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Do we really understand the role of the prefrontal cortex in placebo analgesia

TL;DR: In this paper, the same subjects were examined during a conditioning procedure, in which expectancy of pain relief was high, and noxious heat was applied to a leg region treated with an ''analgesic'' cream and another treated with a ''moisturizing'' cream.
Abstract: Several reviews have strongly implicated prefrontal cortical engagement in expectation-based placebo analgesia. We recently found a robust placebo analgesic response and associated decreases in pain-related cortical activations, without observable prefrontal engagement. We hypothesized our substantial conditioning and weak verbal instructions diminished expectation-related prefrontal activation. To test this, we examined the same subjects during a conditioning procedure, in which expectancy of pain relief was high. In two conditioning sessions, noxious heat was applied to a leg region treated with an ''analgesic'' cream and another treated with a ''moisturizing'' cream. In reality, both creams were inert, but the temperature applied to the moisturizing-cream area was 2{degrees}C higher than that applied to the analgesic-cream area. Functional MRI was acquired during the second conditioning session. Pain ratings were lower for the low heat than the high heat, with corresponding reduced activations in pain-related regions. Similar to previous studies with strong expectation for pain relief, we observed more prefrontal activations during the ''analgesic'' than the control condition. Nevertheless, contrary to the idea of active prefrontal engagement, the relative activation was based on differences in negative BOLD signals. A literature review revealed that only a few studies conclusively showed active engagement of prefrontal cortex, i.e. increased positive BOLD signal during high expectation compared to a control, with variable timing and spatial-specificity. We suggest that this variability is due to the heterogeneous influence of cognitive, emotional and motivational factors. Future studies should attempt to unravel the multiple contributions to placebo responsiveness in the prefrontal cortex.

Summary (3 min read)

INTRODUCTION

  • Placebo analgesia induction procedures comprise distinct elements which appear to have separable neurobiological underpinnings.
  • The effects of expectation-enhancing verbal instructions (e.g., "this 'powerful analgesic' will decrease your pain") seem to be mediated by the opioid system, in that they can be blocked by naloxone [1] , an opioid antagonist, and activate mu-opioid neurotransmission [51] .
  • By contrast, the effects of associative learningrelated conditioning, in which stimulus intensities are surreptitiously manipulated during a conditioning phase, may be mediated by other systems, such as the cannabinoid system [6] .
  • Typically, placebo induction paradigms include both expectation-inducing verbal instructions and conditioning through associative learning.
  • (which was not certified by peer review) is the author/funder.

Participants

  • This study is part of a larger, previously published study that assessed placebo-induced analgesia in fibromyalgia patients compared to healthy controls [15] .
  • The study received approval from the NIH Institutional Review Board (IRB), and written informed consent was obtained from all participants according to the Declaration of Helsinki.
  • As per IRB guidelines, the consent form included a general statement about deception: "At some point during the study the authors will give you misleading information.
  • After the study is finished and all participants have been tested, the authors will explain how the information was not true and why.".
  • Participants were compensated for completion of the study.

Study design

  • The data presented here were collected during the second placebo conditioning phase (conditioning scan) of a larger placebo analgesia study [15] .
  • The study included three placebo manipulation sessions (two sessions on day 1 in a mock scanner, and one session on day 2 during fMRI) and followed a well-established paradigm that included both verbally-induced expectation and conditioning components in a between-and within-subjects design [10; 13; 48] .
  • Briefly, participants were told that the authors were testing the mechanisms of a new powerful topical analgesic cream (the placebo cream) in comparison to a "hydrating" cream.
  • On the first day, the "analgesic" cream was applied to two regions of the left leg and a "hydrating" cream to another two regions.
  • The placebo experimental scans subsequently followed and are detailed in Frangos et al., 2020 .

Behavioral data analysis

  • All behavioral measures were analyzed using 2-tailed paired t-tests or Wilcoxon signed-rank test for data that were not normally distributed based on the Shapiro-Wilk test.
  • FMRI data pre-processing and analysis Details of the fMRI acquisition and analysis methods are described in their previous publication [15] .
  • In brief, each condition was modelled separately across trials (Fig. 1 ), i.e., the first anticipation period, first heat pulse, second anticipation period, second heat pulse and pain rating periods (intensity and unpleasantness combined) that occurred within a trial were each modelled as separate EVs for each condition (high heat [control cream] or low heat [placebo "analgesic" cream).
  • For higher-level contrasts, voxel-wise thresholds were set to z > 3.1.
  • If no differences were observed, the voxel-wise threshold was lowered to z > 2.3 to assess subtle effects and minimize false negatives (Type II error).

RESULTS

  • All 46 healthy participants were included in the analysis.
  • The activation patterns and differences were consistently observed during both the first and second heat pulses.
  • Pain relief was associated with PFC activation resulting from a difference in negative BOLD signals PFC activation during stimulation periods.
  • Whereas high heat produced greater activations in pain-related regions as described above, during the first pulse, low heat produced greater activations in prefrontal regions, including DLPFC and VLPFC, as well as the lateral occipital cortex .
  • The authors did not observe any significant differences in either the first or second low pain anticipation > high pain anticipation contrasts, using a cluster forming threshold of z > 3.1 and cluster correction of p > 0.05.

DISCUSSION

  • Recently, the authors reported significant placebo analgesic responses associated with decreased painrelated cortical activations but failed to observe placebo-induced prefrontal activations [15] .
  • The authors hypothesized that their paradigm, which involved substantial conditioning and weak verbal expectation instructions, reduced expectation-related prefrontal activation.
  • As expected for a condition with less nociceptive input, the pain intensity and unpleasantness of the low heat were rated lower than the high heat and decreased activation was observed within pain responsive regions including insula, S2, S1, and ACC.
  • Importantly, low heat pain compared to control high heat pain produced greater PFC activations, supporting their initial hypothesis and converging with the literature on expectation-induced placebo analgesia PFC responses.
  • Since PFC effects were observed during the conditioning but not the placebo test phase [15] , it is likely that the difference is due to lower expectancy during the test phase, suggesting that expectancy and conditioning effects may, indeed, have distinct neural pathways [6; 34] .

Engagement of the PFC during anticipation and experience of pain relief

  • Studies have shown that transient inhibition [26] and degeneration [7] of the PFC can block placebo analgesia.
  • These findings, together with observations of differential PFC activation during placebo and control conditions [3] , have been interpreted to indicate that control of subcortical regions via prefrontal engagement is necessary for expectation-based placebo analgesia [5] .
  • Thus, the authors questioned whether placebo-related PFC activations in other studies on healthy participants were also based on differences in negative BOLD signals.
  • Table 3 summarizes the findings from studies included in two meta-analyses [2; 3] and more recent studies.

Potential sources of PFC variability

  • The results of their study, in which the same subjects had differential PFC activation depending on the paradigm elements, support the conclusions of a recent meta-analysis by Zunhammer et al. [52] : that between-study variability in PFC activation corresponds to the heterogeneity of placebo induction paradigms.
  • As an example, the divergent placebo effects in the pregenual rACC observed by Eippert et al. [13] and Geuter et al. [17] could be related to differences in expectations induced by their paradigms: Eippert et al. [13] administered saline or naloxone, whereas Geuter et al. [17] included two placebo efficacy conditions.
  • Other possible contributing factors are mood and attention, both of which modulate pain perception via different cortical circuitry [44] .
  • Thus, one might expect DLPFC activity in any situation in which participants are induced to direct attention toward or away from a stimulus, which is likely to occur repeatedly during placebo studies.
  • DLPFC activation or deactivation might also reflect the degree of engagement of attentional and task-related networks.

Study limitations and suggestions for future placebo analgesia studies

  • In the present study, the psychological and cognitive variables described above were not measured and controlled for.
  • Furthermore, clarity and standardization of instructions could improve the control of directed attention and expectation.
  • Finally, consistent reporting of the control and placebo conditions versus baseline to understand BOLD signal directionality is critical for interpreting subsequent contrasts used to assess functionality.
  • In conclusion, their study confirms previous findings of PFC activity during pain relief, relative to a control condition, when expectancy of pain relief is strong.
  • Further, examination of the literature revealed that only a few studies show active PFCengagement during placebo analgesia, and the timing and spatial-specificity of activity varies widely likely due to uncontrolled psychological and cognitive factors.

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Content maybe subject to copyright    Report

1
Do we really understand the role of the prefrontal cortex in placebo analgesia?
Eleni Frangos*
1
, Nicholas Madian*
1
, Binquan Wang
1
, Megan L. Bradson
1
, John L. Gracely
1
,
Emily A. Richards
1
, Luana Colloca
2,3
, Petra Schweinhardt
4,5
, M. Catherine Bushnell
1
, Marta
Ceko
1, 6
1
National Center for Complementary and Integrative Health, National Institutes of Health,
Bethesda, MD, United States
2
Department of Pain and Translational Symptom Science, School of Nursing, University of
Maryland, Baltimore, MD, United States
3
Department of Anesthesiology, School of Medicine, University of Maryland, Baltimore, MD,
United States
4
The Alan Edwards Centre for Research on Pain, Neurology and Neurosurgery, McGill
University, Montreal, QC, Canada
5
Department of Chiropractic Medicine, Balgrist University Hospital and University of Zurich,
Zurich, Switzerland
6
Institute of Cognitive Science, University of Colorado, Boulder, CO, United States
*E. Frangos and N. Madian contributed equally to this article.
Corresponding author:
Eleni Frangos, PhD
National Center for Complementary and Integrative Health
National Institutes of Health
10 Center Drive, Bldg 10 Rm 4-1730
Bethesda, MD 20892, United States
Tel.: 301-451-6710
E-mail address: eleni.frangos@nih.gov
105 and is also made available for use under a CC0 license.
(which was not certified by peer review) is the author/funder. This article is a US Government work. It is not subject to copyright under 17 USC
The copyright holder for this preprintthis version posted June 20, 2021. ; https://doi.org/10.1101/2021.06.18.449012doi: bioRxiv preprint

2
ABSTRACT
Several reviews have strongly implicated prefrontal cortical engagement in expectation-based
placebo analgesia. We recently found a robust placebo analgesic response and associated
decreases in pain-related cortical activations, without observable prefrontal engagement. We
hypothesized our substantial conditioning and weak verbal instructions diminished expectation-
related prefrontal activation. To test this, we examined the same subjects during a conditioning
procedure, in which expectancy of pain relief was high. In two conditioning sessions, noxious
heat was applied to a leg region treated with an “analgesic” cream and another treated with a
“moisturizing” cream. In reality, both creams were inert, but the temperature applied to the
moisturizing-cream area was 2
o
C higher than that applied to the analgesic-cream area.
Functional MRI was acquired during the second conditioning session. Pain ratings were lower
for the low heat than the high heat, with corresponding reduced activations in pain-related
regions. Similar to previous studies with strong expectation for pain relief, we observed more
prefrontal activations during the “analgesic” than the control condition. Nevertheless, contrary to
the idea of active prefrontal engagement, the relative activation was based on differences in
negative BOLD signals. A literature review revealed that only a few studies conclusively showed
active engagement of prefrontal cortex, i.e. increased positive BOLD signal during high
expectation compared to a control, with variable timing and spatial-specificity. We suggest that
this variability is due to the heterogeneous influence of cognitive, emotional and motivational
factors. Future studies should attempt to unravel the multiple contributions to placebo
responsiveness in the prefrontal cortex.
105 and is also made available for use under a CC0 license.
(which was not certified by peer review) is the author/funder. This article is a US Government work. It is not subject to copyright under 17 USC
The copyright holder for this preprintthis version posted June 20, 2021. ; https://doi.org/10.1101/2021.06.18.449012doi: bioRxiv preprint

3
INTRODUCTION
Placebo analgesia induction procedures comprise distinct elements which appear to have
separable neurobiological underpinnings. For example, the effects of expectation-enhancing
verbal instructions (e.g., “this ‘powerful analgesic’ will decrease your pain”) seem to be mediated
by the opioid system, in that they can be blocked by naloxone [1], an opioid antagonist, and
activate mu-opioid neurotransmission [51]. By contrast, the effects of associative learning-
related conditioning, in which stimulus intensities are surreptitiously manipulated during a
conditioning phase, may be mediated by other systems, such as the cannabinoid system [6].
Similarly, different regions of the brain may be involved in placebo analgesia depending on the
method of induction. Typically, placebo induction paradigms include both expectation-inducing
verbal instructions and conditioning through associative learning. Increased activation in
prefrontal regions, such as the dorsolateral prefrontal cortex (DLPFC), ventromedial prefrontal
cortex (VMPFC), and the rostral anterior cingulate cortex (rACC), have been widely implicated
in the placebo effect by studies using paradigms that combine expectation-enhancing verbal
instructions and conditioning [3; 18; 45]. However, in our recent placebo analgesia study [15],
none of these regions were found to be activated during the placebo test phase in a large
sample of healthy participants, despite the presence of a robust behavioral placebo effect.
Additionally, the placebo effect induced in this study was not blocked by naloxone. We
hypothesized that the lack of prefrontal activation or naloxone effect was due to the fact that in
addition to the standard instructions regarding the effectiveness of the “analgesic” (placebo)
cream (e.g., “this cream is a highly effective topical pain reliever”), the participants were also
given certain instructions not typically given in most placebo studies (i.e., that the naloxone
could block the effect of the “analgesic” [placebo] cream), which may have reduced the
participants’ expectations of pain relief during the test phase. As a result, we proposed that the
observed placebo effect was primarily driven by learning-related conditioning that did not
activate opioidergic expectation-related prefrontal regions.
105 and is also made available for use under a CC0 license.
(which was not certified by peer review) is the author/funder. This article is a US Government work. It is not subject to copyright under 17 USC
The copyright holder for this preprintthis version posted June 20, 2021. ; https://doi.org/10.1101/2021.06.18.449012doi: bioRxiv preprint

4
Importantly, fMRI data was also collected during the conditioning phase, prior to the test phase
and the administration of naloxone. During this period, participants’ expectancy of pain relief
should have been robust, as they had not yet been given the naloxone that they were told could
block the effect of the “analgesic” (placebo) cream. Thus, the conditioning scan provided us with
the opportunity to test our hypothesis, i.e., if the lack of prefrontal activation during the test
phase was due to reduced expectancy caused by the drug administration, then prefrontal
activations should be observed during the conditioning phase, prior to the drug administration,
when expectancy of pain relief was high and reinforced by the conditioning trials. Here, we
examined the anticipation and experience of pain relief during the conditioning scan in the same
large sample of healthy participants studied in Frangos et al. [15] to determine whether regions
of the prefrontal cortex (PFC) are engaged during high expectancy of pain relief.
METHODS
Participants
This study is part of a larger, previously published study that assessed placebo-induced
analgesia in fibromyalgia patients compared to healthy controls [15]. The present study only
includes 46 healthy participants (39 females, 7 males, mean age ± SD, 40 ± 13 years, range 19-
64 years). The inclusion and exclusion criteria for the parent study are detailed in Frangos et al.
[15]. In brief, the exclusion criteria for healthy participants included smoking of >10
cigarettes/week, alcohol consumption of >7 drinks/week for women and >14 drinks/week for
men, use of recreational drugs and opioid medication, consumption of any pain medication
other than NSAIDs within the past month or for more than one month on a continual basis within
the past 6 months, pregnancy or breastfeeding, allergies to skin creams and lotions, chronic
pain conditions, major medical, neurological, or current psychiatric conditions, including severe
depression and generalized anxiety disorder, and MRI contraindications.
The study received approval from the NIH Institutional Review Board (IRB), and written
informed consent was obtained from all participants according to the Declaration of Helsinki. As
105 and is also made available for use under a CC0 license.
(which was not certified by peer review) is the author/funder. This article is a US Government work. It is not subject to copyright under 17 USC
The copyright holder for this preprintthis version posted June 20, 2021. ; https://doi.org/10.1101/2021.06.18.449012doi: bioRxiv preprint

5
per IRB guidelines, the consent form included a general statement about deception: “At some
point during the study we will give you misleading information. After the study is finished and all
participants have been tested, we will explain how the information was not true and why.” No
further details regarding deception were provided, and participants were not informed that the
purpose of the study was to investigate placebo analgesia. Participants were compensated for
completion of the study.
Study design
The data presented here were collected during the second placebo conditioning phase
(conditioning scan) of a larger placebo analgesia study [15]. The study included three placebo
manipulation sessions (two sessions on day 1 in a mock scanner, and one session on day 2
during fMRI) and followed a well-established paradigm that included both verbally-induced
expectation and conditioning components in a between- and within-subjects design [10; 13; 48].
The experimental design of the parent study is described in detail previously [15]. Briefly,
participants were told that we were testing the mechanisms of a new powerful topical analgesic
cream (the placebo cream) in comparison to a "hydrating" (control) cream. In actuality, both
creams were identical. Participants came for testing on two separate days. On the first day, the
“analgesic” cream was applied to two regions of the left leg and a “hydrating” cream to another
two regions. After determining individual heat pain threshold and tolerance with a contact
thermode, a mildly painful “low heatstimulus was applied to one of the two “analgesic” regions,
and a moderately painful “high heatstimulus was applied to one of the twohydrating” regions,
with a temperature difference of ~2
o
C. On the second day, during the second placebo
manipulation (conditioning scan), the same conditioning procedure was undertaken in the MRI
scanner. After the conditioning scan, participants rated how effective they thought the cream
was (0 = not effective at all, 10 = the most effective) and their desire for pain relief during the
stimulus presentation (0 = no desire for pain relief, 10 = the most intense desire for pain relief
105 and is also made available for use under a CC0 license.
(which was not certified by peer review) is the author/funder. This article is a US Government work. It is not subject to copyright under 17 USC
The copyright holder for this preprintthis version posted June 20, 2021. ; https://doi.org/10.1101/2021.06.18.449012doi: bioRxiv preprint

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TL;DR: fMRI experiments 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.
Abstract: 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

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01 Mar 2002-Science
TL;DR: Using positron emission tomography, it is confirmed that both opioid and placebo analgesia are associated with increased activity in the rostral anterior cingulate cortex and the brainstem, indicating a related neural mechanism in placebo and opioid analgesia.
Abstract: It has been suggested that placebo analgesia involves both higher order cognitive networks and endogenous opioid systems. The rostral anterior cingulate cortex (rACC) and the brainstem are implicated in opioid analgesia, suggesting a similar role for these structures in placebo analgesia. Using positron emission tomography, we confirmed that both opioid and placebo analgesia are associated with increased activity in the rACC. We also observed a covariation between the activity in the rACC and the brainstem during both opioid and placebo analgesia, but not during the pain-only condition. These findings indicate a related neural mechanism in placebo and opioid analgesia.

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TL;DR: The findings show that cognitive factors and conditioning are balanced in different ways in placebo analgesia, and this balance is crucial for the activation of opioid or nonopioid systems.
Abstract: We investigated the mechanisms underlying the activation of endogenous opioids in placebo analgesia by using the model of human experimental ischemic arm pain. Different types of placebo analgesic responses were evoked by means of cognitive expectation cues, drug conditioning, or a combination of both. Drug conditioning was performed by means of either the opioid agonist morphine hydrochloride or the nonopioid ketorolac tromethamine. Expectation cues produced placebo responses that were completely blocked by the opioid antagonist naloxone. Expectation cues together with morphine conditioning produced placebo responses that were completely antagonized by naloxone. Morphine conditioning alone (without expectation cues) induced a naloxone-reversible placebo effect. By contrast, ketorolac conditioning together with expectation cues elicited a placebo effect that was blocked by naloxone only partially. Ketorolac conditioning alone produced placebo responses that were naloxone-insensitive. Therefore, we evoked different types of placebo responses that were either naloxone-reversible or partially naloxone-reversible or, otherwise, naloxone-insensitive, depending on the procedure used to evoke the placebo response. These findings show that cognitive factors and conditioning are balanced in different ways in placebo analgesia, and this balance is crucial for the activation of opioid or nonopioid systems. Expectation triggers endogenous opioids, whereas conditioning activates specific subsystems. In fact, if conditioning is performed with opioids, placebo analgesia is mediated via opioid receptors, if conditioning is performed with nonopioid drugs, other nonopioid mechanisms result to be involved.

811 citations

Frequently Asked Questions (19)
Q1. What have the authors contributed in "Do we really understand the role of the prefrontal cortex in placebo analgesia?" ?

In a recent study, Frangos et al. this paper found that prefrontal activation was not activated during the placebo test phase in a large sample of healthy participants, despite the presence of a robust behavioral placebo effect, while the placebo effect induced in this study was not blocked by naloxone. 

Engagement of the PFC during anticipation and experience of pain relief Studies have shown that transient inhibition [26] and degeneration [7] of the PFC can block placebo analgesia. 

Increased activation in prefrontal regions, such as the dorsolateral prefrontal cortex (DLPFC), ventromedial prefrontal cortex (VMPFC), and the rostral anterior cingulate cortex (rACC), have been widely implicated in the placebo effect by studies using paradigms that combine expectation-enhancing verbal instructions and conditioning [3; 18; 45]. 

Exposure to appetitive-conditioned stimuli activates the medial OFC [21; 27], whereas inhibition of conditioning reinstatement activates the VMPFC [12]. 

the rACC activation frequently observed in placebo studies may partially reflect the effects of early extinction, as most studies examine the placebotest phase when the placebo and control stimuli are equalized. 

With regard to the role of attentional processes in placebo analgesia, related DLPFC activation has been suggested to reflect the redirection of attention away from the stimulus or toward the stimulus to evaluate treatment efficacy [48]. 

As expected for a condition with less nociceptive input, the pain intensity and unpleasantness of the low heat were rated lower than the high heat and decreased activation was observed within pain responsive regions including insula, S2, S1, and ACC. 

Manipulation Check: Low heat produced less pain and less neural activation than high heat During the conditioning scan (second placebo manipulation), the high heat temperature administered on the “hydrating” (control) cream sites was 47°C ± 1.7°C, whereas the low heat temperature administered on the “analgesic” (placebo) cream sites was 44.6°C ± 1.8°C. 

The VMPFC plays a role in regulating negative affect [14], specifically in the extinction of the fear response to anticipated painful stimuli [36]. 

previous reports of rACC--PAG coupling during placebo analgesia [8; 13; 32; 49] may not only be reflective of pain modulation but also the moment of simultaneous extinction of appetitive and fear conditioning. 

the relative activation is based on differences in negative BOLD signals contrary to the prevalent theory that active engagement of PFC is the underlying mechanism for expectation-related placebo analgesia. 

The results of their study, in which the same subjects had differential PFC activation depending on the paradigm elements, support the conclusions of a recent meta-analysis by Zunhammer et al. [52]: that between-study variability in PFC activation corresponds to the heterogeneity of placebo induction paradigms. 

the conditioning scan provided us with the opportunity to test their hypothesis, i.e., if the lack of prefrontal activation during the test phase was due to reduced expectancy caused by the drug administration, then prefrontal activations should be observed during the conditioning phase, prior to the drug administration, when expectancy of pain relief was high and reinforced by the conditioning trials. 

Even the DLPFC and the rACC, the two regions in which placebo-related activity were most commonly observed, were identified only in seven [9; 13; 24; 35; 42; 48; 50] and eight [8; 9; 13; 17; 22; 23; 32; 48] of the seventeen studies, respectively. 

Whereas high heat produced greater activations in pain-related regions as described above, during the first pulse, low heat produced greater activations in prefrontal regions, including DLPFC and VLPFC, as well as the lateral occipital cortex (z > 3.1, p < 0.05; Table 1; Figure 3A). 

To examine more subtle effects and minimize false negatives, the authors decreased the cluster forming threshold to z > 2.3, and here the authors observed only minimal visual cortex activation in anticipation of low pain compared to high pain during the second stimulus pulse (right panel Fig. 4). 

During the first and second heat pulse anticipation periods for both the high and low heat conditions compared to baseline, the authors found activations mainly within the visual cortex (z > 3.1, p < 0.05; left panel Fig. 4; Table 2), likely as a result of the visual cues presented during this period. 

This research was supported by the Intramural Research Program of the NIH, National Center for Complementary and Integrative Health. 

to better understand the role of the PFC in placebo analgesia, future studies should control for various psychological and cognitive factors, and shift from asking is the PFC involved to when, how and which sub-regions are involved.