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Correspondence

Evidence against pain specificity in the dorsal posterior insula

[version 1; peer review: 3 approved]
PUBLISHED 24 Jul 2015
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Abstract

The search for a “pain centre” in the brain has long eluded neuroscientists.  Although many regions of the brain have been shown to respond to painful stimuli, all of these regions also respond to other types of salient stimuli. In a recent paper, Segerdahl et al. (Nature Neuroscience, 2015)  claims that the dorsal posterior insula (dpIns) is a pain-specific region based on the observation that the magnitude of regional cerebral blood flow (rCBF) fluctuations in the dpIns correlated with the magnitude of evoked pain.  However, such a conclusion is, simply, not justified by the experimental evidence provided.  Here we discuss three major factors that seriously question this claim.

Keywords

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-touch1820. 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.

Comments on this article Comments (2)

Version 1
VERSION 1 PUBLISHED 24 Jul 2015
  • Reader Comment 25 Jan 2016
    André Mouraux, Université catholique de Louvain, Belgium
    25 Jan 2016
    Reader Comment
    The brief communication by Segerdahl et al. (2015) on the role of the dorsal posterior insula (dpIns) in human pain triggered a lively and stimulating debate in the pain neuroscience ... Continue reading
  • Reader Comment 08 Sep 2015
    Petra Schweinhardt, McGill University, Canada
    08 Sep 2015
    Reader Comment
    Many things said in the Nature Neuroscience article by Segerdahl et al. are correct – a huge body of literature supports the view that the dorsal posterior insular cortex plays ... Continue reading
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Davis KD, Bushnell MC, Iannetti GD et al. Evidence against pain specificity in the dorsal posterior insula [version 1; peer review: 3 approved]. F1000Research 2015, 4:362 (https://doi.org/10.12688/f1000research.6833.1)
NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article.
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Open Peer Review

Current Reviewer Status: ?
Key to Reviewer Statuses VIEW
ApprovedThe paper is scientifically sound in its current form and only minor, if any, improvements are suggested
Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.
Not approvedFundamental flaws in the paper seriously undermine the findings and conclusions
Version 1
VERSION 1
PUBLISHED 24 Jul 2015
Views
156
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Reviewer Report 12 Oct 2015
Joel D. Greenspan, Department of Pain and Neural Sciences, University of Maryland, Baltimore, MD, USA 
Approved
VIEWS 156
The discussion initiated by Davis et al. 1, in their critical commentary of Segendahl et al.’s publication in Nature Neuroscience 2 should be recognized as a valuable contribution to our attempt to understand how brain function relates to pain perception.  Davis et ... Continue reading
CITE
CITE
HOW TO CITE THIS REPORT
Greenspan JD. Reviewer Report For: Evidence against pain specificity in the dorsal posterior insula [version 1; peer review: 3 approved]. F1000Research 2015, 4:362 (https://doi.org/10.5256/f1000research.7347.r9718)
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.
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190
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Reviewer Report 07 Sep 2015
Apkar Vania Apkarian, Department of Surgery and Anesthesia, Northwestern University, Chicago, IL, USA 
Approved
VIEWS 190
The correspondence by K. Davis and colleagues regarding the recently published study by Segerdahl et al. raises important and valid concerns regarding the conclusion of the paper. The issue is important as the report appeared in a high visibility journal, ... Continue reading
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CITE
HOW TO CITE THIS REPORT
Apkarian AV. Reviewer Report For: Evidence against pain specificity in the dorsal posterior insula [version 1; peer review: 3 approved]. F1000Research 2015, 4:362 (https://doi.org/10.5256/f1000research.7347.r9627)
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.
Views
256
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Reviewer Report 28 Jul 2015
David Borsook, Department of Radiology, Massachusetts General Hospital, Boston, MA, USA 
Approved
VIEWS 256
When Research Reports may be Painful - Open Discourse should Prevail

Karen Davis and coauthors, including notable researchers in the pain imaging field, including Robert Coghill and Catherine Bushnell 1, argue strongly against the concept reported in Nature Neuroscience by Segerdahl ... Continue reading
CITE
CITE
HOW TO CITE THIS REPORT
Borsook D. Reviewer Report For: Evidence against pain specificity in the dorsal posterior insula [version 1; peer review: 3 approved]. F1000Research 2015, 4:362 (https://doi.org/10.5256/f1000research.7347.r9663)
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.

Comments on this article Comments (2)

Version 1
VERSION 1 PUBLISHED 24 Jul 2015
  • Reader Comment 25 Jan 2016
    André Mouraux, Université catholique de Louvain, Belgium
    25 Jan 2016
    Reader Comment
    The brief communication by Segerdahl et al. (2015) on the role of the dorsal posterior insula (dpIns) in human pain triggered a lively and stimulating debate in the pain neuroscience ... Continue reading
  • Reader Comment 08 Sep 2015
    Petra Schweinhardt, McGill University, Canada
    08 Sep 2015
    Reader Comment
    Many things said in the Nature Neuroscience article by Segerdahl et al. are correct – a huge body of literature supports the view that the dorsal posterior insular cortex plays ... Continue reading
Alongside their report, reviewers assign a status to the article:
Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested
Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.
Not approved - fundamental flaws in the paper seriously undermine the findings and conclusions
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