Individual variability in brain representations of pain
Lada Kohoutová, Lauren Y Atlas, Christian Büchel, Jason T Buhle, Stephan Geuter, Marieke Jepma, Leonie Koban, Anjali Krishnan, Dong Hee Lee, Sungwoo Lee, Mathieu Roy, Scott M Schafer, Liane Schmidt, Tor D Wager, Choong-Wan Woo, Lada Kohoutová, Lauren Y Atlas, Christian Büchel, Jason T Buhle, Stephan Geuter, Marieke Jepma, Leonie Koban, Anjali Krishnan, Dong Hee Lee, Sungwoo Lee, Mathieu Roy, Scott M Schafer, Liane Schmidt, Tor D Wager, Choong-Wan Woo
Abstract
Characterizing cerebral contributions to individual variability in pain processing is crucial for personalized pain medicine, but has yet to be done. In the present study, we address this problem by identifying brain regions with high versus low interindividual variability in their relationship with pain. We trained idiographic pain-predictive models with 13 single-trial functional MRI datasets (n = 404, discovery set) and quantified voxel-level importance for individualized pain prediction. With 21 regions identified as important pain predictors, we examined the interindividual variability of local pain-predictive weights in these regions. Higher-order transmodal regions, such as ventromedial and ventrolateral prefrontal cortices, showed larger individual variability, whereas unimodal regions, such as somatomotor cortices, showed more stable pain representations across individuals. We replicated this result in an independent dataset (n = 124). Overall, our study identifies cerebral sources of individual differences in pain processing, providing potential targets for personalized assessment and treatment of pain.
© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.
Figures
References
- Coghill RC The Distributed Nociceptive System: A Framework for Understanding Pain. Trends Neurosci, doi:10.1016/j.tins.2020.07.004 (2020).
- Tracey I. & Mantyh PW The cerebral signature for pain perception and its modulation. Neuron 55, 377–391, doi:10.1016/j.neuron.2007.07.012 (2007).
- Apkarian AV, Bushnell MC, Treede RD & Zubieta JK Human brain mechanisms of pain perception and regulation in health and disease. Eur J Pain 9, 463–484, doi:10.1016/j.ejpain.2004.11.001 (2005).
- Xu A. et al. Convergent neural representations of experimentally-induced acute pain in healthy volunteers: A large-scale fMRI meta-analysis. Neurosci Biobehav Rev 112, 300–323, doi:10.1016/j.neubiorev.2020.01.004 (2020).
- Kucyi A. & Davis KD The dynamic pain connectome. Trends Neurosci 38, 86–95, doi:10.1016/j.tins.2014.11.006 (2015).
- Greenspan JD, Lee RR & Lenz FA Pain sensitivity alterations as a function of lesion location in the parasylvian cortex. Pain 81, 273–282, doi:Doi 10.1016/S0304-3959(99)00021-4 (1999).
- Greenspan JD et al. Quantitative somatic sensory testing and functional imaging of the response to painful stimuli before and after cingulotomy for obsessive-compulsive disorder (OCD). Eur J Pain 12, 990–999, doi:10.1016/j.ejpain.2008.01.007 (2008).
- Valet M. et al. Distraction modulates connectivity of the cingulo-frontal cortex and the midbrain during pain--an fMRI analysis. Pain 109, 399–408, doi:10.1016/j.pain.2004.02.033 (2004).
- Berna C. et al. Induction of Depressed Mood Disrupts Emotion Regulation Neurocircuitry and Enhances Pain Unpleasantness. Biological Psychiatry 67, 1083–1090, doi:10.1016/j.biopsych.2010.01.014 (2010).
- López-Solà M, Koban L. & Wager TD Transforming pain with prosocial meaning: an fMRI study. Psychosomatic medicine 80, 814 (2018).
- Losin EAR et al. Neural and sociocultural mediators of ethnic differences in pain. Nat Hum Behav, doi:10.1038/s41562-020-0819-8 (2020).
- Hashmi JA & Davis KD Deconstructing sex differences in pain sensitivity. Pain 155, 10–13, doi:10.1016/j.pain.2013.07.039 (2014).
- Raja SN et al. The revised International Association for the Study of Pain definition of pain: concepts, challenges, and compromises. Pain (2020).
- Gordon EM et al. Precision Functional Mapping of Individual Human Brains. Neuron 95, 791–807, doi:10.1016/j.neuron.2017.07.011 (2017).
- Laumann TO et al. Functional System and Areal Organization of a Highly Sampled Individual Human Brain. Neuron 87, 657–670, doi:10.1016/j.neuron.2015.06.037 (2015).
- Davis KD et al. Discovery and validation of biomarkers to aid the development of safe and effective pain therapeutics: challenges and opportunities. Nat Rev Neurol 16, 381–400, doi:10.1038/s41582-020-0362-2 (2020).
- Wager TD et al. An fMRI-Based Neurologic Signature of Physical Pain. New Engl J Med 368, 1388–1397, doi:10.1056/NEJMoa1204471 (2013).
- Lee JJ et al. A neuroimaging biomarker for sustained experimental and clinical pain. Nat Med 27, 174–182, doi:10.1038/s41591-020-1142-7 (2021).
- Woo C-W et al. Quantifying cerebral contributions to pain beyond nociception. Nat Commun 8 (2017).
- Yeo BT et al. The organization of the human cerebral cortex estimated by intrinsic functional connectivity. J Neurophysiol 106, 1125–1165, doi:10.1152/jn.00338.2011 (2011).
- Kragel PA, Koban L, Barrett LF & Wager TD Representation, Pattern Information, and Brain Signatures: From Neurons to Neuroimaging. Neuron 99, 257–273, doi:10.1016/j.neuron.2018.06.009 (2018).
- Hong YW, Yoo Y, Han J, Wager TD & Woo CW False-positive neuroimaging: Undisclosed flexibility in testing spatial hypotheses allows presenting anything as a replicated finding. Neuroimage 195, 384–395, doi:10.1016/j.neuroimage.2019.03.070 (2019).
- Kriegeskorte N, Mur M. & Bandettini P. Representational similarity analysis–connecting the branches of systems neuroscience. Frontiers in systems neuroscience 2 (2008).
- Margulies DS et al. Situating the default-mode network along a principal gradient of macroscale cortical organization. Proc Natl Acad Sci U S A 113, 12574–12579, doi:10.1073/pnas.1608282113 (2016).
- Favilla S. et al. Ranking brain areas encoding the perceived level of pain from fMRI data. Neuroimage 90, 153–162, doi:10.1016/j.neuroimage.2014.01.001 (2014).
- Kong J. et al. Exploring the brain in pain: activations, deactivations and their relation. Pain 148, 257–267, doi:10.1016/j.pain.2009.11.008 (2010).
- Senkowski D, Hofle M. & Engel AK Crossmodal shaping of pain: a multisensory approach to nociception. Trends in Cognitive Sciences 18, 319–327, doi:10.1016/j.tics.2014.03.005 (2014).
- Elkhetali AS, Vaden RJ, Pool SM & Visscher KM Early visual cortex reflects initiation and maintenance of task set. Neuroimage 107, 277–288 (2015).
- Seminowicz DA & Davis KD Interactions of pain intensity and cognitive load: the brain stays on task. Cereb Cortex 17, 1412–1422 (2007).
- Dum RP, Levinthal DJ & Strick PL The spinothalamic system targets motor and sensory areas in the cerebral cortex of monkeys. J Neurosci 29, 14223–14235, doi:10.1523/JNEUROSCI.3398-09.2009 (2009).
- Almeida TF, Roizenblatt S. & Tufik S. Afferent pain pathways: a neuroanatomical review. Brain research 1000, 40–56 (2004).
- Shackman AJ et al. The integration of negative affect, pain and cognitive control in the cingulate cortex. Nat Rev Neurosci 12, 154–167, doi:10.1038/nrn2994 (2011).
- Tan LL et al. A pathway from midcingulate cortex to posterior insula gates nociceptive hypersensitivity. Nat Neurosci 20, 1591–1601, doi:10.1038/nn.4645 (2017).
- Kulkarni B. et al. Attention to pain localization and unpleasantness discriminates the functions of the medial and lateral pain systems. Eur J Neurosci 21, 3133–3142, doi:10.1111/j.1460-9568.2005.04098.x (2005).
- Hutchison WD, Davis KD, Lozano AM, Tasker RR & Dostrovsky JO Pain-related neurons in the human cingulate cortex. Nat Neurosci 2, 403–405, doi:10.1038/8065 (1999).
- Kragel PA et al. Generalizable representations of pain, cognitive control, and negative emotion in medial frontal cortex. Nature Neuroscience 21, 283-+, doi:10.1038/s41593-017-0051-7 (2018).
- Segerdahl AR, Mezue M, Okell TW, Farrar JT & Tracey I. The dorsal posterior insula subserves a fundamental role in human pain. Nat Neurosci 18, 499–500, doi:10.1038/nn.3969 (2015).
- Kross E, Berman MG, Mischel W, Smith EE & Wager TD Social rejection shares somatosensory representations with physical pain. Proceedings of the National Academy of Sciences 108, 6270–6275 (2011).
- Evrard HC, Logothetis NK & Craig AD Modular architectonic organization of the insula in the macaque monkey. J Comp Neurol 522, 64–97, doi:10.1002/cne.23436 (2014).
- Ashar YK, Chang LJ & Wager TD Brain mechanisms of the placebo effect: an affective appraisal account. Annual review of clinical psychology 13, 73–98 (2017).
- Woo C-W, Roy M, Buhle JT & Wager TD Distinct brain systems mediate the effects of nociceptive input and self-regulation on pain. Plos Biol 13, e1002036 (2015).
- Seminowicz DA & Davis KD Cortical responses to pain in healthy individuals depends on pain catastrophizing. Pain 120, 297–306, doi:10.1016/j.pain.2005.11.008 (2006).
- Tinnermann A, Geuter S, Sprenger C, Finsterbusch J. & Buchel C. Interactions between brain and spinal cord mediate value effects in nocebo hyperalgesia. Science 358, 105–108, doi:10.1126/science.aan1221 (2017).
- Bonnici HM & Maguire EA Two years later–Revisiting autobiographical memory representations in vmPFC and hippocampus. Neuropsychologia 110, 159–169 (2018).
- Ciaramelli E, De Luca F, Monk AM, McCormick C. & Maguire EA What” wins” in VMPFC: Scenes, situations, or schema? Neuroscience & Biobehavioral Reviews (2019).
- Zunhammer M, Spisak T, Wager TD, Bingel U. & Placebo Imaging C. Meta-analysis of neural systems underlying placebo analgesia from individual participant fMRI data. Nat Commun 12, 1391, doi:10.1038/s41467-021-21179-3 (2021).
- Claassen J. et al. Cerebellum is more concerned about visceral than somatic pain. Journal of Neurology, Neurosurgery & Psychiatry 91, 218–219 (2020).
- Huntenburg JM, Bazin PL & Margulies DS Large-Scale Gradients in Human Cortical Organization. Trends Cogn Sci 22, 21–31, doi:10.1016/j.tics.2017.11.002 (2018).
- Finn ES et al. Functional connectome fingerprinting: identifying individuals using patterns of brain connectivity. Nature neuroscience 18, 1664 (2015).
- Farrell SM, Green A. & Aziz T. The Current State of Deep Brain Stimulation for Chronic Pain and Its Context in Other Forms of Neuromodulation. Brain Sci 8, doi:10.3390/brainsci8080158 (2018).
- Yang S. & Chang MC Effect of Repetitive Transcranial Magnetic Stimulation on Pain Management: A Systematic Narrative Review. Front Neurol 11, 114, doi:10.3389/fneur.2020.00114 (2020).
- Zhang S. et al. Pain Control by Co-adaptive Learning in a Brain-Machine Interface. Curr Biol 30, 3935–3944 e3937, doi:10.1016/j.cub.2020.07.066 (2020).
- Meloto CB et al. Human pain genetics database: a resource dedicated to human pain genetics research. Pain 159, 749–763, doi:10.1097/j.pain.0000000000001135 (2018).
- Kohl A, Rief W. & Glombiewski JA Acceptance, Cognitive Restructuring, and Distraction as Coping Strategies for Acute Pain. Journal of Pain 14, 305–315, doi:10.1016/j.jpain.2012.12.005 (2013).
- Coghill RC, McHaffie JG & Yen YF Neural correlates of interindividual differences in the subjective experience of pain. Proc Natl Acad Sci U S A 100, 8538–8542, doi:10.1073/pnas.1430684100 (2003).
- Mehta S. et al. Identification and Characterization of Unique Subgroups of Chronic Pain Individuals with Dispositional Personality Traits. Pain Res Manag 2016, doi:10.1155/2016/5187631 (2016).
- Haxby JV et al. A common, high-dimensional model of the representational space in human ventral temporal cortex. Neuron 72, 404–416, doi:10.1016/j.neuron.2011.08.026 (2011).
- Coghill RC, Gilron I. & Iadarola MJ Hemispheric lateralization of somatosensory processing. J Neurophysiol 85, 2602–2612, doi:10.1152/jn.2001.85.6.2602 (2001).
- Pruim RHR et al. ICA-AROMA: A robust ICA-based strategy for removing motion artifacts from fMRI data. Neuroimage 112, 267–277, doi:10.1016/j.neuroimage.2015.02.064 (2015).
- Atlas LY, Bolger N, Lindquist MA & Wager TD Brain mediators of predictive cue effects on perceived pain. J Neurosci 30, 12964–12977, doi:10.1523/JNEUROSCI.0057-10.2010 (2010).
- Atlas LY, Lindquist MA, Bolger N. & Wager TD Brain mediators of the effects of noxious heat on pain. Pain 155, 1632–1648, doi:10.1016/j.pain.2014.05.015 (2014).
- Wager TD & Nichols TE Optimization of experimental design in fMRI: a general framework using a genetic algorithm. Neuroimage 18, 293–309, doi:10.1016/S1053-8119(02)00046–0 (2003).
- Lindquist MA & Gelman A. Correlations and Multiple Comparisons in Functional Imaging: A Statistical Perspective (Commentary on Vul et al., 2009). Perspect Psychol Sci 4, 310–313, doi:10.1111/j.1745-6924.2009.01130.x (2009).
- Diedrichsen J, Balsters JH, Flavell J, Cussans E. & Ramnani N. A probabilistic MR atlas of the human cerebellum. Neuroimage 46, 39–46, doi:10.1016/j.neuroimage.2009.01.045 (2009).
- Shattuck DW et al. Construction of a 3D probabilistic atlas of human cortical structures. Neuroimage 39, 1064–1080, doi:10.1016/j.neuroimage.2007.09.031 (2008).
- Wager TD, Scott DJ & Zubieta JK Placebo effects on human mu-opioid activity during pain. Proc Natl Acad Sci U S A 104, 11056–11061, doi:10.1073/pnas.0702413104 (2007).
- Wager TD, Davidson ML, Hughes BL, Lindquist MA & Ochsner KN Prefrontal-subcortical pathways mediating successful emotion regulation. Neuron 59, 1037–1050, doi:10.1016/j.neuron.2008.09.006 (2008).
- Szucs D. & Ioannidis JP Sample size evolution in neuroimaging research: An evaluation of highly-cited studies (1990–2012) and of latest practices (2017–2018) in high-impact journals. Neuroimage 221, 117164, doi:10.1016/j.neuroimage.2020.117164 (2020).
Source: PubMed