We found the spot
In March 2015, a group of researchers (Segerdahl et al 2015) from the Oxford Centre for Functional Magnetic Resonance Imaging of the Brain published a paper in Nature Neuroscience entitled The dorsal posterior insula subserves a fundamental role in human pain (sorry, behind a paywall). The researchers took 17 healthy human subjects, applied a capsaicin cream to their legs and stuck them in a big magnet (fMRI). A clever part of the design was the use of capsaicin cream to induce a dynamic pain experience – when the cream is first applied it is quite innocuous, but over time it begins to feel warm, then hot, then painfully hot. Segerdahl et al (2015) looked at how brain activity changed as the subjects’ reports of pain increased (and decreased) over time.
Segerdahl et al (2015) reported:
“Human neuroimaging studies that measure how nociceptive inputs are encoded to produce pain experiences have yet to identify regional activity specific to pain. Many cortical regions are activated, but pain is a multifactorial experience that encompasses altered attention, anxiety, threat and many other non-specific features reflected in these activations. Despite extensive study using sophisticated psychological and pharmacological procedures that aim to disambiguate pain-specific from nonspecific components, we have yet to identify a pain-specific brain region. Part of the difficulty relates to limitations of neuroimaging tools and confounds in protocol designs.
…we were able to identify the dpIns [dorsal posterior insula] as subserving a fundamental role in pain and the likely human homolog of the nociceptive region identified from animal studies. Future work targeting dpIns activity might provide a window to explore fundamental mechanisms related to how pain emerges from nociception as well as new therapeutic approaches to treating certain chronic pain conditions.”
The ‘Ouch zone’
The press around the study was, however, a bit more ‘robust’ than the findings may have lead one to believe. The University of Oxford published a press release suggesting:
“The results, published in the journal Nature Neuroscience, show that activity in only one brain area, the dorsal posterior insula, reflected the participants’ ratings of how much the pain hurt.
‘We have identified the brain area likely to be responsible for the core, ‘it hurts’, experience of pain,’ said Professor Irene Tracey, University of Oxford, whose team made the discovery. ‘Pain is a complex, multidimensional experience, which causes activity in many brain regions involved with things like attention, feeling emotions such as fear, locating where the pain is, and so on. But the dorsal posterior insula seems to be specific to the actual ‘hurt level’ of pain itself.'” (emphasis added)
It certainly behooves the author of a press release (or blog post…) to write a snappy, attention grabbing headline, but, the transition from “we were able to identify the dpIns as subserving a fundamental role in pain” to “We have identified the brain area likely to be responsible for the core, ‘it hurts’, experience of pain” does seem like a bit of a stretch. However the research came from a well-respected research group, led by one of the real heavyweights in brain imaging and pain (Professor Irene Tracey) and the ‘brain’s ouch zone’ became a thing and escaped out into the wilds of the internet.
In response to Segerdahl et al
Later in 2015, things got a little interesting. A different group of eight researchers (including past EP3 2015 speaker Robert Coghill, and future EP3 2016 speaker Gian Domenico Iannetti) published a highly critical paper via F1000Research (an interesting open access science publishing platform that uses an open peer review process). Davis et al (2015) pulled no punches:
“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.”
The peer reviewers for the Davis et al (2015) response were equally strong in their criticisms of the design, methods, and findings of the original Segendahl et al (2015) paper:
Vania Apkarian (Department of Surgery and Anesthesia, Northwestern University, Chicago, IL, USA):
“Perhaps it would be informative to elaborate on this issue, specifically regarding how an underpowered study can lead into discovering a brain “specific center” for pain perception, the validity of which is doubted by senior scientists in the field.
…Borsook’s commentary on the problems associated with Segerdahl et al. publication is also very astute. He points that [sic] the competition to publish in high end journals pushes the scientist into making more extravagant conclusions than even the author herself or himself actually does not trust. Yet ultimately responsibility rests on the peer review process, and the latter is not guaranteed to be full proof.”
David Borsook (Department of Radiology, Massachusetts General Hospital, Boston, MA, USA):
“At best, the Segerdahal contribution has raised a vibrant discussion in the field, at is worst it is setting the field back not only because of its purported methodological inaccuracy (as evaluated by Davis et al.), lack of acknowledgement of what has come before, perhaps being too enthusiastic about the results and therefore pushing a notion that is unlikely to be true – finding a single brain area that is a pain specific region.”
In response to your response
There’s nothing like a good old fashioned rumble played out in the scientific literature, and Segerdahl and his colleagues (Segerdahl et al 2015response) came out swinging, posting a response to the response, via F1000:
“An interesting and valuable discussion has arisen from our recent article (Segerdahl, Mezue et al., 2015) and we are pleased here to have the opportunity to expand on the various points we made. Equally important, we wish to correct several important misunderstandings that were made by Davis and colleagues that possibly contributed to their concerns about power when assessing our paper…” (emphasis added)
If them’s aren’t fighting words I don’t know what are. Segerdahl et al (2015r) also make the very valid point:
“At no point in the paper do we say that by identifying this ‘fundamental role for the dpIns’ in tracking pain intensity does this mean we’re “promoting the concept of a single spot”, as Davis and colleagues have themselves interpreted from our data. Nor do we ever suggest that the results presented as a Brief Communication should be used to regress back to an expired ‘one region fits all’ pedagogy of where ‘pain is in the brain’. Indeed, that view would be completely contrary to the view and concept about ‘pain representation in the brain’ that we’ve long held and have written extensively about via original studies, reviews and editorials over the past 16 years” [stick that in your pipe and smoke it]. (emphasis and pipe smoking reference, added)
Technical and statistical issues aside, this seems to be a key point – as Segerdahl et al (2015r) point out, the original Segerdahl et al (2015) paper never suggests that the dpIns is ‘the’ pain centre yet, for instance, in his peer review report, Apkarian states:
“the authors make the strong claim that they have identified a single “pain center” in the cortex”
What I find fascinating, is the prospect that Davis et al (2015) and their peer reviewers were not just responding to the Segerdahl et al (2015) paper prima facie, but responding also to the hype in the media and quotes such as “We have identified the brain area likely to be responsible for the core, ‘it hurts’, experience of pain” from Professor Tracey. Fascinating, because it perhaps demonstrates the increasing influence and power of social media and internet reporting not just on the lay public, but on scientists themselves. It also might serve to remind us that scientists are, after all, humans with all of the inherent foibles that make life interesting (looking at the author affiliations and locations, one might begin to wonder if there might be some cross-pond rivalry).
One, okay two, more things
One. The argument is far from over – as recently as 25 January this year, Andre Mouraux (now there is someone who knows how to write a snappy, popular-culture-referencing title for a paper) weighed in on the debate via a comment on the Davis et al (2015) response. You can read his entire comment if you scroll down to the bottom of the document here, but in essence, Mouraux questions the very premise that the dpIns is tracking specific ‘pain intensity’, and suggests that instead it might reflect a broader role for the dpIns in responding to ‘salience’ or ‘stimulation intensity’, severely criticising Segerdahl et al (2015) method for not controlling adequately for this.
Two. If you have the time to read them all, the original paper and subsequent response, the response peer review reports, the comments on the response, the response to the response, and the peer review reports of the response to the response, provide a rich trove of the most current (and critical) thinking from some of the real rockstars of brain and pain research (AD ‘Bud’ Craig is one of the peer reviewers for Segerdahl et al (2015r) and offers an entirely new interpretation of the results).
But are we any closer to an answer to the question “oh pain, where art thou?” Perhaps those looking for answers to where in the brain are looking for pain in all the wrong places, perhaps they have become “brain-bound” and need to look further afield?
To ponder this, here are some smooth sounds from The Soggy Bottom Boys
NOIgroup is heading around Australia in 2016 – Townsville, Noosa, Adelaide with details to come on our teaching visits to The Australian Institute of Sport in the Australian Capital Territory, and Perth