Distinct neural networks subserve placebo analgesia and nocebo hyperalgesia

Fu, Junjun; Wu, Shuyi; Liu, Cuizhen; Camilleri, Julia A.; Eickhoff, Simon B.; Yu, Rongjun

doi:10.1016/j.neuroimage.2021.117833

Cited by 20 publications

(14 citation statements)

References 218 publications

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“…Thus, alternatively, our findings could also indicate that the involvement of reward processing is different in placebo compared with nocebo effects. This would be in line with recent evidence that shows that activity in the ventral striatum differs between placebo and nocebo effects, likely because placebo responding may be a form of reward processing, whereas nocebo responding may engage aversive networks in the brain ( Fu et al, 2021 ). BAS traits have been found to consistently correlate with activity of this brain region in response to positive stimuli (see for example, Kennis et al, 2013 ).…”

Section: Discussionsupporting

confidence: 88%

Associations Between Interindividual Differences, Expectations and Placebo and Nocebo Effects in Itch

et al. 2021

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Introduction: Placebo and nocebo effects are positive and negative health outcomes that can be elicited by the psychosocial context. They can be mediated by expectations, and may emerge in somatic symptoms even when people are aware of these effects. Interindividual differences (e.g., in personality, affective states) could impact placebo and nocebo responding, but findings are inconsistent.Methods: The current work examined expectation as a mediator of the association between verbal placebo and nocebo suggestions (VSs) and histamine-induced itch across three experimental studies. Moreover, we examined whether interindividual differences (e.g., in optimism, neuroticism, behavioral activation system (BAS), body ignorance) modulated: (1) the direct association between VSs and itch (direct moderation), and (2) the indirect, expectation-mediated association between VSs and itch (moderated mediation). Positive VSs were compared to neutral instructions (Study 1; n = 92) or negative VSs (Studies 2+3; n = 203) in an open-label (i.e., explaining placebo and nocebo effects) or closed-label (concealed) context using PROCESS. First, mediation of VSs effects on itch by expectations was tested. Next, moderation by individual traits was explored using conditional process analyses.Results: The effects of VSs on itch were significantly mediated by expectation in Study 1 and in the open-label (but not closed-label) contexts of Studies 2 and 3. Ignorance of bodily signals marginally moderated the direct effects of VSs on itch when closed-label suggestions were given: at low levels of body ignorance, effects of positive and negative VSs were stronger. Moreover, moderated mediation was observed in the open-label groups of Studies 2 and 3: The expectation-mediated effects of VSs on itch were stronger when BAS drive was lower.Conclusion: Overall, the effects of VSs on itch were mediated by expectations in the open-label, but not the closed-label context. Moreover, the current work suggests that placebo and nocebo effects may be moderated by ignorance of bodily signals and the BAS. There was limited evidence that other interindividual differences modulated placebo and nocebo responding in itch.

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Section: Discussionsupporting

confidence: 88%

Associations Between Interindividual Differences, Expectations and Placebo and Nocebo Effects in Itch

et al. 2021

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“…Second, further research must investigate whether the shifts in time of nocebo hyperalgesia are associated with a neurophysiological response. As demonstrated by the present study, HR is not a good measure to detect nocebo hyperalgesia; future studies could consider using central measures such as electroencephalography and functional magnetic resonance imaging, which are effective at picking up signals associated with nocebo hyperalgesia ( 56 , 57 ). Third, future designs should investigate whether the same temporal effects would be found with longer time-windows.…”

Section: Discussionmentioning

confidence: 71%

The Temporal Modulation of Nocebo Hyperalgesia in a Model of Sustained Pain

et al. 2022

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BackgroundThe direction and the magnitude of verbal suggestions have been shown to be strong modulators of nocebo hyperalgesia, while little attention has been given to the role of their temporal content. Here, we investigate whether temporal suggestions modulate the timing of nocebo hyperalgesia in an experimental model of sustained pain.MethodsFifty-one healthy participants were allocated to one of three groups. Participants received an inert cream and were instructed that the agent had either hyperalgesic properties setting in after 5 (Nocebo 5, N5) or 30 (Nocebo 30, N30) minutes from cream application, or hydrating properties (No Expectation Group, NE). Pain was induced by the Cold Pressure Test (CPT) which was repeated before cream application (baseline) and after 10 (Test10) and 35 (Test35) minutes. Changes in pain tolerance and in HR at each test point in respect to baseline were compared between the three groups.ResultsTolerance change at Test 10 (Δ10) was greater in N5 (MED = −36.8; IQR = 20.9) compared to NE (MED = −5.3; IQR = 22.4; p < 0.001) and N30 (MED = 0.0; IQR = 23.1; p < 0.001), showing that hyperalgesia was only present in the group that expected the effect of the cream to set in early. Tolerance change at Test 35 (Δ35) was greater in N5 (MED = −36.3; IQR = 35.3; p = 0.002) and in N30 (MED = −33.3; IQR = 34.8; p = 0.009) compared to NE, indicating delayed onset of hyperalgesia in N30, and sustained hyperalgesia in N5. No group differences were found for HR.ConclusionsOur study demonstrated that temporal expectations shift nocebo response onset in a model of sustained pain.

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“…Nevertheless, it must be considered that placebo analgesia deals with positive expectations whereas mindfulness may protect against negative expectations. Since positive and negative expectations have shown to have different neural correlates [8], there are limitations on the extent to which our results can support this type of intervention. Future studies should analyse whether the precision of sensory input is also a protective factor against the nocebo effect.…”

Section: Discussionmentioning

confidence: 88%

Resistance to placebo analgesia is explained by greater reliance on somatic input: a Bayesian model comparison study

Delgado-Sanchez¹,

Trujillo-Barreto²,

Brown³

et al. 2022

Preprint

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In placebo analgesia, the expectation of pain reduction results in actual reduction in pain experience. Yet, there is substantial variability between participants in the magnitude of the placebo response, allowing a data-driven discrimination between placebo “responders” and “non-responders”. The mechanisms driving the difference between these groups remains unclear. Here we propose that placebo responders, when rating painfulness, place a higher relative weight on their prior experience relative to current nociceptive inputs. We analysed participants’ pain ratings from an experimental placebo paradigm, involving nociceptive laser stimulation and a fake analgesic cream. We compared three alternative linear predictive models that varied in the factors assumed to predict pain responses: either past experience, nociceptive stimulation or both. We carried out single trial inferences for each model using a Bayesian framework with belief updating priors on the prediction weights at each trial. Model comparison showed that dynamic changes in pain ratings in placebo responders is best explained by past experience, and in non-responders by both past experience and stimulation. This is the first account of placebo analgesia resistance being associated with greater nociceptive information processing. This conclusion fits with previous research highlighting the importance of attention to the body as a way to reduce the effect of expectancy-related bias. Our results also support the use of Bayesian models as phenotyping tools, which have potential uses for personalised medicine.

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Distinct neural networks subserve placebo analgesia and nocebo hyperalgesia

Cited by 20 publications

References 218 publications

Associations Between Interindividual Differences, Expectations and Placebo and Nocebo Effects in Itch

Associations Between Interindividual Differences, Expectations and Placebo and Nocebo Effects in Itch

The Temporal Modulation of Nocebo Hyperalgesia in a Model of Sustained Pain

Resistance to placebo analgesia is explained by greater reliance on somatic input: a Bayesian model comparison study

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