Altered mesocorticolimbic functional connectivity in chronic low back pain patients at rest and following sad mood induction

  • Janelle E. LetzenEmail author
  • Jeff Boissoneault
  • Landrew S. Sevel
  • Michael E. Robinson


Depressive symptoms are common among individuals with chronic pain. Previous work suggests that chronic pain patients have difficulty regulating emotional responses, which is a risk factor for the development of major depressive disorder (MDD). Function of the mesocorticolimbic system, a neural network associated with reward processing, contributes to emotion regulation. This network’s dysfunction has been described in chronic pain and MDD research and potentially underlies the relationship among emotion dysregulation, chronic pain, and MDD development. Given that mood induction paradigms have been used to measure emotion regulation, the present study examined intrinsic mesocorticolimbic functional connectivity (FC) after induced sad mood in individuals with and without chronic low back pain (cLBP). Thirty-three MDD-free individuals (17 cLBP) underwent resting-state scanning before and after sad memory-evoked mood induction. A Group [cLBP, healthy control (HC)] x Mood (Neutral, Sadness) repeated measures ANCOVA was conducted on seed-based FC data using a mesolimbic a priori region of interest. Interaction effects were identified in the orbital frontal cortex and inferior frontal gyrus [F(2,29) = 21.07, pFDR < .05. hp2 = .5]. Whereas cLBP showed significantly greater FC between these two regions and the mesolimbic seed under neutral mood, FC among these regions increased in HC and decreased in cLBP under sad mood. Exploratory graph theory analyses further describe between-group differences in mesocorticolimbic network properties. Findings support previous literature describing mesocorticolimbic dysfunction in cLBP and demonstrate aberrant function in emotion regulation. Mesocorticolimbic dysfunction during emotion regulation might contribute to the development of certain depressive phenotypes in chronic pain patients.


Chronic pain Functional connectivity Mesocorticolimbic circuitry Pain affect 



This work was supported by grants from the National Institutes of Health to MER (PI: NIH-NCCIH R01AT001424; Co-PI: NIH-NINR R01NR015314) and JEL (F31AT007898; F32HL143941).


This work was supported by grants from the National Institutes of Health to MER (PI: NIH-NCCIH R01AT001424; Co-PI: NIH-NINR R01NR015314) and JEL (F31AT007898; F32HL143941).

Compliance with ethical standards

Conflict of interest

All authors declare that they have no conflict of interest. All procedures were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.


  1. Bair, M. J., Robinson, R. L., Katon, W., & Kroenke, K. (2003). Depression and pain comorbidity: A literature review. Archives of Internal Medicine, 163(20), 2433–2445.Google Scholar
  2. Baliki, M. N., Geha, P. Y., Fields, H. L., & Vania Apkarian, A. (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.Google Scholar
  3. Baliki, M. N., et al. (2012). Corticostriatal functional connectivity predicts transition to chronic Back pain. Nature Neuroscience, 15(8), 1117–1119. Retrieved ( Accessed Sept 2017.Google Scholar
  4. Becerra, L., & Borsook, D. (2008). Signal valence in the nucleus Accumbens to pain onset and offset. European Journal of Pain, 12(7), 866–869.Google Scholar
  5. Becerra, L., Navratilova, E., Porreca, F., & Borsook, D. (2013). Analogous responses in the nucleus Accumbens and cingulate cortex to pain onset (aversion) and offset (relief) in rats and humans. Journal of Neurophysiology, 110(5), 1221–1226.Google Scholar
  6. Beck, A. T., Steer, R. A., & Brown, G. K. (1996). Beck depression inventory-II. San Antonio.Google Scholar
  7. Behzadi, Y., Restom, K., Liau, J., & Liu, T. T. (2007). A component based noise correction method (CompCor) for BOLD and perfusion based FMRI. NeuroImage, 37(1), 90–101. Retrieved ( Accessed Sept 2017.Google Scholar
  8. Benarroch, E. E. (2016). Involvement of the nucleus Accumbens and dopamine system in chronic pain. Neurology, 87(16), 1720–1726.Google Scholar
  9. Berna, C., et al. (2010). Induction of depressed mood disrupts emotion regulation Neurocircuitry and enhances pain unpleasantness. Biological Psychiatry, 67(11), 1083–1090.Google Scholar
  10. Bullmore, E., & Sporns, O. (2009). Complex brain networks: Graph theoretical analysis of structural and functional systems. Nature Reviews. Neuroscience, 10(3), 186–198.Google Scholar
  11. Bullmore, E., & Sporns, O. (2012). The economy of brain network organization. Nature Reviews. Neuroscience, 13(5), 336–349.Google Scholar
  12. Chai, X. J., Ofen, N., Gabrieli, J. D. E., & Whitfield-Gabrieli, S. (2014). Selective development of Anticorrelated networks in the intrinsic functional Organization of the Human Brain. Journal of Cognitive Neuroscience, 26(3), 501–513.Google Scholar
  13. Chang, P.-C., et al. (2014). Role of nucleus Accumbens in neuropathic pain: Linked multi-scale evidence in the rat transitioning to neuropathic pain. PAIN®, 155(6), 1128–1139.Google Scholar
  14. Clyde, Z. (2002). DeC. Williams AC. Depression and mood. New Avenues for the Prevention of Chronic Musculoskeletal Pain and Disability. Pain Research and Clinical Management (pp. 67–82). Amsterdam: Elsevier.Google Scholar
  15. Compare, A., Zarbo, C., Shonin, E., Van Gordon, W., & Marconi, C. (2014). Emotional regulation and depression: A potential mediator between heart and mind. Cardiovascular Psychiatry and Neurology, 2014, 324374.Google Scholar
  16. Desikan, R. S., et al. (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.Google Scholar
  17. Donofry, S. D., Roecklein, K. A., Wildes, J. E., Miller, M. A., & Erickson, K. I. (2016). Alterations in emotion generation and regulation Neurocircuitry in depression and eating disorders: A comparative review of structural and functional neuroimaging studies. Neuroscience and Biobehavioral Reviews, 68, 911–927.Google Scholar
  18. Dore, B. P., et al. (2018). Negative autobiographical memory in depression reflects elevated amygdala-hippocampal reactivity and Hippocampally associated emotion regulation. Biological Psychiatry. Cognitive Neuroscience and Neuroimaging, 3(4), 358–366.Google Scholar
  19. Droutman, V., Read, S. J., & Bechara, A. (2015). Revisiting the role of the insula in addiction. Trends in Cognitive Sciences, 19(7), 414–420.Google Scholar
  20. Drysdale, A. T., et al. (2017). Resting-state connectivity biomarkers define neurophysiological subtypes of depression. Nature Medicine, 23(1), 28–38.Google Scholar
  21. Ehring, T., Tuschen-Caffier, B., Schnülle, J., Fischer, S., & Gross, J. J. (2010). Emotion regulation and vulnerability to depression: Spontaneous versus instructed use of emotion suppression and reappraisal. Emotion, 10(4), 563–572.Google Scholar
  22. Finan, P. H., & Smith, M. T. (2013). The comorbidity of insomnia, chronic pain, and depression: Dopamine as a putative mechanism. Sleep Medicine Reviews, 17(3), 173–183.Google Scholar
  23. Folstein, M. F., Robins, L. N., & Helzer, J. E. (1983). The mini-mental state examination. Archives of General Psychiatry, 40(7), 812.Google Scholar
  24. Geisser, M. E., Roth, R. S., & Robinson, M. E. (1997). Assessing depression among persons with chronic pain using the Center for Epidemiological Studies-Depression Scale and the Beck depression inventory: A comparative analysis. The Clinical Journal of Pain, 13(2), 163–170.Google Scholar
  25. Grabenhorst, F., & Rolls, E. T. (2011). Value, pleasure and choice in the ventral prefrontal cortex. Trends in Cognitive Sciences, 15(2), 56–67.Google Scholar
  26. Grecucci, A., Giorgetta, C., Bonini, N., & Sanfey, A. G. (2013). Reappraising social emotions: The role of inferior frontal gyrus, Temporo-parietal junction and insula in interpersonal emotion regulation. Frontiers in Human Neuroscience, 7, 523.Google Scholar
  27. Gross, J. J. (1998). The emerging field of emotion regulation: An integrative review. Review of General Psychology, 2(3), 271.Google Scholar
  28. Haber, S. N., & Knutson, B. (2010). The reward circuit: Linking primate anatomy and human imaging. Neuropsychopharmacology, 35(1), 4–26.Google Scholar
  29. Hadjipavlou, G., Dunckley, P., Behrens, T. E., & Tracey, I. (2006). Determining anatomical Connectivities between cortical and brainstem pain processing regions in humans: A diffusion tensor imaging study in healthy controls. Pain, 123(1), 169–178.Google Scholar
  30. 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.Google Scholar
  31. Harrison, B. J., et al. (2008). Modulation of brain resting-state networks by sad mood induction. PLoS One, 3(3), e1794–e1794.Google Scholar
  32. Heller, A. S. (2016). Cortical-subcortical interactions in depression: From animal models to human psychopathology. Frontiers in Systems Neuroscience, 10, 20.Google Scholar
  33. Heshmati, M., & Russo, S. J. (2015). Anhedonia and the brain reward circuitry in depression. Current Behavioral Neuroscience Reports, 2(3), 146–153. Retrieved ( Accessed Sept 2018.Google Scholar
  34. Honey, C. J., et al. (2009). Predicting human resting-state functional connectivity from structural connectivity. Proceedings of the National Academy of Sciences, 106(6), 2035–2040.Google Scholar
  35. Hou, J., et al. (2017). Review on neural correlates of emotion regulation and music: Implications for emotion dysregulation. Frontiers in Psychology, 8, 501.Google Scholar
  36. Ikemoto, S. (2010). Brain reward circuitry beyond the mesolimbic dopamine system: A neurobiological theory. Neuroscience & Biobehavioral Reviews, 35(2), 129–150.Google Scholar
  37. Keller, J., et al. (2013). Trait anhedonia is associated with reduced reactivity and connectivity of mesolimbic and Paralimbic reward pathways. Journal of Psychiatric Research, 47(10), 1319–1328.Google Scholar
  38. Kelly, S., Lloyd, D., Nurmikko, T., & Roberts, N. (2007). Retrieving autobiographical memories of painful events activates the anterior cingulate cortex and inferior frontal gyrus. The Journal of Pain, 8(4), 307–314.Google Scholar
  39. Kerns, R. D., Bayer, L. A., & Findley, J. C. (1999). Motivation and adherence in the Management of Chronic Pain. In Handbook of pain syndromes: Biopsychosocial perspectives (pp. 99–121).Google Scholar
  40. Kerns, R. D., et al. (2014). Can we improve cognitive-behavioral therapy for chronic Back pain treatment engagement and adherence? A controlled trial of tailored versus standard therapy. Health Psychology : Official Journal of the Division of Health Psychology, American Psychological Association, 33(9), 938–947.Google Scholar
  41. Koechlin, H., Coakley, R., Schechter, N., Werner, C., & Kossowsky, J. (2018). The role of emotion regulation in chronic pain: A systematic literature review. Journal of Psychosomatic Research, 107, 38–45. Retrieved ( Accessed Sept 2018.Google Scholar
  42. Kringelbach, M. L. (2005). The human orbitofrontal cortex: Linking reward to hedonic experience. Nature Reviews Neuroscience, 6(9), 691–702.Google Scholar
  43. Krüger, S., Seminowicz, D., Goldapple, K., Kennedy, S. H., & Mayberg, H. S. (2003). State and trait influences on mood regulation in bipolar disorder: Blood flow differences with an acute mood challenge. Biological Psychiatry, 54(11), 1274–1283.Google Scholar
  44. Kukull, W. A., et al. (1994). The mini-mental state examination score and the clinical diagnosis of dementia. Journal of Clinical Epidemiology, 47(9), 1061–1067.Google Scholar
  45. Letzen, J. E., & Robinson, M. E. (2017). Negative mood influences default mode network functional connectivity in patients with chronic low Back pain: Implications for functional neuroimaging biomarkers. Pain, 158(1), 48–57.Google Scholar
  46. Lichter, D. G., & Cummings, J. L. (2001). Frontal-subcortical circuits in psychiatric and neurological disorders. Guilford Press.Google Scholar
  47. Liu, X., et al. (2014). Overgeneral autobiographical memory in patients with chronic pain. Pain Medicine, 15(3), 432–439 Retrieved 10.1111/pme.12355).Google Scholar
  48. Ma, S. T., Abelson, J. L., Okada, G., Taylor, S. F., & Liberzon, I. (2017). Neural circuitry of emotion regulation: Effects of appraisal, attention, and cortisol administration. Cognitive, Affective, & Behavioral Neuroscience, 17(2), 437–451.Google Scholar
  49. McCracken, L. M. (1997). Attention’ to pain in persons with chronic pain: A behavioral approach. Behavior Therapy, 28(2), 271–284.Google Scholar
  50. Meyer, P., Karl, A., & Flor, H. (2015). Pain can produce systematic distortions of autobiographical memory. Pain Medicine, 16(5), 905–910 Retrieved (10.1111/pme.12716).Google Scholar
  51. Nees, F., & Becker, S. (2017). Psychological processes in chronic pain: Influences of reward and fear learning as key mechanisms - behavioral evidence, neural circuits, and maladaptive changes. Neuroscience. Google Scholar
  52. Nestler, E. J., & Carlezon, W. A. (2006). The mesolimbic dopamine reward circuit in depression. Biological Psychiatry, 59(12), 1151–1159.Google Scholar
  53. Poole, H., White, S., Blake, C., Murphy, P., & Bramwell, R. (2009). Depression in chronic pain patients: Prevalence and measurement. Pain Practice, 9(3), 173–180.Google Scholar
  54. Rauch, S. L., et al. (1995). A positron emission tomographic study of simple phobic symptom provocation. Archives of General Psychiatry, 52(1), 20–28.Google Scholar
  55. Rayner, L., et al. (2016). Depression in patients with chronic pain attending a specialised pain treatment Centre: Prevalence and impact on health care costs. Pain, 157(7), 1472–1479 Retrieved ( Scholar
  56. Rubinov, M., & Sporns, O. (2010). Complex network measures of brain connectivity: Uses and interpretations. Neuroimage, 52(3), 1059–1069.Google Scholar
  57. Russo, S. J., & Nestler, E. J. (2013). The brain reward circuitry in mood disorders. Nature Reviews Neuroscience, 14(9), 609–625.Google Scholar
  58. Salamone, John D. et al. (2015). “Mesolimbic dopamine and the regulation of motivated behavior.” pp. 231–57 in Behavioral Neuroscience of Motivation. Springer.Google Scholar
  59. Schwartz, N., et al. (2014). Decreased motivation during chronic pain requires long-term depression in the nucleus Accumbens. Science, 345(6196), 535–542.Google Scholar
  60. Sheng, J., Liu, S., Wang, Y., Cui, R., & Zhang, X. (2017). The link between depression and chronic pain: Neural mechanisms in the brain. Neural Plasticity, 2017, 9724371.Google Scholar
  61. Spitzer, W. O., & LeBlanc, F. E. (1987). Scientific approach to the assessment and Management of Activity-Related Spinal Disorders: A monograph for clinicians: Report of the Quebec task force on spinal disorders. Harper & Row.Google Scholar
  62. Taylor, A. M. W., Becker, S., Schweinhardt, P., & Cahill, C. (2016). Mesolimbic dopamine signaling in acute and chronic pain: Implications for motivation, analgesia, and addiction. Pain, 157(6), 1194–1198.Google Scholar
  63. Thomas, M. J., Malenka, R. C., & Bonci, A. (2000). Modulation of long-term depression by dopamine in the mesolimbic system. Journal of Neuroscience, 20(15), 5581–5586.Google Scholar
  64. Vachon-Presseau, E., et al. (2016). The emotional brain as a predictor and amplifier of chronic pain. Journal of Dental Research., 95, 605–612.Google Scholar
  65. Vendetti, M. S., & Bunge, S. A. (2014). Evolutionary and developmental changes in the lateral Frontoparietal network: A little Goes a long way for higher-level cognition. Neuron, 84(5), 906–917.Google Scholar
  66. Visted, E., Vøllestad, J., Nielsen, M. B., & Schanche, E. (2018). Emotion regulation in current and remitted depression: A systematic review and meta-analysis. Frontiers in Psychology, 9, 756. Retrieved ( Accessed Sept 2018.Google Scholar
  67. Volman, S. F., et al. (2013). New insights into the specificity and plasticity of reward and aversion encoding in the mesolimbic system. Journal of Neuroscience, 33(45), 17569–17576.Google Scholar
  68. Wacker, J., Dillon, D. G., & Pizzagalli, D. A. (2009). The role of the nucleus Accumbens and rostral anterior cingulate cortex in anhedonia: Integration of resting EEG, FMRI, and volumetric techniques. NeuroImage, 46(1), 327–337.Google Scholar
  69. Wager, T. D., Davidson, M. L., Hughes, B. L., Lindquist, M. A., & Ochsner, K. N. (2008). Neural mechanisms of emotion regulation: Evidence for two independent prefrontal-subcortical pathways. Neuron, 59(6), 1037–1050.Google Scholar
  70. Wager, T. D., et al. (2013). An FMRI-based neurologic signature of physical pain. The New England Journal of Medicine, 368(15), 1388–1397 Retrieved ( Scholar
  71. Wang, J., et al. (2009). Parcellation-dependent small-world brain functional networks: A resting-state FMRI study. Human Brain Mapping, 30(5), 1511–1523.Google Scholar
  72. Wang, J., Zuo, X., & He, Y. (2010). Graph-based network analysis of resting-state functional MRI. Frontiers in Systems Neuroscience, 4.Google Scholar
  73. Winecoff, A., Labar, K. S., Madden, D. J., Cabeza, R., & Huettel, S. A. (2011). Cognitive and neural contributors to emotion regulation in aging. Social Cognitive and Affective Neuroscience, 6(2), 165–176.Google Scholar
  74. Woo, C.-W., Krishnan, A., & Wager, T. D. (2014). Cluster-extent based thresholding in FMRI analyses: Pitfalls and recommendations. Neuroimage, 91, 412–419.Google Scholar
  75. Yarkoni, T., Poldrack, R. A., Nichols, T. E., Van Essen, D. C., & Wager, T. D. (2011). Large-scale automated synthesis of human functional neuroimaging data. Nature Methods, 8(8), 665–670.Google Scholar
  76. Young, C. B., et al. (2016). Anhedonia and general distress show dissociable ventromedial prefrontal cortex connectivity in major depressive disorder. Translational Psychiatry, 6(5), e810. Retrieved ( Accessed Sept 2018.Google Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Janelle E. Letzen
    • 1
    Email author
  • Jeff Boissoneault
    • 2
  • Landrew S. Sevel
    • 3
  • Michael E. Robinson
    • 2
  1. 1.Department of Psychiatry and Behavioral SciencesJohns Hopkins UniversityBaltimoreUSA
  2. 2.Department of Clinical and Health PsychologyUniversity of FloridaGainesvilleUSA
  3. 3.Department of Psychiatry and Behavioral SciencesVanderbilt UniversityNashvilleUSA

Personalised recommendations