Skip to main content

Advertisement

Log in

Insular Cortex is Critical for the Perception, Modulation, and Chronification of Pain

  • Review
  • Published:
Neuroscience Bulletin Aims and scope Submit manuscript

Abstract

An increasing body of neuroimaging and electrophysiological studies of the brain suggest that the insular cortex (IC) integrates multimodal salient information ranging from sensation to cognitive-affective events to create conscious interoception. Especially with regard to pain experience, the IC has been supposed to participate in both sensory-discriminative and affective-motivational aspects of pain. In this review, we discuss the latest data proposing that subregions of the IC are involved in isolated pain networks: the posterior sensory circuit and the anterior emotional network. Due to abundant connections with other brain areas, the IC is likely to serve as an interface where cross-modal shaping of pain occurs. In chronic pain, however, this mode of emotional awareness and the modulation of pain are disrupted. We highlight some of the molecular mechanisms underlying the changes of the pain modulation system that contribute to the transition from acute to chronic pain in the IC.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Ture U, Yasargil DC, Al-Mefty O, Yasargil MG. Topographic anatomy of the insular region. J Neurosurg 1999, 90: 720–733.

    Article  CAS  PubMed  Google Scholar 

  2. Cechetto DF, Saper CB. Evidence for a viscerotopic sensory representation in the cortex and thalamus in the rat. J Comp Neurol 1987, 262: 27–45.

    Article  CAS  PubMed  Google Scholar 

  3. Mesulam MM, Mufson EJ. Insula of the old world monkey. I. Architectonics in the insulo-orbito-temporal component of the paralimbic brain. J Comp Neurol 1982, 212: 1–22.

    Article  CAS  PubMed  Google Scholar 

  4. Craig AD. How do you feel? Interoception: the sense of the physiological condition of the body. Nat Rev Neurosci 2002, 3: 655–666.

    Article  CAS  PubMed  Google Scholar 

  5. Moriarty O, McGuire BE, Finn DP. The effect of pain on cognitive function: a review of clinical and preclinical research. Prog Neurobiol 2011, 93: 385–404.

    Article  PubMed  Google Scholar 

  6. Holzel BK, Carmody J, Vangel M, Congleton C, Yerramsetti SM, Gard T, et al. Mindfulness practice leads to increases in regional brain gray matter density. Psychiatry Res 2011, 191: 36–43.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Lutz A, McFarlin DR, Perlman DM, Salomons TV, Davidson RJ. Altered anterior insula activation during anticipation and experience of painful stimuli in expert meditators. Neuroimage 2013, 64: 538–546.

    Article  PubMed  PubMed Central  Google Scholar 

  8. DeSouza DD, Davis KD, Hodaie M. Reversal of insular and microstructural nerve abnormalities following effective surgical treatment for trigeminal neuralgia. Pain 2015, 156: 1112–1123.

    PubMed  Google Scholar 

  9. Qiu S, Zhang M, Liu Y, Guo Y, Zhao H, Song Q, et al. GluA1 phosphorylation contributes to postsynaptic amplification of neuropathic pain in the insular cortex. J Neurosci 2014, 34: 13505–13515.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Craig AD, Bushnell MC, Zhang ET, Blomqvist A. A thalamic nucleus specific for pain and temperature sensation. Nature 1994, 372: 770–773.

    Article  CAS  PubMed  Google Scholar 

  11. Frot M, Mauguiere F. Dual representation of pain in the operculo-insular cortex in humans. Brain 2003, 126: 438–450.

    Article  PubMed  Google Scholar 

  12. Frot M, Magnin M, Mauguiere F, Garcia-Larrea L. Cortical representation of pain in primary sensory-motor areas (S1/M1): a study using intracortical recordings in humans. Hum Brain Mapp 2013, 34: 2655–2668.

    Article  PubMed  Google Scholar 

  13. Baumgartner U, Tiede W, Treede RD, Craig AD. Laser-evoked potentials are graded and somatotopically organized anteroposteriorly in the operculoinsular cortex of anesthetized monkeys. J Neurophysiol 2006, 96: 2802–2808.

    Article  PubMed  Google Scholar 

  14. Frot M, Rambaud L, Guenot M, Mauguiere F. Intracortical recordings of early pain-related CO2-laser evoked potentials in the human second somatosensory (SII) area. Clin Neurophysiol 1999, 110: 133–145.

    Article  CAS  PubMed  Google Scholar 

  15. Luppino G, Matelli M, Camarda R, Rizzolatti G. Corticocortical connections of area F3 (SMA-proper) and area F6 (pre-SMA) in the macaque monkey. J Comp Neurol 1993, 338: 114–140.

    Article  CAS  PubMed  Google Scholar 

  16. Critchley HD, Wiens S, Rotshtein P, Ohman A, Dolan RJ. Neural systems supporting interoceptive awareness. Nat Neurosci 2004, 7: 189–195.

    Article  CAS  PubMed  Google Scholar 

  17. Dosenbach NU, Visscher KM, Palmer ED, Miezin FM, Wenger KK, Kang HC, et al. A core system for the implementation of task sets. Neuron 2006, 50: 799–812.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Peltz E, Seifert F, DeCol R, Dorfler A, Schwab S, Maihofner C. Functional connectivity of the human insular cortex during noxious and innocuous thermal stimulation. Neuroimage 2011, 54: 1324–1335.

    Article  PubMed  Google Scholar 

  19. Segerdahl AR, Mezue M, Okell TW, Farrar JT, Tracey I. The dorsal posterior insula subserves a fundamental role in human pain. Nat Neurosci 2015, 18: 499–500.

    Article  CAS  PubMed  Google Scholar 

  20. Benison AM, Chumachenko S, Harrison JA, Maier SF, Falci SP, Watkins LR, et al. Caudal granular insular cortex is sufficient and necessary for the long-term maintenance of allodynic behavior in the rat attributable to mononeuropathy. J Neurosci 2011, 31: 6317–6328.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Ogawa H, Hasegawa K, Murayama N. Difference in taste quality coding between two cortical taste areas, granular and dysgranular insular areas, in rats. Exp Brain Res 1992, 91: 415–424.

    CAS  PubMed  Google Scholar 

  22. Jasmin L, Burkey AR, Granato A, Ohara PT. Rostral agranular insular cortex and pain areas of the central nervous system: a tract-tracing study in the rat. J Comp Neurol 2004, 468: 425–440.

    Article  PubMed  Google Scholar 

  23. Cliffer KD, Burstein R, Giesler GJ, Jr. Distributions of spinothalamic, spinohypothalamic, and spinotelencephalic fibers revealed by anterograde transport of PHA-L in rats. J Neurosci 1991, 11: 852–868.

    CAS  PubMed  Google Scholar 

  24. Stehberg RM-AaJ. The Insular Cortex and the Amygdala: Shared Functions and Interactions. InTech 2012.

  25. Fox MD, Snyder AZ, Vincent JL, Corbetta M, Van Essen DC, Raichle ME. The human brain is intrinsically organized into dynamic, anticorrelated functional networks. Proc Natl Acad Sci USA 2005, 102: 9673–9678.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Lane RD, Schwartz GE. Levels of emotional awareness: a cognitive-developmental theory and its application to psychopathology. Am J Psychiatry 1987, 144: 133–143.

    Article  CAS  PubMed  Google Scholar 

  27. Farmer MA, Baliki MN, Apkarian AV. A dynamic network perspective of chronic pain. Neurosci Lett 2012, 520: 197–203.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. De Luca M, Beckmann CF, De Stefano N, Matthews PM, Smith SM. fMRI resting state networks define distinct modes of long-distance interactions in the human brain. Neuroimage 2006, 29: 1359–1367.

    Article  PubMed  Google Scholar 

  29. Fox MD, Corbetta M, Snyder AZ, Vincent JL, Raichle ME. Spontaneous neuronal activity distinguishes human dorsal and ventral attention systems. Proc Natl Acad Sci USA 2006, 103: 10046–10051.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Seeley WW, Menon V, Schatzberg AF, Keller J, Glover GH, Kenna H, et al. Dissociable intrinsic connectivity networks for salience processing and executive control. J Neurosci 2007, 27: 2349–2356.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Greicius MD, Krasnow B, Reiss AL, Menon V. Functional connectivity in the resting brain: a network analysis of the default mode hypothesis. Proc Natl Acad Sci USA 2003, 100: 253–258.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Sridharan D, Levitin DJ, Menon V. A critical role for the right fronto-insular cortex in switching between central-executive and default-mode networks. Proc Natl Acad Sci USA 2008, 105: 12569–12574.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Lamm C, Decety J, Singer T. Meta-analytic evidence for common and distinct neural networks associated with directly experienced pain and empathy for pain. Neuroimage 2011, 54: 2492–2502.

    Article  PubMed  Google Scholar 

  34. Inui K, Tsuji T, Kakigi R. Temporal analysis of cortical mechanisms for pain relief by tactile stimuli in humans. Cereb Cortex 2006, 16: 355–365.

    Article  PubMed  Google Scholar 

  35. Inui K, Tran TD, Qiu Y, Wang X, Hoshiyama M, Kakigi R. A comparative magnetoencephalographic study of cortical activations evoked by noxious and innocuous somatosensory stimulations. Neuroscience 2003, 120: 235–248.

    Article  CAS  PubMed  Google Scholar 

  36. Ramachandran VS, McGeoch PD, Williams L, Arcilla G. Rapid relief of thalamic pain syndrome induced by vestibular caloric stimulation. Neurocase 2007, 13: 185–188.

    Article  PubMed  Google Scholar 

  37. Corbetta M, Shulman GL. Control of goal-directed and stimulus-driven attention in the brain. Nat Rev Neurosci 2002, 3: 201–215.

    Article  CAS  PubMed  Google Scholar 

  38. Ploner M, Lee MC, Wiech K, Bingel U, Tracey I. Flexible cerebral connectivity patterns subserve contextual modulations of pain. Cereb Cortex 2011, 21: 719–726.

    Article  PubMed  Google Scholar 

  39. Ohara S, Crone NE, Weiss N, Lenz FA. Analysis of synchrony demonstrates ‘pain networks’ defined by rapidly switching, task-specific, functional connectivity between pain-related cortical structures. Pain 2006, 123: 244–253.

    Article  CAS  PubMed  Google Scholar 

  40. Keil J, Muller N, Ihssen N, Weisz N. On the variability of the McGurk effect: audiovisual integration depends on prestimulus brain states. Cereb Cortex 2012, 22: 221–231.

    Article  PubMed  Google Scholar 

  41. Pomares FB, Faillenot I, Barral FG, Peyron R. The ‘where’ and the ‘when’ of the BOLD response to pain in the insular cortex. Discussion on amplitudes and latencies. Neuroimage 2013, 64: 466–475.

    PubMed  Google Scholar 

  42. Hauck M, Domnick C, Lorenz J, Gerloff C, Engel AK. Top-down and bottom-up modulation of pain-induced oscillations. Front Hum Neurosci 2015, 9: 375.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Petrovic P, Kalso E, Petersson KM, Ingvar M. Placebo and opioid analgesia– imaging a shared neuronal network. Science 2002, 295: 1737–1740.

    Article  CAS  PubMed  Google Scholar 

  44. Menon V, Uddin LQ. Saliency, switching, attention and control: a network model of insula function. Brain Struct Funct 2010, 214: 655–667.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Mufson EJ, Mesulam MM, Pandya DN. Insular interconnections with the amygdala in the rhesus monkey. Neuroscience 1981, 6: 1231–1248.

    Article  CAS  PubMed  Google Scholar 

  46. Friedman DP, Murray EA. Thalamic connectivity of the second somatosensory area and neighboring somatosensory fields of the lateral sulcus of the macaque. J Comp Neurol 1986, 252: 348–373.

    Article  CAS  PubMed  Google Scholar 

  47. Starr CJ, Sawaki L, Wittenberg GF, Burdette JH, Oshiro Y, Quevedo AS, et al. Roles of the insular cortex in the modulation of pain: insights from brain lesions. J Neurosci 2009, 29: 2684–2694.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Seeley WW, Merkle FT, Gaus SE, Craig AD, Allman JM, Hof PR. Distinctive neurons of the anterior cingulate and frontoinsular cortex: a historical perspective. Cereb Cortex 2012, 22: 245–250.

    Article  PubMed  Google Scholar 

  49. Allman JM, Watson KK, Tetreault NA, Hakeem AY. Intuition and autism: a possible role for Von Economo neurons. Trends Cogn Sci 2005, 9: 367–373.

    Article  PubMed  Google Scholar 

  50. Allman JM, Tetreault NA, Hakeem AY, Manaye KF, Semendeferi K, Erwin JM, et al. The von Economo neurons in the frontoinsular and anterior cingulate cortex. Ann N Y Acad Sci 2011, 1225: 59–71.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Coffeen U, Manuel Ortega-Legaspi J, Lopez-Munoz FJ, Simon-Arceo K, Jaimes O, Pellicer F. Insular cortex lesion diminishes neuropathic and inflammatory pain-like behaviours. Eur J Pain 2011, 15: 132–138.

    Article  PubMed  Google Scholar 

  52. Gu X, Hof PR, Friston KJ, Fan J. Anterior insular cortex and emotional awareness. J Comp Neurol 2013, 521: 3371–3388.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Apkarian AV, Bushnell MC, Treede RD, Zubieta JK. Human brain mechanisms of pain perception and regulation in health and disease. Eur J Pain 2005, 9: 463–484.

    Article  PubMed  Google Scholar 

  54. Schweinhardt P, Glynn C, Brooks J, McQuay H, Jack T, Chessell I, et al. An fMRI study of cerebral processing of brush-evoked allodynia in neuropathic pain patients. Neuroimage 2006, 32: 256–265.

    Article  PubMed  Google Scholar 

  55. Geha PY, Baliki MN, Harden RN, Bauer WR, Parrish TB, Apkarian AV. The brain in chronic CRPS pain: abnormal gray-white matter interactions in emotional and autonomic regions. Neuron 2008, 60: 570–581.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Gustin SM, Peck CC, Wilcox SL, Nash PG, Murray GM, Henderson LA. Different pain, different brain: thalamic anatomy in neuropathic and non-neuropathic chronic pain syndromes. J Neurosci 2011, 31: 5956–5964.

    Article  CAS  PubMed  Google Scholar 

  57. Pievani M, de Haan W, Wu T, Seeley WW, Frisoni GB. Functional network disruption in the degenerative dementias. Lancet Neurol 2011, 10: 829–843.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Cauda F, Sacco K, Duca S, Cocito D, D’Agata F, Geminiani GC, et al. Altered resting state in diabetic neuropathic pain. PLoS One 2009, 4: e4542.

    Article  PubMed  PubMed Central  Google Scholar 

  59. Baliki MN, Baria AT, Apkarian AV. The cortical rhythms of chronic back pain. J Neurosci 2011, 31: 13981–13990.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Shergill SS, Brammer MJ, Williams SC, Murray RM, McGuire PK. Mapping auditory hallucinations in schizophrenia using functional magnetic resonance imaging. Arch Gen Psychiatry 2000, 57: 1033–1038.

    Article  CAS  PubMed  Google Scholar 

  61. Doan L, Manders T, Wang J. Neuroplasticity underlying the comorbidity of pain and depression. Neural Plast 2015, 2015: 504691.

    PubMed  PubMed Central  Google Scholar 

  62. Yalcin I, Barthas F, Barrot M. Emotional consequences of neuropathic pain: insight from preclinical studies. Neurosci Biobehav Rev 2014, 47: 154–164.

    Article  PubMed  Google Scholar 

  63. Hashmi JA, Baliki MN, Huang L, Baria AT, Torbey S, Hermann KM, Schnitzer TJ, Apkarian AV. Shape shifting pain: chronification of back pain shifts brain representation from nociceptive to emotional circuits. Brain Res 2013, 136: 2751–2768.

    Google Scholar 

  64. Sliz D, Hayley S. Major depressive disorder and alterations in insular cortical activity: a review of current functional magnetic imaging research. Front Hum Neurosci 2012, 6: 323.

    Article  PubMed  PubMed Central  Google Scholar 

  65. Mutschler I, Ball T, Wankerl J, Strigo IA. Pain and emotion in the insular cortex: evidence for functional reorganization in major depression. Neurosci Lett 2012, 520: 204–209.

    Article  CAS  PubMed  Google Scholar 

  66. Gard T, Holzel BK, Sack AT, Hempel H, Lazar SW, Vaitl D, et al. Pain attenuation through mindfulness is associated with decreased cognitive control and increased sensory processing in the brain. Cereb Cortex 2012, 22: 2692–2702.

    Article  PubMed  PubMed Central  Google Scholar 

  67. Emmert K, Breimhorst M, Bauermann T, Birklein F, Van De Ville D, Haller S. Comparison of anterior cingulate vs. insular cortex as targets for real-time fMRI regulation during pain stimulation. Front Behav Neurosci 2014, 8: 350.

    Google Scholar 

  68. Jasmin L, Rabkin SD, Granato A, Boudah A, Ohara PT. Analgesia and hyperalgesia from GABA-mediated modulation of the cerebral cortex. Nature 2003, 424: 316–320.

    Article  CAS  PubMed  Google Scholar 

  69. Richfield EK, Young AB, Penney JB. Comparative distributions of dopamine D-1 and D-2 receptors in the cerebral cortex of rats, cats, and monkeys. J Comp Neurol 1989, 286: 409–426.

    Article  CAS  PubMed  Google Scholar 

  70. Gaspar P, Bloch B, Le Moine C. D1 and D2 receptor gene expression in the rat frontal cortex: cellular localization in different classes of efferent neurons. Eur J Neurosci 1995, 7: 1050–1063.

    Article  CAS  PubMed  Google Scholar 

  71. Ohara PT, Granato A, Moallem TM, Wang BR, Tillet Y, Jasmin L. Dopaminergic input to GABAergic neurons in the rostral agranular insular cortex of the rat. J Neurocytol 2003, 32: 131–141.

    Article  CAS  PubMed  Google Scholar 

  72. Sotres-Bayon F, Torres-Lopez E, Lopez-Avila A, del Angel R, Pellicer F. Lesion and electrical stimulation of the ventral tegmental area modify persistent nociceptive behavior in the rat. Brain Res 2001, 898: 342–349.

    Article  CAS  PubMed  Google Scholar 

  73. Lopez-Avila A, Coffeen U, Ortega-Legaspi JM, del Angel R, Pellicer F. Dopamine and NMDA systems modulate long-term nociception in the rat anterior cingulate cortex. Pain 2004, 111: 136–143.

    Article  CAS  PubMed  Google Scholar 

  74. Floyd NS, Price JL, Ferry AT, Keay KA, Bandler R. Orbitomedial prefrontal cortical projections to distinct longitudinal columns of the periaqueductal gray in the rat. J Comp Neurol 2000, 422: 556–578.

    Article  CAS  PubMed  Google Scholar 

  75. Jung MJ, Lippert B, Metcalf BW, Bohlen P, Schechter PJ. gamma-Vinyl GABA (4-amino-hex-5-enoic acid), a new selective irreversible inhibitor of GABA-T: effects on brain GABA metabolism in mice. J Neurochem 1977, 29: 797–802.

    Article  CAS  PubMed  Google Scholar 

  76. Watkins LR, Wiertelak EP, McGorry M, Martinez J, Schwartz B, Sisk D, et al. Neurocircuitry of conditioned inhibition of analgesia: effects of amygdala, dorsal raphe, ventral medullary, and spinal cord lesions on antianalgesia in the rat. Behav Neurosci 1998, 112: 360–378.

    Article  CAS  PubMed  Google Scholar 

  77. Rodriguez-Raecke R, Niemeier A, Ihle K, Ruether W, May A. Brain gray matter decrease in chronic pain is the consequence and not the cause of pain. J Neurosci 2009, 29: 13746–13750.

    Article  CAS  PubMed  Google Scholar 

  78. Qiu S, Chen T, Koga K, Guo YY, Xu H, Song Q, et al. An increase in synaptic NMDA receptors in the insular cortex contributes to neuropathic pain. Sci Signal 2013, 6: ra34.

    Article  PubMed  Google Scholar 

  79. Kam AY, Liao D, Loh HH, Law PY. Morphine induces AMPA receptor internalization in primary hippocampal neurons via calcineurin-dependent dephosphorylation of GluR1 subunits. J Neurosci 2010, 30: 15304–15316.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Oh MC, Derkach VA, Guire ES, Soderling TR. Extrasynaptic membrane trafficking regulated by GluR1 serine 845 phosphorylation primes AMPA receptors for long-term potentiation. J Biol Chem 2006, 281: 752–758.

    Article  CAS  PubMed  Google Scholar 

  81. Li HL, Huang BS, Vishwasrao H, Sutedja N, Chen W, Jin I, et al. Dscam mediates remodeling of glutamate receptors in Aplysia during de novo and learning-related synapse formation. Neuron 2009, 61: 527–540.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Derkach VA, Oh MC, Guire ES, Soderling TR. Regulatory mechanisms of AMPA receptors in synaptic plasticity. Nat Rev Neurosci 2007, 8: 101–113.

    Article  CAS  PubMed  Google Scholar 

  83. Ahmad M, Polepalli JS, Goswami D, Yang X, Kaeser-Woo YJ, Sudhof TC, et al. Postsynaptic complexin controls AMPA receptor exocytosis during LTP. Neuron 2012, 73: 260–267.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Katano T, Furue H, Okuda-Ashitaka E, Tagaya M, Watanabe M, Yoshimura M, et al. N-ethylmaleimide-sensitive fusion protein (NSF) is involved in central sensitization in the spinal cord through GluR2 subunit composition switch after inflammation. Eur J Neurosci 2008, 27: 3161–3170.

    Article  PubMed  Google Scholar 

  85. Park JS, Voitenko N, Petralia RS, Guan X, Xu JT, Steinberg JP, et al. Persistent inflammation induces GluR2 internalization via NMDA receptor-triggered PKC activation in dorsal horn neurons. J Neurosci 2009, 29: 3206–3219.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Thomas GM, Huganir RL. MAPK cascade signalling and synaptic plasticity. Nat Rev Neurosci 2004, 5: 173–183.

    Article  CAS  PubMed  Google Scholar 

  87. Cao H, Ren WH, Zhu MY, Zhao ZQ, Zhang YQ. Activation of glycine site and GluN2B subunit of NMDA receptors is necessary for ERK/CREB signaling cascade in rostral anterior cingulate cortex in rats: implications for affective pain. Neurosci Bull 2012, 28: 77–87.

    Article  CAS  PubMed  Google Scholar 

  88. Imbe H, Kimura A, Donishi T, Kaneoke Y. Repeated forced swim stress enhances CFA-evoked thermal hyperalgesia and affects the expressions of pCREB and c-Fos in the insular cortex. Neuroscience 2014, 259: 1–11.

    Article  CAS  PubMed  Google Scholar 

  89. Boly M, Balteau E, Schnakers C, Degueldre C, Moonen G, Luxen A, et al. Baseline brain activity fluctuations predict somatosensory perception in humans. Proc Natl Acad Sci USA 2007, 104: 12187–12192.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Ploner M, Lee MC, Wiech K, Bingel U, Tracey I. Prestimulus functional connectivity determines pain perception in humans. Proc Natl Acad Sci USA 2010, 107: 355–360.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Wiech K, Lin CS, Brodersen KH, Bingel U, Ploner M, Tracey I. Anterior insula integrates information about salience into perceptual decisions about pain. J Neurosci 2010, 30: 16324–16331.

    Article  CAS  PubMed  Google Scholar 

  92. Paulus MP, Stein MB. An insular view of anxiety. Biol Psychiatry 2006, 60: 383–387.

    Article  PubMed  Google Scholar 

  93. Burkey AR, Carstens E, Jasmin L. Dopamine reuptake inhibition in the rostral agranular insular cortex produces antinociception. J Neurosci 1999, 19: 4169–4179.

    CAS  PubMed  Google Scholar 

  94. Kawasaki Y, Kohno T, Zhuang ZY, Brenner GJ, Wang H, Van Der Meer C, et al. Ionotropic and metabotropic receptors, protein kinase A, protein kinase C, and Src contribute to C-fiber-induced ERK activation and cAMP response element-binding protein phosphorylation in dorsal horn neurons, leading to central sensitization. J Neurosci 2004, 24: 8310–8321.

    Article  CAS  PubMed  Google Scholar 

  95. Ji RR, Rupp F. Phosphorylation of transcription factor CREB in rat spinal cord after formalin-induced hyperalgesia: relationship to c-fos induction. J Neurosci 1997, 17: 1776–1785.

    CAS  PubMed  Google Scholar 

  96. Bushnell MC, Ceko M, Low LA. Cognitive and emotional control of pain and its disruption in chronic pain. Nat Rev Neurosci 2013, 14: 502–511.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Chan CS, Guzman JN, Ilijic E, Mercer JN, Rick C, Tkatch T, et al. ‘Rejuvenation’ protects neurons in mouse models of Parkinson’s disease. Nature 2007, 447: 1081–1086.

    Article  CAS  PubMed  Google Scholar 

  98. Jahr CE, Stevens CF. Voltage dependence of NMDA-activated macroscopic conductances predicted by single-channel kinetics. J Neurosci 1990, 10: 3178–3182.

    CAS  PubMed  Google Scholar 

  99. Imbe H, Kimura A. Repeated forced swim stress prior to complete Freund’s adjuvant injection enhances mechanical hyperalgesia and attenuates the expression of pCREB and DeltaFosB and the acetylation of histone H3 in the insular cortex of rat. Neuroscience 2015, 301: 12–25.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This review was supported by the National Natural Science Foundation of China (31371120) and the Foundation for Returned Overseas Students of Ministry of Education, China (HG3503).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Hui Xu.

Additional information

Changbo Lu and Tao Yang have contributed equally to this review.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lu, C., Yang, T., Zhao, H. et al. Insular Cortex is Critical for the Perception, Modulation, and Chronification of Pain. Neurosci. Bull. 32, 191–201 (2016). https://doi.org/10.1007/s12264-016-0016-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12264-016-0016-y

Keywords

Navigation