Keywords
Pain, insula, brain imaging, ASL
Pain, insula, brain imaging, ASL
There are three major factors that we feel negate the claims of the recent study by Segerdahl et al.1 that the dorsal posterior insula (dpIns) is a pain-specific area of the brain.
First, the evidence that the dpIns is specific is lacking based on the experimental design and data analysis employed. The methodological approach used by Segerdahl et al.1 was to induce an ongoing pain with capsaicin and then to correlate pain intensity ratings with brain perfusion changes using arterial spin labeling (ASL). ASL is an MRI-based perfusion method that can measure fluctuations in rCBF (akin to PET imaging) without the need for a stimulus, and so its application to study ongoing pain is promising. ASL has been previously used by others2,3 to identify acute and chronic pain-related changes in regional cerebral blood flow (rCBF) but the way Segerdahl et al.1 applied it has several shortcomings. The choice of Segerdahl et al.1 to collect multi-delay ASL data resulted in rCBF images sampled at infrequent intervals of ~45s, which represents a statistically challenging condition because of the small number of data collected. The control experiment using vibrotactile stimuli comprised a very short scan with even fewer data points in only seven subjects – a design that did not match the already low statistical power of the capsaicin experiment. Therefore, the analysis was underpowered and does not constitute a valid control for the pain experiment. This likely contributed to the minimal activation detected anywhere in the brain during the vibrotactile stimulation. The skin is richly innervated by rapidly adapting, low-threshold mechanoreceptors, so this absence of activation is of substantial concern. Even very early PET studies of regional cerebral blood flow (CBF) found robust vibrotactile activation of primary and secondary somatosensory cortex (S1, S2), and the adjacent posterior insula4,5. Most importantly, unlike previous investigations where CBF was directly and statistically compared between pain and innocuous stimulation to evaluate specificity of activation5,6, the Segerdahl et al.1 study performed no such key statistical comparison. Without this direct comparison, and in the absence of a control for vibration intensity, or for stimulus saliency, claims of specificity and pain intensity coding simply cannot be made7. This comparison is crucial given the evidence of a vast predominance of low threshold mechanoreceptive neurons in the posterior insula8 and robust vibrotactile activation of the insula (e.g., see 4).
Second, the proposition of a very specific “spot” dedicated to pain is critically dependent on the ability of the methodology to localize findings precisely. However, it is challenging to derive an accurate, group-averaged localization of activation within the dpIns given 1) the large intersubject anatomical variability of the insula, in particular the posterior gyri9 and 2) the method of realignment and morphing of brain anatomy into a common space to produce group maps. Inspection of the reported dpIns peak coordinate in the Juelich histologic atlas reveals that this peak activation has a 63% probability of being in the parietal operculum (S2, OP2), and only a 31% probability of being in the insular cortex. These areas are in close approximation, but S2 has a well-documented involvement in both nociceptive and innocuous somatosensory processing (e.g., see 8). No additional procedures were performed to functionally distinguish these two regions.
Third, the interpretation of the findings and proposition of a specific pain center was made without taking into consideration a large body of scientific evidence addressing the brain mechanisms that contribute to pain. Theories of pain have been debated for centuries10, and we still do not know how pain is represented in the brain despite decades of searching for a pain specific brain center. This pursuit for a simple, single pain center however is no longer necessary given the enormity of human neuroimaging data indicating that there is no such dedicated center. Each and every brain area that contains nociceptive neurons also contains non-nociceptive neurons, and neuroimaging has shown that each brain area that responds to noxious stimuli can also respond to non-noxious stimuli11. Rather, multiple, converging lines of evidence strongly indicate that the experience of pain - as any other conscious experience - is constructed from highly distributed cortical processes5,12. For example, many brain regions exhibit activity related to pain intensity (e.g., 12,13). Furthermore, there are several clinical cases of preserved pain perception despite lesions of critical regions including the insula, anterior cingulate, and even the entire contralateral hemisphere14,15. Other studies have shown that interactions among multiple brain regions are critical for distinguishing a state of pain from other highly salient events16.
It is also useful to place the findings of Segerdahl et al.1 in context given the historical view of insular function. Morphological, physiological and imaging studies throughout the 1980s and 1990s, divided the insula into anterior agranular and posterior granular subregions, with pain-related function attributed to the anterior part, and a variety of other functions, including tactile recognition, attributed to the posterior part (e.g., see 8). Since that time, the anterior insula has been established to be part of a non-specific network related to attention and salience. In addition, there is anatomical and electrophysiological evidence for thermoreceptive processing in the dpIns via a spinal cord lamina 1 pathway17. Although neuroimaging has shown that the dpIns likely has a role in pain and intensity coding, it is critical to reiterate that intensity-coding has also been found for non-pain modalities in this region, including C-fiber mediated pleasant-touch18–20. The last decades have seen several theories of insula function being put forward21. This balanced view of potential dpIns functions is surprisingly absent from the discussion of Segerdahl et al.1. One important theory to consider, put forth by Apkarian’s group13, is that of the “how much” general magnitude-detector function of the insula. Another important theory developed by Craig and colleagues17, proposes the dpIns to be a center for interoceptive integration and awareness. Thus, there are several important issues22 that need to be considered to fully interpret the findings of Segerdahl et al.1. One assumption that drove the approach taken was that of the critical role of intensity-coding as being central to finding a “pain specific” center. We challenge this because although intensity certainly is one classic dimension of pain, there are many other dimensions including location, quality, and unpleasantness that together comprise the experience of pain. Furthermore, none of these dimensions are actually required for a fundamental feeling of pain (see the recent theory put forth by Davis et al.23).
In conclusion, the extensive evidence about the role of the dpIns is not considered by Segerdahl et al.1 and we note that they do not refute this evidence in their claim to have identified a novel, specific pain center in the dpIns. Such simplistic notions of a specific pain center are incorrect, and therefore dangerous at both an intellectual as well as a clinical level. Here, we suggest an alternate concept of the function of the dpIns based on previous theories and a large body of data that strongly indicate that the dpIns likely is involved in pain but overall is a non-specific perceptual way-station, rather than a specific pain centre. Failure to recognize that many regions activated during nociceptive stimulation are engaging in computational processes related to many things other than pain, lead to interpretations that are fraught with reverse inference11, and they encourage neurosurgeons to pursue lesions for pain control, an approach that has largely been shown to be ineffective since the 1960's24. Their promotion of the concept of a single spot in the brain for pain is even more surprising given the enormous amount of data emerging over the last decade showing the representation of brain function in functional networks, rather than “spots” and the newer view of a “dynamic pain connectome”25. Implications of their concept are far-reaching – from basic theories of pain, to development of “pain-o-meter” type diagnostic tests, to establishing a therapeutic target for clinical pain management26,27.
KDD and RC prepared the first draft of the manuscript. All authors (KDD, MCB, GI, KSL, and RC) were involved in the revision of the draft manuscript and have agreed to the final content.
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References
1. Davis KD, Bushnell MC, Iannetii GD, St Lawrence K, et al.: Evidence against pain specificity in the dorsal posterior insula [version 1; referees: 2 approved]. F1000Research. 2015; 4: 362 PubMed Abstract | Free Full Text | Publisher Full Text | Reference SourceCompeting Interests: No competing interests were disclosed.
References
1. Apkarian AV, Bushnell MC, Treede RD, Zubieta JK: Human brain mechanisms of pain perception and regulation in health and disease. Eur J Pain. 2005; 9 (4): 463-484 PubMed Abstract | Publisher Full Text | Reference SourceCompeting Interests: No competing interests were disclosed.
References
1. Davis KD, Bushnell MC, Iannetti G, St Lawrence K, et al.: Evidence against pain specificity in the dorsal posterior insula. v1; ref status: approved 1, http://f1000r.es/5o3. F1000Res. 2015; 4 (362). Publisher Full Text | Reference SourceCompeting Interests: No competing interests were disclosed.
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Segerdahl and collaborators addressed some of the suggested shortcomings highlighted by Davis et al., such as the absence of a direct statistical comparison between cerebral blood flow (CBF) changes triggered by painful and tactile stimulation, and the precise anatomical localization of the dpIns.
While we agree with most of the criticisms raised by Davis et al., we find that they do not address the two most problematic issues of the paper, which we summarize in the following three points.
The first issue lies in the ambiguity of the term “fundamental”. Simply stating that the dpIns subserves a fundamental role in the perception of pain, as Segerdahl et al. do in the title of their brief communication and as they remark upon in their correspondence, does not per se imply specificity. Nevertheless, the Authors refer to the pain-specificity of the dpIns in multiple points of their brief communication (e.g., «To validate the pain-specificity of our dpIns results», p. 1; «specific to the tonic heat pain», Online Methods). These statements are toned down in the last part of the Author’s response to Davis et al., where the Authors state that the dpIns is just potentially responsive to only nociceptive inputs. Segerdahl et al. state this this point is simply “arguing semantics”. Instead, we believe that this is actually a pivotal point for the interpretation of the findings.
The assumption that the CBF changes triggered in the dpIns are pain-specific is based on reverse inference, and the likelihood of this inference being correct depends on the exclusivity of the relationship between these changes and the experience of pain. This consideration leads to the second issue, namely the fact that the experimental design used in the study cannot justify the claim that the dpIns is pain-specific. Precisely, the design does not allow ruling out the hypothesis that the changes in CBF in the dpIns may be related to the salience of the tonic pain stimulation, and not the the fact that it was painful (Legrain et al. 2011; Iannetti and Mouraux 2010). In other words, it is possible that any type of stimulation could trigger similar changes in CBF in the dpIns provided that it is sufficiently intense and/or salient, and regardless of whether the stimulation was nociceptive or painful (Liberati et al. 2016).
To counter this concern, Segerdahl et al. state that the salience of painful and innocuous stimuli was “closely matched”. However, this claim is not substantiated by any data, as there was no direct comparison of any measure of stimulus salience. Anyone who has been previously exposed to the effects of topical capsaicin will know that applying heat to the sensitized skin area is going to be a pretty intense, gruesome and attention-grabbing experience. The sensations generated by this procedure were thus obviously much more salient than the sensations generated by the gentle 1-2 Hz oscillations of the control mechanical stimulus. In fact, we were very surprised to find that the authors referred to this control stimulus as a vibrotactile stimulus, as the very low frequency used by Segerdahl et al. was way outside the preferred frequency range of rapidly-adapting mechanoreceptors involved in the perception of either flutter or vibration. Most importantly, considering the results of previous psychophysical studies in the field of touch, one can only expect that such a stimulus generated, at best, a very mild and evanescent tactile sensation. If it were possible for us to reproduce that stimulus[1], we would not be surprised to find out that participants are barely able to perceive such a stimulus applied to the foot. This would constitute a very straightforward explanation as to why the innocuous stimulation not only did not trigger changes of CBF in the dpIns, but also, did not trigger any measurable response in S1 or S2 (Burton et al. 1993; Coghill et al. 1994).
But this is probably not the most critical issue. To assess whether measured changes in CBF correlate with changes in intensity of perception, it is crucial for the intensity of perception (i.e. the explanatory variable) to vary over time. This was clearly the case when Segerdahl et al. applied capsaicin and heat: during the procedure, the intensity of pain perception varied between no pain or very little pain (“baseline”, “habituation”, and “relief” periods) and very high pain ratings (“onset”, “peak” and “rekindle” periods). In contrast, nothing is known about how much the intensity of the percept elicited by tactile stimulus varied over time. One can only guess that the variations in perception magnitude generated by applying a tactile stimulus oscillating between 1 and 2 Hz at pseudo-random intervals during 7 minutes were very slight, especially if these were compared to variations in the intensity of the perception elicited by capsaicin and heat. For this reason, it is not at all surprising that “no significant correlation was observed between absolute CBF and either the ongoing vibration intensity levels applied or with the ongoing perceived stimulus intensity levels reported by the subjects”.
In conclusion, the finding that CBF in the dpIns correlated with the variations in pain intensity generated by capsaicin and heat but did not correlate with the variations in the intensity of the sensation elicited by the tactile stimulus does not in any way constitute evidence for “a specific role for the dorsal posterior insula in pain”. When Segerdahl et al. conclude that «the contralateral dpIns was the only region that was observed to track pain intensity», they do not take into account that “pain intensity” could as well be replaced by “salience” or “stimulation intensity”.
[1] We would be happy to confirm or infirm directly this claim by assessing the percept generated by the tactile stimulus. Unfortunately, this is not possible as it is not adequately described in the article. Indeed, the authors report the amplitude of the mechanical vibrations using an unrelated physical unit of electrical current intensity (mA).
André Mouraux & Giulia Liberati
Bibliography
Apkarian, V. 2015. Referee Report For: Evidence against pain specificity in the dorsal posterior insula [version 1; referees: 3 approved] F1000Research 2015, 4:362 (doi: 10.5256/f1000research.7347.r9627). F1000Research 4, p. 362.
Borsook, D. 2015. Referee Report For: Evidence against pain specificity in the dorsal posterior insula [version 1; referees: 3 approved] F1000Research 2015, 4:362 (doi: 10.5256/f1000research.7347.r9663). F1000Research.
Burton, H., Videen, T.O. and Raichle, M.E. 1993. Tactile-vibration-activated foci in insular and parietal-opercular cortex studied with positron emission tomography: mapping the second somatosensory area in humans. Somatosensory & motor research 10(3), pp. 297–308.
Coghill, R.C., Talbot, J.D., Evans, A.C., Meyer, E., Gjedde, A., Bushnell, M.C. and Duncan, G.H. 1994. Distributed processing of pain and vibration by the human brain. The Journal of Neuroscience 14(7), pp. 4095–4108.
Davis, K.D., Bushnell, M.C., Iannetti, G.D., St Lawrence, K. and Coghill, R. 2015. Evidence against pain specificity in the dorsal posterior insula. [version 1; referees: 3 approved]. F1000Research 4, p. 362.
Iannetti, G.D. and Mouraux, A. 2010. From the neuromatrix to the pain matrix (and back). Experimental Brain Research 205(1), pp. 1–12.
Legrain, V., Iannetti, G.D., Plaghki, L. and Mouraux, A. 2011. The pain matrix reloaded: a salience detection system for the body. Progress in Neurobiology 93(1), pp. 111–124.
Liberati, G., Klöcker, A., Safronova, M.M., Ferrão Santos, S., Ribeiro Vaz, J.G., Raftopoulos, C. and Mouraux, A. 2016. Nociceptive Local Field Potentials Recorded from the Human Insula Are Not Specific for Nociception. PLoS Biology 14(1), p. e1002345.
Segerdahl, A.R., Mezue, M., Okell, T.W., Farrar, J.T. and Tracey, I. 2015. The dorsal posterior insula subserves a fundamental role in human pain. Nature Neuroscience 18(4), pp. 499–500.
Segerdahl and collaborators addressed some of the suggested shortcomings highlighted by Davis et al., such as the absence of a direct statistical comparison between cerebral blood flow (CBF) changes triggered by painful and tactile stimulation, and the precise anatomical localization of the dpIns.
While we agree with most of the criticisms raised by Davis et al., we find that they do not address the two most problematic issues of the paper, which we summarize in the following three points.
The first issue lies in the ambiguity of the term “fundamental”. Simply stating that the dpIns subserves a fundamental role in the perception of pain, as Segerdahl et al. do in the title of their brief communication and as they remark upon in their correspondence, does not per se imply specificity. Nevertheless, the Authors refer to the pain-specificity of the dpIns in multiple points of their brief communication (e.g., «To validate the pain-specificity of our dpIns results», p. 1; «specific to the tonic heat pain», Online Methods). These statements are toned down in the last part of the Author’s response to Davis et al., where the Authors state that the dpIns is just potentially responsive to only nociceptive inputs. Segerdahl et al. state this this point is simply “arguing semantics”. Instead, we believe that this is actually a pivotal point for the interpretation of the findings.
The assumption that the CBF changes triggered in the dpIns are pain-specific is based on reverse inference, and the likelihood of this inference being correct depends on the exclusivity of the relationship between these changes and the experience of pain. This consideration leads to the second issue, namely the fact that the experimental design used in the study cannot justify the claim that the dpIns is pain-specific. Precisely, the design does not allow ruling out the hypothesis that the changes in CBF in the dpIns may be related to the salience of the tonic pain stimulation, and not the the fact that it was painful (Legrain et al. 2011; Iannetti and Mouraux 2010). In other words, it is possible that any type of stimulation could trigger similar changes in CBF in the dpIns provided that it is sufficiently intense and/or salient, and regardless of whether the stimulation was nociceptive or painful (Liberati et al. 2016).
To counter this concern, Segerdahl et al. state that the salience of painful and innocuous stimuli was “closely matched”. However, this claim is not substantiated by any data, as there was no direct comparison of any measure of stimulus salience. Anyone who has been previously exposed to the effects of topical capsaicin will know that applying heat to the sensitized skin area is going to be a pretty intense, gruesome and attention-grabbing experience. The sensations generated by this procedure were thus obviously much more salient than the sensations generated by the gentle 1-2 Hz oscillations of the control mechanical stimulus. In fact, we were very surprised to find that the authors referred to this control stimulus as a vibrotactile stimulus, as the very low frequency used by Segerdahl et al. was way outside the preferred frequency range of rapidly-adapting mechanoreceptors involved in the perception of either flutter or vibration. Most importantly, considering the results of previous psychophysical studies in the field of touch, one can only expect that such a stimulus generated, at best, a very mild and evanescent tactile sensation. If it were possible for us to reproduce that stimulus[1], we would not be surprised to find out that participants are barely able to perceive such a stimulus applied to the foot. This would constitute a very straightforward explanation as to why the innocuous stimulation not only did not trigger changes of CBF in the dpIns, but also, did not trigger any measurable response in S1 or S2 (Burton et al. 1993; Coghill et al. 1994).
But this is probably not the most critical issue. To assess whether measured changes in CBF correlate with changes in intensity of perception, it is crucial for the intensity of perception (i.e. the explanatory variable) to vary over time. This was clearly the case when Segerdahl et al. applied capsaicin and heat: during the procedure, the intensity of pain perception varied between no pain or very little pain (“baseline”, “habituation”, and “relief” periods) and very high pain ratings (“onset”, “peak” and “rekindle” periods). In contrast, nothing is known about how much the intensity of the percept elicited by tactile stimulus varied over time. One can only guess that the variations in perception magnitude generated by applying a tactile stimulus oscillating between 1 and 2 Hz at pseudo-random intervals during 7 minutes were very slight, especially if these were compared to variations in the intensity of the perception elicited by capsaicin and heat. For this reason, it is not at all surprising that “no significant correlation was observed between absolute CBF and either the ongoing vibration intensity levels applied or with the ongoing perceived stimulus intensity levels reported by the subjects”.
In conclusion, the finding that CBF in the dpIns correlated with the variations in pain intensity generated by capsaicin and heat but did not correlate with the variations in the intensity of the sensation elicited by the tactile stimulus does not in any way constitute evidence for “a specific role for the dorsal posterior insula in pain”. When Segerdahl et al. conclude that «the contralateral dpIns was the only region that was observed to track pain intensity», they do not take into account that “pain intensity” could as well be replaced by “salience” or “stimulation intensity”.
[1] We would be happy to confirm or infirm directly this claim by assessing the percept generated by the tactile stimulus. Unfortunately, this is not possible as it is not adequately described in the article. Indeed, the authors report the amplitude of the mechanical vibrations using an unrelated physical unit of electrical current intensity (mA).
André Mouraux & Giulia Liberati
Bibliography
Apkarian, V. 2015. Referee Report For: Evidence against pain specificity in the dorsal posterior insula [version 1; referees: 3 approved] F1000Research 2015, 4:362 (doi: 10.5256/f1000research.7347.r9627). F1000Research 4, p. 362.
Borsook, D. 2015. Referee Report For: Evidence against pain specificity in the dorsal posterior insula [version 1; referees: 3 approved] F1000Research 2015, 4:362 (doi: 10.5256/f1000research.7347.r9663). F1000Research.
Burton, H., Videen, T.O. and Raichle, M.E. 1993. Tactile-vibration-activated foci in insular and parietal-opercular cortex studied with positron emission tomography: mapping the second somatosensory area in humans. Somatosensory & motor research 10(3), pp. 297–308.
Coghill, R.C., Talbot, J.D., Evans, A.C., Meyer, E., Gjedde, A., Bushnell, M.C. and Duncan, G.H. 1994. Distributed processing of pain and vibration by the human brain. The Journal of Neuroscience 14(7), pp. 4095–4108.
Davis, K.D., Bushnell, M.C., Iannetti, G.D., St Lawrence, K. and Coghill, R. 2015. Evidence against pain specificity in the dorsal posterior insula. [version 1; referees: 3 approved]. F1000Research 4, p. 362.
Iannetti, G.D. and Mouraux, A. 2010. From the neuromatrix to the pain matrix (and back). Experimental Brain Research 205(1), pp. 1–12.
Legrain, V., Iannetti, G.D., Plaghki, L. and Mouraux, A. 2011. The pain matrix reloaded: a salience detection system for the body. Progress in Neurobiology 93(1), pp. 111–124.
Liberati, G., Klöcker, A., Safronova, M.M., Ferrão Santos, S., Ribeiro Vaz, J.G., Raftopoulos, C. and Mouraux, A. 2016. Nociceptive Local Field Potentials Recorded from the Human Insula Are Not Specific for Nociception. PLoS Biology 14(1), p. e1002345.
Segerdahl, A.R., Mezue, M., Okell, T.W., Farrar, J.T. and Tracey, I. 2015. The dorsal posterior insula subserves a fundamental role in human pain. Nature Neuroscience 18(4), pp. 499–500.