Abstract
Analgesic treatments that aim to eliminate pain display marginal success in relieving chronic pain and may increase pain vulnerability. Repeated exposure to pain may result in increased pain modulation via engagement of anti-nociceptive brain regions. It was hypothesized that repeated exposure to delayed onset muscle soreness (DOMS) would result in increased pain modulatory capacity (PMC) via functional neural adaptation. 23 healthy participants completed Baseline and Follow Up resting-state fMRI and quantitative sensory testing (QST) visits 40 days apart. Participants were randomized to two groups: A Repeated DOMS Group (RD Group) that received four, weekly DOMS inductions and a Control Group that received one baseline induction. Daily pain ratings were collected for seven days post-induction, as were quantitative sensory testing (QST) metrics at baseline and Follow Up. Regional functional connectivity (FC) was estimated among areas involved in pain modulation. Seed and network FC was estimated among areas involved in pain modulation and sensory processing. Changes in FC were compared between groups. The RD Group displayed significant reductions in post-DOMS pain ratings and significant changes in thermal QST measures. RD Group participants displayed greater adaptation in nucleus accumbens-medial prefrontal cortex (NAc-mPFC) FC and in sensorimotor network (SMN) connectivity with the dorsomedial, ventromedial, and rostromedial prefrontal cortices. Changes in SMN-PFC connectivity correlated with reductions in post-DOMS affective distress. Results suggest that repeated exposure to clinically-relevant pain results in adaptations among brain regions involved in pain modulation. Repeated exposure to clinically-relevant pain may serve as a mechanism to increase PMC via inhibition of emotional valuation of painful stimuli.
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References
Alshelh, Z., Di Pietro, F., Youssef, A. M., Reeves, J. M., Macey, P. M., Vickers, E. R., et al. (2016). Chronic neuropathic pain: It’s about the rhythm. Journal of Neuroscience, 36(3), 1008–1018. https://doi.org/10.1523/JNEUROSCI.2768-15.2016.
Altier, N., & Stewart, J. (1999). Minireview the role of dopamine in the nucleus Accumbens in analgesia. Life Sciences, 65(22), 2269–2287.
Apkarian, A. V., Hashmi, J. A., & Baliki, M. N. (2011). Pain and the brain: Specificity and plasticity of the brain in clinical chronic pain. Pain, 152(SUPPL.3), S49–S64. https://doi.org/10.1016/j.pain.2010.11.010.
Apkarian, A., Baliki, M. N., & Farmer, M. A. (2013). Predicting transition to chronic pain. Current Opinion in Neurology, 26(4), 360–367. https://doi.org/10.1097/WCO.0b013e32836336ad.
Baliki, M. N., Geha, P. Y., Fields, H. L., & Apkarian, A. V. (2010). Predicting value of pain and analgesia: Nucleus Accumbens response to noxious stimuli changes in the presence of chronic pain. Neuron, 66(1), 149–160. https://doi.org/10.1016/j.neuron.2010.03.002.
Baliki, M. N., Baria, A. T., & Apkarian, A. V. (2011). The cortical rhythms of chronic back pain. Journal of Neuroscience, 31(39), 13981–13990. https://doi.org/10.1523/JNEUROSCI.1984-11.2011.
Baliki, M. N., Petre, B., Torbey, S., Herrmann, K. M., Huang, L., Schnitzer, T. J., Fields, H. L., & Apkarian, A. V. (2012). Corticostriatal functional connectivity predicts transition to chronic back pain. Nature Neuroscience, 15(8), 1117–1119. https://doi.org/10.1038/nn.3153.
Becker, S., Gandhi, W., Pomares, F., Wager, T. D., & Schweinhardt, P. (2017). Orbitofrontal cortex mediates pain inhibition by monetary reward. Social Cognitive and Affective Neuroscience, 12(4), 651–661. https://doi.org/10.1093/scan/nsw173.
Bingel, U., Lorenz, J., Schoell, E., Weiller, C., & Büchel, C. (2006). Mechanisms of placebo analgesia: rACC recruitment of a subcortical antinociceptive network. Pain, 120(1–2), 8–15. https://doi.org/10.1016/j.pain.2005.08.027.
Bingel, U., Schoell, E., Herken, W., Büchel, C., & May, A. (2007). Habituation to painful stimulation involves the antinociceptive system. Pain, 131(1–2), 21–30. https://doi.org/10.1016/j.pain.2006.12.005.
Bishop, M. D., Horn, M. E., & George, S. Z. (2011a). Exercise-induced pain intensity predicted by pre-exercise fear of pain and pain sensitivity. Clinical Journal of Pain, 27(5), 398–404. https://doi.org/10.1097/AJP.0b013e31820d9bbf.
Bishop, M. D., Horn, M. E., George, S. Z., & Robinson, M. E. (2011b). Self-reported pain and disability outcomes from an endogenous model of muscular back pain. BMC Musculoskeletal Disorders, 12, 35. https://doi.org/10.1186/1471-2474-12-35.
Borsook, D., Becerra, L., & Hargreaves, R. (2011). Biomarkers for chronic pain and analgesia. Part 1: The need, reality, challenges, and solutions. Discovery Medicine, 11(58), 197–207 ISSN: 1539-6509.
Calhoun, V. D., Adali, T., Pearlson, G. D., & Pekar, J. J. (2001). A method for making group inferences from functional MRI data using independent component analysis. Human Brain Mapping, 14(3), 140–151. https://doi.org/10.1002/hbm.1048.
Cheng, J. C., Erpelding, N., Kucyi, A., DeSouza, D. D., & Davis, K. D. (2015). Individual differences in temporal summation of pain reflect Pronociceptive and Antinociceptive brain structure and function. Journal of Neuroscience, 35(26), 9689–9700. https://doi.org/10.1523/JNEUROSCI.5039-14.2015.
Damoiseaux, J. S., Beckmann, C. F., Arigita, E. J. S., Barkhof, F., Scheltens, P., Stam, C. J., Smith, S. M., & Rombouts, S. A. R. B. (2008). Reduced resting-state brain activity in the “default network” in normal aging. Cerebral Cortex, 18(8), 1856–1864. https://doi.org/10.1093/cercor/bhm207.
Dannecker, E. A., Koltyn, K. F., Riley, J. L., & Robinson, M. E. (2002). The influence of endurance exercise on delayed onset muscle soreness. Journal of Sports Medicine and Physical Fitness, 42(4), 458–465.
Dannecker, E. A., Hausenblas, H. A., Kaminski, T. W., & Robinson, M. E. (2005). Sex differences in delayed onset muscle soreness. Clinical Journal of Pain, 21(2), 120–126.
Desikan, R. S., Ségonne, F., Fischl, B., Quinn, B. T., Dickerson, B. C., Blacker, D., Buckner, R. L., Dale, A. M., Maguire, R. P., Hyman, B. T., Albert, M. S., & Killiany, R. J. (2006). An automated labeling system for subdividing the human cerebral cortex on MRI scans into gyral based regions of interest. NeuroImage, 31(3), 968–980. https://doi.org/10.1016/j.neuroimage.2006.01.021.
Frazier, J. A., Chiu, S., Breeze, J. L., Makris, N., Lange, N., Kennedy, D. N., Herbert, M. R., Bent, E. K., Koneru, V. K., Dieterich, M. E., Hodge, S. M., Rauch, S. L., Grant, P. E., Cohen, B. M., Seidman, L. J., Caviness, V. S., & Biederman, J. (2005). Structural brain magnetic resonance imaging of limbic and thalamic volumes in pediatric bipolar disorder. American Journal of Psychiatry, 162(7), 1256–1265. https://doi.org/10.1176/appi.ajp.162.7.1256.
Gear, R. W., & Levine, J. D. (2011). Nucleus accumbens facilitates nociception. Experimental Neurology, 229(2), 502–506. https://doi.org/10.1016/j.expneurol.2011.03.021.
Goldstein, J. M., Seidman, L. J., Makris, N., Ahern, T., O’Brien, L. M., Caviness, V. S., et al. (2007). Hypothalamic abnormalities in schizophrenia: Sex effects and genetic vulnerability. Biological Psychiatry, 61(8), 935–945. https://doi.org/10.1016/j.biopsych.2006.06.027.
Hagelberg, N., Jääskeläinen, S. K., Martikainen, I. K., Mansikka, H., Forssell, H., Scheinin, H., et al. (2004). Striatal dopamine D2 receptors in modulation of pain in humans: A review. European Journal of Pharmacology, 500(1–3 SPEC. ISS), 187–192. https://doi.org/10.1016/j.ejphar.2004.07.024.
Hardy, S. G. P., & Leichnetz, G. R. (1981). Frontal cortical projections to the periaqueductal gray in the rat: A retrograde and orthograde horseradish peroxidase study. Neuroscience Letters, 23(1), 13–17. https://doi.org/10.1016/0304-3940(81)90183-X.
Harris, P. A., Taylor, R., Thielke, R., Payne, J., Gonzalez, N., & Conde, J. G. (2009). Research electronic data capture (REDCap)-A metadata-driven methodology and workflow process for providing translational research informatics support. Journal of Biomedical Informatics, 42(2), 377–381. https://doi.org/10.1016/j.jbi.2008.08.010.
Hyldahl, R. D., & Hubal, M. J. (2014). Lengthening our perspective: Morphological, cellular, and molecular responses to eccentric exercise. Muscle and Nerve, 49(2), 155–170. https://doi.org/10.1002/mus.24077.
Kalisch, R., & Gerlicher, A. M. V. (2014). Making a mountain out of a molehill: On the role of the rostral dorsal anterior cingulate and dorsomedial prefrontal cortex in conscious threat appraisal, catastrophizing, and worrying. Neuroscience and Biobehavioral Reviews, 42, 1–8. https://doi.org/10.1016/j.neubiorev.2014.02.002.
King, T., Ossipov, M. H., Vanderah, T. W., Porreca, F., & Lai, J. (2005). Is paradoxical pain induced by sustained opioid exposure an underlying mechanism of opioid antinociceptive tolerance? NeuroSignals, 14(4), 194–205. https://doi.org/10.1159/000087658.
Leknes, S., Berna, C., Lee, M. C., Snyder, G. D., Biele, G., & Tracey, I. (2013). The importance of context: When relative relief renders pain pleasant. Pain, 154(3), 402–410. https://doi.org/10.1016/j.pain.2012.11.018.
Letzen, J. E., Boissoneault, J., Sevel, L. S., & Robinson, M. E. (2016). Test-retest reliability of pain-related functional brain connectivity compared with pain self-report. Pain, 157(3), 546–551. https://doi.org/10.1097/j.pain.0000000000000356.
Makris, N., Goldstein, J. M., Kennedy, D., Hodge, S. M., Caviness, V. S., Faraone, S. V., Tsuang, M. T., & Seidman, L. J. (2006). Decreased volume of left and total anterior insular lobule in schizophrenia. Schizophrenia Research, 83(2–3), 155–171. https://doi.org/10.1016/j.schres.2005.11.020.
Maldjian, J. A., Laurienti, P. J., Kraft, R. A., & Burdettea, J. H. (2003). An automated method for neuroanatomic and cytoarchitectonic\ratlas-based interrogation of fMRI data sets. NeuroImage, 19(3), 1233–1239. https://doi.org/10.1016/S1053-8119(03)00169-1.
Mitsi, V., & Zachariou, V. (2016). Modulation of pain, nociception, and analgesia by the brain reward center. Neuroscience, 338, 81–92. https://doi.org/10.1016/j.neuroscience.2016.05.017.
Navratilova, E., Xie, J. Y., Okun, A., Qu, C., Eyde, N., Ci, S., Ossipov, M. H., King, T., Fields, H. L., & Porreca, F. (2012). Pain relief produces negative reinforcement through activation of mesolimbic reward-valuation circuitry. Proceedings of the National Academy of Sciences, 109(50), 20709–20713. https://doi.org/10.1073/pnas.1214605109.
Northoff, G. (2005). Emotional-cognitive integration, the self, and cortical midline structures. Behavioral and Brain Sciences, 28(2), 211–212. https://doi.org/10.1017/S0140525X05400047.
Ochsner, K. N., Ray, R. D., Cooper, J. C., Robertson, E. R., Chopra, S., Gabrieli, J. D. E., & Gross, J. J. (2004). For better or for worse: Neural systems supporting the cognitive down- and up-regulation of negative emotion. NeuroImage, 23(2), 483–499. https://doi.org/10.1016/j.neuroimage.2004.06.030.
Peciña, M., Azhar, H., Love, T. M., Lu, T., Fredrickson, B. L., Stohler, C. S., & Zubieta, J. K. (2013). Personality trait predictors of placebo analgesia and neurobiological correlates. Neuropsychopharmacology, 38(4), 639–646. https://doi.org/10.1038/npp.2012.227.
Power, J. D., Mitra, A., Laumann, T. O., Snyder, A. Z., Schlaggar, B. L., & Petersen, S. E. (2014). Methods to detect, characterize, and remove motion artifact in resting state fMRI. NeuroImage, 84, 320–341. https://doi.org/10.1016/j.neuroimage.2013.08.048.
Power, J. D., Schlaggar, B. L., & Petersen, S. E. (2015). Recent progress and outstanding issues in motion correction in resting state fMRI. NeuroImage, 105, 536–551. https://doi.org/10.1016/j.neuroimage.2014.10.044.
Price, D. D., & Dubner, R. (1977). Mechanisms of first and second pain in the peripheral and central nervous systems. Journal of Investigative Dermatology, 69(1), 167–171. https://doi.org/10.1111/1523-1747.ep12497942.
Price, D. D., Hu, J. W., Dubner, R., & Gracely, R. H. (1977). Peripheral suppression of first pain and central summation of second pain evoked by noxious heat pulses. Pain, 3(1), 57–68. https://doi.org/10.1016/0304-3959(77)90035-5.
Price, D. D., McGrath, P. A., Rafii, A., & Buckingham, B. (1983). The validation of visual analogue scales as ratio scale measures for chronic and experimental pain. Pain, 17(1), 45–56. https://doi.org/10.1016/0304-3959(83)90126-4.
Price, D. D., Finniss, D. G., & Benedetti, F. (2008). A comprehensive review of the placebo effect: Recent advances and current thought. Annual Review of Psychology, 59(1), 565–590. https://doi.org/10.1146/annurev.psych.59.113006.095941.
Riedl, V., Valet, M., Wöller, A., Sorg, C., Vogel, D., Sprenger, T., Boecker, H., Wohlschläger, A. M., & Tölle, T. R. (2011). Repeated pain induces adaptations of intrinsic brain activity to reflect past and predict future pain. NeuroImage, 57(1), 206–213. https://doi.org/10.1016/j.neuroimage.2011.04.011.
Rivat, C., & Ballantyne, J. (2016). The dark side of opioids in pain management. PAIN Reports, 1(2), e570. https://doi.org/10.1097/PR9.0000000000000570.
Rogachov, A., Cheng, J. C., Erpelding, N., Hemington, K. S., Crawley, A. P., & Davis, K. D. (2016). Regional brain signal variability: A novel indicator of pain sensitivity and coping. Pain, 157(11), 2483–2492. https://doi.org/10.1097/j.pain.0000000000000665.
Roy, M., Shohamy, D., & Wager, T. D. (2012). Ventromedial prefrontal-subcortical systems and the generation of affective meaning. Trends in Cognitive Sciences, 16(3), 147–156. https://doi.org/10.1016/j.tics.2012.01.005.
Seery, M. D. (2011). Challenge or threat? Cardiovascular indexes of resilience and vulnerability to potential stress in humans. Neuroscience and Biobehavioral Reviews, 35(7), 1603–1610. https://doi.org/10.1016/j.neubiorev.2011.03.003.
Seery, M. D., Leo, R. J., Holman, E. A., & Silver, R. C. (2010). Lifetime exposure to adversity predicts functional impairment and healthcare utilization among individuals with chronic back pain. Pain, 150(3), 507–515. https://doi.org/10.1016/j.pain.2010.06.007.
Sinha, R., Lacadie, C. M., Constable, R. T., & Seo, D. (2016). Dynamic neural activity during stress signals resilient coping. Proceedings of the National Academy of Sciences, 113(31), 8837–8842. https://doi.org/10.1073/pnas.1600965113.
Sorg, C., Riedl, V., Muhlau, M., Calhoun, V. D., Eichele, T., Laer, L., Drzezga, A., Forstl, H., Kurz, A., Zimmer, C., & Wohlschlager, A. M. (2007). Selective changes of resting-state networks in individuals at risk for Alzheimer’s disease. Proceedings of the National Academy of Sciences, 104(47), 18760–18765. https://doi.org/10.1073/pnas.0708803104.
Tzourio-Mazoyer, N., Landeau, B., Papathanassiou, D., Crivello, F., Etard, O., Delcroix, N., Mazoyer, B., & Joliot, M. (2002). Automated anatomical labeling of activations in SPM using a macroscopic anatomical parcellation of the MNI MRI single-subject brain. NeuroImage, 15(1), 273–289. https://doi.org/10.1006/nimg.2001.0978.
Vachon-Presseau, E., Centeno, M. V., Ren, W., Berger, S. E., Tétreault, P., Ghantous, M., Baria, A., Farmer, M., Baliki, M. N., Schnitzer, T. J., & Apkarian, A. V. (2016). The emotional brain as a predictor and amplifier of chronic pain. Journal of Dental Research, 95(6), 605–612. https://doi.org/10.1177/0022034516638027.
Wager, T. D., Rilling, J. K., Smith, E. E., Sokolik, A., Casey, K. L., Davidson, R. J., et al. (2004). Placebo-induced changes in fMRI in the anticipation and experience of pain. Science, 303(5661), 1162–1167. https://doi.org/10.1126/science.1093065.
Wager, T. D., Atlas, L. Y., Leotti, L. A., & Rilling, J. K. (2011). Predicting individual differences in placebo analgesia: Contributions of brain activity during anticipation and pain experience. Journal of Neuroscience, 31(2), 439–452. https://doi.org/10.1523/JNEUROSCI.3420-10.2011.
Wang, G., Erpelding, N., & Davis, K. D. (2014). Sex differences in connectivity of the subgenual anterior cingulate cortex. Pain, 155(4), 755–763. https://doi.org/10.1016/j.pain.2014.01.005.
Waugh, C. E., Lemus, M. G., & Gotlib, I. H. (2014). The role of the medial frontal cortex in the maintenance of emotional states. Social Cognitive and Affective Neuroscience, 9(12), 2001–2009. https://doi.org/10.1093/scan/nsu011.
Waugh, C. E., Zarolia, P., Mauss, I. B., Lumian, D., Ford, B., Davis, T., et al. (2016). Emotion regulation changes the duration of the BOLD response to emotional stimuli. Social Cognitive and Affective Neuroscience, 11(10), 1550–1559.
Whitfield-Gabrieli, S., & Nieto-Castanon, A. (2012). Conn : A functional connectivity toolbox for correlated and anticorrelated brain networks. Brain Connectivity, 2(3), 125–141. https://doi.org/10.1089/brain.2012.0073.
Wiech, K., & Tracey, I. (2013). Pain, decisions, and actions: A motivational perspective. Frontiers in Neuroscience, 7(7 APR), 46. https://doi.org/10.3389/fnins.2013.00046.
Wiech, K., Ploner, M., & Tracey, I. (2008). Neurocognitive aspects of pain perception. Trends in Cognitive Sciences, 12(8), 306–313. https://doi.org/10.1016/j.tics.2008.05.005.
Woo, C. W., Krishnan, A., & Wager, T. D. (2014). Cluster-extent based thresholding in fMRI analyses: Pitfalls and recommendations. NeuroImage, 91, 412–419. https://doi.org/10.1016/j.neuroimage.2013.12.058.
Woo, C. W., Roy, M., Buhle, J. T., & Wager, T. D. (2015). Distinct brain systems mediate the effects of nociceptive input and self-regulation on pain. PLoS Biology, 13(1), e1002036. https://doi.org/10.1371/journal.pbio.1002036.
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Research reported in this publication (REDCap access and support) was supported by the University of Florida Clinical and Translational Science Institute, which is supported in part by the NIH National Center for Advancing Translational Sciences under award number UL1TR001427. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
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Sevel, L., Boissoneault, J., Alappattu, M. et al. Training endogenous pain modulation: a preliminary investigation of neural adaptation following repeated exposure to clinically-relevant pain. Brain Imaging and Behavior 14, 881–896 (2020). https://doi.org/10.1007/s11682-018-0033-8
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DOI: https://doi.org/10.1007/s11682-018-0033-8