
==== Front
Nat Commun
Nat Commun
Nature Communications
2041-1723
Nature Publishing Group UK London

39256345
51911
10.1038/s41467-024-51911-8
Matters Arising
Reply to: Interindividual differences in pain can be explained by fMRI, sociodemographic, and psychological factors
http://orcid.org/0000-0002-9872-7739
Hoeppli M. E. marie-eve.hoeppli@mail.mcgill.ca

12
Nahman-Averbuch H. 123
Hinkle W. A. 1
http://orcid.org/0000-0002-6731-4878
Leon E. 12
Peugh J. 24
López-Solà M. 567
http://orcid.org/0000-0002-0089-7386
King C. D. 124
Goldschneider K. R. 18
http://orcid.org/0000-0003-3828-1605
Coghill R. C. 124
1 https://ror.org/01hcyya48 grid.239573.9 0000 0000 9025 8099 Pediatric Pain Research Center (PPRC) Cincinnati Children’s Hospital Medical Center, Cincinnati, OH USA
2 https://ror.org/01hcyya48 grid.239573.9 0000 0000 9025 8099 Division of Behavioral Medicine and Clinical Psychology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH USA
3 grid.4367.6 0000 0001 2355 7002 Division of Clinical and Translational Research and Washington University Pain Center, Department of Anesthesiology, Washington University School of Medicine, St Louis, MO USA
4 https://ror.org/01e3m7079 grid.24827.3b 0000 0001 2179 9593 Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH USA
5 https://ror.org/021018s57 grid.5841.8 0000 0004 1937 0247 Serra Hunter Programme, Department of Medicine, School of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain
6 grid.5841.8 0000 0004 1937 0247 Institute of Neurosciences, University of Barcelona, Barcelona, Spain
7 grid.10403.36 0000000091771775 Instituto de Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS), Barcelona, Spain
8 https://ror.org/01hcyya48 grid.239573.9 0000 0000 9025 8099 Pain Management Center, Department of Anesthesiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH USA
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© The Author(s) 2024
2024
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Subject terms

Pain
Cognitive neuroscience
issue-copyright-statement© Springer Nature Limited 2024
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pmcreplying to S. Gim et al. Nature Communications 10.1038/s41467-024-51910-9 (2024)

We first would like to thank the Matters Arising’s authors, S. Gim, Dr. D.H. Lee, Dr. S. Lee, and Dr. C.-W. Woo, for their interest in our manuscript. We are painfully aware of the impact that our manuscript will have on the use of BOLD to study pain mechanisms, but we hope our negative finding will motivate novel avenues of research into aspects of both acute and chronic pain mechanisms. Indeed, for all of us in the field, the ultimate goal of any pain research should be the improvement in the understanding, diagnosis, and treatment of chronic pain conditions. Studying healthy participants remains, therefore, a means to an end, a first step to delineate and understand pain mechanisms that might be significant to further our understanding of mechanisms underlying chronic pain.

First, Gim et al. raise questions about our finding that individual differences in pain could not be explained by sociodemographic and psychological factors and implemented a multiple regression analysis on our data to further assess this potential relationship. Although we agree with Gim et al. on the importance of such factors on pain, their question, i.e. “can we predict pain using sociodemographic and psychological factors?”, goes beyond the scope of our manuscript, which focused on identifying brain mechanisms of interindividual differences in pain. Analyses performed on these factors and reported in our manuscript were only done to further describe differences and similarities among the 3 identified groups of pain sensitivity. Furthermore, studying pain-free individuals, who experience short experimental pain and who are generally psychologically healthy, is a very different situation from patients with chronic pain who are often diagnosed with major psychological comorbidities. This is most likely the reason that the new analyses of our data by Gim et al. identified a relatively weak relationship explaining roughly 7% of variance between individual differences in pain sensitivity and sociodemographic/psychological factors (r = 0.26 and r = 0.27). This magnitude of effect is consistent with other papers1,2. Moreover, this analysis was performed in a subset of our data, such that only 73 out of 101 participants were included (due to missing data). Although the effect observed by Gim et al. might be statistically significant and interesting in a research context, the low explained variance in a generally healthy population raises questions about its translational value to clinical populations.

Second, Gim et al. performed analyses similar to those described in our manuscript on an archival dataset from their lab. Their massive univariate analysis identified several regions which displayed a significant relationship with perceived pain intensity and survived FDR correction for multiple comparisons. Although the detected areas in Gim et al. have been previously described in studies of pain, limited evidence supports a direct role of areas like the visual cortex and the supplementary motor area in pain processing per se. Such activations may be more epiphenomena related to the experimental paradigm. A multivariate pattern analysis (LASSO-PCR) identified additional regions including the anterior insula and ventromedial prefrontal cortex that were related to individual differences in pain intensity, while the application of the NPS also identified a significant relationship with pain intensity. Despite having a very homogenous population of young healthy Korean individuals, the association between pain ratings and brain activation observed in Gim et al. only explains a very low variance (LASSO-PCR: 6%, NPS: 4%). Of note, their experimental paradigm included a movie designed to manipulate pain, and this holds the potential to amplify mechanisms supporting the construction and modulation of an experience of pain. Thus, subtle differences between their experimental design and ours might also contribute somewhat to the discrepant findings between studies.

An important difference between Gim et al.’s dataset and ours is the heterogeneity of the dataset. Although using a homogenous dataset has advantages when testing hypotheses, heterogeneity in the data seems desirable when studying interindividual differences in pain. A homogenous sample of healthy young adult participants might provide a narrow view of brain mechanisms of pain and hinder the definition of biomarkers for interindividual differences in pain that might translate to clinically significant biomarkers. Nevertheless, such approaches may represent a starting point for the advancement of methodologies for the identification of potential biomarkers.

To replicate and to better understand our findings, Gim et al. reanalyzed our preprocessed fMRI data using different tools. Their results largely converged with our findings. Gim et al. suggest that the limited sample size (n = 101) might be responsible for the discrepancy between the results obtained using our dataset and theirs. If a lack of power is responsible for the null results and a greater sample size is needed to account for the variability in our population, we are concerned that BOLD signals related to interindividual differences in pain may be too small to reliably overcome between-individual variability present in the population.

In conclusion, we need to be mindful of the potential limitations of BOLD activation studies in delineating processes that extend beyond acute nociceptive processing into pain. While BOLD studies of acute experimental pain have provided us with a rich understanding of brain mechanisms of nociceptive processing, we need to augment these findings with new approaches to better understand the myriad mechanistic disruptions associated with chronic pain.

Acknowledgements

This work is supported by the National Institute of Neurological Disorders and Stroke (R01 NS085391), the Serra Hunter Programme (MLS), and the National Insitutes of Health (NIH) Clinical and Translational Science Award (CTSA) program (2UL1TR001425; REDCap).

Author contributions

Writing – original draft, M.E.H. and R.C.C.; Writing – review & editing, M.E.H., W.A.H, E.L., J.P., R.C.C., C.D.K., M.L.S., K.R.G., and H.N.A.; Funding acquisition, R.D.C.; Resources, R.D.C.; Supervision, K.R.G.

Peer review

Peer review information

Nature Communications thanks David Seminowicz and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Competing interests

The authors declare no competing interests.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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References

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Plinsinga, M. L. et al. Pain-related cognitions and emotional distress are not associated with conditioned pain modulation: an explorative analysis of 1142 participants with acute, subacute, and chronic pain. Pain 164, 1593–1599 (2023).36728470 10.1097/j.pain.0000000000002864
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