Keywords
Pain, Expectancy, Nocebo, Bayesian Coding, Unpleasantness
Pain, Expectancy, Nocebo, Bayesian Coding, Unpleasantness
One of the most striking breakthroughs in pain research has been the discovery of expectancy modulations, according to which subjective experiences do not only reflect nociceptive input but also individuals’ previous knowledge and beliefs1. Expectancy modulations are noteworthy for their clinical implications, as convincing individuals of the effectiveness of an analgesic might induce a strong pain relief (placebo effect), sometimes comparable to the effects of active agents2. Furthermore, expectancy effects have sparkled a major theoretical debate, with influential models suggesting that pain symptoms might be better explained through a Bayesian framework, where the brain estimates the (posterior) probability of body damage, based on the integration of sensory inputs and prior representations3–6.
Many studies investigated the neural structures underlying expectancy modulations of pain, pointing to an extensive network including, among other regions, the insular cortex1,7–10. In particular, whereas the posterior portion of the insula is known to receive thalamic nociceptive projections11–13 and thought to process bottom-up components of the painful experience8, the middle-anterior portions may integrate such bottom-up signals with prior expectations7,8, and generate prediction-error signals, serving to update the representation of future events8. However, the insular cortex (like other interconnected regions such as the cingulate cortex) does not respond to pain specifically, but also to a wide range of aversive events14, including disgust15,16, negatively-valenced pictures17,18, or even unfairness15,19,20. Accordingly, a part of pain-evoked activity in this region might reflect supramodal dimensions of affect or motivation, such as unpleasantness15, arousal or even salience21,22. This raises the question about the nature of the predictive information encoded on the middle-anterior insula, and whether it relates to pain-specifically (“this will hurt”), or rather to an undistinctive negative event (“this will be bad”).
Addressing this issue is not a trivial matter, as it would require testing whether pain-evoked activity in the middle-anterior insula is also sensitive to the expectation of a painless event of same unpleasantness or salience. Interestingly, two recent independent studies (each unbeknownst to the other) did precisely this, reaching remarkably similar results23,24. The first study from Sharvit and others23 compared the expectancy of pain with that of a disgusting odorant of similar unpleasantness (see also Sharvit and others25 for an earlier behavioral implementation of the task), whereas the second from Fazeli and Büchel24 used as control pictures of aversive content. By expanding on well-known paradigms of pain expectancy7,8, both studies were able to replicate evidence that the middle-anterior insula integrated bottom-up nociceptive information with signals from predictive cues, but this did not occur when cues were incongruent with the subsequent event (e.g., disgust/image cues followed by painful stimulus)23,24. Such convergence between researches with important differences in sensory stimuli, task structures, and data analyses23,24, provides a compelling case that expectancy modulations of pain in the insular cortex are sensory-specific, and do not generalize to a broad code of unpleasantness. This also accords with other work showing for shared and segregated portions in insula for representations of pain, disgust, and unfairness15.
Although sharing a similar take-home message, the two cross-modal experiments by Sharvit and Fazeli differ (and in some case complement each other) concerning the information coded by the middle-anterior insula. By employing rigorous Bayesian modelling, Fazeli and Büchel24 dissociated a portion in the middle and dorsal-anterior portion of the insula, responsible for integrating bottom-up signals with prior expectancies, from a portion in ventral-anterior insula, responsible for generating error signals whenever the painful stimulus greatly diverged from what was predicted by the cues (see Figure 1). This was not the case in Sharvit and others23 who adopted a paradigm where divergences between cues and subsequent stimuli were purposefully subtle to pass unnoticed7,25. It is interestingly to notice, however, that Sharvit and others23 reported a dissociation between the middle insula, exerting a mediatory role in the way in which predictive cues influenced subjective reports (as previously found7), and the most anterior insula, exerting instead an opposite role of suppression. Hence, in Sharvit and others23 activity in the anterior insula seemed to prevent individuals from being influenced by their expectations, an effect that is consistent with the notion of prediction-error modeled by Fazeli and Büchel24. The two studies also differ regarding the insular sub-sections involved: Sharvit and others23 mapped mediation and suppression effects along the middle-to-anterior axis, whereas Fazeli and Büchel24 described expectancy and prediction-error effects also along the dorsal-to-ventral axis of the anterior insula (Figure 1). Future studies will need to further clarify how different components of expectancy relate to the various insula portions.
A further, and critical, point of divergence relates to whether the insular cortex is also susceptible to sensory-specific expectancy for other events than pain. This question was addressed only by Sharvit and others23 who described complementary effects to those observed in pain, also for the case of olfactory disgust. These results suggested that the middle-anterior insula may hold multiple predictive representations of upcoming events, which are then updated by bottom-up sensory input. Hence, although the middle-anterior insula appears sensitive to a wide range of stimuli14, it may retain sensory-specific information about each of them. Anatomical studies on primates subfields in this region26, with a level of detail that exceeds that derived from neuroimaging research in humans27,28. It is therefore foreseeable that different kinds of sensory events might be represented in the anterior insula through neighbouring, but distinct, neuronal populations, which could be difficult to distinguish through radiological imaging, but nonetheless selectively dissociated through well-crafted expectancy manipulations.
All data underlying the results are available as part of the article and no additional source data are required.
The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: CCD is supported by the Swiss National Science Foundation [PP00O1_157424/1].
The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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Is the rationale for commenting on the previous publication clearly described?
Yes
Are any opinions stated well-argued, clear and cogent?
Yes
Are arguments sufficiently supported by evidence from the published literature or by new data and results?
Yes
Is the conclusion balanced and justified on the basis of the presented arguments?
Yes
References
1. Fazeli S, Büchel C: Pain-Related Expectation and Prediction Error Signals in the Anterior Insula Are Not Related to Aversiveness.J Neurosci. 2018; 38 (29): 6461-6474 PubMed Abstract | Publisher Full TextCompeting Interests: No competing interests were disclosed.
Reviewer Expertise: cognitive neuroscience, experimental psychology and neuropsychology. One focus of my research is how body representation and multisensory integration influence the pain perception.
Is the rationale for commenting on the previous publication clearly described?
Yes
Are any opinions stated well-argued, clear and cogent?
Yes
Are arguments sufficiently supported by evidence from the published literature or by new data and results?
Partly
Is the conclusion balanced and justified on the basis of the presented arguments?
Partly
References
1. Sharvit G, Corradi-DellʼAcqua C, Vuilleumier P: Modality-specific effects of aversive expectancy in the anterior insula and medial prefrontal cortex.Pain. 2018; 159 (8): 1529-1542 PubMed Abstract | Publisher Full TextCompeting Interests: No competing interests were disclosed.
Reviewer Expertise: Pain, Expectancy, FMRI, Placebo, Learning
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Version 1 06 Feb 19 |
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