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Placebo-Induced Changes in fMRI in the Anticipation and Experience of Pain


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The experience of pain arises from both physiological and psychological factors, including one's beliefs and expectations. Thus, placebo treatments that have no intrinsic pharmacological effects may produce analgesia by altering expectations. However, controversy exists regarding whether placebos alter sensory pain transmission, pain affect, or simply produce compliance with the suggestions of investigators. In two functional magnetic resonance imaging (fMRI) experiments, we found that placebo analgesia was related to decreased brain activity in pain-sensitive brain regions, including the thalamus, insula, and anterior cingulate cortex, and was associated with increased activity during anticipation of pain in the prefrontal cortex, providing evidence that placebos alter the experience of pain.
(A) Time course of a single trial in Study 1. Twenty-four participants were scanned by fMRI as they received painful and nonpainful electric shocks to their right wrist. We modeled our design after a study by Ploghaus et al. (58), which allowed us to distinguish the brain's response to pain from its anticipation of pain. The experiment consisted of five blocks of 15 trials. Each trial lasted 30 s and began with a 3-s warning cue-a red or blue spiral icon-that indicated whether the upcoming shock would be intense or mild, respectively (18). An ensuing anticipation epoch varied between 3 and 12 s, and was followed by a 6-s epoch of either intense or mild shock. After the shock, participants rated the intensity of the shock on a 10-point scale, followed by a variable rest period until the end of the trial. Shocks were randomly omitted on one-third of all trials, in order to increase the number of total test trials without compromising expectations regarding pain. Participants were told that they were taking part in a study of brain responses to a new analgesic cream. In the first block of trials, participants received shocks without any treatment. After Block 1, an investigator applied a skin cream to the participant's right wrist with the participant still in the scanner. Half the participants were told that this was an analgesic cream that would reduce but not eliminate the pain of the shocks. After Blocks 2 and 3 were completed in this placebo condition, the cream was removed and the same cream was reapplied. Then participants were told that the cream was actually a different, ineffective cream needed as a control. Participants then completed Blocks 4 and 5. For the other half of the participants, we reversed the order of placebo and control conditions. Our measures of the placebo effect were the differences in reported ratings of pain and regional brain activity in the control versus placebo conditions (controlplacebo in both behavior and brain). During pain and rest periods, participants saw a fixation cross. (B) Time course of a trial in Study 2. The design was similar to that of Study 1, with the following differences. The cue was the words "Get ready!" in red letters (1 s duration). A painful thermal stimulus was applied for 20 s (17 s peak, 1.5 s ramp up/down), allowing us to analyze pain responses in three separate segments (early, peak, and late). Different patches of skin on the left forearm (38) were treated with placebo and control topical creams (which were identical). Thermal stimuli were applied to these patches of skin in three phases. During the calibration phase, the stimulus was varied to identify temperatures corresponding to reported pain levels of 2, 5, and 8 on a 10-point scale (1 just painful; 10 unbearable pain) for each participant (59). This was followed by the manipulation phase, included to enhance
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DOI: 10.1126/science.1093065
, 1162 (2004); 303Science
et al.Tor D. Wager,
Anticipation and Experience of Pain
Placebo-Induced Changes in fMRI in the (this information is current as of November 16, 2006 ):
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from the German Academy of Natural Sciences
Leopoldina, Halle, with the grant BMBF-LPD 9901/8-
73 from the Ministry of Education and Science, by the
Wellcome Department of Imaging Neuroscience, and
by the University College of London. R.J.D. and C.D.F.
are in receipt of Wellcome Trust program grants. We
thank S. Kiebel, J. Schultz, K. Wiech, R. Kalisch, P.
Aston, E. Featherstone, and P. Allen for their help.
Supporting Online Material
Materials and Methods
Fig. S1
Tables S1 to S5
11 November 2003; accepted 23 December 2003
Placebo-Induced Changes in fMRI
in the Anticipation and
Experience of Pain
Tor D. Wager,
* James K. Rilling,
Edward E. Smith,
Alex Sokolik,
Kenneth L. Casey,
Richard J. Davidson,
Stephen M. Kosslyn,
Robert M. Rose,
Jonathan D. Cohen
The experience of pain arises from both physiological and psychological factors,
including one’s beliefs and expectations. Thus, placebo treatments that have no
intrinsic pharmacological effects may produce analgesia by altering expecta-
tions. However, controversy exists regarding whether placebos alter sensory
pain transmission, pain affect, or simply produce compliance with the sugges-
tions of investigators. In two functional magnetic resonance imaging (fMRI)
experiments, we found that placebo analgesia was related to decreased brain
activity in pain-sensitive brain regions, including the thalamus, insula, and
anterior cingulate cortex, and was associated with increased activity during
anticipation of pain in the prefrontal cortex, providing evidence that placebos
alter the experience of pain.
The idea that sensory experience is shaped
by one’s attitudes and beliefs has gained
currency among psychologists, physicians,
and the general public. Perhaps nowhere is
this more apparent than in our ability to
modulate pain perception. A special case of
this phenomenon is placebo analgesia, in
which the mere belief that one is receiving
an effective analgesic treatment can reduce
pain (15 ). Recently, some researchers
have attributed placebo effects to response
bias and/or to publication biases (6), which
raises the issue of whether placebo treat-
ments actually influence the sensory, affec-
tive, and cognitive processes that mediate
the experience of pain.
One important piece of evidence that
placebo effects are not simply due to re-
sponse or publication bias is that such ef-
fects can be reversed by the mu-opioid
antagonist naloxone (2, 3, 7 ), suggesting
that some kinds of placebo effects may be
mediated by the opioid system. However,
naloxone has also been shown to produce
hyperalgesia independent of placebo, in
some cases offsetting rather than blocking
the effects of placebo analgesia (8). Al-
though pharmacological blockade provides
suggestive evidence regarding the neuro-
chemical mechanisms mediating placebo
effects, such data do not illuminate the
nature of the information-processing sys-
tem that gives rise to such effects. Neuro-
imaging data can provide complementary
evidence of how pain processing in the
brain is affected by placebos and about the
time course of pain processing. Identifying
placebo-induced changes in brain activity
in regions associated with sensory, affec-
tive, and cognitive pain processing (9) may
provide insight into which components of
pain processing are affected by placebo. In
addition, identifying changes that occur at par-
ticular times—in anticipation of pain, early or
late during pain processing—may shed light on
how cognitive systems mediating expectancy
interact with pain and opioid systems.
In two functional magnetic resonance
imaging (fMRI) experiments (n 24 and
n 23), we examined two hypotheses re-
garding the psychological and neural mech-
anisms that underlie placebo analgesia. Our
first hypothesis was that if placebo manip-
ulations reduce the experience of pain,
pain-responsive regions of the brain should
show a reduced fMRI blood oxygen level–
dependent (BOLD) signal (a measure relat-
ed to neural activity) during pain. [Pain-
responsive regions, or the “pain matrix,”
include thalamus, somatosensory cortex,
insula, and anterior cingulate cortex (10
14).] Our second hypothesis was that pla-
cebo modulates activity of the pain matrix
by creating expectations for pain relief,
which in turn inhibit activity in pain-
processing regions. Converging evidence
suggests that the prefrontal cortex (PFC),
the dorsolateral aspect (DLPFC) in partic-
ular, acts to maintain and appropriately up-
date internal representations of goals and
expectations, which modulate processing in
other brain areas (15, 16). Thus, stronger
PFC activation during the anticipation of
pain should correlate with greater placebo-
induced pain relief as reported by participants
and greater placebo-induced reductions in neu-
ral activity within pain regions (17 ).
Placebo reduces reported pain and
brain activity in Study 1 (shock pain). The
design of Study 1 is illustrated in Fig. 1A
(see the figure legend for a description)
(18). First, to confirm that application of
shock elicited a neural response in pain-
related areas, we compared brain activity in
the intense shock versus no shock condi-
tions. This revealed activation of the classic
pain matrix (11, 14, 19, 20), including thal-
amus, primary somatosensory cortex/
primary motor cortex (S1/M1), secondary
somatosensory cortex (SII), midbrain, an-
terior insula, anterior cingulate cortex
(ACC), ventrolateral prefrontal cortex, and
cerebellum (fig. S1). As expected, activa-
tions in thalamus, S1, SII, and M1 were
larger in the left hemisphere, contralateral
to the wrist where shocks were applied,
whereas cerebellar activation was ipsilater-
al, although some bilateral activation was
observed in each of these areas. We also
Department of Psychology, University of Michi-
gan, 525 East University, Ann Arbor, MI 48109
1109, USA.
Center for the Study of Brain, Mind and
Behavior, Princeton University, Princeton, NJ
08544, USA.
Department of Neurology, Veterans
Affairs Medical Center, University of Michigan, Ann
Arbor, MI 48109, USA.
Department of Psychology,
University of Wisconsin, Madison, WI 53706, USA.
Department of Psychology, Harvard University,
Cambridge, MA 02138, USA.
Mind Brain Body and
Health Initiative, University of Texas Medical
Branch, Galveston, TX 77555, USA.
Department of
Psychology, Princeton University, Princeton, NJ
08544, USA.
*To whom correspondence should be addressed. E-mail:,
Present address: Department of Psychology, Colum-
bia University, 1190 Amsterdam Avenue, New York,
NY 10027, USA.
20 FEBRUARY 2004 VOL 303 SCIENCE www.sciencemag.org1162
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compared intense shock with mild shock to
determine which pain regions responded
more specifically to the painful aspects of
the stimulus, which produced a similar net-
work of activated regions (Fig. 1C and
table S1). These regions, which we refer to
as pain-responsive regions because they
track the magnitude of painful stimulation
(10), constituted the pain-sensitive regions
of interest (ROIs) in which we expected to
find placebo effects (21). Anticipation of
shock activated contralateral S1, SII, M1,
and dorsal amygdala (fig. S2).
Turning to placebo effects, we first as-
sessed the placebo effect based on partici-
pants reports, calculated as the difference
between the average rating of intense
shocks in the placebo and control condi-
tions. Reported pain was greater for control
than for placebo conditions across partici-
pants (x¯ 0.21, ␴⫽0.47, t(23) 2.20,
P 0.05), indicating a significant analge-
sic effect of the placebo. However, the
relatively high variability in the placebo
response across participants (only 8 of the
24 participants both showed a placebo ef-
fect in our measure and reported some pain
relief in a postsession debriefing) allowed
us to examine correlations between mea-
sures of reported pain relief and corre-
sponding neural responses, as discussed be-
low. In contrast to intense shocks, we found
no placebo effect for the ratings of mild
shocks for the group as a whole [x¯ 0.04,
␴⫽0.54, t(23) 0.36], and thus will not
further discuss findings from this condition.
Our first prediction was that the placebo
treatment would attenuate activation within
pain ROIs. We found that the magnitude of
the reduction between control and placebo
trials in reported pain (hereafter referred to
as control placebo, a measure of experi-
enced placebo analgesia) correlated with
the magnitude of reduction in neural activ-
ity during the shock period (control pla-
cebo, a measure of placebo analgesia in the
brain) in pain-responsive portions of sever-
al brain structures. These structures includ-
ed the rostral anterior cingulate cortex
(rACC) at the junction between rostral and
caudal ACC (r 0.66), contralateral insula
(r 0.59), and the contralateral thalamus
(r 0.53) (22). These findings were all
significant at P 0.005, and are shown in
Fig. 2A, C, and E, respectively. [All brain-
behavior correlations we report compare
the magnitudes of placebo effects (control
placebo) on reported pain with magnitudes
of placebo effects in neural activity (control
placebo).] Because the thalamus is the
major cortical relay for afferent pain fibers,
this correlation is predicted by theories of
placebo that hypothesize inhibition of af-
ferent sensory pain transmission (23). The
insula has been associated with both the
sensory-discriminative and affective com-
ponents of pain (10, 24 ), and the rACC has
been shown to track changes in reported
pain induced by hypnosis (25 ), at coordi-
nates [7 20 29], 5 mm from the center of
our activation.
Placebo increases prefrontal activity in
anticipation of painful shock. To evaluate
our second hypothesisthat expectation of
pain relief is represented in PFC and medi-
ates placebo analgesiawe examined cor-
relations between reported placebo effects
in ratings (control placebo) and fMRI
activity in the anticipation period (place-
bo control). We restricted our analysis to
DLPFC and orbitofrontal cortex (OFC),
Fig. 1. (A) Time course of a single trial in Study 1. Twenty-four
participants were scanned by fMRI as they received painful and
nonpainful electric shocks to their right wrist. We modeled our
design after a study by Ploghaus et al.(58), which allowed us to
distinguish the brain’s response to pain from its anticipation of
pain. The experiment consisted of five blocks of 15 trials. Each
trial lasted 30 s and began with a 3-s warning cue—a red or blue
spiral icon—that indicated whether the upcoming shock would
be intense or mild, respectively (18). An ensuing anticipation
epoch varied between 3 and 12 s, and was followed by a 6-s
epoch of either intense or mild shock. After the shock, partici-
pants rated the intensity of the shock on a 10-point scale,
followed by a variable rest period until the end of the trial.
Shocks were randomly omitted on one-third of all trials, in order
to increase the number of total test trials without compromis-
ing expectations regarding pain. Participants were told that they
were taking part in a study of brain responses to a new analgesic
cream. In the first block of trials, participants received shocks
without any treatment. After Block 1, an investigator applied a
skin cream to the participant’s right wrist with the participant
still in the scanner. Half the participants were told that this was
an analgesic cream that would reduce but not eliminate the pain
of the shocks. After Blocks 2 and 3 were completed in this
placebo condition, the cream was removed and the same cream
was reapplied. Then participants were told that the cream was
actually a different, ineffective cream needed as a control. Participants
then completed Blocks 4 and 5. For the other half of the participants, we
reversed the order of placebo and control conditions. Our measures of the
placebo effect were the differences in reported ratings of pain and
regional brain activity in the control versus placebo conditions (control
placebo in both behavior and brain). During pain and rest periods,
participants saw a fixation cross. (B) Time course of a trial in Study 2. The
design was similar to that of Study 1, with the following differences. The
cue was the words “Get ready!” in red letters (1 s duration). A painful
thermal stimulus was applied for 20 s (17 s peak, 1.5 s ramp up/down),
allowing us to analyze pain responses in three separate segments (early,
peak, and late). Different patches of skin on the left forearm (38) were
treated with placebo and control topical creams (which were identical).
Thermal stimuli were applied to these patches of skin in three phases.
During the calibration phase, the stimulus was varied to identify temper-
atures corresponding to reported pain levels of 2, 5, and 8 on a 10-point
scale (1 just painful; 10 unbearable pain) for each participant (59).
This was followed by the manipulation phase, included to enhance
participants’ expectations of pain relief and thereby increase placebo
responding. In this phase, pain was surreptitiously reduced in the placebo
condition (5, 60). During one block of trials the stimuli were applied to
the placebo-treated patch of skin, and during another block the stimuli
were applied to the control-treated patch (order counterbalanced across
participants). Participants were told that all stimuli were at level 8.
However, they were administered at level 2 in the placebo-treated patch
and at level 8 in the control-treated patch. Finally, during the test phase,
two additional blocks of stimuli were administered to placebo- and
control-treated patches of skin. Again, participants were told these
were at level 8, but both were delivered at level 5, in keeping with the
paradigm used in (5). Because the stimuli were identical, any differ-
ences in reported pain (control placebo) during this phase are
attributable to placebo effects. (C) Pain-responsive regions, identified
by their significance in (intense mild stimulation) contrasts in Study
1 or Study 2. These regions were ROIs in which we looked for placebo
effects. ACC: anterior cingulate; rACC: rostral anterior cingulate; SII:
secondary somatosensory cortex; INS: insula; TH: thalamus.
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based on our hypothesis. OFC is thought to
play an important role in configuring con-
trol mechanisms and learning based on re-
ward information (2631). Regions within
bilateral DLPFC showed significant corre-
lations [r 0.62 within both left (L) and
right (R) hemispheres] (32). Regions within
bilateral OFC showed similar correlations
(OFC; r 0.65/0.76 in L/R hemispheres,
respectively) (Fig. 3B) (32). Previous re-
search (33) suggests that rACC may also
serve as a control region, because it was
activated in placebo relative to control con-
ditions. Our data support this notion, as we
also found correlations of the form de-
scribed above for rACC (32). Correlations
between reported placebo effects and pre-
frontal activation are consistent with the
hypothesis that regions involved in gener-
ating and maintaining expectations contrib-
ute to placebo-related analgesia.
We also tested for correlations between
anticipation activity in expectancy areas
and pain activity in pain regions. Negative
correlations would support the view that
prefrontal activity is an antecedent to re-
duction in pain. Placebo-induced increases
in DLPFC were correlated with placebo-
induced reductions during pain in several
regions: (i) contralateral thalamus, r
0.56/0.38 for L and R DLPFC; correla-
tions whose absolute value is greater than
0.4 are significant at P 0.05; (ii) insula,
r ⫽⫺0.59/0.26 for L and R DLPFC; and
(iii) rACC, r ⫽⫺0.44/0.45 for L and R
DLPFC. Similar correlations were observed
between placebo increases in OFC and pla-
cebo reductions in pain activity: (i) thala-
mus, r ⫽⫺0.52/0.63 for L and R OFC;
(ii) insula, r ⫽⫺0.61/0.56 for L and R
OFC; (iii) rACC: r ⫽⫺0.65/0.70 for L
and R OFC.
We also found increased activity (place-
bo control) during the anticipation peri-
od in the midbrain, in the vicinity of the
periaqueductal grey (PAG), which contains
a high concentration of opiate neurons with
descending spinal efferents (23, 34). Mid-
brain placebo increases (placebo control,
at coordinates [10 26 14]) (35), were
positively correlated with both reported
placebo effects (control placebo) and
brain placebo effects (control placebo) in
some pain areas (r 0.47 for thalamus and
r 0.48 for rACC) (36 ). Furthermore,
midbrain placebo control activity was
correlated with anticipation-period activa-
tion (placebo control) of the right PFC
(r 0.51) and OFC (r 0.48/0.39 for L
and R hemispheres) (37).
Placebo reduces reported pain and brain
activity in Study 2 (thermal pain). In Study 2
we used a stronger placebo induction, a
different pain modality, and an experimen-
tal design that allowed us to analyze the
time course of placebo-related effects dur-
ing the pain epoch. These manipulations
provided greater power to test the influence
of the placebo manipulation on activation
of the pain matrix, and to test further hy-
potheses regarding the mechanisms of pla-
cebo action. For example, if placebo can
affect the pain matrix through expectation
alone, we expect such effects to occur early
during pain, whereas if placebo effects also
involve direct (e.g., opioid release) or indi-
rect (cognitive reappraisal) processes that
evolve over time (e.g., in response to the
sensory stimulus), we expect them to occur
later during pain stimulation. The sequence
of events on each trial is shown in Fig. 1B,
and other aspects of the design are dis-
cussed in the figure legend (18, 38, 39).
Fifty participants were studied using the
procedures described above before fMRI
scanning, including a manipulation phase
designed to enhance placebo-related expec-
tations. On average, placebo resulted in a
22% decrease in reported pain during the
test phase, with 72% of participants show-
ing effects in the expected direction
[t(49) 5.87, P 0.0001] (fig. S3A). This
high rate of response confirmed that we had
effectively enhanced participants belief in
the placebo. Placebo responders were invit-
ed to return for fMRI scanning (40, 41).
As in Study 1, we found significant pain
activation in expected regions (averaging
over control and placebo), shown in red in
fig. S1. These included bilateral insula,
S1/M1, SII, thalamus, and anterior and dor-
solateral PFC, as well as ACC, medial PFC,
and cerebellar vermis. Comparing intense
(level 8) pain with mild (level 2) pain
during the manipulation phase produced
activations within all of these regions (table
S1). We used these regions to test for pla-
cebo effects.
The results provided further support for
our first hypothesis, that placebo would
reduce activity in pain-responsive areas.
We expected main effects of placebo (con-
trol placebo) in Study 2, because only
placebo responders were selected as partic-
ipants; thus, the range of the placebo re-
sponse was restricted in Study 2, although
this selection procedure does not preclude
finding correlations as well. As in Study 1,
contralateral thalamus, anterior insula, and
rACC all showed significant placebo ef-
fects. In the rACC pain region (Fig. 2B),
reported placebo effects (control place-
bo) were correlated with neural placebo
effects (control placebo) in the early heat
period (r 0.58) (42). In contralateral
Fig. 2. Pain regions showing corre-
lations between placebo effects in
reported pain (control placebo)
and placebo effects in neural pain
(control placebo). (A) Rostral
anterior cingulate (rACC) effects in
Study 1. (B) rACC effects in early
heat in Study 2. (C) Contralateral
(left) insula (INS) in Study 1, z
4 mm. (D) Contralateral (right)
INS effects in Study 2, z ⫽⫺4
mm. The parahippocampal cortex
(PHCP) activations extended into
the basal forebrain and are contig-
uous with thalamic activations;
however, only thalamic activations
are in pain-sensitive regions. (E)
Contralateral INS and thalamus
(TH) in Study 1, z 6. (F) Con-
tralateral INS and TH in Study 2,
z 6 mm.
20 FEBRUARY 2004 VOL 303 SCIENCE www.sciencemag.org1164
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insula and thalamus (Fig. 2, D and F), main
effects of placebo (control placebo) were
found in the late heat period (43). Thalamic
activations extended into the basal fore-
brain and medial temporal cortex (Fig. 2E),
which has been implicated in enhanced
pain due to anxiety (44). All these placebo
activations fell within pain-sensitive regions,
consistent with the hypothesis that they reflect
modulation of the pain experience.
Time courses of neural placebo effects
(Fig. 4) show the predominant decrease late
in the pain response, after stimulus offset
(although there is a trend toward control
placebo effects earlier in stimulation as
well) (45). The late decreases suggest that
placebo effects may require a period of pain
to develop, and may modulate pain signals
most strongly after stimulation is removed.
This may be especially true of protracted
painful stimuli, such as the thermal stimu-
lus used in Study 2. The late decreases may
reflect cognitive reappraisal of the signifi-
cance of pain, resulting in decreases in pain
affect and pain experience (5, 8). Alterna-
tively, the late decreases may reflect en-
gagement of opioid mechanisms triggered
by prolonged pain.
Placebo increases prefrontal cortex
and midbrain activity in anticipation of
thermal pain. Study 2 also provided fur-
ther support for our second hypothesis, that
the expectation of pain relief is mediated by
PFC. Regions within both right and left
DLPFC, similar to those observed in Study
1 and shown in Fig. 3C, were significantly
more active during anticipation in the pla-
cebo versus control conditions (placebo
control) (46 ). Study 2 also confirmed pla-
cebo-increased activation during the antic-
ipation period of a midbrain region contain-
ing the PAG (46) (Fig. 3D), which again
correlated significantly with DLPFC activ-
ity (r 0.60 for both L and R DLPFC)
(Fig. 3E). Finally, Study 2 showed the ex-
pected placebo-induced activation of rACC
(47 ). Interestingly, this is the same area in
which we found placebo-induced decreases
during early heat, suggesting that this pain-
responsive region may also serve as part of
the network for cognitive control.
Overall impact of the studies. These
two studies provide important insights into
the neural mechanisms underlying placebo
analgesia. First, they support the hypothesis
that placebo manipulations decrease neural
responses in brain regions that are pain
sensitive. In addition, the magnitude of
these neural decreases correlates with re-
duction in reported pain. These findings
provide strong refutation of the conjecture
that placebo responses reflect nothing more
than report bias (6 ).
Our findings also provide support for a
specific hypothesis regarding one potential
mechanism of placebo action, the repre-
sentation of expectations within regions
of PFC that modulate activity in pain-
responsive areas. We found significant cor-
relations of DLPFC and OFC activity with
placebo response, measured both behavior-
ally (as the reported experience of pain)
and neurally (as activity in pain-responsive
areas). The DLPFC is an area that has
consistently been associated with the rep-
resentation and maintenance of information
needed for cognitive control (16, 48 ),
whereas the OFC is more frequently asso-
ciated with representing evaluative and re-
Fig. 3. Prefrontal re-
gions activated with
placebo during antici-
pation. Regions in
Study 1 showed posi-
tive correlations be-
tween reported place-
bo effects (placebo
control) and brain pla-
cebo effects (place-
bo control). Regions
in Study 2, in which
placebo responders
were preselected for
fMRI, showed main ef-
fects of placebo (pla-
cebo control). (A)
Right dorsolateral pre-
frontal cortex (DLPFC)
in Study 1, z 28
mm. Left DLPFC acti-
vation (found superior
to this slice) is not
shown. (B) Regions of
orbitofrontal cortex
(OFC) showing corre-
lations in Study 1, z
12. (C) Right and
left DLPFC showing
main effects (placebo control) in Study 2, z 30 mm. (D) Midbrain placebo-induced activations
(placebo control) in anticipation, z ⫽⫺10 mm, Study 2. (E) Scatterplot showing the correlation
between midbrain placebo effects and right DLPFC placebo effects in Study 1 (green triangles, solid
line) and Study 2 (blue x’s, dashed line).
Fig. 4. Time courses of pain responses for regions showing main effects of placebo (control
placebo) in late heat in Study 2. For display, time courses were extracted from regions showing a
main effect of pain at Z 4.1. (A) Group-averaged, finite impulse-response deconvolved responses
to pain for placebo (blue) and control (red) in the contralateral insula (the exact region is shown
in red in the slice at left), partialing out signal contributions from the anticipation and response
periods. Black bars show average timing of trial events, although timing varied from trial to trial.
(B) Time courses in contralateral thalamus, as in (A).
on November 16, 2006 www.sciencemag.orgDownloaded from
ward information relevant to the allocation
of control (26, 27, 29).
Previously, Petrovic et al.(33) found in-
creases in OFC in placebo during pain,
whereas the current studies found it during
anticipation (49). However, the Petrovic
study used positron emission tomography and
did not include an anticipation period, and so
could not discriminate neural responses dur-
ing anticipation from those associated with
the painful stimulus itself. Nevertheless, it
may be that the OFC is involved in processes
that occur in advance of pain only if warning
stimuli signal that pain is imminent, and oth-
erwise occur during pain itself. Affective and
motivational responses to pain are examples
of such processes.
Both DLPFC and OFC activation corre-
lated with midbrain activation during antic-
ipation, consistent with the idea that pre-
frontal mechanisms trigger opioid release
in the midbrain. An alternative interpreta-
tion is that DLPFC redirects attention away
from pain, as it has also been implicated in
general attentional processes (10, 50).
However, OFC and midbrain regions are
not typically associated with directed atten-
tion; rather, activation of these regions
seems more consistent with the view that
anticipation during placebo involves a spe-
cific expectancy process that may be relat-
ed to opioid system activation. Although
the results do not provide definitive evi-
dence for a causal role of PFC in placebo,
they were predicted by and are consistent
with the hypothesis that PFC activation
reflects a form of externally elicited top-
down control that modulates the experience
of pain.
The studies also provide additional in-
formation about which aspects of pain
sensory, affective, or cognitive evaluation
are affected by placebo. Previous studies
showing reversal of placebo effects by opi-
oid antagonists (2, 3), coupled with theories
implicating opioids in the inhibition of
spinal pain afferents (23), suggest that
placebo affects sensory pain transmission
at the earliest stages. Inhibition of spinal
afferents might be expected to produce pla-
cebo decreases throughout the pain matrix;
however, we found such reductions only in
a few regions (table S1). Our findings
provide evidence for multiple components
of expectation-induced placebo effects,
with (potentially) opioid-containing regions
in the midbrain active during anticipation,
anterior cingulate showing decreased re-
sponses early in pain, and contralateral
thalamus and insula showing decreases
only after more prolonged pain (Study 2).
Although our results are consistent with the
hypotheses that at least a part of the place-
bo effect is mediated by afferent pain fiber
inhibition, a major portion of the placebo
effect may be mediated centrally by chang-
es in specific pain regions. This account
acknowledges that pain is a psychological-
ly constructed experience that includes
cognitive evaluation of the potential for
harm and affect as well as sensory compo-
nents (24, 51).
References and Notes
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17. Expectation generation is conceptually distinct from sim-
ple direction of attention away from painful stimuli, which
has also been shown to modulate pain (5255). The critical
distinction is that expectation-induced analgesia should (i)
engage prefrontal regions primarily during anticipation of
pain; (ii) potentially activate opioid systems in the mid-
brain PAG; and (iii) activate affective regulation mecha-
nisms in OFC and anterior medial PFC (56, 57). General
attention effects, on the other hand, should be mediated
by a distributed attentional network that remains active
throughout pain and is not linked to affective regulation
and/or opioid activity.
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21. To avoid missing pain regions due to power issues, we
defined stimulation-responsive (intense-none) and
pain-responsive regions (intense-mild) as those that
responded in these comparisons in either Study 1 or
Study 2. This procedure also makes the pain masks
comparable across the two studies.
22. Placebo effects in brain (control placebo) that were
positively correlated with experienced pain (control
placebo) in stimulation-responsive ROIs (defined by
pain baseline) included rACC ([4 23 27], 27 contigu-
ous voxels, Z 3.56; and [2 32 19], 16 voxels, Z
3.12) and left (contralateral) insula ([44 14 3], 19
voxels, Z 3.04). These activations overlapped with
pain-responsive ROIs (defined by intense-mild pain) in
3, 5, and 8 voxels, respectively. Thalamic placebo effects
were just below the 10-voxel extent threshold ([11 5
14], 8 voxels, Z 2.65, 3 voxels in pain-sensitive
regions), but stronger support for thalamic involvement
was found in Study 2.
23. R. Melzack, P. D. Wall, Science 150, 971 (1965).
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29. R. Dias, T. W. Robbins, A. C. Roberts, J. Neurosci. 17,
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31. G. Schoenbaum, B. Setlow, Learn. Mem. 8, 134 (2001).
32. DLPFC correlations were [52 18 28], 42 voxels, Z 3.3; [42
6 30], 14 voxels, Z 3.3; [36 20 38], 13 voxels, Z 3.00;
[30 4 42], 22 voxels, Z 3.30. OFC correlations were
[26 38 12], 32 voxels, r 0.64; [24 30 12], 62 voxels;
r 0.79. Correlations were also found in other areas,
including rostral (rACC) and caudal (cACC) anterior cingu-
late, which may be part of an “executive” circuit mediating
cognitive control functions. rACC correlation loci were [6
14 26], 40 voxels, Z 4.23; [4 26 26], 21 voxels, Z
3.68; [10 32 32], 20 voxels, Z 3.36. The cACC correlation
locus was [2 8 24], 68 voxels, Z 3.5.
33. P. Petrovic, E. Kalso, K. M. Petersson, M. Ingvar, Science
295, 1737 (2002).
34. I. Tracey et al., J. Neurosci. 22, 2748 (2002).
35. Only one voxel was significant at P 0.005 in Study
1. However, Study 2 replicated this finding with a
substantially larger activation.
36. Pearson’s r 0.4 are significant at P 0.05.
37. If midbrain activation were related to opioid system
activity, we might expect placebo increases in activa-
tion throughout the period when participants experi-
enced pain, rather than during the period when they
anticipated it. However, pain-induced opioid release—
an endogenous response to pain expected to be greater
in the more painful control condition—may have offset
placebo increases during pain, resulting in no overall
placebo control differences.
38. Stimulation of the left arm in Study 2 (as opposed to
the right arm in Study 1) allowed us to test whether
placebo effects occurred contralateral to stimulation,
or always occurred in the same hemisphere.
39. At the conclusion of the manipulation phase, partic-
ipants were asked to rate how effective they expect-
ed the analgesic to be during subsequent testing. We
administered stimulation on separate, nonoverlap-
ping patches of skin in the calibration, manipulation,
and test phases to avoid physiological sensitization
and habituation effects due to repeated stimulation.
40. Of the 24 participants who returned, 22 reported a
reduction of pain in the placebo condition during the
fMRI scanning session, revealing a highly significant
test-retest reliability of the placebo effect (r 0.62, P).
41. Data were analyzed in the general linear model framework,
with five regressors to model BOLD responses during the
trials. Regressors were unconvolved epochs (to avoid as-
suming a particular response shape) shifted by4stoallow
for the hemodynamic lag. The five time periods modeled
were (i) early anticipation, 4 to 8 s after the cue; (ii) late
anticipation, 8 to 13 s after cue offset; (iii) early pain, 4 to
14 s after stimulation onset; (iv) peak pain, 14 to 24 s after
stimulation onset; and (v) late pain, 24 to 34 s after heat
onset (stimulation offset was at 20 s). During fMRI scan-
ning, each block of six C or P test trials constituted a
separate scanner run, and BOLD responses to anticipation
and pain were compared to the baseline interval immedi-
ately after each trial. An additional regressor for the be-
havioral response (4 to 8 s after cue to respond) was
included but not analyzed further.
42. rACC: [3 18 34], 37 contiguous voxels within pain-
responsive regions, Z 2.92.
43. The following pain-responsive regions showing placebo
effects in late heat: Right (contralateral) insula ([41 7 1],
207 voxels, Z 3.24); right medial thalamus ([2 15 9],
10 voxels, Z 2.63). Additional effects in left SII ([58
6 10], 145 voxels, Z 3.37) were found in Study 2
but not in Study 1. See table S2 for additional regions.
44. A. Ploghaus et al., J. Neurosci. 21, 9896 (2001).
45. Placebo-induced decreases in right insula and medial
thalamus pain-responsive regions were significantly
greater during the late heat period than during the
early heat period. Results from ROIs, averaging over
voxels, for the insula: 41% larger placebo decreases in
late heat; t (22) 1.75, P 0.09; for early heat,
t (22) 3.73, P 0.001 for late heat, and t(22)
2.33, P 0.05 in a paired t test for the difference. For
the thalamus: 20-fold larger placebo decreases in late
heat; t(22) 0.18. P 0.86 for early heat, t(22)
2.95, P 0.008 for late heat, and t(22) 2.94, P
0.008 in a paired t test for the difference.
46. Right DLPFC: [42 4 30], 55 voxels, Z 2.79; left
DLPFC: [42 14 30], 100 voxels, z 3.34. Midbrain:
20 FEBRUARY 2004 VOL 303 SCIENCE www.sciencemag.org1166
on November 16, 2006 www.sciencemag.orgDownloaded from
[2 26 12], 251 voxels, Z 3.56. Midbrain and
DLPFC activations did not correlate with the magni-
tude of the behavioral placebo effect in Study 2.
However, Study 2 was conducted only on placebo
responders, and so was expected to produce main
effects rather than correlations. Study 2 also failed to
replicate the correlation of OFC activity with report-
ed placebo effects. However, this may be due to the
use of spiral gradient-echo imaging at3TinStudy2,
which was subject to substantially more signal drop-
out in the relevant regions of OFC than was the
echo-planar magnetic resonance imaging sequence
used in Study 1 (fig. S4).
47. rACC placebo control: [10, 16, 20], 79 voxels, Z
2.91, 3 mm from similar findings in Study 1.
48. A. W. MacDonald III, J. D. Cohen, V. A. Stenger, C. S.
Carter, Science 288, 1835 (2000).
49. The correlation between placebo-induced increases
in OFC and reported placebo effects was significantly
greater during the anticipation period than during the
shock period (right OFC: Z ⫽⫺4.50 for anticipation,
Z 0.49 for shock, difference Z 5.01, P 0.0001;
left OFC: Z –3.55 for anticipation, Z 2.02 for
shock, difference Z 5.57, P 0.0001).
50. We also observed placebo activations (placebo control)
during pain in frontal and parietal cortical areas, consistent
with activation of a general attentional network. However,
these regions did not correlate with placebo reductions in
experienced pain in either study, and they lie outside the
scope of the current hypotheses.
51. D. D. Price, Science 288, 1769 (2000).
52. R. Peyron et al., Brain 122, 1765 (1999).
53. P. Petrovic, K. M. Petersson, P. H. Ghatan, S. Stone-
Elander, M. Ingvar, Pain 85, 19 (2000).
54. J. C. Brooks, T. J. Nurmikko, W. E. Bimson, K. D. Singh,
N. Roberts, Neuroimage 15, 293 (2002).
55. S. J. Bantick et al., Brain 125, 310 (2002).
56. E. T. Rolls, in The Cognitive Neurosciences, M. S. Gazzanaga,
Ed. (MIT Press, Cambridge, MA, 1995) pp. 1091–1106.
57. W. C. Drevets, Biol. Psychiatry 48, 813 (2000)).
58. A. Ploghaus et al., Science 284, 1979 (1999).
59. Temperatures were 45.4°C 1.1 (mean SD) for level 2,
47.0°C 0.9 for level 5, and 48.1°C 1.0 for level 8.
60. N. J. Voudouris, C. L. Peck, G. Coleman, Pain 38, 109
61. We thank J. Gelfand, R. Jones, L. Hernandez, D. Noll, K.
Newnham, and Y. Granovsky for assistance with various
aspects of these experiments. This research was spon-
sored (in part) by the Mind Brain Body and Health
Initiative, funded by the John D. and Catherine T.
MacArthur Foundation, the Rockefeller Family and As-
sociates, and the Kohlberg Foundation; by the Center
for the Study of Brain, Mind and Behavior (Princeton
University); by a NSF Graduate Research Fellowship (to
T.D.W.); and by the Programme in Cognitive Science
and Cognitive Neuroscience (University of Michigan).
Supporting Online Material
Materials and Methods
Tables S1 to S3
Figs. S1 to S5
28 October 2003; accepted 30 December 2003
Fragmentation in Massive
Star Formation
Henrik Beuther
* and Peter Schilke
Studies of evolved massive stars indicate that they form in a clustered mode.
During the earliest evolutionary stages, these regions are embedded within their
natal cores. Here we present high-spatial-resolution interferometric dust con-
tinuum observations disentangling the cluster-like structure of a young massive
star–forming region. The derived protocluster mass distribution is consistent
with the stellar initial mass function. Thus, fragmentation of the initial massive
cores may determine the initial mass function and the masses of the final stars.
This implies that stars of all masses can form via accretion processes, and
coalescence of intermediate-mass protostars appears not to be necessary.
There is a general consensus that massive
stars [8 solar masses (M
)] form exclusive-
ly in a clustered mode, but the detailed phys-
ical processes are far from clear. Although
high enough accretion rates and accretion
through disks are capable of forming mas-
sive stars, scenarios such as the merging of
intermediate-mass protostars at the dense
centers of evolving clusters are also possible
(14). Furthermore, one needs to understand
why the stellar clusters have a universal mass
spectrum that is fairly independent of envi-
ronmental conditions and how this mass
spectrum evolves. Therefore, it is crucial to
study the earliest evolutionary stages at
high spatial resolution, preferably in the
millimeter-wavelength regime, where dust
emission is strong and optically thin, tracing
all dust along the line of sight. The dust
emission is directly proportional to the col-
umn density of dense gas within the regions;
thus, observing the millimeter-continuum
emission in very young massive starforming
regions allows us to study the gas and dust
distributions, the possible fragmentation of
the larger-scale cores, and physical parame-
ters such as masses and column densities.
We recently imaged dust continuum emis-
sion at 1.3 and 3 mm from the massive
starforming region IRAS 194102336 with
the Plateau de Bure Interferometer [PdBI
(5)]. The region IRAS 194102336 is in an
early stage of high-mass star formation be-
fore forming a hot corea dense hot clump
of gas heated by a massive protostar (6 ). It is
at a distance of 2 kiloparsecs (kpc) and has
an integrated bolometric luminosity of about
solar luminosities. The region is part of a
large sample of high-mass protostellar ob-
jects that has been studied extensively at
wavelengths ranging from centimeters to x-
rays (711).
The PdBI consists of six 15-m antennas,
and we have observed the source in three
different configurations, with projected base-
line lengths between 15 and 330 m. The
two-dimensional representation of projected
baselines on the plane of the skythe uv
planeis covered extremely well in this
range, providing high image fidelity at the
corresponding spatial frequencies (12). At 1.3
mm, the synthesized beam is 1.5⬘⬘ 1⬘⬘ and
at3mmitis5.5⬘⬘ 3.5⬘⬘. Additionally, we
present single-dish 1.2-mm observations of
the same region obtained with the Institut de
Radioastronomie Milimetrique (IRAM) 30-m
telescope at 11⬘⬘ spatial resolution (8). Thus,
we are able to analyze the evolving cluster at
several spatial scales down to a linear reso-
lution of 2000 astronomical units (AU; 1⬘⬘ at
a distance of 2 kpc).
The large-scale emission observed at a
wavelength of 1.2 mm with the IRAM 30-m
telescope (Fig. 1A) shows two massive gas
cores roughly aligned in a north-south direc-
tion. Based on the single-dish intensity pro-
files, we predicted that the cores should split
up into substructures at scales between 3⬘⬘
and 5⬘⬘ (8). PdBI 3-mm data at more than
twice the spatial resolution show that both
sources split up into substructures at the pre-
viously predicted scales, about four sources
in the southern core and four in the northern
core (Fig. 1B). At the highest spatial resolu-
tion (Fig. 1, C and D), we observe that pre-
viously known gas clumps resolve into even
more subsources. We find small clusters of
gas and dust condensations with at least 12
sources per large-scale core. Each of the pro-
Harvard-Smithsonian Center for Astrophysics, 60
Garden Street, Cambridge, MA 02138, USA.
Planck-Institute for Astrophysics, Auf dem Huegel 69,
53121 Bonn, Germany.
*To whom correspondence should be addressed. E-
on November 16, 2006 www.sciencemag.orgDownloaded from
... It is through this mesolimbic circuit that pleasurable music has been found to decrease pain, as the experience of pleasure can activate endogenous opioid and dopaminergic signaling (Leknes and Tracey, 2008;Porreca and Navratilova, 2017;Laeng et al., 2021). Finally, cognitive integration in this network has been shown to provide relief from pain through corticomesolimbic interactions including subregions of the frontal cortex, ACC, amygdala, hypothalamus, NAc, periaqueductal gray matter (PAG), and rostral ventromedial medulla (RVM) (Becerra et al., 2001;Wager et al., 2004;Brodersen et al., 2012;Lee et al., 2013;Porreca and Navratilova, 2017). Our cognitive and emotional states are powerful modulators of our experience of pain and are therefore, essential elements in the examination of healthy and maladaptive pain states. ...
... In 2001, through early fMRI studies, Becerra et al. (2001) found that signaling in reward pathways (including the VTA and NAc) correlated with activity in the PAG in an early period of pain anticipation, while the pattern of concurrent signaling reverted back to default pain circuitry in late anticipation of pain. Wager et al. (2004) have since suggested that the prefrontal cortex signals to opioidergic midbrain regions during the anticipation of pain in order to dampen the pain response, and although these regions may not directly be associated with attention, the expectation of pain may involve specific opioid signaling activation. This evidence lead to Fields' "decision hypothesis" of pain anticipation where individuals must consider potential tissue damage in order for reward pathways to access early information regarding noxious stimuli, also suggesting that "reward" pathways should be renamed "decision circuitry" (Fields, 2006). ...
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Our psychological state greatly influences our perception of sensations and pain, both external and visceral, and is expected to contribute to individual pain sensitivity as well as chronic pain conditions. This investigation sought to examine the integration of cognitive and emotional communication across brainstem regions involved in pain modulation by comparing data from previous functional MRI studies of affective modulation of pain. Data were included from previous studies of music analgesia (Music), mood modulation of pain (Mood), and individual differences in pain (ID), totaling 43 healthy women and 8 healthy men. The Music and Mood studies were combined into an affective modulation group consisting of runs with music and positive-valenced emotional images plus concurrent presentation of pain, and a control group of runs with no-music, and neutral-valenced images with concurrent presentation of pain. The ID group was used as an independent control. Ratings of pain intensity were collected for each run and were analyzed in relation to the functional data. Differences in functional connectivity were identified across conditions in relation to emotional, autonomic, and pain processing in periods before, during and after periods of noxious stimulation. These differences may help to explain healthy pain processes and the cognitive and emotional appraisal of predictable noxious stimuli, in support of the Fields’ Decision Hypothesis. This study provides a baseline for current and future investigation of expanded neural networks, particularly within higher limbic and cortical structures. The results obtained by combining data across studies with different methods of pain modulation provide further evidence of the neural signaling underlying the complex nature of pain.
... Similarly, in a task-fMRI study of controllable vs. uncontrollable pain in healthy adults, increased negative connectivity between the bilateral dlPFC and painrelated regions during the controllable (thermal) pain task was associated with reduced pain, suggesting that the dlPFC suppressed activity in these regions (85). In pain-free adults, placebo analgesia was associated with increased dlPFC and orbitofrontal activation during pain anticipation, and this increased activity correlated with reduced activity in sensory regions during the pain phase, suggesting an inhibitory effect on sensory regions to reduce pain intensity (86). ...
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Background There is evidence of altered corticolimbic circuitry in adults with chronic pain, but relatively little is known of functional brain mechanisms in adolescents with neuropathic pain (NeuP). Pediatric NeuP is etiologically and phenotypically different from NeuP in adults, highlighting the need for pediatric-focused research. The amygdala is a key limbic region with important roles in the emotional-affective dimension of pain and in pain modulation. Objective To investigate amygdalar resting state functional connectivity (rsFC) in adolescents with NeuP. Methods This cross-sectional observational cohort study compared resting state functional MRI scans in adolescents aged 11–18 years with clinical features of chronic peripheral NeuP ( n = 17), recruited from a tertiary clinic, relative to healthy adolescents ( n = 17). We performed seed-to-voxel whole-brain rsFC analysis of the bilateral amygdalae. Next, we performed post hoc exploratory correlations with clinical variables to further explain rsFC differences. Results Adolescents with NeuP had stronger negative rsFC between right amygdala and right dorsolateral prefrontal cortex (dlPFC) and stronger positive rsFC between right amygdala and left angular gyrus (AG), compared to controls (P FDR <0.025). Furthermore, lower pain intensity correlated with stronger negative amygdala-dlPFC rsFC in males ( r = 0.67, P = 0.034, n = 10), and with stronger positive amygdala-AG rsFC in females ( r = −0.90, P = 0.006, n = 7). These amygdalar rsFC differences may thus be pain inhibitory. Conclusions Consistent with the considerable affective and cognitive factors reported in a larger cohort, there are rsFC differences in limbic pain modulatory circuits in adolescents with NeuP. Findings also highlight the need for assessing sex-dependent brain mechanisms in future studies, where possible.
... In our study, 50% of the patients were over the age of 50 years in the m/M group whereas in the S/S+ group, 66% of the patients were over the age of 50 years. Neuroimaging studies have revealed the anatomical proximity of brain areas controlling stress, emotion, cognition [64][65][66][67], and pain [68][69][70][71], and a placebo effect has been visualized in fMRI, where the alleviation of pain and/or negative feelings have been implicated [72][73][74]. Pain itself involves cognitive-emotional aspects and interacts with stress [64,75], and stress is largely present in many chronic pain syndromes and may increase and maintain pain in FM [76]. Another study, exploring transcranial direct current stimulation (tDCS) and its impact on quality of life (QoL) using the SF-36 questionnaire, observed a non-specific effect on this parameter, which may be due to the placebo [77]. ...
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Patients suffering from fibromyalgia often report stress and pain, with both often refractory to usual drug treatment. Magnesium supplementation seems to improve fibromyalgia symptoms, but the level of evidence is still poor. This study is a randomized, controlled, double-blind trial in fibromyalgia patients that compared once a day oral magnesium 100 mg (Chronomag®, magnesium chloride technology formula) to placebo, for 1 month. The primary endpoint was the level of stress on the DASS-42 scale, and secondary endpoints were pain, sleep, quality of life, fatigue, catastrophism, social vulnerability, and magnesium blood concentrations. After 1 month of treatment, the DASS-42 score decreased in the magnesium and placebo groups but not significantly (21.8 ± 9.6 vs. 21.6 ± 10.8, respectively, p = 0.930). Magnesium supplementation significantly reduced the mild/moderate stress subgroup (DASS-42 stress score: 22.1 ± 2.8 to 12.3 ± 7.0 in magnesium vs. 21.9 ± 11.9 to 22.9 ± 11.9 in placebo, p = 0.003). Pain severity diminished significantly (p = 0.029) with magnesium while the other parameters were not significantly different between both groups. These findings show, for the first time, that magnesium improves mild/moderate stress and reduces the pain experience in fibromyalgia patients. This suggests that daily magnesium could be a useful treatment to improve the burden of disease of fibromyalgia patients and calls for a larger clinical trial.
... On the other hand, it is also possible that the placebo system is deactivated. The placebo system is significantly influenced by the activation of the dopaminergic system and the release of endorphins and endogenic opioid system (48)(49)(50). In addition, selective attention could be an important modulator (51,52), and the specific modulator and mechanisms should be investigated in further research. ...
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Background: Reducing postoperative pain immediately after surgery is crucial because severe postoperative pain reduces quality of life and increases the likelihood that patients develop chronic pain. Even though postoperative pain has been widely studied and there are national guidelines for pain management, the postoperative course is differently from one patient to the next. Different postoperative courses could be explained by factors related to the treatment context and the patients. Preoperative emotional states and treatment expectations are significant predictors of postoperative pain. However, the interaction between emotional states and preoperative treatment expectations and their effect on postoperative pain have not yet been studied. The aim of our study was to identify the interaction between emotional states, treatment expectation and early postsurgical acute pain. Methods: In this prospective clinical trial, we enrolled patients who had received a TKR at a German hospital between October 2015 and March 2019. Patients rated their preoperative pain on a numeric rating scale (NRS) 0-10 (0 = no pain and 10 = worst pain imaginable), their emotional states preoperatively on the Pain and State of Health Inventory (PHI), their preoperative treatment expectations on the Stanford Expectation of Treatment Scale (SETS), and their postoperative level of pain on a NRS 0-10. Findings: The questionnaires were completed by 122 patients (57% female). Emotional states predict negative treatment expectation F(6, 108) = 8.32, p < 0.001, with an excellent goodness-of-fit, R2 = 0.31. Furthermore, a mediator analysis revealed that the indirect effects and therefore relationship between the emotional states sad (ab = 0.06, 95% CI[0.01, 0.14]), anxious (ab = 0.13, 95% CI[0.04, 0.22]), and irritable (ab = 0.09, 95% CI[0.03, 0.17]) and postoperative pain is fully mediated by negative treatment expectations. Whereas the emotional states tired (ab = 0.09, 95% CI[0.03, 0.17]), dizzy/numb (ab = 0.07, 95% CI[0.01, 0.20]), weak (ab = 0.08, 95% CI[0.03, 0.16] are partially mediated by negative treatment expectations. Conclusion: The relationship between emotional states and postoperative pain is mediated by negative treatment expectations. Therefore, innovative treatment strategies to reduce postoperative pain should focus on eliminating negative treatment expectation through establishing a differentiated preoperative expectation management program that also focuses on emotional states.
... Multisystem and full brain representations were the most pain predictive, most specific, and supported the greatest learning capacity across studies. Converging evidence implicates anterolateral, midbrain, and cerebellar brain systems in cognitive evaluation, more posterolateral areas in detection of physical stimulus properties, and thalamic and frontal midline regions in both cognitive and physical evaluation of painful stimuli [60,[67][68][69][70][71][72][73][74][75][76][77]. Although characterizing the diversity of pain information in the brain exceeds the scope of this study, this was precisely the scope of [78] and [79] who use Study 2 and Study 5 (respectively) to identify expectation mediators in dorsolateral PFC, amygdala, pons, and dorsal striatum, thermal stimulus mediators in somatomotor areas and cerebellum, and mediators of both components in dorsal ACC, anterior insula, and thalamus. ...
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Information is coded in the brain at multiple anatomical scales: locally, distributed across regions and networks, and globally. For pain, the scale of representation has not been formally tested, and quantitative comparisons of pain representations across regions and networks are lacking. In this multistudy analysis of 376 participants across 11 studies, we compared multivariate predictive models to investigate the spatial scale and location of evoked heat pain intensity representation. We compared models based on (a) a single most pain-predictive region or resting-state network; (b) pain-associated cortical–subcortical systems developed from prior literature (“multisystem models”); and (c) a model spanning the full brain. We estimated model accuracy using leave-one-study-out cross-validation (CV; 7 studies) and subsequently validated in 4 independent holdout studies. All spatial scales conveyed information about pain intensity, but distributed, multisystem models predicted pain 20% more accurately than any individual region or network and were more generalizable to multimodal pain (thermal, visceral, and mechanical) and specific to pain. Full brain models showed no predictive advantage over multisystem models. These findings show that multiple cortical and subcortical systems are needed to decode pain intensity, especially heat pain, and that representation of pain experience may not be circumscribed by any elementary region or canonical network. Finally, the learner generalization methods we employ provide a blueprint for evaluating the spatial scale of information in other domains.
The negative effect of prolonged cognitive demands on psychomotor skills in athletes has been demonstrated. Transcranial direct current stimulation (tDCS) could be used to mitigate this effect. This study examined the effects of tDCS over the left dorsolateral prefrontal cortex (DLPFC) during a 30-min inhibitory Stroop task on cognitive and shooting performances of professional female basketball players. Following a randomized, double-blinded, sham-controlled, cross-over design, players were assigned to receive anodal tDCS (a-tDCS, 2mA for 20 min) or sham-tDCS in two different sessions. Data from 8 players were retained for analysis. Response Time decreased significantly over time (p < 0.001; partial ƞ2 = 0.44; no effect of condition, or condition vs. time interaction). No difference in mean accuracy and shooting performance was observed between tDCS conditions. The results suggest that a-tDCS exert no additional benefits in reducing the negative effects of prolonged cognitive demands on technical performance compared to sham (placebo).
Movement limitation is a common characteristic of chronic pain such that pain prevents the very movement and activity that is most likely to promote recovery. This is particularly the case for pathological pain states such as complex regional pain syndrome (CRPS). One clinical approach to CRPS that has growing evidence of efficacy involves progressive movement imagery training. Graded Motor Imagery (GMI) targets clinical and neurophysiological effects through a stepwise progression through implicit and explicit movement imagery training, mirror therapy and then functional tasks. Here we review experiences from over 20 years of clinical and research experience with GMI. We situate GMI in terms of its historical underpinnings, the benefits and outstanding challenges of its implementation, its potential application beyond CRPS. We then review the neuropathological targets of GMI and current thought on its effects on neurophysiological biomarkers. Perspective This article provides an overview over experiences made with graded motor imagery training over the last 20 years focussing on the treatment of CRPS. It does both cover the theoretical underpinnings for this treatment approach, biomarkers which indicate potential changes driven by GMI, and experiences for achieving optimal treatment results.
Chronic pain often has an unknown cause, and many patients with chronic pain learn to accept that their pain is incurable and pharmacologic treatments are only temporarily effective. Complementary and integrative health approaches for pain are thus in high demand. One such approach is soft touch, e.g., adhesion of pyramidal thorn patches in a pain region. The effects of patch adhesion on pain relief have been confirmed in patients with various types of pain. A recent study using near-infrared spectroscopy revealed that the dorsolateral prefrontal cortex (DLPFC), especially the left side, is likely to be inactivated in patients experiencing pain relief during patch treatment. Mindfulness meditation is another well-known complementary and integrative approach for achieving pain relief. The relation between pain relief due to mindfulness meditation and changes in brain regions, including the DLPFC, has long been examined. In the present review article, we survey the literature describing the effects of the above-mentioned complementary and integrative treatments on pain relief, and outline the important brain regions, including the DLPFC, that are involved in analgesia. We hope that the present article will provide clues to researchers who hope to advance neurosensory treatments for pain relief without medication.
Objective The object of this longitudinal cohort study was to investigate whether chronotype affects the incidence of chemotherapy-induced nausea and vomiting (CINV) among patients with breast cancer. Methods The study included a total of 203 breast cancer patients who received neoadjuvant chemotherapy using a regimen of doxorubicin and cyclophosphamide with high emetogenicity. Patients received four cycles of chemotherapy in approximately three months. Patients completed questionnaires including the Munich Chronotype Questionnaire (MCTQ) before the first chemotherapy and the Multinational Association of Supportive Care in Cancer Antiemesis Tool (MAT) after each of the four chemotherapy sessions. To confirm the effect of chronotype on CINV during the four cycles, we performed statistical analyses using a generalized estimating equation (GEE). Results CINV occurred in 108 (53.2%), 112 (55.2%), 102 (50.3%), and 62 (30.5%) patients during four cycles of treatment. In the GEE approach, late and early chronotypes (vs. intermediate chronotype) were associated with an increased risk of CINV (late chronotype: odds ratio [OR], 2.06; 95% confidence interval [CI], 1.41–2.99; p < 0.001, early chronotype: OR, 1.84; CI, 1.25–2.73; p = 0.002), which remained significant even after adjusting for age, BMI, antiemetic treatment, history of nausea and vomiting, anxiety, and sleep quality. Conclusion Chronotype affected CINV across the four cycles of neoadjuvant chemotherapy in patients with breast cancer, suggesting the need to consider chronotype in predicting and managing CINV.
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Recent evidence demonstrating multiple regions of human cerebral cortex activated by pain has prompted speculation about their individual contributions to this complex experience. To differentiate cortical areas involved in pain affect, hypnotic suggestions were used to alter selectively the unpleasantness of noxious stimuli, without changing the perceived intensity. Positron emission tomography revealed significant changes in pain-evoked activity within anterior cingulate cortex, consistent with the encoding of perceived unpleasantness, whereas primary somatosensory cortex activation was unaltered. These findings provide direct experimental evidence in humans linking frontal-lobe limbic activity with pain affect, as originally suggested by early clinical lesion studies.
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Attentional set-shifting and discrimination reversal are sensitive to prefrontal damage in the marmoset in a manner qualitatively similar to that seen in man and Old World monkeys, respectively (Dias et al., 1996b). Preliminary findings have demonstrated that although lateral but not orbital prefrontal cortex is the critical locus in shifting an attentional set between perceptual dimensions, orbital but not lateral prefrontal cortex is the critical locus in reversing a stimulus-reward association within a particular perceptual dimension (Dias et al., 1996a). The present study presents this analysis in full and extends the results in three main ways by demonstrating that (1) mechanisms of inhibitory control and "on-line" processing are independent within the prefrontal cortex, (2) impairments in inhibitory control induced by prefrontal damage are restricted to novel situations, and (3) those prefrontal areas involved in the suppression of previously established response sets are not involved in the acquisition of such response sets. These findings suggest that inhibitory control is a general process that operates across functionally distinct regions within the prefrontal cortex. Although damage to lateral prefrontal cortex causes a loss of inhibitory control in attentional selection, damage to orbitofrontal cortex causes a loss of inhibitory control in affective processing. These findings provide an explanation for the apparent discrepancy between human and nonhuman primate studies in which disinhibition as measured on the Wisconsin Card Sort Test is associated with dorsolateral prefrontal damage, whereas disinhibition as measured on discrimination reversal is associated with orbitofrontal damage.
Theories of the regulation of cognition suggest a system with two necessary components: one to implement control and another to monitor performance and signal when adjustments in control are needed. Event-related functional magnetic resonance imaging and a task-switching version of the Stroop task were used to examine whether these components of cognitive control have distinct neural bases in the human brain. A double dissociation was found. During task preparation, the left dorsolateral prefrontal cortex (Brodmann's area 9) was more active for color naming than for word reading, consistent with a role in the implementation of control. In contrast, the anterior cingulate cortex (Brodmann's areas 24 and 32) was more active when responding to incongruent stimuli, consistent with a role in performance monitoring.
Studies of hypnotic and placebo analgesia have labored under a double burden. Both the independent variables of hypnotic and placebo treatments and the multiple components of pain experience, which are the dependent variables, are subjective phenomena. Partly as a consequence, precise measurement of subjective independent and dependent variables of hypnotic and placebo analgesia experiments may be considered to lack the precise control, which is present in physiological or pharmacological studies. This chapter describes an alternative view of the possibility of precise analysis and measurement of both the independent and dependent variables associated with placebo and hypnotic analgesia. In the context of providing this alternative view, a general explanation of the neural and psychological mechanisms that may underlie these forms of analgesia will be presented. An understanding of these mechanisms has implications for the treatment and management of pain. The factors that evoke pain reduction extend from psychosocial, including interactions between therapist and patient, to neurophysiological factors that influence the actual transmission of pain signals within the patient. The discussion in this chapter considers: 1. the demand characteristics of the hypnotic analgesia situation; 2. the role of hypnotic state and the possible interactions between hypnotic state and incorporation of hypnotic suggestions, and 3. psychological, and neural mechanisms that help explain hypnotic analgesia. This discussion includes a consideration of how hypnotic interventions influence the multiple dimensions of pain, and at least in a general sense, the neural processing of pain.
Brain activity was studied by fMRI in 18 healthy subjects during stimulation of the thenar eminence of the hand with either warm (non-painful, 40 degrees C) or hot (painful, 46-49 degrees C) stimuli using a contact thermode. Experiments were performed on the right and left hand independently and with two attentional contexts: subjects either attended to pain or attended to a visual global motion discrimination task (to distract them from pain). Group analysis demonstrated that attended warm stimulation of the right hand did not produce any significantly activated clusters. Painful thermal stimulation of either hand elicited significant activity over a large network of brain regions, including insula, inferior frontal gyrus, cingulate gyrus, secondary somatosensory cortex, cerebellum, and medial frontal gyrus (corrected P < 0.05). Insula activity was distributed along its anterior-posterior axis and depended on the hand stimulated and attentional context. In particular, activity within the posterior insula was contralateral to the site of stimulation, tested using regions of interest (ROI) analysis: significant side x site interaction (P = 0.001). With attention diverted from the painful stimulus bilateral anterior insula activity moved posteriorly to midinsula and decreased in extent (ROI analysis: significant main effect of attention (P = 0.03)). The role of the insula in thermosensation and attention is discussed.
Following our earlier research [37], we further investigated a model that conceptualizes placebo phenomena as the result of conditioning [40] and attempted to extend and replicate the finding that placebo responses can be conditioned in human subjects. Two groups of 10 subjects were told that they were receiving an analgesic which was in fact a placebo. During the conditioning, placebo administration was surreptitiously paired with an increase in the painful stimulus for half of the subjects and with a decrease for the other half. Subjects were tested pre and post conditioning for a placebo response. A second type of experimental pain was also used to determine stimulus generalization. The results confirmed a previous finding that placebo responses can be conditioned in human subjects. The implications for clinical practice of a learning model of placebo behavior are discussed.
Connectionist models are used to explore the relationship between cognitive deficits and biological abnormalities in schizophrenia. Schizophrenic deficits in tasks that tap attention and language processing are reviewed, as are biological disturbances involving prefrontal cortex and the mesocortical dopamine system. Three computer models are then presented that simulate normal and schizophrenic performance in the Stroop task, the continuous performance test, and a lexical disambiguation task. They demonstrate that a disturbance in the internal representation of contextual information can provide a common explanation for schizophrenic deficits in several attention- and language-related tasks. The models also show that these behavioral deficits may arise from a disturbance in a model parameter (gain) corresponding to the neuromodulatory effects of dopamine, in a model component corresponding to the function of prefrontal cortex.
The discovery of an endogenous opioid-mediated analgesic system has led to the search for its physiological roles and how it might be activated in natural conditions. Environmental and surgical stress and certain forms of transcutaneous electrical stimulation or acupuncture appear to activate this system. Several studies also suggest that this opioid system mediates placebo analgesia. Placebo reduces post-surgical pain in comparison with no treatment, and this analgesia is apparently reversed by the opioid antagonist, naloxone. However, these studies did not indicate whether naloxone and placebo exert their effects by common or by separate mechanisms. By administering hidden infusions of naloxone (in subjects unaware that the medication was being given) separate from the administration of a placebo, we were able to assess the effects of these two treatments independently. We report here evidence that placebo analgesia can occur after blockade of opioid mechanisms by naloxone and that naloxone can produce hyperalgesia independent of the placebo effect. The combined action of these effects is sufficient to explain the reversal of placebo analgesia by naloxone.
The aims of the study were to use functional magnetic resonance imaging (fMRI) to 1) locate pain-related regions in the anterior cingulate cortex (ACC) of normal human subjects and 2) determine whether each subject's pain-related activation is congruent with ACC regions involved in attention-demanding cognitive processes. Ten normal subjects underwent fMRI with a 1.5-T standard commercial MRI scanner. A conventional gradient echo technique was used to obtain data from a single 4-mm sagittal slice of the left ACC, approximately 3.5 mm from midline. For each subject, interleaved sets of 6 images were obtained during a pain task, an attention-demanding task, and at rest, for a total of 36 images per task. Pain of different intensities was evoked via electrical stimulation of the right median nerve. The attention-demanding task consisted of silent word generation (verbal fluency). Additional experiments obtained data from the right ACC. A pixel-by-pixel statistical analysis of task versus rest images was used to determine task-related activated regions. The pain task resulted in a 1.6-4.0% increase in mean signal intensity within a small region of the ACC. The exact location of this activation varied from subject to subject, but was typically in the posterior part of area 24. The signal intensity changes within this region correlated with pain intensity reported by the subject. The attention-demanding tasks increased the mean signal intensity by 1.3-3.3% in a region anterior and/or superior to the pain-related activation in each subject. The activated region was typically larger than the pain-related activation. In some cases this activation was at or superior to the ACC border, near the supplementary motor area. These regions did not show any pain-intensity-related activation. In one subject both right and left ACC were imaged, revealing bilateral ACC activation during the attention task but only contralateral pain-related activation. These findings shed light on pain- and attention-related cognitive processes. The results provide evidence for a region in the posterior part of the ACC that is involved in pain and a more anterior region involved in other attention-demanding cognitive tasks.