Do we really understand the role of the prefrontal cortex in placebo analgesia
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- (which was not certified by peer review) is the author/funder.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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Frequently Asked Questions (19)
Q2. What is the effect of the placebo on the prefrontal network?
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.
Q3. What are the main components of the placebo effect?
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].
Q4. What is the effect of conditioning on the medial OFC?
Exposure to appetitive-conditioned stimuli activates the medial OFC [21; 27], whereas inhibition of conditioning reinstatement activates the VMPFC [12].
Q5. What is the significance of rACC activation in the placebo study?
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.
Q6. What is the role of the DLPFC in analgesia?
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].
Q7. What was the effect of the low heat on the visual cortex?
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.
Q8. What was the effect of the low heat on the pain processing regions?
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.
Q9. What is the role of the VMPFC in regulating negative affect?
The VMPFC plays a role in regulating negative affect [14], specifically in the extinction of the fear response to anticipated painful stimuli [36].
Q10. What is the effect of rACC--PAG coupling?
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.
Q11. What is the role of the PFC in analgesia?
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.
Q12. What is the significance of the results of the meta-analysis?
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.
Q13. What is the reason for the lack of prefrontal activation during the conditioning phase?
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.
Q14. What are the commonly observed PFC regions?
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.
Q15. What is the corresponding effect of the low heat on the pain response?
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).
Q16. What was the effect of the low heat pain anticipation contrast?
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).
Q17. What is the corresponding effect of the heat on the visual cortex?
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.
Q18. which research was supported by the NIH?
This research was supported by the Intramural Research Program of the NIH, National Center for Complementary and Integrative Health.
Q19. What should be the main focus of future studies?
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.