm axial slices (obliquely oriented) through the
mesencephalon. Each functional volume was acquired using a navigator
echo-corrected, interleaved multishot (four shots) echo planar
imaging pulse sequence with a 128 × 128 matrix size and a
total volume acquisition time of 2.5 sec [echo time (TE), 15 msec;
flip angle, 50°; field of view (FOV), 22.0 cm]. During each imaging session, high-resolution (256 × 256) three-dimensional T1-weighted structural volumes were acquired in the same FOV and orientation as the functional images (TE, 6 msec; repetition time, 11 msec; inversion time, 500 msec; flip angle, 11°). The
resulting acquisition produced 64 contiguous structural images, each
with a slice thickness of 1.0 mm.
Image processing and quantification. Image processing and
statistical analyses were performed with MEDx (Sensor Systems,
Sterling, VA). All volumes were realigned and smoothed with a
3.0 × 3.0 × 3.0 mm3
(full-width at half-maximum) Gaussian kernel, and the average signal
intensity of every volume was normalized to the same mean value.
Temporal filtering was applied (high-pass cutoff of 200 sec), and
activation maps were calculated (for illustrative purposes only) by
parametric unpaired t tests between volumes collected during
noxious heat stimulation and those collected during non-noxious warm
stimulation (denoted pain minus warm or "P W").
Mean difference images were generated by subtracting BOLD signal time
course data obtained during non-noxious warm stimulation from the BOLD
signal time course data obtained during noxious heat stimulation. These
mean difference images were resliced into high-resolution space so that
a manually defined mask of the periaqueductal gray, defined by the
tissue borders seen on the high-resolution anatomical images, could be
overlaid onto the mean difference images. The mean signal intensity
difference for each voxel within the PAG between noxious heat and
non-noxious warm stimulation for each subject was determined under both
conditions using this mask [denoted (PW)+A for the attending to pain
relative to warm condition and (PW)+NA for the not attending to pain
relative to warm condition]. A Student's t test (matched,
one-tailed) of these results was performed between the (PW)+A and
(PW)+NA conditions to test whether a significant increase in
activation occurred during the (PW)+NA condition. This was to
determine whether a larger perceptual decrease in pain intensity or
aversiveness correlated with a larger total activity within the PAG.
This method of analysis is a more objective measure of the total
activity within the PAG compared with a threshold-based activity
summary (whether calculated from Z statistic or activation
level images). The latter depends more subjectively on factors of
little relative interest (such as noise levels) and arbitrary
objectivity (such as actual thresholds used). In addition, a
correlation analysis was done between the total change in visual
analog score (VAS) rating (intensity and aversiveness) and total change
in activity within the PAG for the two conditions.
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RESULTS |
Behavioral responses to stimuli
Figure 1, A and
B, displays the pain scores for intensity and aversiveness
during the two attentional conditions [perceived pain while not
attending to pain (P+NA) and perceived pain while attending to pain
(P+A)]. A significant decrease in the rating for pain was found during
the P+NA condition compared with the P+A condition (mean ± SE;
P+A, 7.8 ± 0.4 vs P+NA, 7.0 ± 0.3; t = 3.51; p = 0.004) was found. Aversiveness (VAS) of the
stimuli was also rated to be lower during the P+NA condition compared with the P+A condition (mean ± SE; P+A, 4.9 ± 0.7 vs P+NA,
4.1 ± 0.4; t = 2.15; p = 0.03).
We did not find any significant differences in the ratings of warm
stimulation during the two conditions (intensity ratings: mean ± SE; warm+A, 2.78 ± 0.32 vs warm+NA, 2.56 ± 0.38; p = 0.26) (aversiveness ratings: mean ± SE;
warm+A, 1.17 ± 0.17 vs warm+NA, 0.94 ± 0.18;
p = 0.09).
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Figure 1.
A, B, Graphs showing
the pain scores (mean ± SE) between conditions for intensity
(A) and aversiveness (B)
(*p < 0.05).
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fMRI measurements of the periaqueductal gray response to
noxious stimulation
Using high-resolution echo planar imaging at 4 tesla, activation
within the PAG in response to noxious thermal stimulation can be
demonstrated even for individual subjects (Fig.
2A). A representative
time course for the single voxel with highest Z statistic in
the activated region is displayed in Figure 2B. This time course is derived from concatenated data taken from the periods when subjects received a warm (marked in yellow outline) or
a painful hot (marked in red outline) stimulus. There was
increased signal intensity (~0.6-1.8%) in the PAG region during
noxious stimulation relative to periods of pleasant warmth. We did not find any significant activation of the PAG region during warm stimulation alone (i.e., during warm minus no stimulation; results not
shown).
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Figure 2.
A, B, Figure showing
representative activation within the periaqueductal gray for one
subject (A). The corresponding time course of MR
signal intensity change during warm (yellow
boxes) and painful (red boxes) stimulation
for the voxel with highest Z statistic is also shown
(B).
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To confirm that PAG activation was enhanced for the pain activation in
the not attend condition [(PW)+NA] condition compared with the pain
activation in the attend condition [(PW)+A] condition, we adopted a
region-of-interest analysis of the time course data from the PW
comparison for each subject. The region-of-interest (defined from a
high-resolution structural scan) was limited to the PAG. For each voxel
within the PAG, the mean difference of PW was obtained on a
voxel-by-voxel basis (see Materials and Methods). These values were
summed for each subject. The contrast of NA-A showed a mean 25%
signal increase [mean ± SE (arbitrary units); NA, 1981 ± 384 vs A, 1487 ± 278] in the total signal intensity within the
PAG (p = 0.02) (Fig.
3A). There was a significant
correlation (p < 0.025) (Fig. 3B)
between the total activity change in the PAG between conditions and the
total change in VAS for intensity, i.e., a greater change in PAG
activity is found when a larger decrease in pain intensity is reported.
There was no significant correlation with the aversiveness ratings. It
is clear from Figure 3, A and B, that there are
reasonable differences in the amount of activation to painful
stimulation within the PAG across subjects; nevertheless, these are not
so great that significant differences in the means and correlation to
subjective behavioral data could not be detected.
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Figure 3.
A, B, Total signal
intensity (arbitrary units) within the periaqueductal gray for the
two attentional conditions (A) (mean ± SE;
*p < 0.05). B, Correlation of total
signal intensity change (arbitrary units) within the periaqueductal
gray and total change in pain intensity (visual analog score) between
the two conditions (p < 0.025).
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DISCUSSION |
Consistent with previous behavioral studies (Bushnell et al.,
1985; Miron et al., 1989; Fields and Basbaum, 1999), we found a
significant decrease in the behavioral ratings of pain for both intensity and aversiveness in the P+NA condition compared with the P+A
condition (Fig. 1A,B). This study
was designed to test whether the PAG is one candidate brain structure
for this "top-down" influence on pain perception.
Our results have demonstrated first that high-field fMRI can be used to
monitor pain-specific activation within the PAG (Fig. 2A,B). Second, we showed a
significant increase in activation associated with our noxious thermal
stimulus specifically within the PAG when subjects were distracted from
the pain (Fig. 3A). That this difference was related
directly to the perception of pain was emphasized by the observation
that the activation difference was significantly correlated with the
total VAS (intensity) change between conditions (Fig. 3B).
That is the total signal within the PAG is greater when the difference
in perceptual rating of pain intensity for the two conditions is higher
(Fig. 3B). In conjunction with previous studies showing that
direct electrical stimulation of the PAG induces analgesia (Reynolds,
1969; Akil et al., 1976; Boivie and Meyerson, 1982; Baskin et al.,
1986), these results support the hypothesis that increased activity
within the PAG correlates with perceptual decreases in pain intensity. It should be noted, however, that because of technical
limitations, we were not able to record task performance for reliable
distraction or subjective pain and warm ratings during the experiment
itself. Subjective ratings of thermal stimulation were taken during
postexperimental interviews. This might therefore introduce memory
bias, and future studies would benefit from concurrent ratings of pain
perception. In addition, future studies should obtain behavioral
measures of attention or distraction to confirm reliable task
performance. However, we believe our results that show a significant
correlation between the behavioral and imaging data support the
conclusion that subjects reported pain ratings reliably and that
neither memory bias nor task performance for reliable distraction were major confounds in this study.
There is a large body of evidence to date suggesting that changes in
pain responses attributable to changes in arousal or attention result
from the action of modulatory networks that control the transmission of
nociceptive signals to the brain (Hagbarth and Kerr, 1954; Duncan et
al., 1987; Oliveras et al., 1990; Petrovic et al., 2000). This evidence
is mostly based on animal studies, because methods to investigate such
modulatory networks in humans have not been available until recently.
One site for modulation of the pain response is the medullary dorsal
horn (trigeminal nucleus caudalis). Electrophysiological studies have
demonstrated that activity of the trigeminal nucleus caudalis is
increased with anticipation of a noxious stimulus (a process
undoubtedly mediated by cortical centers) in a similar way to increases
with pain itself (Duncan et al., 1987). Another site proposed, and one
of the first regions suggested as being responsible for pain modulation, was the PAG (Reynolds, 1969; Mayer et al., 1971; Mayer and
Price, 1976). However, it is not known whether cortical inputs to the
PAG are a route by which such cognitive inputs can exert their
influence on sensory afferent input in humans.
Neuroanatomical evidence suggests that the PAG could mediate central
modulation of ascending sensory responses. The PAG receives major
inputs from the frontal cortex, hypothalamus (Beitz, 1982), frontal granular, insular cortex (Hardy and Leichnetz, 1981), and
amygdala (Gray and Magnuson, 1992). In addition, there are several
major brainstem inputs to the PAG (Basbaum and Fields, 1984; Herbert
and Saper, 1992). The caudal PAG projects to the rostral ventromedial
medulla (RVM), which in turn sends projections to pain-transmitting
neurons in the dorsal horn of the spinal cord and the trigeminal
nucleus caudalis. Just like stimulation of the PAG, electrical
stimulation of the RVM produces analgesia and inhibits dorsal horn pain
transmission neurons (Akil et al., 1976; Baskin et al., 1986).
Pain-modulating neurons in the PAG and RVM have very large, virtually
total body "receptive fields" that project diffusely to multiple
levels of the neuroaxis, including the trigeminal nucleus, the dorsal
horn at multiple spinal levels, and RVM neurons. Cells throughout this
network can fire at the same time, suggesting that the PAG-RVM network
functions as a unit and exerts global rather than topographically
discrete control over dorsal horn pain transmission neurons. Such an
arrangement is therefore consistent with this system being integrated
with behavioral functions of arousal and attention. It is therefore
possible that the RVM is also critical for attentional modulation of
descending mechanisms. We were not able to test this directly with the
present experiment, because to obtain adequate spatial resolution to
determine PAG activation, we were limited in the number of slices that
could be taken per volume. This prevented us from prescribing slices as
far down as the medulla. Additional work is needed to characterize these other regions and their role in mediating top-down pain modulation.
One mechanism by which the PAG modulates pain perception involves the
release of endogenous opioids. The PAG contains significant quantities
of all families of endogenous opioid peptides, and it is known that µ opioids act by releasing PAG projection cells from GABAergic inhibition
(Fields and Basbaum, 1999). Stress-induced analgesia in animals and
placebo analgesia in humans with postoperative pain are reduced by the
opioid antagonist naloxone (Akil et al., 1976; Watkins and Mayer, 1982;
Watkins et al., 1982). It is possible, therefore, that attentional
mechanisms act by releasing endogenous opioids within the PAG.
One possible model for our findings is that, during distraction, there
is increasing activation of the PAG to enable release of endogenous
opioids that exert their antinociceptive effect through the opioid
synapses of the RVM system. In the PAG to RVM system, opiates inhibit
RVM "off" cells (Fields and Basbaum, 1999). Disinhibition of off
cells enables them to exert their antinociceptive effect on dorsal horn
pain transmission neurons. A test of this hypothesis would be to
administer the opiate antagonist naloxone, which should abolish the
attentional modulation of perceived pain intensity but not the
increased PAG activation with distraction. A study by Moret et al.
(1991), however, suggests that one form of cognitive analgesia
(hypnotic analgesia) was not reversed by naloxone, suggesting that the
opiate endorphin system might not primarily mediate all forms of
cognitive analgesia. Future work will investigate specifically how
higher cognitive brain structures during distraction tasks activate the PAG.
There are precedents for central attentional modulation of brainstem
nuclei by attentional tasks. For example, McGlone found that fMRI
activation in the human superior colliculus was modulated during a
tactile attention task (McGlone et al., 1999). Lavernhe-Lemaire and
Robier (1997) had subjects alternately relax or focus their attention
on auditory input from one side only during simultaneous recording of
brainstem-evoked potentials. The brainstem wave III amplitude was
decreased on the side where attention was focused, providing evidence
that, when attention is focused, as done in our study, one can lower
brainstem-evoked potentials. This supports the notion that distraction
from sensory perception may reduce inhibition of specific brainstem centers.
To our knowledge, the present study therefore is the first imaging
study to show that cognitive processes can modulate pain-associated activity specifically within the PAG. Our method provides an in vivo assay for objectively monitoring pain modulation in humans and provides evidence that the PAG is a route for top-down influences on the descending pain inhibitory pathways in humans.
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FOOTNOTES |
Received May 7, 2001; revised Jan. 11, 2002; accepted Jan. 15, 2002.
This work was supported by the Medical Research Council (UK) (I.T.,
S.S., and P.M.M.). We thank Dermot Dobson for technical support.
Correspondence should be addressed to Dr. Irene Tracey, Centre for
Functional Magnetic Resonance Imaging of the Brain, John Radcliffe
Hospital, Headington, Oxford OX3 9DU, UK. E-mail:
irene{at}fmrib.ox.ac.uk.
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REFERENCES |
-
Akil H,
Mayer DJ,
Liebeskind JC
(1976)
Antagonism of stimulation-produced analgesia by naloxone, a narcotic antagonist.
Science
191:961-962[Abstract/Free Full Text].
-
Albe-Fessard D,
Berkley KJ,
Kruger L,
Ralston III HJ,
Willis Jr WD
(1985)
Diencephalic mechanisms of pain sensation.
Brain Res
3:217-296.
-
Basbaum AI,
Fields HL
(1984)
Endogenous pain control systems: brainstem spinal pathways and endorphin circuitry.
Annu Rev Neurosci
7:309-338[ISI][Medline].
-
Baskin DS,
Mehler WR,
Hosobuchi Y,
Richardson DE,
Adams JE,
Flitter MA
(1986)
Autopsy analysis of the safety, efficacy and cartography of electrical stimulation of the central gray in humans.
Brain Res
371:231-236[Medline].
-
Beitz AJ
(1982)
The sites of origin brain stem neurotensin and serotonin projections to the rodent nucleus raphe magnus.
J Neurosci
2:829-842[Abstract].
-
Boivie J,
Meyerson BA
(1982)
A correlative anatomical and clinical study of pain suppression by deep brain stimulation.
Pain
13:113-126[Medline].
-
Bushnell MC,
Duncan GH,
Dubner R,
Jones RL,
Maixner W
(1985)
Attentional influences on noxious and innocuous cutaneous heat detection in humans and monkeys.
J Neurosci
5:1103-1110[Abstract].
-
Duncan GH,
Bushnell MC,
Bates R,
Dubner R
(1987)
Task-related responses of monkey medullary dorsal horn neurons.
J Neurophysiol
57:289-310[Abstract/Free Full Text].
-
Fields HL,
Basbaum AI
(1999)
Central nervous system mechanisms of pain modulation.
In: Textbook of pain (Wall PD,
Melzack R,
eds), pp 309-329. London: Churchill Livingstone.
-
Gati JS,
Menon RS,
Ugurbil K,
Rutt BK
(1997)
Experimental determination of the BOLD field strength dependence in vessels and tissue.
Magn Reson Med
38:296-302[ISI][Medline].
-
Gaughan AM, Gracely RH (1989) A somatization model of
repressed negative emotion: defensiveness increases affective ratings
of thermal pain sensations. Soc Behav Med [Abstr].
-
Good M,
Stanton HM,
Grass JA,
Cranston AG,
Choi C,
Schoolmeesters LJ,
Salman A
(1999)
Relief of postoperative pain with jaw relaxation, music and their combination.
Pain
81:163-172[ISI][Medline].
-
Gray TS,
Magnuson DJ
(1992)
Peptide immunoreactive neurons in the amygdala and the bed nucleus of the stria terminalis project to the midbrain central gray in the rat.
Peptides
13:451-460[ISI][Medline].
-
Hagbarth KE,
Kerr DIB
(1954)
Central influences on spinal afferent conduction.
J Neurophysiol
17:295-307[Free Full Text].
-
Hardy SG,
Leichnetz GR
(1981)
Cortical projections to the periaqueductal gray in the monkey: a retrograde and orthograde horseradish peroxidase study.
Neurosci Lett
22:97-101[ISI][Medline].
-
Head H,
Holmes G
(1911)
Sensory disturbances from cerebral lesions.
Brain
34:102-254[Free Full Text].
-
Herbert H,
Saper CB
(1992)
Organization of medullary adrenergic and noradrenergic projections to the periaqueductal gray matter in the rat.
J Comp Neurol
315:34-52[ISI][Medline].
-
Lavernhe-Lemaire MC,
Robier A
(1997)
Is the afferent auditory message modulated by the cortex (in French)?
Arch Physiol Biochem
105:645-654[Medline].
-
Mayer DJ,
Price DD
(1976)
Central nervous system mechanisms of analgesia.
Pain
2:379-404[ISI][Medline].
-
Mayer DJ,
Wolfle TL,
Akil H,
Carder B,
Liebeskind JC
(1971)
Analgesia from electrical stimulation in the brainstem of the rat.
Science
174:1351-1354[Abstract/Free Full Text].
-
McGlone F,
Francis S,
Lloyd DM,
Newton J,
Bowtell R
(1999)
The role of the superior colliculus in tactile attention: an fMRI study.
J Cognit Neurosci [Suppl]
11:56.
-
Melzack R,
Wall PD,
Ty TC
(1982)
Acute pain in an emergency clinic: latency of onset and descriptor patterns related to different injuries.
Pain
14:33-43[ISI][Medline].
-
Miron D,
Duncan GH,
Bushnell MC
(1989)
Effects of attention on the intensity and unpleasantness of thermal pain.
Pain
39:345-352[ISI][Medline].
-
Moret V,
Forster A,
Laverriere MC,
Lambert H,
Gaillard RC,
Bourgeois P,
Haynal A,
Gemperle M,
Buchser E
(1991)
Mechanism of analgesia induced by hypnosis and acupuncture: is there a difference?
Pain
45:135-140[ISI][Medline].
-
Oliveras J-L,
Martin G,
Montagne J,
Vos B
(1990)
Single unit activity at ventromedial medulla level in the awake, freely moving rat: effects of noxious heat and light tactile stimuli onto convergent neurons.
Brain Res
506:19-30[ISI][Medline].
-
Petrovic P,
Petersson KM,
Ghatan PH,
Stone ES,
Ingvar M
(2000)
Pain-related cerebral activation is altered by a distracting cognitive task.
Pain
85:19-30[ISI][Medline].
-
Ploghaus A,
Tracey I,
Gati JS,
Clare S,
Menon RS,
Matthews P,
Rawlins J
(1999)
Dissociating pain from its anticipation in the human brain.
Science
284:1979-1981[Abstract/Free Full Text].
-
Ploghaus A,
Tracey I,
Clare S,
Gati JS,
Rawlins J,
Matthews P
(2000)
The neural substrate of the prediction error for aversive events.
Proc Natl Acad Sci USA
97:9281-9286[Abstract/Free Full Text].
-
Ploner M,
Freund HJ,
Schnitzler A
(1999)
Pain affect without pain sensation in a patient with a postcentral lesion.
Pain
81:211-213[ISI][Medline].
-
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].
-
Reynolds DV
(1969)
Surgery in the rat during electrical analgesia induced by focal brain stimulation.
Science
164:444-445[Abstract/Free Full Text].
-
Tracey I,
Becerra L,
Chang I,
Breiter H,
Jenkins L,
Borsook D,
Gonzalez RG
(2000)
Noxious hot and cold stimulation produce common patterns of brain activation in humans: a functional magnetic resonance imaging study.
Neurosci Lett
288:159-162[ISI][Medline].
-
Wall PD,
Melzack R
(1999)
In: In: Textbook of pain. London: Churchill Livingstone.
-
Watkins LR,
Mayer DJ
(1982)
Organization of endogenous opiate and nonopiate pain control systems.
Science
216:1185-1192[Abstract/Free Full Text].
-
Watkins LR,
Cobelli DA,
Mayer DJ
(1982)
Classical conditioning of front paw and hind paw footshock induced analgesia (FSIA): naloxone reversibility and descending pathways.
Brain Res
243:119-132[ISI][Medline].
Copyright © 2002 Society for Neuroscience 0270-6474/02/2272748-05$05.00/0
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|
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|
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|
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|
|
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|
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|
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|
|
|
|
|
|
|
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|
|
|
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|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
|
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[Full Text]
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
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ABSTRACT
INTRODUCTION
