Background & Aims

The promise of functional magnetic resonance imaging (fMRI) to detect robust inter-individual differences in health and behavioural outcomes and its potential use as a biomarker has been increasingly called into question. In a recent study (Hoeppli et al., 2022), the authors argued that, in the context of pain perception, fMRI was sensitive to small differences in applied noxious stimuli within an individual, but failed at predicting inter-individual differences. Here, we test whether this absent predictive power can be restored by accounting for inter-individual variance and the use of clearly distinguishable experimental conditions. We show that fMRI can provide valuable information about inter-individual differences in pain perception.

Methods

We re-analysed data of six studies (Geuter et al., 2013; Hoeppli et al., 2022; Kessner et al., 2013, 2014; Rütgen et al., 2015; Wrobel et al., 2014) that applied noxious stimuli while recording fMRI. As our main variable of interest, we made use of the neurological pain signature (NPS), a multivariate pain classifier based on blood oxygenation level dependent (BOLD) fMRI (Wager et al., 2013). To test the influence of inter-individual variance and the choice of experimental conditions we performed three regression analyses. First, we used absolute NPS scores of noxious stimuli to predict the corresponding pain rating. Second, we used individual NPS differences between two painful conditions to predict the differences in their pain ratings. Third, we used individual NPS differences between a painful and a non-painful, yet warm condition to predict the rating of the painful stimulus. All analyses were carried out on study-level and additionally pooled across studies.

Results

Out of six studies, only one (Geuter et al., 2013) showed a statistically significant relationship between absolute NPS scores and pain ratings (r = .44, p < .01). In all other studies we replicated the null-finding by Hoeppli et al. (2022). However, we observed a significant positive linear relationship between the difference in NPS and the difference in pain ratings between two painful stimuli across all analysed studies (pooled result: r = .29, p < .01). More importantly, all analysed studies showed a significant positive linear relationship between the difference in NPS (comparing a painful and a non-painful, yet warm condition) and the rating of the painful condition (pooled result: r = .44, p < .01).

Conclusions

Our results demonstrate that a fMRI-based multivariate pain classifier has predictive power for inter-individual differences in pain ratings. We conclude that two main factors influence its success: Inter-individual variance in the fMRI BOLD signal and the choice of experimental conditions. In addition to using robust intra-individual differences between experimental conditions to reduce inter-individual variance, future studies should explore the potential benefit of post-hoc rescaling of BOLD fMRI data using resting-state or vascular residuals. Alternatively, BOLD could also be replaced by an inherent quantitative contrast.

References

Geuter, S., Eippert, F., Hindi Attar, C., & Büchel, C. (2013). Cortical and subcortical responses to high and low effective placebo treatments. NeuroImage, 67, 227–236. https://doi.org/10.1016/j.neuroimage.2012.11.029
Hoeppli, M. E., Nahman-Averbuch, H., Hinkle, W. A., Leon, E., Peugh, J., Lopez-Sola, M., King, C. D., Goldschneider, K. R., & Coghill, R. C. (2022). Dissociation between individual differences in self-reported pain intensity and underlying fMRI brain activation. Nature Communications, 13(1), Article 1. https://doi.org/10.1038/s41467-022-31039-3
Kessner, S., Forkmann, K., Ritter, C., Wiech, K., Ploner, M., & Bingel, U. (2014). The Effect of Treatment History on Therapeutic Outcome: Psychological and Neurobiological Underpinnings. PLOS ONE, 9(10), e109014. https://doi.org/10.1371/journal.pone.0109014
Kessner, S., Sprenger, C., Wrobel, N., Wiech, K., & Bingel, U. (2013). Effect of Oxytocin on Placebo Analgesia: A Randomized Study. JAMA, 310(16), 1733–1735. https://doi.org/10.1001/jama.2013.277446
Rütgen, M., Seidel, E.-M., Silani, G., Rie?anský, I., Hummer, A., Windischberger, C., Petrovic, P., & Lamm, C. (2015). Placebo analgesia and its opioidergic regulation suggest that empathy for pain is grounded in self pain. PNAS, 112(41), E5638–E5646. https://doi.org/10.1073/pnas.1511269112
Wager, T. D., Atlas, L. Y., Lindquist, M. A., Roy, M., Woo, C.-W., & Kross, E. (2013). An fMRI-Based Neurologic Signature of Physical Pain. New England Journal of Medicine, 368(15), 1388–1397. https://doi.org/10.1056/NEJMoa1204471
Wrobel, N., Wiech, K., Forkmann, K., Ritter, C., & Bingel, U. (2014). Haloperidol blocks dorsal striatum activity but not analgesia in a placebo paradigm. Cortex, 57, 60–73. https://doi.org/10.1016/j.cortex.2014.02.023

Presenting Author

Ole Goltermann

Poster Authors

Ole Goltermann

MSc

University Medical Center Hamburg-Eppendorf

Lead Author

E-mail

Topics

  • Pain Imaging