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Timing is everything



The 2024 Global Year will examine what is known about sex and gender differences in pain perception and modulation and address sex-and gender-related disparities in both the research and treatment of pain.

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Human brain mapping doesn’t go back as far as one might think.  The first brain activation studies used positron emission tomography (PET) back in the late 1980s.   Functional magnetic resonance imaging, or fMRI, followed in the early 90s and went on to radically change neuroimaging [1].

Given that it’s such early days for brain mapping, it makes sense that most of the experiments we see follow similar formats, particularly when it comes to data analysis.  This paper by Pujol and colleagues[2] is refreshing—it’s broken one of the ‘rules’.  I recommend checking it out here.

In analysing the images taken in an fMRI experiment it’s common to specify a model based on assumptions about the typical time courses of activation in the brain.   Specifying the times of stimulation and rest results in a contrast—if all goes according to plan—between these conditions.

These authors cite a problem with this, particularly in investigations of pain or emotion.  They reckon we can’t anticipate response duration in these states, and it’s likely that brain responses typically persist after withdrawal of the nociceptive or evocative stimulus.  Hence this group explored temporal dynamics; they had no a priori hypothesis with regard to expected activation time courses.

In adjusting the generated activation maps for the duration of the brain responses (termed, data-driven analysis) this group captured some stuff that’s been missed with traditional methods.  They found more robust activation patterns in the “pain matrix” than have been found in the past and they also provide evidence for a comparatively stronger correlation with subjective pain levels.

This study compared brain activation maps of nine patients with fibromyalgia to two groups of healthy controls.  Control group 1 served to compare brain response to a fixed mechanical pressure able to provoke severe pain in the fibromyalgia patients (4kg/cm2), while control group 2 was instead matched to the patients on levels of perceived pain; 6.8 kg/cm2 produced a similar pain severity level in both groups.  Pressure was applied to the subjects’ thumbnails in nine-second stimulation blocks, interleaved with 21-second periods of rest.

Here are the findings that I think were most interesting…  In a temporal analysis of brain activation at 4kg/cm2 of pressure, signal changes were of similar duration in patients and controls in the somatosensory components of the brain (bilateral parietal cortex) and persisted, in both groups, for twice the duration of the applied stimulus.  When looking at the insular component however, only the fibromyalgia patients had consistent signal increases which persisted long after stimulus withdrawal.  In light of the prevailing theory that the insula is part of the medial pain system, involved with assigning meaning and emotion to the pain experience [3], I think it’s possible that the pain evoked greater emotion in the patients than the controls.

Pain scores were widely correlated with brain activation in the data-driven analysis, involving much of the pain matrix.  But a conventional model-driven approach didn’t show this correlation with subjective pain.

In comparing the activation patterns between the fibromyalgia patients and the second control group, again responses in the regions involved with the sensory aspects of nociception were similar across groups.  However the patients again showed significantly greater activation in sub-cortical structures as compared with the healthy controls—despite being matched, this time, for perceived pain levels.

I think that the temporal analysis aspect of this paper is of great significance.  These investigators have bravely thought outside the brain-mapping-box and in doing so have come up with some compelling findings.  The evidence of prolonged activation in medial structures in the fibromyalgia patients is likely to be particularly important to our understanding of the emotional and affective dimension of the pain experience.

Flavia Di Pietro

Flavia Di Pietro Body in MindFlavia Di Pietro is a PhD student in the Body and Mind Research Group, Sydney. She is investigating the development of Complex Regional Pain Syndrome (CRPS) after wrist fracture. Specifically, Flavia’s PhD involves brain scanning people who are in a higher than usual amount of pain in the first 3 weeks after the fracture, and then following them for a few months. Her question concerns whether or not there are changes in brain activation patterns that emerge before the CRPS does and if so, what do they tell us about the condition? Here is Flavia talking about what she does and a link to her published researchBiM author’s downloadable PDFs can be found here.



[1] Friston, K.J. (2002) A short history of statistical parametric mapping in functional neuroimaging. Technical report, Wellcome Department of Imaging Neuroscience, ION, UCL.

[2] Pujol J, López-Solà M, Ortiz H, Vilanova JC, Harrison BJ, et al. 2009 Mapping Brain Response to Pain in Fibromyalgia Patients Using Temporal Analysis of fMRI. PLoS ONE 4(4): e5224. doi:10.1371/journal.pone.0005224

[3] Kulkarni, B., Bentley, D., Elliott, R., Youell, P., Watson, A., Derbyshire, S., Frackowiak, R., Friston, K., & Jones, A. (2005). Attention to pain localization and unpleasantness discriminates the functions of the medial and lateral pain systems European Journal of Neuroscience, 21 (11), 3133-3142 DOI: 10.1111/j.1460-9568.2005.04098.x

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