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The Journal of Neuroscience, December 15, 2001, 21(24):9896-9903
Exacerbation of Pain by Anxiety Is Associated with Activity in a
Hippocampal Network
Alexander
Ploghaus1, 2,
Charvy
Narain1,
Christian
F.
Beckmann1,
Stuart
Clare1,
Susanna
Bantick1,
Richard
Wise1,
Paul M.
Matthews1,
J. Nicholas P.
Rawlins2, and
Irene
Tracey1
1 Oxford Centre for Functional Magnetic Resonance
Imaging of the Brain, Department of Clinical Neurology, University of
Oxford, John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom, and
2 Department of Experimental Psychology, University of
Oxford, Oxford OX1 3UD, United Kingdom
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ABSTRACT |
It is common clinical experience that anxiety about pain can
exacerbate the pain sensation. Using event-related functional magnetic
resonance imaging (FMRI), we compared activation responses to
noxious thermal stimulation while perceived pain intensity was
manipulated by changes in either physical intensity or induced anxiety.
One visual signal, which reliably predicted noxious stimulation of
moderate intensity, came to evoke low anxiety about the impending pain.
Another visual signal was followed by the same, moderate-intensity stimulation on most of the trials, but occasionally by discriminably stronger noxious stimuli, and came to evoke higher anxiety. We found
that the entorhinal cortex of the hippocampal formation responded
differentially to identical noxious stimuli, dependent on whether the
perceived pain intensity was enhanced by pain-relevant anxiety. During
this emotional pain modulation, entorhinal responses predicted activity
in closely connected, affective (perigenual cingulate), and intensity
coding (mid-insula) areas. Our finding suggests that accurate
preparatory information during medical and dental procedures alleviates
pain by disengaging the hippocampus. It supports the proposal that
during anxiety, the hippocampal formation amplifies aversive events to
prime behavioral responses that are adaptive to the worst possible outcome.
Key words:
hyperalgesia; hippocampus; classical fear conditioning; anterior cingulate; insula; causal associative learning; medial
temporal lobe; surprise; aversive emotional learning; anticipation; functional neuroimaging
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INTRODUCTION |
The positive relationship between
anxiety and pain is a common experience in clinical settings
(Sternbach, 1968 ; Melzack, 1973; Grachev et al., 2001). For example,
anxiety levels have been shown to predict pain severity and pain
behavior in acute and chronic pain patients (Kain et al., 2000; van den
Hout et al., 2001), and anxiety reduction techniques and anxiolytic
drugs have been reported to be successful in ameliorating pain
associated with medical procedures (Suls and Wan, 1989; Dellemijn and
Fields, 1994). Experimental studies have confirmed the enhancing effect of anxiety on pain for different components and measures of pain, e.g.,
ratings of pain intensity (Al Absi and Rokke, 1991) and unpleasantness
(Weisenberg et al., 1984), pain threshold (Rhudy and Meagher, 2000),
and pain discrimination (Schumacher and Velden, 1984). Anxiolytic drugs
reverse the experimental effect (Gracely et al., 1978; Janssen and
Arntz, 1999).
Functional neuroimaging studies have greatly advanced our understanding
of the neural mechanisms mediating the emotional consequences of tissue
stress (Rainville et al., 1997; Tölle et al., 1999; Casey et al.,
2001). In contrast, little is known about the human forebrain
mechanisms underlying the reverse causality, i.e., the pathways whereby
emotions, particularly anxiety, can enhance pain sensitivity. In a
previous study, we used functional magnetic resonance imaging
(FMRI) to reveal distinct neural substrates for pain and its
anticipation (Ploghaus et al., 1999). However, this and related
experiments (Reiman et al., 1989; Hsieh et al., 1999; Sawamoto et al.,
2000; Naliboff et al., 2001) did not assess the effect of anticipation
on pain perception. The study by Ploghaus et al. (2000), the first
neuroimaging study to demonstrate that brain responses to surprising
events are predicted by formal associative learning theory, was
designed to exclude the modulatory effect of anxiety on pain. Emotional
pain modulation has been studied extensively in experimental animals
(Fanselow, 1985; Maier, 1986; Helmstetter, 1992), but there is
currently no animal model of anxiety-induced hyperalgesia.
The present study examined the neural mechanism by which anxiety causes
hyperalgesia and contrasted it with the process by which enhanced
nociceptive stimulation increases pain. We used event-related FMRI
(Davis et al., 1998a), and we adapted a differential Pavlovian delay
conditioning task to the within-subject within-session requirements of
FMRI. In the task, one visual signal was always followed by the same,
lower-temperature nociceptive stimulation (LT) to the left hand. This
signal came to evoke low anxiety about the impending pain. Another
visual signal was followed by LT on most of the trials, but
occasionally by a higher-temperature noxious stimulus (HT). This signal
came to evoke higher anxiety. We obtained anxiety and pain ratings for
each trial. This task allowed us to assess whether pain ratings and
localized brain responses to physically identical noxious stimuli vary
as a function of pain-relevant anxiety levels. We hypothesized that
anxiety-induced hyperalgesia is associated with activity in a subset of
the brain regions that respond to experimental nociceptive stimulation
(for review, see Casey, 1999; Gelnar et al., 1999; Treede et al., 1999;
Davis, 2000; Peyron et al., 2000).
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MATERIALS AND METHODS |
Subjects and neuroimaging. Eight healthy,
right-handed male volunteers with ages ranging from 22 to 40 years
participated in the study. All subjects gave informed consent, and the
study was approved by the Oxfordshire Committee for Research Ethics. Data were acquired on a 3T whole-body scanner (Siemens, Erlangen, Germany) with a quadrature birdcage head coil. Head movements were
restrained with foam pads. In each of 21 contiguous planes, 579 blood-oxygenation level-dependent (BOLD) images were acquired continuously by using multishot echoplanar imaging (EPI) with TE of
30 msec, TR of 3 sec, flip angle of 90°, in-plane resolution of 3.5 mm, slice thickness of 8 mm, and no slice gap. Slices were prescribed in coronal orientation perpendicular to the anterior commissure-posterior commissure (AC-PC) line and covered the
entire brain volume (Tracey et al., 2000). Structural images were
obtained with a standard T1-weighted pulse sequence.
Psychological task. Thermal stimuli were applied to the
dorsum of the left hand with a 1.5 × 2 cm thermal resistor
designed and built in-house. Visual stimuli (square, triangle, circle) were presented using prism glasses and a back projection screen at feet
level outside the scanner. Subjects were presented with thermal stimuli
of different temperatures and 6 sec duration throughout scanner setup
and were asked to rate their intensity using a five-button box at their
right hand as soon as a five-point Likert scale (5 = "extreme
pain") was shown. In this study, we used a sensory scale (pain
intensity) rather than an emotive one (pain unpleasantness) because a
sensory measure is less prone to bias by the concomitant emotional
state of anxiety (Gross and Collins, 1981). The scale was presented for
a period of 6 sec, starting 12 sec after the offset of the thermal
stimulus. It was explained that the rating concerned the sensory
intensity, not the unpleasantness of pain (Price, 1988). A temperature
rated as "moderate pain" in an adaptive sequence (Gracely and
Naliboff, 1996) and confirmed on two retest trials, one of which
included an EPI noise sample, was used as the LT. The temperature
established for LT was increased by 2.5°C to obtain an HT. This
substantial increase was chosen to ensure clear discrimination between
HT and all other painful stimulations. HT was only presented during the
experiment itself.
The experimental paradigm (Fig. 1) used
delay-conditioning contiguities. In conditioning studies, subjects
learn causal relations between stimuli by experience, so instructions
are limited to necessary information about the constituent stimuli and
required responses. Subjects were instructed that they would see shapes on the screen and would receive heat bursts to the back of the left
hand. They were asked to figure out the significance of the shapes and
rate pain intensity as practiced during thresholding. Experimental
conditions were applied in a pseudorandom sequence within a single
imaging session for each subject to avoid confounding effects of
repetitive noxious heat stimulation, as revealed by Casey et al.
(2001). One visual signal was always followed by the LT. This signal
came to evoke low anxiety (LA) about the impending pain. The second
visual signal was followed by LT on all but two trials (trials 2 and
4), when it was followed by the higher-temperature pain stimulus (HT).
This signal came to elicit higher anxiety (HA) about the impending
pain. On additional trials, a third signal was presented alone or in
compound with HA or LA and was not followed by thermal stimulation.
These trials are irrelevant in the present context but can be used to
study the neural substrate of a different process, Pavlovian
conditioned inhibition. A crossed design would have included a
condition HT/LA, but this is impossible because a signal predicting
strong noxious stimulation cannot evoke low anxiety.
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Figure 1.
Relevant experimental conditions. Visual signals
predicted painful heat stimulation to the back of the left hand.
Painful stimulation was delivered either at a lower
(LT) or at a discriminably higher
(HT) temperature. One visual signal (here:
triangle) was consistently followed by LT and came to
evoke low anxiety (LA). Another signal (here:
square) was followed by LT on most of the trials, but
occasionally by HT, and came to evoke higher anxiety
(HA). We studied anxiety-induced increases in perceived
pain intensity by comparing brain responses to pain in conditions LT/HA
and LT/LA. We also assessed temperature-induced increases in perceived
pain intensity by comparing brain responses to pain in conditions HT/HA
and LT/HA.
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The delay between signal onset and onset of thermal stimulation (CS-US
interval) was pseudorandomized with a mean of 10.4 sec (range, 6-15
sec) to optimize aversive conditioning and minimize inhibition of
delay. The intertrial interval was also pseudorandomized with a mean of
58 sec (range, 36-72 sec) to prevent overshadowing of the signals by
temporal cues. After each trial, subjects rated the perceived pain
intensity in exactly the same way as practiced during thresholding. The
12 sec delay between trial offset and scale onset was chosen to allow
for clear separation of trial- and rating-related hemodynamic
responses. Heart rate was recorded from the left index finger
throughout the experiment using an MR-compatible pulse oximeter (MR
Equipment Corp., Bay Shore, NY).
The experiment was also performed in a separate group of nine subjects
outside the scanner. The difference was that this group was instructed
to rate anxiety about the impending painful stimulus on a five-point
Likert scale (5 = "extreme anxiety about impending pain")
after the onset of each visual signal, but before the onset of thermal
stimulation, using the five-button box. It is important to obtain
anxiety and pain ratings in separate groups of subjects, because
conscious self-assessment of both processes in the same subject can
lead to a hypothesis-driven correlation artifact (Gross and Collins,
1981).
Cardiac data analysis. Heart rate responses during aversive
signals consist of a series of functionally distinct components (Obrist, 1981). Because the present study used a range of CS-US intervals (6-15 sec), only the initial 6 sec of every signal
presentation contain functionally equivalent heart rate components.
Accordingly, cardiac data analysis was restricted to this initial
interval. Heart rates were converted into percentage of signal change
relative to baseline before signal onset.
Event-related FMRI data analysis. The image analysis package
FEAT [Centre for Functional Magnetic Resonance Imaging of the Brain (FMRIB), University of Oxford, UK;
www.fmrib.ox.ac.uk/fsl] was used for all data processing except motion
correction, which was performed using SPM99 (Wellcome Department of
Cognitive Neurology, London, UK). The initial four scans of each data
set were discarded because of nonequilibrium magnetization, and
independent component analysis was applied to detect and remove
artifacts from the FMRI time series (Beckmann et al., 2000; Brown et
al., 2001). The data were specifically examined for medial temporal
lobe susceptibility artifacts by looking at the animated residual time
series (Büchel et al., 1998). This procedure revealed no
event-related changes in susceptibility. Head motion was corrected, and
the data were smoothed in the spatial domain with a three-dimensional 8 mm (full width at half maximum) isotropic Gaussian kernel. All volumes were scaled by a single factor to obtain the same grand mean across subjects, and the data were filtered in the temporal domain using a
nonlinear high-pass filter with a cutoff period of 150 sec.
Statistical analysis was based on a least-squares estimation using a
general linear model approach (Friston et al., 1995) with nonparametric
local autocorrelation correction implemented in FILM (FMRIB, University
of Oxford; Woolrich et al., 2000). Boxcar reference functions modeling
separately all task components (types of visual signals, types of
conditional pain stimuli) as main effects as well as interactions with
time were convolved with a  -variate model of the hemodynamic
response (Cohen, 1997) and its first derivative with respect to time
(Josephs et al., 1997). Visual and pain stimuli constituting the first
presentation of each trial type were entered separately as regressors
of no interest, because their neural representations had not been
modified by experience of the experimental contingencies. Linear
contrasts between parameter estimates for conditions LT/HA and LT/LA,
as well as HT/HA and LT/HA, resulted in mean difference images for each
subject. These images were warped into Talairach and Tournoux (1988)
stereotaxic space using transformations generated by the two-level,
12-parameter affine registration method implemented in FLIRT
(FMRIB, University of Oxford; Jenkinson and Smith, 2001).
Our hypothesis specified our region of interest (ROI) as the pain
matrix, and activations were considered to satisfy this criterion if
their Talairach coordinates were located in one of the component
structures of the pain matrix as tabulated in Peyron et al. (2000). Two
SPM thresholding conventions for ROI-based fixed-effects analysis have
evolved, (1) p = 0.001, uncorrected (Elliott et al.,
2000), and (2) p = 0.05, corrected for multiple comparisons given the ROI and the smoothness of the underlying Z statistic image (Büchel et al., 1999). We adopted
method (1), but also report in Table 1
the Z thresholds derived by method (2), where the ROI was
defined by an average pain activation obtained from an independent data
set (Ploghaus et al., 2000). All activations reported here are revealed
by both methods. Event-related FMRI is insensitive to stimulus-induced
motion (Birn et al., 1999), but we also directly examined the response
peak latencies of significant activations. The earliest response peaks
were found ~7 sec after pain onset, which renders stimulus-correlated
motion unlikely (Birn et al., 1999).
We also examined the potential input-output pathways of regions
activated during anxiety-induced pain modulation. For this purpose, we
set individual subjects' FMRI signal values for the activated region
to the time course average except for the time points associated with
the response to LT/HA and LT/LA (see Fig. 4B),
normalized the function, and correlated it with the FMRI time course at
every other voxel.
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RESULTS |
Behavioral results
Ratings of pain-related anxiety before the onset of LT were
significantly higher for HA than LA (Wilcoxon signed rank test, two-tailed, Z = 2.67; p < 0.05).
Anxiety scores were 3.73 ± 1.11 (mean ± SD) and 2.28 ± 0.91 for HA and LA, respectively (Fig. 2A). Heart rate (Fig.
2B) was significantly higher during presentation of
LA than HA (Wilcoxon signed rank test, two-tailed, Z = 2.29; p < 0.05). Presentation of LA resulted in heart
rate acceleration relative to baseline (percentage of change, 2.05 ± 4.38), whereas heart rate deceleration was found during presentation
of HA (percentage of change,  0.35 ± 4.58). The painful stimulus
LT was rated as significantly more intense when signaled by HA than LA
(Wilcoxon signed rank test, two-tailed, Z = 2.37;
p < 0.05). Scores of perceived pain intensity were
1.95 ± 0.79 and 2.33 ± 0.88 for LT/LA and LT/HA,
respectively (Fig. 2C). Ratings of pain intensity were significantly higher during presentation of HT/HA (3.19 ± 0.54) than LT/HA (Wilcoxon signed rank test, two-tailed, Z = 2.52; p < 0.05).
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Figure 2.
Behavioral results. A, Ratings of
anxiety during presentation of signals HA and LA before the onset of
pain LT (bench control group, mean ± one SEM). B,
Heart rate changes during presentation of signals HA and LA (scanner
group, mean ± one SEM). C, Ratings of perceived
pain intensity in conditions LT/LA, LT/HA, and HT/HA (scanner group,
mean ± one SEM).
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Ratings of anxiety elicited by signals HA and LA were tested for linear
and quadratic trends over time using repeated measures ANOVA.
Anxiety associated with LA did not change after the first LA trial, and
anxiety associated with HA did not change after the second HA trial.
Therefore, within-subject variability in pain ratings and BOLD
responses after these trials cannot be accounted for by changes in
anxiety, and hence forms part of the error variance. Postexperimental
interview confirmed clear intensity discrimination in all subjects of
the two HT/HA trials and the other trials involving HA, thus precluding
the possibility that the higher pain intensity rating of LT/HA relative
to LT/LA was simply because of generalization from HT/HA.
FMRI results
Conditions HT/HA and LT/HA were equated for anxiety and differed
in the intensity of thermal stimulation, whereas conditions LT/HA and
LT/LA were equated for stimulation intensity and differed in
pain-related anxiety. Thus, we compared hemodynamic responses to pain
in conditions HT/HA and LT/HA to reveal regional activation associated
with temperature-related changes in perceived pain intensity.
Crucially, we also compared hemodynamic responses to pain in conditions
LT/HA and LT/LA to reveal regional activation associated with
anxiety-related changes in perceived pain intensity.
Temperature-induced pain modulation
Comparison of conditions HT/HA and LT/HA revealed bilateral
activation in primary somatosensory-motor cortex (SI-MI),
midcingulate cortex, orbitofrontal cortex, thalamus, hippocampus
proper, and posterior insula around the superior marginal sulcus (Fig.
3A). Talairach coordinates and
Z values associated with these activations are shown in
Table 1. Hippocampal time courses of FMRI signal for this contrast are
shown in Figure 4A.
These findings are consistent with the results of neuroimaging studies
correlating brain activation with perceived pain intensity (Derbyshire
et al., 1997; Porro et al., 1998; Coghill et al., 1999, 2001) and
demonstrations of orbitofrontal activity during pain (for review, see
Petrovic et al., 2000) and abstract punishment (O'Doherty et al.,
2001).
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Figure 3.
Group Z value maps thresholded at
p < 0.001 and superimposed on an average
anatomical MRI of participating subjects in Talairach space
(radiological convention). A, Significant activations
associated with temperature-related increases in perceived pain (HT/HA
vs LT/HA). The coronal view (left, y = 16) shows activations bilaterally in primary somatosensory cortex
(SI), dorsal margin of the posterior insula
(pI), thalamus, midcingulate cortex, and
in the right hippocampus. The horizontal view (right,
z = 14) depicts bilateral hippocampus as well as
orbitofrontal cortex. B, Anxiety-related increases in
perceived pain (LT/HA vs LT/LA) are associated with significant
activation in the left entorhinal cortex. The activation area is shown
in coronal (left, y = 16) and
horizontal (right, z = 26) view.
C, Areas showing activity significantly correlated with
the entorhinal FMRI signal during pain modulation by anxiety (LT/HA and
LT/LA). The coronal view (left, y = 36) and the horizontal view (right,
z = 6) show activation in the perigenual cingulate
cortex, and the horizontal view depicts bilateral activity in the
mid-insular and parainsular cortices.
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Figure 4.
Significantly different hemodynamic responses in
the hippocampus proper and entorhinal cortex (group mean ± one
SEM). Regional time courses of FMRI signal represent percentage of
change from the rest period preceding each trial, averaged across
trials and subjects. The period of painful stimulation is shaded.
A, The hippocampus proper was significantly activated
bilaterally during HT/HA ( ) relative to LT/HA ( ).
B, The left entorhinal cortex was significantly
activated during LT/HA () relative to LT/LA ( ), as well as
relative to baseline. The right entorhinal cortex shows similar, but
smaller responses, which is consistent with observations of
left-lateralized processing of explicit aversive conditioning in the
medial temporal lobes.
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Anxiety-induced pain modulation
Comparison of conditions LT/HA and LT/LA revealed significant
activation in the left parahippocampal gyrus (Fig. 3B, Table 1). MR volumetric analysis showed that the activation area corresponded to the entorhinal cortex of the hippocampal formation (Insausti et al.,
1998). Time courses of FMRI signal in the left entorhinal cortex (Fig.
4B) revealed a positive hemodynamic response in
condition LT/HA and a negative hemodynamic response in condition LT/LA. However, the left entorhinal activation found in comparison LT/HA versus LT/LA cannot be accounted for by deactivation in condition LT/LA
because the region also activated significantly in the comparison LT/HA
versus baseline (maximum Z = 3.96, mean
Z = 3.40, p < 0.001). The right
entorhinal cortex showed similar, but smaller responses (Fig.
4B).
There was a trend toward a positive association between individual
subjects' mean difference in pain ratings between condition LT/HA and
LT/LA, and their mean difference in entorhinal hemodynamic responses
(average of volumes 3-5 after pain onset) in these conditions (Pearson
r = 0.59, p = 0.058). A correlation
analysis was performed to obtain some preliminary evidence of the
afferent or efferent pathways involved. Individual subjects' time
courses of FMRI signal in the entorhinal cortex during conditions LT/HA
and LT/LA correlated significantly with time courses in the perigenual
cingulate and in the mid-insula around the inferior marginal sulcus
(Fig. 3C, Table 1).
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DISCUSSION |
The present study shows that pain-related anxiety can increase
perceived pain intensity. Event-related FMRI revealed that pain
modulation by anxiety is associated with activation changes in the
entorhinal cortex of the hippocampal formation. The entorhinal hemodynamic response was significant both relative to a low-anxiety control condition and relative to baseline, and was predictive of
activity in the perigenual cingulate and mid-insula. Pain modulation by
temperature also activated the hippocampal formation, but the hemodynamic response originated in the more dorsal region of the hippocampus proper.
Pain processing in the hippocampal formation
Melzack and Casey (1968) proposed that the hippocampus and
associated cortices participate in mediating the aversive drive and
affect characteristic of pain. Subsequent studies confirmed a
hippocampal role in pain processing (Lathe, 2001) using extracellular recordings (Zheng and Khanna, 1999), intracellular recordings (Wei et
al., 2000), hippocampal EEG (Archer and Roth, 1997), in vivo
microdialysis (Ceccarelli et al., 1999), immediate-early gene
expression (Pearse et al., 2001), long-term potentiation (Wei et al.,
2000), and functional neuroimaging (Hsieh et al., 1995; Derbyshire et
al., 1997; Becerra et al., 1999; Casey, 1999; Peyron et al., 1999;
Schneider et al., 2001). Wei et al. (2000) demonstrated that the
amplitude of EPSPs in hippocampal CA1 pyramidal cells is
positively related to the intensity of nociceptive stimulation. This is
consistent with our observation that hippocampus proper activity varies
as a function of the physical intensity of noxious stimulation.
The aforementioned studies cannot rule out the possibility that
hippocampal activation during pain signifies processes that are not
pain-specific, e.g., memory encoding and retrieval or contextual
conditioning. However, stimulation and lesion studies confirm that pain
processing is a primary function of the hippocampus. Prado and Roberts
(1985) showed that the dorsal hippocampus is one of the two brain
regions where electrical stimulation alters nociception, but where,
crucially, the electrical stimulation itself is not perceived as
aversive. Sinha et al. (1999) found that stimulation of the hippocampus
disrupts the jaw-opening reflex evoked by phasic tooth pulp pain.
McKenna and Melzack (1992) demonstrated that injection of the local
anesthetic lidocaine into the dentate gyrus reduces pain sensitivity in
rats. Interestingly, the amnesic patient H.M., who underwent bilateral
hippocampectomy to alleviate severe epilepsy, had marked impairments in
pain perception (Hebben et al., 1985).
Neuropharmacological findings single out the entorhinal cortex as one
possible source of pain modulation in the hippocampal formation (Hurd,
1996; Fiore et al., 1999). In particular, there appears to be an
association between unconditioned pain modulation and expression of the
immediate-early gene c-fos in the entorhinal cortex. Pain of moderate
intensity leads to hyperalgesia (King et al., 1996) and increased
entorhinal c-fos expression (Funahashi et al., 1999), whereas strong
pain leads to hypoalgesia (King et al., 1996) and decreased entorhinal
c-fos expression (Funahashi et al., 1999). Our finding provides an
experimental demonstration of the apparent association between
entorhinal activity and pain modulation and shows that the entorhinal
cortex mediates not only unconditioned, but also conditioned
hyperalgesia. The left entorhinal cortex showed a stronger response
than the right one, which is consistent with the preferential
engagement of left medial temporal lobe structures during explicit
conditioning tasks (Morris et al., 1998; Chun and Phelps, 1999).
Entorhinal interactions with cingulate and insula
Our preliminary evidence of entorhinal interactions with the
perigenual cingulate and mid-insula is consistent with direct projections between these regions. Generally, the pattern of cortical connectivity of the entorhinal cortex resembles that of the amygdala (Van Hoesen, 1995). The entorhinal cortex maintains a substantial reciprocal connection with the perigenual cingulate, which is much
stronger than its connection with the midcingulate (Insausti et al.,
1987; Amaral and Insausti, 1990). Within the insular region, the
entorhinal cortex projects most heavily to the parainsular cortex
(Insausti et al., 1987), which forms part of the activation area we
identified in the mid-insula. The mid-insula, in turn, has stronger
connections with the perigenual cingulate than the anterior insula
(Vogt et al., 1996).
The perigenual cingulate has been termed the affective subdivision of
the anterior cingulate cortex (Devinsky et al., 1995; Bush et al.,
2000) and has a demonstrated role in anxiety. It is activated by
aversive conditioned stimuli (Büchel et al., 1999; Ploghaus et
al., 1999), and lesions attenuate endocrine and autonomic (Devinsky et
al., 1995) as well as avoidance (Johansen et al., 2001) responses to
such stimuli. The perigenual cingulate also responds to symptom
provocation in patients with anxiety disorders (Rauch et al., 1995).
The correlated activity we observed in this region during pain
modulation by anxiety may therefore reflect the changes in anxiety itself.
The mid-posterior insula mediates thermosensitivity (Craig et al.,
2000), e.g., the sensory dimension of thermal pain (Peyron et al.,
1999; Hofbauer et al., 2001). The present study found that objective
increases in noxious thermal stimulation activated the posterior
insula, whereas correlated activity during anxiety-induced pain
modulation occurred in the mid-insula. Perceptual modulation of an
innocuous stimulus by uncertain expectation of pain activates the
posterior insula (Sawamoto et al., 2000). Painful stimulation activates
both areas (Craig et al., 1996; Davis et al., 1998b; Iadarola et al.,
1998; Treede et al., 2000) as a function of perceived pain intensity
(Derbyshire et al., 1997; Coghill et al., 1999, 2001; Casey et al.,
2001). Our finding may therefore suggest that the entorhinal cortex
mediates anxiety-induced hyperalgesia by influencing intensity coding
in the mid-insula. This would be consistent with the Gray-McNaughton
theory of hippocampal function, which predicts that during anxiety, the
hippocampal formation increases pain by sending amplifying signals to
the neural representation of the pain stimulus.
Gray-McNaughton theory and pain modulation
The Gray-McNaughton theory (Gray and McNaughton, 2000) proposes
that the hippocampal formation responds to aversive events (e.g., pain)
whenever they form part of a behavioral conflict. It resolves the
conflict by sending amplification signals to the neural representation
of the aversive event, thereby biasing the organism toward a behavior
that is adaptive to the worst possible outcome. This process is
accompanied by anxiety. A role for the entorhinal cortex in detecting
conflict has also been proposed in memory models of the hippocampus
(Lavenex and Amaral, 2000; Witter et al., 2000).
Applied to the present experiment, behavioral conflict may arise in
condition LT/HA because signal HA is not a reliable predictor of pain
intensity. Therefore, without intervention of the hippocampal formation, responses adaptive to different levels of pain would compete
until asymptotic pain intensity becomes clear (at pain offset at the
latest). The hippocampus may resolve this conflict earlier by
amplifying pain intensity, thereby giving priority to responses
adaptive to the more intense pain, HT. Signal LA, in contrast, reliably
predicts asymptotic pain intensity so that no behavioral conflict
arises. The Gray-McNaughton theory therefore predicts that during
LT/HA relative to LT/LA, there should be (1) higher anxiety, (2)
stronger pain, and increased activity in (3) the hippocampal formation
and (4) neural representations of pain and anxiety. We found supporting
evidence for the first three predictions, and preliminary evidence
consistent with prediction (4).
Behavioral studies have established that during medical and dental
procedures, pain is alleviated by accurate preparatory information or,
in other words, by reliable prediction (for review, see Miller, 1981;
Suls and Wan, 1989). Our finding suggests that this intervention is
effective by disengaging the hippocampal formation. Heart rate changes
observed in the present study may support this interpretation. Subjects
showed heart rate decreases during HA and increases during LA. The
defense cascade model (Lang et al., 2000) suggests that with decreasing
defensive distance (i.e., increasing certainty about the impending
aversive event), heart rate first decreases, and then increases
relative to baseline. Similarly, Obrist (1981) reports that behavioral
conflict leads to cardiodeceleration, whereas reliable prediction of an
aversive outcome results in cardioacceleration.
Anxiety has been defined as "... apprehension, tension, or
uneasiness that stems from the anticipation of danger. The
manifestations of anxiety ... include motor tension, autonomic
hyperactivity, apprehensive expectation, and vigilance and
scanning... " (American Psychiatric Association, 1987, p. 392).
Thus, anxiety is defined by the shaping of cognitive and other
processes toward detecting and eliminating threat (Keogh et al., 2001),
and therefore provides a more specific explanation of our results than
its component processes in their general form (e.g.,
"expectation"). In addition, the hypoalgesic effect of anxiolytic
drugs makes it appear unlikely that, in the present study, any of the
component processes make an important hyperalgesic contribution
independently of the state of anxiety.
Conclusion
The present study showed that anxiety-induced hyperalgesia is
associated with activation in the entorhinal cortex of the hippocampal formation. This is consistent with the Gray-McNaughton theory, which
proposes that during anxiety, the hippocampal formation increases the
valence of aversive events to prime behavioral responses adaptive to
the worst possible outcome. Our observation helps to interpret
anatomical, neuropharmacological, and electrophysiological evidence
implicating the hippocampal formation in pain modulation. Our finding
suggests that accurate preparatory information during medical and
dental procedures alleviates pain by disengaging the hippocampal
formation. Searching for interventions to specifically modulate
hippocampal activation offers an approach to identifying new treatments
for procedural pain and some forms of chronic pain.
| |
FOOTNOTES |
Received Aug. 7, 2001; revised Sept. 26, 2001; accepted Oct. 2, 2001.
We thank Michael Fanselow, Gary Van Hoesen, Stuart Derbyshire, and
Predrag Petrovic for helpful comments. A.P. holds a Junior Research
Fellowship at Merton College (Oxford, UK), and I.T. and the Oxford
Centre for Functional Magnetic Resonance Imaging of the Brain are
funded by the Medical Research Council (UK).
Correspondence should be addressed to Alexander Ploghaus, Department of
Neuroradiology, Massachusetts General Hospital and Harvard
Medical School, 13th Street, Building 149, Charlestown, MA 02129. E-mail: ploghaus{at}nmr.mgh.harvard.edu.
| |
REFERENCES |
-
Al Absi M,
Rokke PD
(1991)
Can anxiety help us tolerate pain?
Pain
46:43-51[Web of Science][Medline].
-
Amaral DG,
Insausti R
(1990)
Hippocampal formation.
In: The human nervous system (Paxinos G,
ed), pp 711-755. San Diego, CA: Academic.
-
American Psychiatric Association
(1987)
In: Diagnostic and statistical manual of mental disorders (Ed 3, revised). Washington: APA.
-
Archer DP,
Roth SH
(1997)
Pharmacodynamics of thiopentone: nocifensive reflex threshold changes correlate with hippocampal electroencephalography.
Br J Anaesth
79:744-749[Abstract/Free Full Text].
-
Becerra LR,
Breiter HC,
Stojanovic M,
Fishman S,
Edwards A,
Comite AR,
Gonzales 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].
-
Beckmann C,
Noble J,
Smith S
(2000)
Artefact detection in FMRI data using independent component analysis.
NeuroImage
11:614.
-
Birn RM,
Bandettini PA,
Cox RW,
Shaker R
(1999)
Event-related fMRI of tasks involving brief motion.
Hum Brain Mapp
7:106-114[Web of Science][Medline].
-
Brown GD,
Yamada S,
Sejnowski TJ
(2001)
Independent component analysis at the neural cocktail party.
Trends Neurosci
24:54-63[Web of Science][Medline].
-
Büchel C,
Morris J,
Dolan RJ,
Friston KJ
(1998)
Brain systems mediating aversive conditioning: an event-related fMRI study.
Neuron
20:947-957[Web of Science][Medline].
-
Büchel C,
Dolan RJ,
Armony JL,
Friston KJ
(1999)
Amygdala-hippocampal involvement in human aversive trace conditioning revealed through event-related functional magnetic resonance imaging.
J Neurosci
19:10869-10876[Abstract/Free Full Text].
-
Bush G,
Luu P,
Posner MI
(2000)
Cognitive and emotional influences in anterior cingulate cortex.
Trends Cogn Sci
4:215-222[Web of Science][Medline].
-
Casey KL
(1999)
Forebrain mechanisms of nociception and pain: analysis through imaging.
Proc Natl Acad Sci USA
96:7668-7674[Abstract/Free Full Text].
-
Casey KL,
Morrow TJ,
Lorenz J,
Minoshima S
(2001)
Temporal and spatial dynamics of human forebrain activity during heat pain: analysis by positron emission tomography.
J Neurophysiol
85:951-959[Abstract/Free Full Text].
-
Ceccarelli I,
Casamenti F,
Massafra C,
Pepeu G,
Scali C,
Aloisi AM
(1999)
Effects of novelty and pain on behavior and hippocampal extracellular ACh levels in male and female rats.
Brain Res
815:169-176[Web of Science][Medline].
-
Chun MM,
Phelps EA
(1999)
Memory deficits for implicit contextual information in amnesic subjects with hippocampal damage.
Nat Neurosci
2:844-847[Web of Science][Medline].
-
Coghill RC,
Sang CN,
Maisog JM,
Iadarola MJ
(1999)
Pain intensity processing within the human brain: a bilateral, distributed mechanism.
J Neurophysiol
82:1934-1943[Abstract/Free Full Text].
-
Coghill RC,
Gilron I,
Iadarola MJ
(2001)
Hemispheric lateralization of somatosensory processing.
J Neurophysiol
85:2602-2612[Abstract/Free Full Text].
-
Cohen MS
(1997)
Parametric analysis of fMRI data using linear systems methods.
NeuroImage
6:93-103[Web of Science][Medline].
-
Craig AD,
Reiman EM,
Evans A,
Bushnell MC
(1996)
Functional imaging of an illusion of pain.
Nature
384:258-260[Medline].
-
Craig AD,
Chen K,
Bandy D,
Reiman EM
(2000)
Thermosensory activation of insular cortex.
Nat Neurosci
3:184-190[Web of Science][Medline].
-
Davis KD
(2000)
Studies of pain using functional magnetic resonance imaging.
In: Pain imaging. Progress in pain research and management, Vol 18 (Casey KL,
Bushnell MC,
eds), pp 195-210. Seattle: IASP.
-
Davis KD,
Kwan CL,
Crawley AP,
Mikulis DJ
(1998a)
Event-related fMRI of pain: entering a new era in imaging pain.
NeuroReport
9:3019-3023[Web of Science][Medline].
-
Davis KD,
Kwan CL,
Crawley AP,
Mikulis DJ
(1998b)
Functional MRI study of thalamic and cortical activations evoked by cutaneous heat, cold, and tactile stimuli.
J Neurophysiol
80:1533-1546[Abstract/Free Full Text].
-
Dellemijn PL,
Fields HL
(1994)
Do benzodiazepines have a role in chronic pain management?
Pain
57:137-152[Web of Science][Medline].
-
Derbyshire SWG,
Jones AKP,
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].
-
Elliott R,
Friston KJ,
Dolan RJ
(2000)
Dissociable neural responses in human reward systems.
J Neurosci
20:6159-6165[Abstract/Free Full Text].
-
Fanselow MS
(1985)
Odors released by stressed rats produce opioid analgesia in unstressed rats.
Behav Neurosci
99:589-592[Web of Science][Medline].
-
Fiore M,
Talamini L,
Angelucci F,
Koch T,
Aloe L,
Korf J
(1999)
Prenatal methylazoxymethanol acetate alters behavior and brain NGF levels in young rats: a possible correlation with the development of schizophrenia-like deficits.
Neuropharmacology
38:857-869[Web of Science][Medline].
-
Friston K,
Holmes AP,
Worsley K,
Poline JB,
Frith C,
Frackowiak RSJ
(1995)
Statistical parametric maps in functional imaging: a general linear approach.
Hum Brain Mapp
2:189-210.
-
Funahashi M,
He YF,
Sugimoto T,
Matsuo R
(1999)
Noxious tooth pulp stimulation suppresses c-fos expression in the rat hippocampal formation.
Brain Res
827:215-220[Web of Science][Medline].
-
Gelnar PA,
Krauss BR,
Sheehe PR,
Szeverenyi NM,
Apkarian AV
(1999)
A comparative fMRI study of cortical representations for thermal painful, vibrotactile, and motor performance tasks.
NeuroImage
10:460-482[Web of Science][Medline].
-
Gracely RH,
McGrath P,
Dubner R
(1978)
Validity and sensitivity of ratio scales of sensory and affective verbal pain descriptors: manipulation of affect by diazepam.
Pain
5:19-29[Web of Science][Medline].
-
Gracely RH,
Naliboff BD
(1996)
Measurement of pain sensation.
In: Pain and touch. Handbook of perception and cognition (Kruger L,
ed), pp 243-313. San Diego, CA: Academic.
-
Grachev ID,
Fredickson BE,
Apkarian AV
(2001)
Dissociating anxiety from pain: mapping the neuronal marker N-acetyl aspartate to perception distinguishes closely interrelated characteristics of chronic pain.
Mol Psychiatry
6:256-260[Web of Science][Medline].
-
Gray JA,
McNaughton N
(2000)
In: The neuropsychology of anxiety. Oxford: Oxford UP.
-
Gross RT,
Collins FL
(1981)
On the relationship between anxiety and pain: a methodological confounding.
Clin Psychol Rev
1:375-386.
-
Hebben N,
Corkin S,
Eichenbaum H,
Shedlack K
(1985)
Diminished ability to interpret and report internal states after bilateral medial temporal resection: case H.M.
Behav Neurosci
99:1031-1039[Web of Science][Medline].
-
Helmstetter FJ
(1992)
The amygdala is essential for the expression of conditioned hypoalgesia.
Behav Neurosci
106:518-528[Web of Science][Medline].
-
Hofbauer RK,
Rainville P,
Duncan GH,
Bushnell MC
(2001)
Cortical representation of the sensory dimension of pain.
J Neurophysiol
86:402-411[Abstract/Free Full Text].
-
Hsieh JC,
Ståhle-Bäckdahl M,
Hägermark Ö,
Stone-Elander S,
Rosenquist G,
Ingvar M
(1995)
Traumatic nociceptive pain activates the hypothalamus and the periaqueductal gray: a positron emission tomography study.
Pain
64:303-314.
-
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].
-
Hurd YL
(1996)
Differential messenger RNA expression of prodynorphin and proenkephalin in the human brain.
Neuroscience
72:767-783[Web of Science][Medline].
-
Iadarola MJ,
Berman KF,
Zeffiro TA,
Byas-Smith MG,
Gracely RH,
Max MB,
Bennett GJ
(1998)
Neural activation during acute capsaicin-evoked pain and allodynia assessed with PET.
Brain
121:931-947[Abstract/Free Full Text].
-
Insausti R,
Amaral DG,
Cowan WM
(1987)
The entorhinal cortex of the monkey: II. Cortical afferents.
J Comp Neurol
264:356-395[Web of Science][Medline].
-
Insausti R,
Juottonen K,
Soininen H,
Insausti AM,
Partanen K,
Vainio P,
Laakso MP,
Pitkänen A
(1998)
MR volumetric analysis of the human entorhinal, perirhinal, and temporopolar cortices.
Am J Neuroradiol
19:659-671[Abstract].
-
Janssen SA,
Arntz A
(1999)
No interactive effect of naltrexone and benzodiazepines on pain during phobic fear.
Behav Res Ther
37:77-86[Web of Science][Medline].
-
Jenkinson M,
Smith SM
(2001)
A global optimisation method for robust affine registration of brain images.
Med Image Anal
5:143-156[Web of Science][Medline].
-
Johansen JP,
Fields HL,
Manning BH
(2001)
The affective component of pain in rodents: direct evidence for a contribution of the anterior cingulate cortex.
Proc Natl Acad Sci USA
98:8077-8082[Abstract/Free Full Text].
-
Josephs O,
Turner R,
Friston KJ
(1997)
Event-related fMRI.
Hum Brain Mapp
5:243-248.
-
Kain ZN,
Sevarino F,
Alexander GM,
Pincus S,
Mayes LC
(2000)
Preoperative anxiety and postoperative pain in women undergoing hysterectomy-a repeated measures design.
J Psychosom Res
49:417-422[Web of Science][Medline].
-
Keogh E,
Ellery D,
Hunt C,
Hannent I
(2001)
Selective attentional bias for pain-related stimuli amongst pain fearful individuals.
Pain
91:91-100[Web of Science][Medline].
-
King TE,
Joynes RL,
Meagher MW,
Grau JW
(1996)
Impact of shock on pain reactivity. II. Evidence for enhanced pain.
J Exp Psychol Anim Behav Proc
22:265-278[Web of Science][Medline].
-
Lang PJ,
Davis M,
Öhman A
(2000)
Fear and anxiety: animal models and human cognitive psychophysiology.
J Affect Disord
61:137-159[Web of Science][Medline].
-
Lathe R
(2001)
Hormones and the hippocampus.
J Endocrinol
169:205-231[Abstract].
-
Lavenex P,
Amaral DG
(2000)
Hippocampal-neocortical interaction: a hierarchy of associativity.
Hippocampus
10:420-430[Web of Science][Medline].
-
Maier SF
(1986)
Stressor controllability and stress-induced analgesia.
Ann NY Acad Sci
467:55-72[Web of Science][Medline].
-
McKenna JE,
Melzack R
(1992)
Analgesia produced by lidocaine microinjection into the dentate gyrus.
Pain
49:105-112[Web of Science][Medline].
-
Melzack R
(1973)
In: The puzzle of pain. New York: Basic Books.
-
Melzack R,
Casey KL
(1968)
Sensory, motivational, and central control determinants of pain.
In: The skin senses (Kenshalo DR,
ed), pp 423-439. Springfield, IL: Thomas.
-
Miller SM
(1981)
Predictability and human stress: toward a clarification of evidence and theory.
In: Advances in experimental social psychology, vol. 14 (Berkowitz L,
ed), pp 203-256. New York: Academic.
-
Morris JS,
Öhman A,
Dolan RJ
(1998)
Conscious and unconscious emotional learning in the human amygdala.
Nature
393:467-470[Medline].
-
Naliboff BD,
Derbyshire SWG,
Munakata J,
Berman S,
Mandelkern M,
Chang L,
Mayer EA
(2001)
Cerebral activation in patients with irritable bowel syndrome and control subjects during rectosigmoid stimulation.
Psychosom Med
63:365-375[Abstract/Free Full Text].
-
Obrist PA
(1981)
In: Cardiovascular psychophysiology, a perspective. New York: Plenum.
-
O'Doherty J,
Kringelbach ML,
Rolls ET,
Hornak J,
Andrews C
(2001)
Abstract reward and punishment representations in the human orbitofrontal cortex.
Nat Neurosci
4:95-102[Web of Science][Medline].
-
Pearse D,
Mirza A,
Leah J
(2001)
Jun, Fos and Krox in the hippocampus after noxious stimulation: simultaneous-input-dependent expression and nuclear speckling.
Brain Res
894:193-208[Web of Science][Medline].
-
Petrovic P,
Petersson KM,
Ghatan PH,
Stone-Elander S,
Ingvar M
(2000)
Pain-related cerebral activation is altered by a distracting cognitive task.
Pain
85:19-30[Web of Science][Medline].
-
Peyron R,
García-Larrea L,
Grégoire MC,
Costes N,
Convers P,
Lavenne F,
Mauguière F,
Michel D,
Laurent B
(1999)
Haemodynamic brain responses to acute pain in humans: sensory and attentional networks.
Brain
122:1765-1779[Abstract/Free Full Text].
-
Peyron R,
Laurent B,
García-Larrea L
(2000)
Functional imaging of brain responses to pain. A review and meta-analysis.
Neurophysiol Clin
30:263-288[Web of Science][Medline].
-
Ploghaus A,
Tracey I,
Gati JS,
Clare S,
Menon RS,
Matthews PM,
Rawlins JNP
(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 JNP,
Matthews PM
(2000)
Learning about pain: the neural substrate of the prediction error for aversive events.
Proc Natl Acad Sci USA
97:9281-9286[Abstract/Free Full Text].
-
Porro CA,
Cettolo V,
Francescato MP,
Baraldi P
(1998)
Temporal and intensity coding of pain in human cortex.
J Neurophysiol
80:3312-3320[Abstract/Free Full Text].
-
Prado WA,
Roberts MH
(1985)
An assessment of the antinociceptive and aversive effects of stimulating identified sites in the rat brain.
Brain Res
340:219-228[Web of Science][Medline].
-
Price DD
(1988)
In: Psychological and neural mechanisms of pain. New York: Raven.
-
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].
-
Rauch SL,
Savage CR,
Alpert NM,
Miguel EC,
Baer L,
Breiter HC,
Fischman AJ,
Manzo PA,
Moretti C,
Jenike MA
(1995)
A positron emission tomographic study of simple phobic symptom provocation.
Arch Gen Psychiatry
52:20-28[Abstract/Free Full Text].
-
Reiman EM,
Fusselman MJ,
Fox PT,
Raichle ME
(1989)
Neuroanatomical correlates of anticipatory anxiety.
Science
243:1071-1074[Abstract/Free Full Text].
-
Rhudy JL,
Meagher MW
(2000)
Fear and anxiety: divergent effects on human pain thresholds.
Pain
84:65-75[Web of Science][Medline].
-
Sawamoto N,
Honda M,
Okada T,
Hanakawa T,
Kanda M,
Fukuyama H,
Konishi J,
Shibasaki H
(2000)
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.
J Neurosci
20:7438-7445[Abstract/Free Full Text].
-
Schneider F,
Habel U,
Holthusen H,
Kessler C,
Posse S,
Müller-Gärtner HW,
Arndt JO
(2001)
Subjective ratings of pain correlate with subcortical-limbic blood flow: an fMRI study.
Neuropsychobiology
43:175-185[Web of Science][Medline].
-
Schumacher R,
Velden M
(1984)
Anxiety, pain experience, and pain report: a signal detection study.
Percept Mot Skills
58:339-349[Web of Science][Medline].
-
Sinha R,
Sharma R,
Mathur R,
Nayar U
(1999)
Hypothalamo-limbic involvement in modulation of tooth-pump stimulation evoked nociceptive response in rats.
Indian J Physiol Pharmacol
43:323-331[Medline].
-
Sternbach RA
(1968)
In: Pain: a psychophysiological analysis. New York: Academic.
-
Suls J,
Wan CK
(1989)
Effect of sensory and procedural information on coping with stressful medical procedures and pain: a meta-analysis.
J Consult Clin Psychol
57:372-379[Web of Science][Medline].
-
Talairach J,
Tournoux P
(1988)
In: Co-planar stereotaxic atlas of the human brain. Stuttgart, Germany: Thieme.
-
Tölle TR,
Kaufmann T,
Siessmeier T,
Lautenbacher S,
Berthele A,
Munz F,
Zieglgänsberger W,
Willoch F,
Schwaiger M,
Conrad B,
Bartenstein P
(1999)
Region-specific encoding of sensory and affective components of pain in the human brain: a positron emission tomography correlation analysis.
Ann Neurol
45:40-47[Web of Science][Medline].
-
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[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].
-
Treede RD,
Apkarian AV,
Bromm B,
Greenspan JD,
Lenz FA
(2000)
Cortical representation of pain: functional characterization of nociceptive areas near the lateral sulcus.
Pain
87:113-119[Web of Science][Medline].
-
van den Hout JH,
Vlaeyen JW,
Houben RM,
Soeters AP,
Peters ML
(2001)
The effects of failure feedback and pain-related fear on pain report, pain tolerance, and pain avoidance in chronic low back pain patients.
Pain
92:247-257[Web of Science][Medline].
-
Van Hoesen GW
(1995)
Anatomy of the medial temporal lobe.
Magn Reson Imaging
13:1047-1055[Web of Science][Medline].
-
Vogt BA,
Derbyshire S,
Jones AK
(1996)
Pain processing in four regions of human cingulate cortex localized with co-registered PET and MR imaging.
Eur J Neurosci
8:1461-1473[Web of Science][Medline].
-
Wei F,
Xu ZC,
Qu Z,
Milbrandt J,
Zhuo M
(2000)
Role of EGR1 in hippocampal synaptic enhancement induced by tetanic stimulation and amputation.
J Cell Biol
149:1325-1334[Abstract/Free Full Text].
-
Weisenberg M,
Aviram O,
Wolf Y,
Raphaeli N
(1984)
Relevant and irrelevant anxiety in the reaction to pain.
Pain
20:371-383[Web of Science][Medline].
-
Witter MP,
Naber PA,
van Haeften T,
Machielsen WC,
Rombouts SA,
Barkhof F,
Scheltens P,
Lopes da Silva FH
(2000)
Cortico-hippocampal communication by way of parallel parahippocampal-subicular pathways.
Hippocampus
10:398-410[Web of Science][Medline].
-
Woolrich M,
Ripley B,
Brady J,
Smith S
(2000)
Nonparametric estimation of temporal autocorrelation in FMRI.
NeuroImage
11:610.
-
Zheng F,
Khanna S
(1999)
Morphine reversed formalin-induced CA1 pyramidal cell suppression via an effect on septohippocampal neural processing.
Neuroscience
89:61-71[Web of Science][Medline].
Copyright © 2001 Society for Neuroscience 0270-6474/01/21249896-08$05.00/0
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100(6):
827 - 833.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. J. Coen, L. J. Gregory, L. Yaguez, E. Amaro Jr., M. Brammer, S. C. R. Williams, and Q. Aziz
Reproducibility of human brain activity evoked by esophageal stimulation using functional magnetic resonance imaging
Am J Physiol Gastrointest Liver Physiol,
July 1, 2007;
293(1):
G188 - G197.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. Papo, A. Douiri, F. Bouchet, J.-C. Bourzeix, J.-P. Caverni, and P.-M. Baudonniere
Time-Frequency Intracranial Source Localization of Feedback-Related EEG Activity in Hypothesis Testing
Cereb Cortex,
June 1, 2007;
17(6):
1314 - 1322.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Suzuki, M. Amata, G. Sakaue, S. Nishimura, T. Inoue, M. Shibata, and T. Mashimo
Experimental Neuropathy in Mice Is Associated with Delayed Behavioral Changes Related to Anxiety and Depression
Anesth. Analg.,
June 1, 2007;
104(6):
1570 - 1577.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. M. Drabant, A. R. Hariri, A. Meyer-Lindenberg, K. E. Munoz, V. S. Mattay, B. S. Kolachana, M. F. Egan, and D. R. Weinberger
Catechol O-methyltransferase Val158Met Genotype and Neural Mechanisms Related to Affective Arousal and Regulation
Arch Gen Psychiatry,
December 1, 2006;
63(12):
1396 - 1406.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Meunier, L. Cirilli, and J. Bachevalier
Responses to affective stimuli in monkeys with entorhinal or perirhinal cortex lesions.
J. Neurosci.,
July 19, 2006;
26(29):
7718 - 7722.
[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]
|
|
|
|
|
|
|
M. J. Farrell, G. F. Egan, F. Zamarripa, R. Shade, J. Blair-West, P. Fox, and D. A. Denton
Unique, common, and interacting cortical correlates of thirst and pain
PNAS,
February 14, 2006;
103(7):
2416 - 2421.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Koyama, J. G. McHaffie, P. J. Laurienti, and R. C. Coghill
The subjective experience of pain: Where expectations become reality
PNAS,
September 6, 2005;
102(36):
12950 - 12955.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. Dunckley, R. G. Wise, M. Fairhurst, P. Hobden, Q. Aziz, L. Chang, and I. Tracey
A Comparison of Visceral and Somatic Pain Processing in the Human Brainstem Using Functional Magnetic Resonance Imaging
J. Neurosci.,
August 10, 2005;
25(32):
7333 - 7341.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
I Tracey and P Dunckley
Importance of anti- and pro-nociceptive mechanisms in human disease
Gut,
November 1, 2004;
53(11):
1553 - 1555.
[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]
|
|
|
|
|
|
|
M. C. Borras, L. Becerra, A. Ploghaus, J. M. Gostic, A. DaSilva, R. G. Gonzalez, and D. Borsook
FMRI Measurement of CNS Responses to Naloxone Infusion and Subsequent Mild Noxious Thermal Stimuli in Healthy Volunteers
J Neurophysiol,
June 1, 2004;
91(6):
2723 - 2733.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. D. Wager, J. K. Rilling, E. E. Smith, A. Sokolik, K. L. Casey, R. J. Davidson, S. M. Kosslyn, R. M. Rose, and J. D. Cohen
Placebo-Induced Changes in fMRI in the Anticipation and Experience of Pain
Science,
February 20, 2004;
303(5661):
1162 - 1167.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. Becerra, M. Iadarola, and D. Borsook
CNS Activation by Noxious Heat to the Hand or Foot: Site-Dependent Delay in Sensory But Not Emotion Circuitry
J Neurophysiol,
January 1, 2004;
91(1):
533 - 541.
[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]
|
|
|
|
|
TOP
ABSTRACT
INTRODUCTION
