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Role of the Anterior Cingulate Cortex in Translational Pain Research

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Abstract

As the most common symptomatic reason to seek medical consultation, pain is a complex experience that has been classified into different categories and stages. In pain processing, noxious stimuli may activate the anterior cingulate cortex (ACC). But the function of ACC in the different pain conditions is not well discussed. In this review, we elaborate the commonalities and differences from accumulated evidence by a variety of pain assays for physiological pain and pathological pain including inflammatory pain, neuropathic pain, and cancer pain in the ACC, and discuss the cellular receptors and signaling molecules from animal studies. We further summarize the ACC as a new central neuromodulation target for invasive and non-invasive stimulation techniques in clinical pain management. The comprehensive understanding of pain processing in the ACC may lead to bridging the gap in translational research between basic and clinical studies and to develop new therapies.

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References

  1. Ashburn MA, Staats PS. Management of chronic pain. Lancet 1999, 353: 1865–1869.

    Article  CAS  PubMed  Google Scholar 

  2. Woolf CJ. Recent advances in the pathophysiology of acute pain. Br J Anaesth 1989, 63: 139–146.

    Article  CAS  PubMed  Google Scholar 

  3. Zhuo M. Neuronal mechanism for neuropathic pain. Mol Pain 2007, 3: 14.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. Campbell JN, Meyer RA. Mechanisms of neuropathic pain. Neuron 2006, 52: 77–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Botvinick M, Nystrom LE, Fissell K, Carter CS, Cohen JD. Conflict monitoring versus selection-for-action in anterior cingulate cortex. Nature 1999, 402: 179–181.

    Article  CAS  PubMed  Google Scholar 

  6. Carter CS, Braver TS, Barch DM, Botvinick MM, Noll D, Cohen JD. Anterior cingulate cortex, error detection, and the online monitoring of performance. Science 1998, 280: 747–749.

    Article  CAS  PubMed  Google Scholar 

  7. Pardo JV, Pardo PJ, Janer KW, Raichle ME. The anterior cingulate cortex mediates processing selection in the Stroop attentional conflict paradigm. Proc Natl Acad Sci U S A 1990, 87: 256–259.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Bush G, Luu P, Posner MI. Cognitive and emotional influences in anterior cingulate cortex. Trends Cogn Sci 2000, 4: 215–222.

    Article  CAS  PubMed  Google Scholar 

  9. Bush G, Vogt BA, Holmes J, Dale AM, Greve D, Jenike MA, et al. Dorsal anterior cingulate cortex: a role in reward-based decision making. Proc Natl Acad Sci U S A 2002, 99: 523–528.

    Article  CAS  PubMed  Google Scholar 

  10. Polli FE, Barton JJ, Cain MS, Thakkar KN, Rauch SL, Manoach DS. Rostral and dorsal anterior cingulate cortex make dissociable contributions during antisaccade error commission. Proc Natl Acad Sci U S A 2005, 102: 15700–15705.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Lu JS, Chen QY, Zhou S, Inokuchi K, Zhuo M. Dual roles of anterior cingulate cortex neurons in pain and pleasure in adult mice. Mol Brain 2018, 11: 72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Price DD. Psychological and neural mechanisms of the affective dimension of pain. Science 2000, 288: 1769–1772.

    Article  CAS  PubMed  Google Scholar 

  13. Bliss TV, Collingridge GL, Kaang BK, Zhuo M. Synaptic plasticity in the anterior cingulate cortex in acute and chronic pain. Nat Rev Neurosci 2016, 17: 485–496.

    Article  CAS  PubMed  Google Scholar 

  14. Ren WH, Guo JD, Cao H, Wang H, Wang PF, Sha H, et al. Is endogenous D-serine in the rostral anterior cingulate cortex necessary for pain-related negative affect? J Neurochem 2006, 96: 1636–1647.

    Article  CAS  PubMed  Google Scholar 

  15. Li TT, Ren WH, Xiao X, Nan J, Cheng LZ, Zhang XH, et al. NMDA NR2A and NR2B receptors in the rostral anterior cingulate cortex contribute to pain-related aversion in male rats. Pain 2009, 146: 183–193.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Cao H, Gao YJ, Ren WH, Li TT, Duan KZ, Cui YH, et al. Activation of extracellular signal-regulated kinase in the anterior cingulate cortex contributes to the induction and expression of affective pain. J Neurosci 2009, 29: 3307–3321.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Xiao X, Yang Y, Zhang Y, Zhang XM, Zhao ZQ, Zhang YQ. Estrogen in the Anterior Cingulate Cortex Contributes to Pain-Related Aversion. Cerebral Cortex 2013, 23: 2190–2203.

    Article  PubMed  Google Scholar 

  18. Han M, Xiao X, Yang Y, Huang RY, Cao H, Zhao ZQ, et al. SIP30 Is Required for Neuropathic Pain-Evoked Aversion in Rats. J Neurosci 2014, 34: 346–355.

    Article  CAS  PubMed  Google Scholar 

  19. Xiao X, Zhang YQ. A new perspective on the anterior cingulate cortex and affective pain. Neurosci Biobehav Rev 2018, 90: 200–211.

    Article  PubMed  Google Scholar 

  20. Coghill RC, Talbot JD, Evans AC, Meyer E, Gjedde A, Bushnell MC, et al. Distributed processing of pain and vibration by the human brain. J Neurosci 1994, 14: 4095–4108.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Derbyshire SW, Vogt BA, Jones AK. Pain and Stroop interference tasks activate separate processing modules in anterior cingulate cortex. Exp Brain Res 1998, 118: 52–60.

    Article  CAS  PubMed  Google Scholar 

  22. Jones AK, Brown WD, Friston KJ, Qi LY, Frackowiak RS. Cortical and subcortical localization of response to pain in man using positron emission tomography. Proc Biol Sci 1991, 244: 39–44.

    Article  CAS  PubMed  Google Scholar 

  23. Kwan CL, Crawley AP, Mikulis DJ, Davis KD. An fMRI study of the anterior cingulate cortex and surrounding medial wall activations evoked by noxious cutaneous heat and cold stimuli. Pain 2000, 85: 359–374.

    Article  PubMed  Google Scholar 

  24. Rainville P, Duncan GH, Price DD, Carrier B, Bushnell MC. Pain affect encoded in human anterior cingulate but not somatosensory cortex. Science 1997, 277: 968–971.

    Article  CAS  PubMed  Google Scholar 

  25. Morris LS, Sprenger C, Koda K, de la Mora DM, Yamada T, Mano H, et al. Anterior cingulate cortex connectivity is associated with suppression of behaviour in a rat model of chronic pain. Brain Neurosci Adv 2018, 2: 2398212818779646.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Sanvanson P, Li Z, Mei L, Kounev V, Kern M, Ward BD, et al. Interplay of spinal and vagal pathways on esophageal acid-related anterior cingulate cortex functional networks in rats. Am J Physiol Gastrointest Liver Physiol 2019, 316: G615–g622.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Jia Z, Chen X, Tang W, Zhao D, Yu S. Atypical functional connectivity between the anterior cingulate cortex and other brain regions in a rat model of recurrent headache. Mol Pain 2019, 15: 1744806919842483.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Davis KD, Taub E, Duffner F, Lozano AM, Tasker RR, Houle S, et al. Activation of the anterior cingulate cortex by thalamic stimulation in patients with chronic pain: a positron emission tomography study. J Neurosurg 2000, 92: 64–69.

    Article  CAS  PubMed  Google Scholar 

  29. Talbot JD, Villemure JG, Bushnell MC, Duncan GH. Evaluation of pain perception after anterior capsulotomy: a case report. Somatosens Mot Res 1995, 12: 115–126.

    Article  CAS  PubMed  Google Scholar 

  30. Salomons TV, Iannetti GD, Liang M, Wood JN. The “Pain Matrix” in pain-free individuals. JAMA Neurol 2016, 73: 755–756.

    Article  PubMed  Google Scholar 

  31. Mogil JS. Animal models of pain: progress and challenges. Nat Rev Neurosci 2009, 10: 283–294.

    Article  CAS  PubMed  Google Scholar 

  32. Ren K, Dubner R. Interactions between the immune and nervous systems in pain. Nature Medicine 2010, 16: 1267–1276.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Xu Q, Yaksh TL. A brief comparison of the pathophysiology of inflammatory versus neuropathic pain. Curr Opin Anaesthesiol 2011, 24: 400–407.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Yang Y, Li H, Li TT, Luo H, Gu XY, Lu N, et al. Delayed activation of spinal microglia contributes to the maintenance of bone cancer pain in female Wistar rats via P2X7 receptor and IL-18. J Neurosci 2015, 35: 7950–7963.

    Article  CAS  PubMed  Google Scholar 

  35. Cui JG, Holmin S, Mathiesen T, Meyerson BA, Linderoth B. Possible role of inflammatory mediators in tactile hypersensitivity in rat models of mononeuropathy. Pain 2000, 88: 239–248.

    Article  CAS  PubMed  Google Scholar 

  36. Sellmeijer J, Mathis V, Hugel S, Li XH, Song Q, Chen QY, et al. Hyperactivity of anterior cingulate cortex areas 24a/24b drives chronic pain-induced anxiodepressive-like consequences. J Neurosci 2018, 38: 3102–3115.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Honore P, Rogers SD, Schwei MJ, Salak-Johnson JL, Luger NM, Sabino MC, et al. Murine models of inflammatory, neuropathic and cancer pain each generates a unique set of neurochemical changes in the spinal cord and sensory neurons. Neuroscience 2000, 98: 585–598.

    Article  CAS  PubMed  Google Scholar 

  38. Schulz E, Stankewitz A, Witkovsky V, Winkler AM, Tracey I. Strategy-dependent modulation of cortical pain circuits for the attenuation of pain. Cortex 2019, 113: 255–266.

    Article  PubMed  Google Scholar 

  39. Crombez G, Eccleston C, Baeyens F, van Houdenhove B, van den Broeck A. Attention to chronic pain is dependent upon pain-related fear. J Psychosom Res 1999, 47: 403–410.

    Article  CAS  PubMed  Google Scholar 

  40. McCracken LM, Gauntlett-Gilbert J, Vowles KE. The role of mindfulness in a contextual cognitive-behavioral analysis of chronic pain-related suffering and disability. Pain 2007, 131: 63–69.

    Article  PubMed  Google Scholar 

  41. Villemure C, Schweinhardt P. Supraspinal Pain Processing: Distinct Roles of Emotion and Attention. Neuroscientist 2010, 16: 276–284.

    Article  PubMed  Google Scholar 

  42. Carrillo M, Han Y, Migliorati F, Liu M, Gazzola V, Keysers C. Emotional Mirror Neurons in the Rat’s Anterior Cingulate Cortex. Curr Biol 2019, 29: 1301–1312.e1306.

    Google Scholar 

  43. Corradi-Dell’Acqua C, Hofstetter C, Vuilleumier P. Felt and seen pain evoke the same local patterns of cortical activity in insular and cingulate cortex. J Neurosci 2011, 31: 17996–18006.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Loeser JD, Melzack R. Pain: an overview. Lancet 1999, 353: 1607–1609.

    Article  CAS  PubMed  Google Scholar 

  45. Albe-Fessard D, Berkley KJ, Kruger L, Ralston HJ, 3rd, Willis WD, Jr. Diencephalic mechanisms of pain sensation. Brain Res 1985, 356: 217–296.

    Article  CAS  PubMed  Google Scholar 

  46. Craig KD. Pain and affectivity in infancy: their interdependence and independence. Cephalalgia 1987, 7 Suppl 6: 115–118.

    Article  PubMed  Google Scholar 

  47. Apkarian AV, Shi T. Squirrel monkey lateral thalamus. I. Somatic nociresponsive neurons and their relation to spinothalamic terminals. J Neurosci 1994, 14: 6779–6795.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Craig AD, Serrano LP. Effects of systemic morphine on lamina I spinothalamic tract neurons in the cat. Brain Res 1994, 636: 233–244.

    Article  CAS  PubMed  Google Scholar 

  49. Shi T, Apkarian AV. Morphology of thalamocortical neurons projecting to the primary somatosensory cortex and their relationship to spinothalamic terminals in the squirrel monkey. J Comp Neurol 1995, 361: 1–24.

    Article  CAS  PubMed  Google Scholar 

  50. Vogt BA, Rosene DL, Pandya DN. Thalamic and cortical afferents differentiate anterior from posterior cingulate cortex in the monkey. Science 1979, 204: 205–207.

    Article  CAS  PubMed  Google Scholar 

  51. Vogt BA, Pandya DN, Rosene DL. Cingulate cortex of the rhesus monkey: I. Cytoarchitecture and thalamic afferents. J Comp Neurol 1987, 262: 256–270.

    Article  CAS  PubMed  Google Scholar 

  52. Robertson RT, Kaitz SS. Thalamic connections with limbic cortex. I. Thalamocortical projections. J Comp Neurol 1981, 195: 501–525.

    Article  CAS  PubMed  Google Scholar 

  53. Musil SY, Olson CR. Organization of cortical and subcortical projections to anterior cingulate cortex in the cat. J Comp Neurol 1988, 272: 203–218.

    Article  CAS  PubMed  Google Scholar 

  54. Yasui Y, Itoh K, Kamiya H, Ino T, Mizuno N. Cingulate gyrus of the cat receives projection fibers from the thalamic region ventral to the ventral border of the ventrobasal complex. J Comp Neurol 1988, 274: 91–100.

    Article  CAS  PubMed  Google Scholar 

  55. Marini G, Pianca L, Tredici G. Thalamocortical projection from the parafascicular nucleus to layer V pyramidal cells in frontal and cingulate areas of the rat. Neurosci Lett 1996, 203: 81–84.

    Article  CAS  PubMed  Google Scholar 

  56. Mansour A, Khachaturian H, Lewis ME, Akil H, Watson SJ. Autoradiographic differentiation of mu, delta, and kappa opioid receptors in the rat forebrain and midbrain. J Neurosci 1987, 7: 2445–2464.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Sadzot B, Price JC, Mayberg HS, Douglass KH, Dannals RF, Lever JR, et al. Quantification of human opiate receptor concentration and affinity using high and low specific activity [11C]diprenorphine and positron emission tomography. J Cereb Blood Flow Metab 1991, 11: 204–219.

    Article  CAS  PubMed  Google Scholar 

  58. Jones AK, Qi LY, Fujirawa T, Luthra SK, Ashburner J, Bloomfield P, et al. In vivo distribution of opioid receptors in man in relation to the cortical projections of the medial and lateral pain systems measured with positron emission tomography. Neurosci Lett 1991, 126: 25–28.

    Article  CAS  PubMed  Google Scholar 

  59. Vogt BA, Wiley RG, Jensen EL. Localization of Mu and delta opioid receptors to anterior cingulate afferents and projection neurons and input/output model of Mu regulation. Exp Neurol 1995, 135: 83–92.

    Article  CAS  PubMed  Google Scholar 

  60. Lenz FA, Rios M, Zirh A, Chau D, Krauss G, Lesser RP. Painful stimuli evoke potentials recorded over the human anterior cingulate gyrus. J Neurophysiol 1998, 79: 2231–2234.

    Article  CAS  PubMed  Google Scholar 

  61. Davis KD, Taylor SJ, Crawley AP, Wood ML, Mikulis DJ. Functional MRI of pain- and attention-related activations in the human cingulate cortex. J Neurophysiol 1997, 77: 3370–3380.

    Article  CAS  PubMed  Google Scholar 

  62. Li JX. The application of conditioning paradigms in the measurement of pain. Eur J Pharmacol 2013, 716: 158–168.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Neafsey EJ. Prefrontal cortical control of the autonomic nervous system: anatomical and physiological observations. Prog Brain Res 1990, 85: 147–165; discussion 165–146.

    Article  CAS  PubMed  Google Scholar 

  64. Yasui Y, Cechetto DF, Saper CB. Evidence for a cholinergic projection from the pedunculopontine tegmental nucleus to the rostral ventrolateral medulla in the rat. Brain Res 1990, 517: 19–24.

    Article  CAS  PubMed  Google Scholar 

  65. Silverman DH, Munakata JA, Ennes H, Mandelkern MA, Hoh CK, Mayer EA. Regional cerebral activity in normal and pathological perception of visceral pain. Gastroenterology 1997, 112: 64–72.

    Article  CAS  PubMed  Google Scholar 

  66. Mertz H, Morgan V, Tanner G, Pickens D, Price R, Shyr Y, et al. Regional cerebral activation in irritable bowel syndrome and control subjects with painful and nonpainful rectal distention. Gastroenterology 2000, 118: 842–848.

    Article  CAS  PubMed  Google Scholar 

  67. Mayer EA, Naliboff BD, Craig AD. Neuroimaging of the brain-gut axis: from basic understanding to treatment of functional GI disorders. Gastroenterology 2006, 131: 1925–1942.

    Article  PubMed  Google Scholar 

  68. Kern M, Shaker R. Further characterization of human brain processing of viscero-sensation: the role of gender and a word of caution. Gastroenterology 2003, 124: 1975–1977.

    Article  PubMed  Google Scholar 

  69. Xiao Z, Martinez E, Kulkarni PM, Zhang Q, Hou Q, Rosenberg D, et al. Cortical pain processing in the rat anterior cingulate cortex and primary somatosensory cortex. Front Cell Neurosci 2019, 13: 165.

    Article  PubMed  PubMed Central  Google Scholar 

  70. Talbot JD, Marrett S, Evans AC, Meyer E, Bushnell MC, Duncan GH. Multiple representations of pain in human cerebral cortex. Science 1991, 251: 1355–1358.

    Article  CAS  PubMed  Google Scholar 

  71. Casey KL, Minoshima S, Morrow TJ, Koeppe RA. Comparison of human cerebral activation pattern during cutaneous warmth, heat pain, and deep cold pain. J Neurophysiol 1996, 76: 571–581.

    Article  CAS  PubMed  Google Scholar 

  72. Casey KL, Minoshima S, Berger KL, Koeppe RA, Morrow TJ, Frey KA. Positron emission tomographic analysis of cerebral structures activated specifically by repetitive noxious heat stimuli. J Neurophysiol 1994, 71: 802–807.

    Article  CAS  PubMed  Google Scholar 

  73. Craig AD, Reiman EM, Evans A, Bushnell MC. Functional imaging of an illusion of pain. Nature 1996, 384: 258–260.

    Article  CAS  PubMed  Google Scholar 

  74. Vogt BA, Derbyshire S, Jones AK. Pain processing in four regions of human cingulate cortex localized with co-registered PET and MR imaging. Eur J Neurosci 1996, 8: 1461–1473.

    Article  CAS  PubMed  Google Scholar 

  75. Derbyshire SW, Jones AK, Gyulai F, Clark S, Townsend D, Firestone LL. Pain processing during three levels of noxious stimulation produces differential patterns of central activity. Pain 1997, 73: 431–445.

    Article  PubMed  Google Scholar 

  76. Svensson P, Minoshima S, Beydoun A, Morrow TJ, Casey KL. Cerebral processing of acute skin and muscle pain in humans. J Neurophysiol 1997, 78: 450–460.

    Article  CAS  PubMed  Google Scholar 

  77. Hsieh JC, Belfrage M, Stone-Elander S, Hansson P, Ingvar M. Central representation of chronic ongoing neuropathic pain studied by positron emission tomography. Pain 1995, 63: 225–236.

    Article  PubMed  Google Scholar 

  78. Davis KD, Hutchison WD, Lozano AM, Dostrovsky JO. Altered pain and temperature perception following cingulotomy and capsulotomy in a patient with schizoaffective disorder. Pain 1994, 59: 189–199.

    Article  PubMed  Google Scholar 

  79. Hutchison WD, Davis KD, Lozano AM, Tasker RR, Dostrovsky JO. Pain-related neurons in the human cingulate cortex. Nat Neurosci 1999, 2: 403–405.

    Article  CAS  PubMed  Google Scholar 

  80. Hurt RW, Ballantine HT, Jr. Stereotactic anterior cingulate lesions for persistent pain: a report on 68 cases. Clin Neurosurg 1974, 21: 334–351.

    Article  CAS  PubMed  Google Scholar 

  81. Devinsky O, Morrell MJ, Vogt BA. Contributions of anterior cingulate cortex to behaviour. Brain 1995, 118 (Pt 1): 279–306.

    Article  PubMed  Google Scholar 

  82. Ballantine HT, Jr., Cassidy WL, Flanagan NB, Marino R, Jr. Stereotaxic anterior cingulotomy for neuropsychiatric illness and intractable pain. J Neurosurg 1967, 26: 488–495.

    Article  PubMed  Google Scholar 

  83. Hassenbusch SJ, Pillay PK, Barnett GH. Radiofrequency cingulotomy for intractable cancer pain using stereotaxis guided by magnetic resonance imaging. Neurosurgery 1990, 27: 220–223.

    Article  CAS  PubMed  Google Scholar 

  84. Santo JL, Arias LM, Barolat G, Schwartzman RJ, Grossman K. Bilateral cingulumotomy in the treatment of reflex sympathetic dystrophy. Pain 1990, 41: 55–59.

    Article  PubMed  Google Scholar 

  85. Wilkinson HA, Davidson KM, Davidson RI. Bilateral anterior cingulotomy for chronic noncancer pain. Neurosurgery 1999, 45: 1129–1134; discussion 1134–1126.

    Article  CAS  PubMed  Google Scholar 

  86. Wong ET, Gunes S, Gaughan E, Patt RB, Ginsberg LE, Hassenbusch SJ, et al. Palliation of intractable cancer pain by MRI-guided cingulotomy. Clin J Pain 1997, 13: 260–263.

    Article  CAS  PubMed  Google Scholar 

  87. Brown S, Schafer EA. An investigaion into the functions of the occipital and pemporal lobes of the monkey’s brain. Philos Trans R Soc Lond B Biol Sci 1888, 48–50.

  88. Horslry V, Schafer EA. A record of experiments upon the functions of the cerebral cortex. Philos Trans R Soc Lond B Biol Sci 1888, 1–7.

  89. Peretz E. The effects of lesions of the anterior cingulate cortex on the behavior of the rat. J Comp Physiol Psychol 1960, 53: 540–548.

    Article  CAS  PubMed  Google Scholar 

  90. Gabriel M, Kubota Y, Sparenborg S, Straube K, Vogt BA. Effects of cingulate cortical lesions on avoidance learning and training-induced unit activity in rabbits. Exp Brain Res 1991, 86: 585–600.

    Article  CAS  PubMed  Google Scholar 

  91. Lubar JF, Perachio AA. One-way and two-way learning and transfer of an active avoidance response in normal and cingulectomized cats. J Comp Physiol Psychol 1965, 60: 46–52.

    Article  CAS  PubMed  Google Scholar 

  92. Lubar JF. Effect of Medial Cortical Lesions on the Avoidance Behavior of the Cat. J Comp Physiol Psychol 1964, 58: 38–46.

    Article  CAS  PubMed  Google Scholar 

  93. Thomas GJ, Slotnick BM. Impairment of avoidance responding by lesions in cingulate cortex in rats depends on food drive. J Comp Physiol Psychol 1963, 56: 959–964.

    Article  CAS  PubMed  Google Scholar 

  94. Thomas GJ, Slotnick B. Effects of lesions in the cingulum one maze learning and avoidance conditioning in the rat. J Comp Physiol Psychol 1962, 55: 1085–1091.

    Article  CAS  PubMed  Google Scholar 

  95. Hsu MM, Shyu BC. Electrophysiological study of the connection between medial thalamus and anterior cingulate cortex in the rat. Neuroreport 1997, 8: 2701–2707.

    Article  CAS  PubMed  Google Scholar 

  96. Kung JC, Shyu BC. Potentiation of local field potentials in the anterior cingulate cortex evoked by the stimulation of the medial thalamic nuclei in rats. Brain Res 2002, 953: 37–44.

    Article  CAS  PubMed  Google Scholar 

  97. Sun JJ, Chuang Kung J, Wang CC, Chen SL, Shyu BC. Short-term facilitation in the anterior cingulate cortex following stimulation of the medial thalamus in the rat. Brain Res 2006, 1097: 101–115.

    Article  CAS  PubMed  Google Scholar 

  98. Yamamura H, Iwata K, Tsuboi Y, Toda K, Kitajima K, Shimizu N, et al. Morphological and electrophysiological properties of ACCx nociceptive neurons in rats. Brain Res 1996, 735: 83–92.

    Article  CAS  PubMed  Google Scholar 

  99. Sikes RW, Vogt BA. Nociceptive neurons in area 24 of rabbit cingulate cortex. J Neurophysiol 1992, 68: 1720–1732.

    Article  CAS  PubMed  Google Scholar 

  100. Koyama T, Tanaka YZ, Mikami A. Nociceptive neurons in the macaque anterior cingulate activate during anticipation of pain. Neuroreport 1998, 9: 2663–2667.

    Article  CAS  PubMed  Google Scholar 

  101. Chen T, Taniguchi W, Chen QY, Tozaki-Saitoh H, Song Q, Liu RH, et al. Top-down descending facilitation of spinal sensory excitatory transmission from the anterior cingulate cortex. Nat Commun 2018, 9: 1886.

    Google Scholar 

  102. Calejesan AA, Kim SJ, Zhuo M. Descending facilitatory modulation of a behavioral nociceptive response by stimulation in the adult rat anterior cingulate cortex. Eur J Pain 2000, 4: 83–96.

    Article  CAS  PubMed  Google Scholar 

  103. Zhang L, Zhang Y, Zhao ZQ. Anterior cingulate cortex contributes to the descending facilitatory modulation of pain via dorsal reticular nucleus. Eur J Neurosci 2005, 22: 1141–1148.

    Article  PubMed  Google Scholar 

  104. Moon HC, Heo WI, Kim YJ, Lee D, Won SY, Kim HR, et al. Optical inactivation of the anterior cingulate cortex modulate descending pain pathway in a rat model of trigeminal neuropathic pain created via chronic constriction injury of the infraorbital nerve. J Pain Res 2017, 10: 2355–2364.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Wang J, Cao B, Yu TR, Jelfs B, Yan J, Chan RH, et al. Theta-frequency phase-locking of single anterior cingulate cortex neurons and synchronization with the medial thalamus are modulated by visceral noxious stimulation in rats. Neuroscience 2015, 298: 200–210.

    Article  CAS  PubMed  Google Scholar 

  106. Gao J, Wu X, Owyang C, Li Y. Enhanced responses of the anterior cingulate cortex neurones to colonic distension in viscerally hypersensitive rats. J Physiol 2006, 570: 169–183.

    Article  CAS  PubMed  Google Scholar 

  107. Ma JH, Xiao TH, Chang CW, Gao L, Wang XL, Gao GD, et al. Activation of anterior cingulate cortex produces inhibitory effects on noxious mechanical and electrical stimuli-evoked responses in rat spinal WDR neurons. Eur J Pain 2011, 15: 895–899.

    Article  PubMed  Google Scholar 

  108. Ikeda H, Takasu S, Murase K. Contribution of anterior cingulate cortex and descending pain inhibitory system to analgesic effect of lemon odor in mice. Mol Pain 2014, 10: 14.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  109. Fuchs PN, Balinsky M, Melzack R. Electrical stimulation of the cingulum bundle and surrounding cortical tissue reduces formalin-test pain in the rat. Brain Res 1996, 743: 116–123.

    Article  CAS  PubMed  Google Scholar 

  110. Ren K, Dubner R. Inflammatory Models of Pain and Hyperalgesia. ILAR J 1999, 40: 111–118.

    Article  PubMed  Google Scholar 

  111. Dubuisson D, Dennis SG. The formalin test: a quantitative study of the analgesic effects of morphine, meperidine, and brain stem stimulation in rats and cats. Pain 1977, 4: 161–174.

    Article  CAS  PubMed  Google Scholar 

  112. Gao YJ, Xu ZZ, Liu YC, Wen YR, Decosterd I, Ji RR. The c-Jun N-terminal kinase 1 (JNK1) in spinal astrocytes is required for the maintenance of bilateral mechanical allodynia under a persistent inflammatory pain condition. Pain 2010, 148: 309–319.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Raghavendra V, Tanga FY, DeLeo JA. Complete Freunds adjuvant-induced peripheral inflammation evokes glial activation and proinflammatory cytokine expression in the CNS. Eur J Neurosci 2004, 20: 467–473.

    Article  PubMed  Google Scholar 

  114. Guo JD, Wang H, Zhang YQ, Zhao ZQ. Alterations of membrane properties and effects of D-serine on NMDA-induced current in rat anterior cingulate cortex neurons after monoarthritis. Neurosci Lett 2005, 384: 245–249.

    Article  CAS  PubMed  Google Scholar 

  115. Gong KR, Cao FL, He Y, Gao CY, Wang DD, Li H, et al. Enhanced excitatory and reduced inhibitory synaptic transmission contribute to persistent pain-induced neuronal hyper-responsiveness in anterior cingulate cortex. Neuroscience 2010, 171: 1314–1325.

    Article  CAS  PubMed  Google Scholar 

  116. Vaccarino AL, Melzack R. Analgesia produced by injection of lidocaine into the anterior cingulum bundle of the rat. Pain 1989, 39: 213–219.

    Article  PubMed  Google Scholar 

  117. Vaccarino AL, Melzack R. Temporal processes of formalin pain: differential role of the cingulum bundle, fornix pathway and medial bulboreticular formation. Pain 1992, 49: 257–271.

    Article  PubMed  Google Scholar 

  118. Donahue RR, LaGraize SC, Fuchs PN. Electrolytic lesion of the anterior cingulate cortex decreases inflammatory, but not neuropathic nociceptive behavior in rats. Brain Res 2001, 897: 131–138.

    Article  CAS  PubMed  Google Scholar 

  119. Ren LY, Lu ZM, Liu MG, Yu YQ, Li Z, Shang GW, et al. Distinct roles of the anterior cingulate cortex in spinal and supraspinal bee venom-induced pain behaviors. Neuroscience 2008, 153: 268–278.

    Article  CAS  PubMed  Google Scholar 

  120. Wu LJ, Toyoda H, Zhao MG, Lee YG, Tang J, Ko SW, et al. Upregulation of forebrain NMDA NR2B receptors contributes to behavioral sensitization after inflammation. J Neurosci 2005, 25: 11107–11116.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Wu LJ, Steenland HW, Kim SS, Isiegas C, Abel T, Kaang BK, et al. Enhancement of presynaptic glutamate release and persistent inflammatory pain by increasing neuronal cAMP in the anterior cingulate cortex. Mol Pain 2008, 4: 40.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  122. Wei F, Qiu CS, Kim SJ, Muglia L, Maas JW, Pineda VV, et al. Genetic elimination of behavioral sensitization in mice lacking calmodulin-stimulated adenylyl cyclases. Neuron 2002, 36: 713–726.

    Article  CAS  PubMed  Google Scholar 

  123. Toyoda H, Zhao MG, Ulzhofer B, Wu LJ, Xu H, Seeburg PH, et al. Roles of the AMPA receptor subunit GluA1 but not GluA2 in synaptic potentiation and activation of ERK in the anterior cingulate cortex. Mol Pain 2009, 5: 46.

    Article  PubMed  PubMed Central  Google Scholar 

  124. Wei F, Zhuo M. Activation of Erk in the anterior cingulate cortex during the induction and expression of chronic pain. Mol Pain 2008, 4: 28.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  125. Zhao MG, Ko SW, Wu LJ, Toyoda H, Xu H, Quan J, et al. Enhanced presynaptic neurotransmitter release in the anterior cingulate cortex of mice with chronic pain. J Neurosci 2006, 26: 8923–8930.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Bie B, Brown DL, Naguib M. Increased synaptic GluR1 subunits in the anterior cingulate cortex of rats with peripheral inflammation. Eur J Pharmacol 2011, 653: 26–31.

    Article  CAS  PubMed  Google Scholar 

  127. Chen S, Kadakia F, Davidson S. Group II metabotropic glutamate receptor expressing neurons in anterior cingulate cortex become sensitized after inflammatory and neuropathic pain. Mol Pain 2020, 16: 1744806920915339.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Li XH, Matsuura T, Liu RH, Xue M, Zhuo M. Calcitonin gene-related peptide potentiated the excitatory transmission and network propagation in the anterior cingulate cortex of adult mice. Mol Pain 2019, 15: 1744806919832718.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Yi M, Zhang H, Lao L, Xing GG, Wan Y. Anterior cingulate cortex is crucial for contra- but not ipsi-lateral electro-acupuncture in the formalin-induced inflammatory pain model of rats. Mol Pain 2011, 7: 61.

    Article  PubMed  PubMed Central  Google Scholar 

  130. Sun J, Shao XM, Fang F, Shen Z, Wu YY, Fang JQ. Electroacupuncture alleviates retrieval of pain memory and its effect on phosphorylation of cAMP response element-binding protein in anterior cingulate cortex in rats. Behav Brain Funct 2015, 11: 9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  131. Fan YF, Guan SY, Luo L, Li YJ, Yang L, Zhou XX, et al. Tetrahydroxystilbene glucoside relieves the chronic inflammatory pain by inhibiting neuronal apoptosis, microglia activation, and GluN2B overexpression in anterior cingulate cortex. Mol Pain 2018, 14: 1744806918814367.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Kang SJ, Kwak C, Lee J, Sim SE, Shim J, Choi T, et al. Bidirectional modulation of hyperalgesia via the specific control of excitatory and inhibitory neuronal activity in the ACC. Mol Brain 2015, 8: 81.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  133. Cao Z, Wu X, Chen S, Fan J, Zhang R, Owyang C, et al. Anterior cingulate cortex modulates visceral pain as measured by visceromotor responses in viscerally hypersensitive rats. Gastroenterology 2008, 134: 535–543.

    Article  CAS  PubMed  Google Scholar 

  134. Wu X, Gao J, Yan J, Fan J, Owyang C, Li Y. Role for NMDA receptors in visceral nociceptive transmission in the anterior cingulate cortex of viscerally hypersensitive rats. Am J Physiol Gastrointest Liver Physiol 2008, 294: G918–927.

    Article  CAS  PubMed  Google Scholar 

  135. Fan J, Wu X, Cao Z, Chen S, Owyang C, Li Y. Up-regulation of anterior cingulate cortex NR2B receptors contributes to visceral pain responses in rats. Gastroenterology 2009, 136: 1732–1740 e1733.

    Google Scholar 

  136. Zhou L, Huang J, Gao J, Zhang G, Jiang J. NMDA and AMPA receptors in the anterior cingulate cortex mediates visceral pain in visceral hypersensitivity rats. Cell Immunol 2014, 287: 86–90.

    Article  CAS  PubMed  Google Scholar 

  137. Li Y, Zhang X, Liu H, Cao Z, Chen S, Cao B, et al. Phosphorylated CaMKII post-synaptic binding to NR2B subunits in the anterior cingulate cortex mediates visceral pain in visceral hypersensitive rats. J Neurochem 2012, 121: 662–671.

    Article  CAS  PubMed  Google Scholar 

  138. Wang J, Zhang X, Cao B, Liu J, Li Y. Facilitation of synaptic transmission in the anterior cingulate cortex in viscerally hypersensitive rats. Cereb Cortex 2015, 25: 859–868.

    Article  PubMed  Google Scholar 

  139. Yan N, Cao B, Xu J, Hao C, Zhang X, Li Y. Glutamatergic activation of anterior cingulate cortex mediates the affective component of visceral pain memory in rats. Neurobiol Learn Mem 2012, 97: 156–164.

    Article  CAS  PubMed  Google Scholar 

  140. Wang XS, Yue J, Hu LN, Tian Z, Yang LK, Lu L, et al. Effects of CPEB1 in the anterior cingulate cortex on visceral pain in mice. Brain Res 2019, 1712: 55–62.

    Article  CAS  PubMed  Google Scholar 

  141. Eto K, Wake H, Watanabe M, Ishibashi H, Noda M, Yanagawa Y, et al. Inter-regional contribution of enhanced activity of the primary somatosensory cortex to the anterior cingulate cortex accelerates chronic pain behavior. J Neurosci 2011, 31: 7631–7636.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Koga K, Shimoyama S, Yamada A, Furukawa T, Nikaido Y, Furue H, et al. Chronic inflammatory pain induced GABAergic synaptic plasticity in the adult mouse anterior cingulate cortex. Mol Pain 2018, 14: 1744806918783478.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Ikeda H, Mochizuki K, Murase K. Astrocytes are involved in long-term facilitation of neuronal excitation in the anterior cingulate cortex of mice with inflammatory pain. Pain 2013, 154: 2836–2843.

    Article  CAS  PubMed  Google Scholar 

  144. Chen FL, Dong YL, Zhang ZJ, Cao DL, Xu J, Hui J, et al. Activation of astrocytes in the anterior cingulate cortex contributes to the affective component of pain in an inflammatory pain model. Brain Res Bull 2012, 87: 60–66.

    Article  CAS  PubMed  Google Scholar 

  145. LaBuda CJ, Fuchs PN. A behavioral test paradigm to measure the aversive quality of inflammatory and neuropathic pain in rats. Exp Neurol 2000, 163: 490–494.

    Article  CAS  PubMed  Google Scholar 

  146. Johansen JP, Fields HL. Glutamatergic activation of anterior cingulate cortex produces an aversive teaching signal. Nat Neurosci 2004, 7: 398–403.

    Article  CAS  PubMed  Google Scholar 

  147. Treede RD, Jensen TS, Campbell JN, Cruccu G, Dostrovsky JO, Griffin JW, et al. Neuropathic pain: redefinition and a grading system for clinical and research purposes. Neurology 2008, 70: 1630–1635.

    Article  CAS  PubMed  Google Scholar 

  148. 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 

  149. Witting N, Kupers RC, Svensson P, Jensen TS. A PET activation study of brush-evoked allodynia in patients with nerve injury pain. Pain 2006, 120: 145–154.

    Article  PubMed  Google Scholar 

  150. Petrovic P, Ingvar M, Stone-Elander S, Petersson KM, Hansson P. A PET activation study of dynamic mechanical allodynia in patients with mononeuropathy. Pain 1999, 83: 459–470.

    Article  CAS  PubMed  Google Scholar 

  151. Peyron R, Garcia-Larrea L, Gregoire MC, Convers P, Lavenne F, Veyre L, et al. Allodynia after lateral-medullary (Wallenberg) infarct. A PET study. Brain 1998, 121 (Pt 2): 345–356.

    PubMed  Google Scholar 

  152. Ducreux D, Attal N, Parker F, Bouhassira D. Mechanisms of central neuropathic pain: a combined psychophysical and fMRI study in syringomyelia. Brain 2006, 129: 963–976.

    Article  PubMed  Google Scholar 

  153. Kim KJ, Yoon YW, Chung JM. Comparison of three rodent neuropathic pain models. Exp Brain Res 1997, 113: 200–206.

    Article  CAS  PubMed  Google Scholar 

  154. Zhao R, Zhou H, Huang L, Xie Z, Wang J, Gan WB, et al. Neuropathic pain causes pyramidal neuronal hyperactivity in the anterior cingulate cortex. Front Cell Neurosci 2018, 12: 107.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  155. Yang Z, Tan Q, Cheng D, Zhang L, Zhang J, Gu EW, et al. The changes of intrinsic excitability of pyramidal neurons in anterior cingulate cortex in neuropathic pain. Front Cell Neurosci 2018, 12: 436.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Metz AE, Yau HJ, Centeno MV, Apkarian AV, Martina M. Morphological and functional reorganization of rat medial prefrontal cortex in neuropathic pain. Proc Natl Acad Sci U S A 2009, 106: 2423–2428.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Narita M, Niikura K, Nanjo-Niikura K, Narita M, Furuya M, Yamashita A, et al. Sleep disturbances in a neuropathic pain-like condition in the mouse are associated with altered GABAergic transmission in the cingulate cortex. Pain 2011, 152: 1358–1372.

    Article  CAS  PubMed  Google Scholar 

  158. Yamashita A, Hamada A, Suhara Y, Kawabe R, Yanase M, Kuzumaki N, et al. Astrocytic activation in the anterior cingulate cortex is critical for sleep disorder under neuropathic pain. Synapse 2014, 68: 235–247.

    Article  CAS  PubMed  Google Scholar 

  159. Tan W, Yao WL, Hu R, Lv YY, Wan L, Zhang CH, et al. Alleviating neuropathic pain mechanical allodynia by increasing Cdh1 in the anterior cingulate cortex. Mol Pain 2015, 11: 56.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  160. Xu H, Wu LJ, Wang H, Zhang X, Vadakkan KI, Kim SS, et al. Presynaptic and postsynaptic amplifications of neuropathic pain in the anterior cingulate cortex. J Neurosci 2008, 28: 7445–7453.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Meng XL, Fu P, Wang L, Yang X, Hong G, Zhao X, et al. Increased EZH2 levels in anterior cingulate cortex microglia aggravate neuropathic pain by inhibiting autophagy following brachial plexus avulsion in rats. Neurosci Bull 2020, 36: 793–805.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Li YD, Ge J, Luo YJ, Xu W, Wang J, Lazarus M, et al. High cortical delta power correlates with aggravated allodynia by activating anterior cingulate cortex GABAergic neurons in neuropathic pain mice. Pain 2020, 161: 288–299.

    Article  CAS  PubMed  Google Scholar 

  163. Li XY, Ko HG, Chen T, Descalzi G, Koga K, Wang H, et al. Alleviating neuropathic pain hypersensitivity by inhibiting PKMzeta in the anterior cingulate cortex. Science 2010, 330: 1400–1404.

    Article  CAS  PubMed  Google Scholar 

  164. Li W, Wang P, Li H. Upregulation of glutamatergic transmission in anterior cingulate cortex in the diabetic rats with neuropathic pain. Neurosci Lett 2014, 568: 29–34.

    Article  CAS  PubMed  Google Scholar 

  165. Yao PW, Wang SK, Chen SX, Xin WJ, Liu XG, Zang Y. Upregulation of tumor necrosis factor-alpha in the anterior cingulate cortex contributes to neuropathic pain and pain-associated aversion. Neurobiol Dis 2019, 130: 104456.

    Article  CAS  PubMed  Google Scholar 

  166. Ko HG, Ye S, Han DH, Park P, Lim CS, Lee K, et al. Transcription-independent expression of PKMzeta in the anterior cingulate cortex contributes to chronically maintained neuropathic pain. Mol Pain 2018, 14: 1744806918783943.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Shen FY, Chen ZY, Zhong W, Ma LQ, Chen C, Yang ZJ, et al. Alleviation of neuropathic pain by regulating T-type calcium channels in rat anterior cingulate cortex. Mol Pain 2015, 11: 7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  168. Takeda R, Watanabe Y, Ikeda T, Abe H, Ebihara K, Matsuo H, et al. Analgesic effect of milnacipran is associated with c-Fos expression in the anterior cingulate cortex in the rat neuropathic pain model. Neurosci Res 2009, 64: 380–384.

    Article  CAS  PubMed  Google Scholar 

  169. Chen Z, Shen X, Huang, Wu H, Zhang M. Membrane potential synchrony of neurons in anterior cingulate cortex plays a pivotal role in generation of neuropathic pain. Sci Rep 2018, 8: 1691.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  170. 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 

  171. Ortega-Legaspi JM, de Gortari P, Garduno-Gutierrez R, Amaya MI, Leon-Olea M, Coffeen U, et al. Expression of the dopaminergic D1 and D2 receptors in the anterior cingulate cortex in a model of neuropathic pain. Mol Pain 2011, 7: 97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Wei F, Li P, Zhuo M. Loss of synaptic depression in mammalian anterior cingulate cortex after amputation. J Neurosci 1999, 19: 9346–9354.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Wei F, Zhuo M. Potentiation of sensory responses in the anterior cingulate cortex following digit amputation in the anaesthetised rat. J Physiol 2001, 532: 823–833.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Bouckoms AJ, Welch CA, Drop LJ, Dao T, Kolton K. Atropine in electroconvulsive therapy. Convuls Ther 1989, 5: 48–55.

    PubMed  Google Scholar 

  175. Pillay PK, Hassenbusch SJ. Bilateral MRI-guided stereotactic cingulotomy for intractable pain. Stereotact Funct Neurosurg 1992, 59: 33–38.

    Article  CAS  PubMed  Google Scholar 

  176. Pereira EA, Paranathala M, Hyam JA, Green AL, Aziz TZ. Anterior cingulotomy improves malignant mesothelioma pain and dyspnoea. Br J Neurosurg 2014, 28: 471–474.

    Article  PubMed  Google Scholar 

  177. Currie GL, Delaney A, Bennett MI, Dickenson AH, Egan KJ, Vesterinen HM, et al. Animal models of bone cancer pain: Systematic review and meta-analyses. Pain 2013, 154: 917–926.

    Article  PubMed  Google Scholar 

  178. Chiou CS, Huang CC, Liang YC, Tsai YC, Hsu KS. Impairment of long-term depression in the anterior cingulate cortex of mice with bone cancer pain. Pain 2012, 153: 2097–2108.

    Article  PubMed  Google Scholar 

  179. Xu Y, Wang G, Zou X, Yang Z, Wang Q, Feng H, et al. siRNA-mediated downregulation of GluN2B in the rostral anterior cingulate cortex attenuates mechanical allodynia and thermal hyperalgesia in a rat model of pain associated with bone cancer. Exp Ther Med 2016, 11: 221–229.

    Article  CAS  PubMed  Google Scholar 

  180. Woolf CJ. Capturing novel non-opioid pain targets. Biol Psychiatry 2020, 87: 74–81.

    Article  PubMed  Google Scholar 

  181. Russo JF, Sheth SA. Deep brain stimulation of the dorsal anterior cingulate cortex for the treatment of chronic neuropathic pain. Neurosurg Focus 2015, 38: E11.

    Article  PubMed  Google Scholar 

  182. Owen SL, Green AL, Stein JF, Aziz TZ. Deep brain stimulation for the alleviation of post-stroke neuropathic pain. Pain 2006, 120: 202–206.

    Article  PubMed  Google Scholar 

  183. Marchand S, Kupers RC, Bushnell MC, Duncan GH. Analgesic and placebo effects of thalamic stimulation. Pain 2003, 105: 481–488.

    Article  PubMed  Google Scholar 

  184. Bittar RG, Burn SC, Bain PG, Owen SL, Joint C, Shlugman D, et al. Deep brain stimulation for movement disorders and pain. J Clin Neurosci 2005, 12: 457–463.

    Article  PubMed  Google Scholar 

  185. Pereira EA, Aziz TZ. Neuropathic pain and deep brain stimulation. Neurotherapeutics 2014, 11: 496–507.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Koller WC, Lyons KE, Wilkinson SB, Pahwa R. Efficacy of unilateral deep brain stimulation of the VIM nucleus of the thalamus for essential head tremor. Mov Disord 1999, 14: 847–850.

    Article  CAS  PubMed  Google Scholar 

  187. Ortiz RM, Scheperjans F, Pekkonen E. Deep brain stimulation for dystonia in Finland during 2007–2016. BMC Neurol 2019, 19: 137.

    Article  PubMed  PubMed Central  Google Scholar 

  188. Kringelbach ML, Jenkinson N, Owen SL, Aziz TZ. Translational principles of deep brain stimulation. Nat Rev Neurosci 2007, 8: 623–635.

    Article  CAS  PubMed  Google Scholar 

  189. Bittar RG, Kar-Purkayastha I, Owen SL, Bear RE, Green A, Wang S, et al. Deep brain stimulation for pain relief: a meta-analysis. J Clin Neurosci 2005, 12: 515–519.

    Article  PubMed  Google Scholar 

  190. Spooner J, Yu H, Kao C, Sillay K, Konrad P. Neuromodulation of the cingulum for neuropathic pain after spinal cord injury. Case report. J Neurosurg 2007, 107: 169–172.

    PubMed  Google Scholar 

  191. Boccard SG, Pereira EA, Moir L, Van Hartevelt TJ, Kringelbach ML, FitzGerald JJ, et al. Deep brain stimulation of the anterior cingulate cortex: targeting the affective component of chronic pain. Neuroreport 2014, 25: 83–88.

    Article  PubMed  Google Scholar 

  192. Boccard SG, Fernandes HM, Jbabdi S, Van Hartevelt TJ, Kringelbach ML, Quaghebeur G, et al. Tractography Study of Deep Brain Stimulation of the Anterior Cingulate Cortex in Chronic Pain: Key to Improve the Targeting. World Neurosurg 2016, 86: 361–370 e361–363.

    Article  Google Scholar 

  193. Boccard SGJ, Prangnell SJ, Pycroft L, Cheeran B, Moir L, Pereira EAC, et al. Long-term results of deep brain stimulation of the anterior cingulate cortex for neuropathic pain. World Neurosurgery 2017, 106: 625–637.

    Article  PubMed  Google Scholar 

  194. Lipsman N, Woodside DB, Giacobbe P, Hamani C, Carter JC, Norwood SJ, et al. Subcallosal cingulate deep brain stimulation for treatment-refractory anorexia nervosa: a phase 1 pilot trial. The Lancet 2013, 381: 1361–1370.

    Article  Google Scholar 

  195. Choi KS, Riva-Posse P, Gross RE, Mayberg HS. Mapping the “Depression Switch” during intraoperative testing of subcallosal cingulate deep brain stimulation. JAMA Neurol 2015, 72: 1252–1260.

    Article  PubMed  PubMed Central  Google Scholar 

  196. Palm U, Keeser D, Schiller C, Fintescu Z, Nitsche M, Reisinger E, et al. Skin lesions after treatment with transcranial direct current stimulation (tDCS). Brain Stimul 2008, 1: 386–387.

    Article  PubMed  Google Scholar 

  197. Rosa MA, Lisanby SH. Somatic treatments for mood disorders. Neuropsychopharmacology 2012, 37: 102–116.

    Article  CAS  PubMed  Google Scholar 

  198. Scholfield CN. Properties of K-currents in unmyelinated presynaptic axons of brain revealed revealed by extracellular polarisation. Brain Res 1990, 507: 121–128.

    Article  CAS  PubMed  Google Scholar 

  199. Meron D, Hedger N, Garner M, Baldwin DS. Transcranial direct current stimulation (tDCS) in the treatment of depression: Systematic review and meta-analysis of efficacy and tolerability. Neurosci Biobehav Rev 2015, 57: 46–62.

    Article  PubMed  Google Scholar 

  200. Beltran Serrano G, Rodrigues LP, Schein B, Souza A, Torres ILS, da Conceicao Antunes L, et al. Comparison of hypnotic suggestion and transcranial direct-current stimulation effects on pain perception and the descending pain modulating system: A crossover randomized clinical trial. Front Neurosci 2019, 13: 662.

    Article  PubMed  PubMed Central  Google Scholar 

  201. Simpson MW, Mak M. The effect of transcranial direct current stimulation on upper limb motor performance in Parkinson’s disease: A systematic review. J Neurol 2019.

  202. Thibaut A, Zafonte R, Morse LR, Fregni F. Understanding negative results in tDCS research: The importance of neural targeting and cortical engagement. Front Neurosci 2017, 11: 707.

    Article  PubMed  PubMed Central  Google Scholar 

  203. Fregni F, Gimenes R, Valle AC, Ferreira MJ, Rocha RR, Natalle L, et al. A randomized, sham-controlled, proof of principle study of transcranial direct current stimulation for the treatment of pain in fibromyalgia. Arthritis Rheum 2006, 54: 3988–3998.

    Article  PubMed  Google Scholar 

  204. Antal A, Terney D, Kuhnl S, Paulus W. Anodal transcranial direct current stimulation of the motor cortex ameliorates chronic pain and reduces short intracortical inhibition. J Pain Symptom Manage 2010, 39: 890–903.

    Article  PubMed  Google Scholar 

  205. Yoon EJ, Kim YK, Kim HR, Kim SE, Lee Y, Shin HI. Transcranial direct current stimulation to lessen neuropathic pain after spinal cord injury: a mechanistic PET study. Neurorehabil Neural Repair 2014, 28: 250–259.

    Article  PubMed  Google Scholar 

  206. Magis D, D’Ostilio K, Lisicki M, Lee C, Schoenen J. Anodal frontal tDCS for chronic cluster headache treatment: a proof-of-concept trial targeting the anterior cingulate cortex and searching for nociceptive correlates. J Headache Pain 2018, 19: 72.

    Article  PubMed  PubMed Central  Google Scholar 

  207. Mariano T, Burgess F, Bowker M, Kirschner J, Wout-Frank Mvt, Halladay C, et al. T187. Transcranial direct current stimulation (tDCS) for the affective symptoms of chronic low back pain (CLBP): A double-blinded, randomized, placebo-controlled trial. Biological Psychiatry 2018, 83: S200–S201.

    Article  Google Scholar 

  208. DaSilva AF, Truong DQ, DosSantos MF, Toback RL, Datta A, Bikson M. State-of-art neuroanatomical target analysis of high-definition and conventional tDCS montages used for migraine and pain control. Front Neuroanat 2015, 9: 89.

    Article  PubMed  PubMed Central  Google Scholar 

  209. Datta A, Bansal V, Diaz J, Patel J, Reato D, Bikson M. Gyri-precise head model of transcranial direct current stimulation: improved spatial focality using a ring electrode versus conventional rectangular pad. Brain Stimul 2009, 2: 201–207, 207.e201.

    Article  PubMed Central  Google Scholar 

  210. To WT, Eroh J, Hart J, Vanneste S. Exploring the effects of anodal and cathodal high definition transcranial direct current stimulation targeting the dorsal anterior cingulate cortex. Scientific Reports 2018, 8: 1–16.

    Article  CAS  Google Scholar 

  211. DosSantos MF, Martikainen IK, Nascimento TD, Love TM, DeBoer MD, Schambra HM, et al. Building up analgesia in humans via the endogenous mu-opioid system by combining placebo and active tDCS: a preliminary report. PLoS One 2014, 9: e102350.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  212. Auvichayapat P, Keeratitanont K, Janyachareon T, Auvichayapat N. The effects of transcranial direct current stimulation on metabolite changes at the anterior cingulate cortex in neuropathic pain: a pilot study. J Pain Res 2018, 11: 2301–2309.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  213. George MS, Lisanby SH, Sackeim HA. Transcranial magnetic stimulation: applications in neuropsychiatry. Arch Gen Psychiatry 1999, 56: 300–311.

    Article  CAS  PubMed  Google Scholar 

  214. Lefaucheur JP. Use of repetitive transcranial magnetic stimulation in pain relief. Expert Rev Neurother 2008, 8: 799–808.

    Article  PubMed  Google Scholar 

  215. George MS, Nahas Z, Molloy M, Speer AM, Oliver NC, Li XB, et al. A controlled trial of daily left prefrontal cortex TMS for treating depression. Biol Psychiatry 2000, 48: 962–970.

    Article  CAS  PubMed  Google Scholar 

  216. Lefaucheur JP, Drouot X, Keravel Y, Nguyen JP. Pain relief induced by repetitive transcranial magnetic stimulation of precentral cortex. Neuroreport 2001, 12: 2963–2965.

    Article  CAS  PubMed  Google Scholar 

  217. Drouot X, Nguyen JP, Peschanski M, Lefaucheur JP. The antalgic efficacy of chronic motor cortex stimulation is related to sensory changes in the painful zone. Brain 2002, 125: 1660–1664.

    Article  PubMed  Google Scholar 

  218. Lefaucheur JP. The use of repetitive transcranial magnetic stimulation (rTMS) in chronic neuropathic pain. Clin Neurophysiol 2006, 36: 117–124.

    Article  CAS  Google Scholar 

  219. Brighina F, De Tommaso M, Giglia F, Scalia S, Cosentino G, Puma A, et al. Modulation of pain perception by transcranial magnetic stimulation of left prefrontal cortex. J Headache Pain 2011, 12: 185–191.

    Article  PubMed  PubMed Central  Google Scholar 

  220. Fierro B, De Tommaso M, Giglia F, Giglia G, Palermo A, Brighina F. Repetitive transcranial magnetic stimulation (rTMS) of the dorsolateral prefrontal cortex (DLPFC) during capsaicin-induced pain: modulatory effects on motor cortex excitability. Exp Brain Res 2010, 203: 31–38.

    Article  PubMed  Google Scholar 

  221. Nardone R, Holler Y, Langthaler PB, Lochner P, Golaszewski S, Schwenker K, et al. rTMS of the prefrontal cortex has analgesic effects on neuropathic pain in subjects with spinal cord injury. Spinal Cord 2017, 55: 20–25.

    Article  CAS  PubMed  Google Scholar 

  222. Fregni F, Boggio PS, Lima MC, Ferreira MJ, Wagner T, Rigonatti SP, et al. A sham-controlled, phase II trial of transcranial direct current stimulation for the treatment of central pain in traumatic spinal cord injury. Pain 2006, 122: 197–209.

    Article  PubMed  Google Scholar 

  223. Nizard J, Esnault J, Bouche B, Suarez Moreno A, Lefaucheur JP, Nguyen JP. Long-term relief of painful bladder syndrome by high-intensity, low-frequency repetitive transcranial magnetic stimulation of the right and left dorsolateral prefrontal cortices. Front Neurosci 2018, 12: 925.

    Article  PubMed  PubMed Central  Google Scholar 

  224. Fregni F, DaSilva D, Potvin K, Ramos-Estebanez C, Cohen D, Pascual-Leone A, et al. Treatment of chronic visceral pain with brain stimulation. Ann Neurol 2005, 58: 971–972.

    Article  PubMed  Google Scholar 

  225. Kanda M, Mima T, Oga T, Matsuhashi M, Toma K, Hara H, et al. Transcranial magnetic stimulation (TMS) of the sensorimotor cortex and medial frontal cortex modifies human pain perception. Clin Neurophysiol 2003, 114: 860–866.

    Article  PubMed  Google Scholar 

  226. Kanda M, Nagamine T, Ikeda A, Ohara S, Kunieda T, Fujiwara N, et al. Primary somatosensory cortex is actively involved in pain processing in human. Brain Res 2000, 853: 282–289.

    Article  CAS  PubMed  Google Scholar 

  227. Tzabazis A, Aparici CM, Rowbotham MC, Schneider MB, Etkin A, Yeomans DC. Shaped magnetic field pulses by multi-coil repetitive transcranial magnetic stimulation (rTMS) differentially modulate anterior cingulate cortex responses and pain in volunteers and fibromyalgia patients. Mol Pain 2013, 9: 33.

    Article  PubMed  PubMed Central  Google Scholar 

  228. Vyshlova I, Karpov S, Starodubtcev A. Non-pharmacological therapy of pain in lumbar region. J NeurolSci 2017, 381: 854–855.

    Google Scholar 

  229. Galhardoni R, Aparecida da Silva V, Garcia-Larrea L, Dale C, Baptista AF, Barbosa LM, et al. Insular and anterior cingulate cortex deep stimulation for central neuropathic pain: Disassembling the percept of pain. Neurology 2019, 92: e2165–e2175.

    PubMed  Google Scholar 

  230. Luu P, Posner MI. Anterior cingulate cortex regulation of sympathetic activity. Brain 2003, 126: 2119–2120.

    Article  PubMed  Google Scholar 

  231. Weston CS. Another major function of the anterior cingulate cortex: the representation of requirements. Neurosci Biobehav Rev 2012, 36: 90–110.

    Article  CAS  PubMed  Google Scholar 

  232. Park SI, Oh JH, Hwang YS, Kim SJ, Chang JW. Electrical stimulation of the anterior cingulate cortex in a rat neuropathic pain model. Acta Neurochir Suppl 2006, 99: 65–71.

    Article  CAS  PubMed  Google Scholar 

  233. McIntyre CC, Mori S, Sherman DL, Thakor NV, Vitek JL. Electric field and stimulating influence generated by deep brain stimulation of the subthalamic nucleus. Clin Neurophysiol 2004, 115: 589–595.

    Article  PubMed  Google Scholar 

  234. Lefaucheur JP, Antal A, Ahdab R, Ciampi de Andrade D, Fregni F, Khedr EM, et al. The use of repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) to relieve pain. Brain Stimul 2008, 1: 337–344.

  235. Green AL, Wang S, Stein JF, Pereira EA, Kringelbach ML, Liu X, et al. Neural signatures in patients with neuropathic pain. Neurology 2009, 72: 569–571.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  236. LeBlanc BW, Cross B, Smith KA, Roach C, Xia J, Chao YC, et al. Thalamic bursts down-regulate cortical theta and nociceptive behavior. Sci Rep 2017, 7: 2482.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  237. Schuerle S, Soleimany AP, Yeh T, Anand GM, Häberli M, Fleming HE, et al. Synthetic and living micropropellers for convection-enhanced nanoparticle transport. Sci Adv 2019, 5: eaav4803.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  238. Wang J, Cao B, Yu TR, Jelfs B, Yan J, Chan RHM, et al. Theta-frequency phase-locking of single anterior cingulate cortex neurons and synchronization with the medial thalamus are modulated by visceral noxious stimulation in rats. Neuroscience 2015, 298: 200–210.

    Article  CAS  PubMed  Google Scholar 

  239. Matsuura T, Li XH, Tao C, Zhuo M. Effects of matrix metalloproteinase inhibitors on N-methyl-D-aspartate receptor and contribute to long-term potentiation in the anterior cingulate cortex of adult mice. Mol Pain 2019, 15: 1744806919842958.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This review was supported by the National Key R&D Program of China (2019YFA0709504), the National Natural Science Foundation of China (31930042, 31771164, 31900719, and 91630314), the Innovative Research Team of High-level Local Universities in Shanghai, Development Project of Shanghai Peak Disciplines Integrated Chinese and Western Medicine, Shanghai Science and Technology Committee Rising-Star Program (19QA1401400), 111 Project (B18015), Key Project of Shanghai Science & Technology (16JC1420402), Shanghai Municipal Science and Technology Major Project (2018SHZDZX01), and ZJLab.

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  1. Key Laboratory of Computational Neuroscience and Brain-Inspired Intelligence, Ministry of Education; Institute of Science and Technology for Brain-Inspired Intelligence, Behavioral and Cognitive Neuroscience Center, Fudan University, Shanghai, 200433, China

    Xiao Xiao & Ming Ding

  2. State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Department of Translational Neuroscience, Jing’an District Centre Hospital of Shanghai, Institutes of Brain Science; Institute of Integrative Medicine, Fudan University, Shanghai, 200032, China

    Yu-Qiu Zhang

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  1. Xiao Xiao
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  2. Ming Ding
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Xiao, X., Ding, M. & Zhang, YQ. Role of the Anterior Cingulate Cortex in Translational Pain Research. Neurosci. Bull. 37, 405–422 (2021). https://doi.org/10.1007/s12264-020-00615-2

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