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Neurocircuitry basis of motor cortex-related analgesia as an emerging approach for chronic pain management

Nature Mental Health volume 2, pages 496–513 (2024)Cite this article

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Abstract

Aside from movement initiation and control, the primary motor cortex (M1) has been implicated in pain modulation mechanisms. A large body of clinical data has demonstrated that stimulation and behavioural activation of M1 result in clinically important pain relief in patients with specific chronic pain syndromes. However, despite its clinical importance, the full range of circuits for motor cortex-related analgesia (MCRA) remains an enigma. This Review draws on insights from experimental and clinical data and provides an overview of the neurobiological mechanisms of MCRA, with particular emphasis on its neurocircuitry basis. On the basis of structural and functional connections of the M1 within the pain connectome, neural circuits for MCRA are discussed at different levels of the neuroaxis, specifically, the endogenous pain modulation system, the thalamus, the extrapyramidal system, non-noxious somatosensory systems and cortico-limbic pain signatures. We believe that insights from this Review will expedite the understanding of M1-induced pain modulation and offer hope for successful mechanism-based refinements of this interventional approach in chronic pain management.

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Fig. 1: Possible neurocircuitry mechanisms underlying recruitment of descending pain control system and modulation of thalamic pain processing by MCRA.
Fig. 2: Scheme illustrating proposed extrapyramidal circuitry mechanisms in MCRA.
Fig. 3: A proposed model for control of nociceptive systems by non-nociceptive somatosensory systems during MCRA.

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References

  1. Dahlhamer, J. et al. Prevalence of chronic pain and high-impact chronic pain among adults - United States. MMWR Morb. Mortal. Wkly. Rep. 67, 1001–1006 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  2. Cohen, S. P., Vase, L. & Hooten, W. M. Chronic pain: an update on burden, best practices, and new advances. Lancet 397, 2082–2097 (2021).

    Article  PubMed  Google Scholar 

  3. Knotkova, H. et al. Neuromodulation for chronic pain. Lancet 397, 2111–2124 (2021).

    Article  PubMed  Google Scholar 

  4. Nguyen, J. P., Nizard, J., Keravel, Y. & Lefaucheur, J. P. Invasive brain stimulation for the treatment of neuropathic pain. Nat. Rev. Neurol. 7, 699–709 (2011).

    Article  PubMed  Google Scholar 

  5. Penfield, W. & Jasper, H. H. Epilepsy and the Functional Anatomy of the Human Brain 1st edn. (Little, Brown, 1954).

  6. Lende, R. A., Kirsch, W. M. & Druckman, R. Relief of facial pain after combined removal of precentral and postcentral cortex. J. Neurosurg. 34, 537–543 (1971).

    Article  PubMed  Google Scholar 

  7. Lindblom, U. F. & Ottosson, J. O. Influence of pyramidal stimulation upon the relay of coarse cutaneous afferents in the dorsal horn. Acta Physiol. Scand. 38, 309–318 (1957).

    Article  PubMed  Google Scholar 

  8. Coulter, J. D., Maunz, R. A. & Willis, W. D. Effects of stimulation of sensorimotor cortex on primate spinothalamic neurons. Brain Res. 65, 351–356 (1974).

    Article  PubMed  Google Scholar 

  9. Adams, J. E., Hosobuchi, Y. & Fields, H. L. Stimulation of internal capsule for relief of chronic pain. J. Neurosurg. 41, 740–744 (1974).

    Article  PubMed  Google Scholar 

  10. Hirayama, T. et al. Chronic changes in activity of thalamic relay neurons following spinothalamic tractomy in cat: effects of motor cortex stimulation. Pain 5, S273 (1990).

    Article  Google Scholar 

  11. Tsubokawa, T., Katayama, Y., Yamamoto, T., Hirayama, T. & Koyama, S. Chronic motor cortex stimulation for the treatment of central pain. Acta Neurochir. Suppl. 52, 137–139 (1991).

    Article  PubMed  Google Scholar 

  12. Tsubokawa, T., Katayama, Y., Yamamoto, T., Hirayama, T. & Koyama, S. Treatment of thalamic pain by chronic motor cortex stimulation. Pacing Clin. Electrophysiol. 14, 131–134 (1991).

    Article  PubMed  Google Scholar 

  13. Lima, M. C. & Fregni, F. Motor cortex stimulation for chronic pain: systematic review and meta-analysis of the literature. Neurology 70, 2329–2337 (2008).

    Article  PubMed  Google Scholar 

  14. Lefaucheur, J. P., Drouot, X. & Nguyen, J. P. Interventional neurophysiology for pain control: duration of pain relief following repetitive transcranial magnetic stimulation of the motor cortex. Neurophysiol. Clin. 31, 247–252 (2001).

    Article  PubMed  Google Scholar 

  15. Fregni, F. 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 122, 197–209 (2006).

    Article  PubMed  Google Scholar 

  16. Lefaucheur, J. P. et al. Evidence-based guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS): an update (2014–2018). Clin. Neurophysiol. 131, 474–528 (2020).

    Article  PubMed  Google Scholar 

  17. Fregni, F. et al. Evidence-based guidelines and secondary meta-analysis for the use of transcranial direct current stimulation in neurological and psychiatric disorders. Int. J. Neuropsychopharmacol. 24, 256–313 (2021).

    Article  PubMed  Google Scholar 

  18. Volz, M. S. et al. Movement observation-induced modulation of pain perception and motor cortex excitability. Clin. Neurophysiol. 126, 1204–1211 (2015).

    Article  PubMed  Google Scholar 

  19. Suso-Martí, L., La Touche, R., Angulo-Díaz-Parreño, S. & Cuenca-Martínez, F. Effectiveness of motor imagery and action observation training on musculoskeletal pain intensity: A systematic review and meta-analysis. Eur. J. Pain 24, 886–901 (2020).

    Article  PubMed  Google Scholar 

  20. Cardenas-Rojas, A., Pacheco-Barrios, K., Giannoni-Luza, S., Rivera-Torrejon, O. & Fregni, F. Noninvasive brain stimulation combined with exercise in chronic pain: a systematic review and meta-analysis. Expert Rev. Neurother. 20, 401–412 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  21. Gunduz, M. E. et al. Effects of combined and alone transcranial motor cortex stimulation and mirror therapy in phantom limb pain: a randomized factorial trial. Neurorehabil. Neural Repair 35, 704–716 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  22. Garcia-Larrea, L. & Peyron, R. Motor cortex stimulation for neuropathic pain: from phenomenology to mechanisms. NeuroImage 37, S71–S79 (2007). Suppl 1.

    Article  PubMed  Google Scholar 

  23. García-Larrea, L. et al. Electrical stimulation of motor cortex for pain control: a combined PET-scan and electrophysiological study. Pain 83, 259–273 (1999).

    Article  PubMed  Google Scholar 

  24. Gan, Z. et al. Layer-specific pain relief pathways originating from primary motor cortex. Science 378, 1336–1343 (2022).

    Article  PubMed  Google Scholar 

  25. Holmes, S. A., Kim, A. & Borsook, D. The brain and behavioral correlates of motor-related analgesia (MRA). Neurobiol. Dis. 148, 105158 (2021).

    Article  PubMed  Google Scholar 

  26. Lefaucheur, J. P. Cortical neurostimulation for neuropathic pain: state of the art and perspectives. Pain 157 (Suppl. 1), S81–S89 (2016).

  27. Di Lazzaro, V. et al. The effects of motor cortex rTMS on corticospinal descending activity. Clin. Neurophysiol. 121, 464–473 (2010).

    Article  PubMed  Google Scholar 

  28. Campos, A. C. P. et al. Motor cortex stimulation reversed hypernociception, increased serotonin in raphe neurons, and caused inhibition of spinal astrocytes in a Parkinson’s disease rat model. Cells 10, 1158 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  29. França, N. R. et al. Antinociception induced by motor cortex stimulation: somatotopy of behavioral response and profile of neuronal activation. Behav. Brain Res. 250, 211–221 (2013).

    Article  PubMed  Google Scholar 

  30. Gan, Z., Li, H., Naser, P. V., Oswald, M. J. & Kuner, R. Suppression of neuropathic pain and comorbidities by recurrent cycles of repetitive transcranial direct current motor cortex stimulation in mice. Sci. Rep. 11, 9735 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  31. Lopes, P. S. S., Campos, A. C. P., Fonoff, E. T., Britto, L. R. G. & Pagano, R. L. Motor cortex and pain control: exploring the descending relay analgesic pathways and spinal nociceptive neurons in healthy conscious rats. Behav. Brain Funct. 15, 5 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  32. Senapati, A. K., Huntington, P. J. & Peng, Y. B. Spinal dorsal horn neuron response to mechanical stimuli is decreased by electrical stimulation of the primary motor cortex. Brain Res. 1036, 173–179 (2005).

    Article  PubMed  Google Scholar 

  33. Viisanen, H., Ansah, O. B. & Pertovaara, A. The role of the dopamine D2 receptor in descending control of pain induced by motor cortex stimulation in the neuropathic rat. Brain Res. Bull. 89, 133–143 (2012).

    Article  PubMed  Google Scholar 

  34. Giannoni-Luza, S. et al. Noninvasive motor cortex stimulation effects on quantitative sensory testing in healthy and chronic pain subjects: a systematic review and meta-analysis. Pain 161, 1955–1975 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  35. Muñoz-Castañeda, R. et al. Cellular anatomy of the mouse primary motor cortex. Nature 598, 159–166 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  36. Goto, T. et al. Diffusion tensor fiber tracking in patients with central post-stroke pain; correlation with efficacy of repetitive transcranial magnetic stimulation. Pain 140, 509–518 (2008).

    Article  PubMed  Google Scholar 

  37. Katayama, Y., Fukaya, C. & Yamamoto, T. Poststroke pain control by chronic motor cortex stimulation: neurological characteristics predicting a favorable response. J. Neurosurg. 89, 585–591 (1998).

    Article  PubMed  Google Scholar 

  38. Liu, Y. et al. Touch and tactile neuropathic pain sensitivity are set by corticospinal projections. Nature 561, 547–550 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  39. Yoshino-Saito, K., Nishimura, Y., Oishi, T. & Isa, T. Quantitative inter-segmental and inter-laminar comparison of corticospinal projections from the forelimb area of the primary motor cortex of macaque monkeys. Neuroscience 171, 1164–1179 (2010).

    Article  PubMed  Google Scholar 

  40. Malmierca, E., Chaves-Coira, I., Rodrigo-Angulo, M. & Nuñez, A. Corticofugal projections induce long-lasting effects on somatosensory responses in the trigeminal complex of the rat. Front. Syst. Neurosci. 8, 100 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  41. Bai, Y. et al. Contralateral C7 nerve transfer in the treatment of upper-extremity paralysis: a review of anatomical basis, surgical approaches, and neurobiological mechanisms. Rev. Neurosci. 33, 491–514 (2022).

    Article  PubMed  Google Scholar 

  42. Millan, M. J. Descending control of pain. Prog. Neurobiol. 66, 355–474 (2002).

    Article  PubMed  Google Scholar 

  43. Canedo, A. Primary motor cortex influences on the descending and ascending systems. Prog. Neurobiol. 51, 287–335 (1997).

    Article  PubMed  Google Scholar 

  44. Gamal-Eltrabily, M., Martínez-Lorenzana, G., González-Hernández, A. & Condés-Lara, M. Cortical modulation of nociception. Neuroscience 458, 256–270 (2021).

    Article  PubMed  Google Scholar 

  45. Nguyen, E., Grajales-Reyes, J. G., Gereau, R. W. 4th & Ross, S. E. Cell type-specific dissection of sensory pathways involved in descending modulation. Trends Neurosci. 46, 539–550 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  46. Yin, W. et al. A central amygdala-ventrolateral periaqueductal gray matter pathway for pain in a mouse model of depression-like behavior. Anesthesiology 132, 1175–1196 (2020).

    Article  PubMed  Google Scholar 

  47. Peyron, R., Faillenot, I., Mertens, P., Laurent, B. & Garcia-Larrea, L. Motor cortex stimulation in neuropathic pain. Correlations between analgesic effect and hemodynamic changes in the brain. A PET study. NeuroImage 34, 310–321 (2007).

    Article  PubMed  Google Scholar 

  48. Pagano, R. L. et al. Transdural motor cortex stimulation reverses neuropathic pain in rats: a profile of neuronal activation. Eur. J. Pain 15, 268.e1–268.e14 (2011).

    PubMed  Google Scholar 

  49. Pagano, R. L. et al. Motor cortex stimulation inhibits thalamic sensory neurons and enhances activity of PAG neurons: possible pathways for antinociception. Pain 153, 2359–2369 (2012).

    Article  PubMed  Google Scholar 

  50. Kim, J. et al. Motor cortex stimulation and neuropathic pain: how does motor cortex stimulation affect pain-signaling pathways? J. Neurosurg. 124, 866–876 (2016).

    Article  PubMed  Google Scholar 

  51. Viisanen, H. & Pertovaara, A. Roles of the rostroventromedial medulla and the spinal 5-HT(1A) receptor in descending antinociception induced by motor cortex stimulation in the neuropathic rat. Neurosci. Lett. 476, 133–137 (2010).

    Article  PubMed  Google Scholar 

  52. Viisanen, H. & Pertovaara, A. Antinociception by motor cortex stimulation in the neuropathic rat: does the locus coeruleus play a role? Exp. Brain Res. 201, 283–296 (2010).

    Article  PubMed  Google Scholar 

  53. Porreca, F., Ossipov, M. H. & Gebhart, G. F. Chronic pain and medullary descending facilitation. Trends Neurosci. 25, 319–325 (2002).

    Article  PubMed  Google Scholar 

  54. Granovsky, Y. Conditioned pain modulation: a predictor for development and treatment of neuropathic pain. Curr. Pain Headache Rep. 17, 361 (2013).

    Article  PubMed  Google Scholar 

  55. Chudler, E. H. & Dong, W. K. The role of the basal ganglia in nociception and pain. Pain 60, 3–38 (1995).

    Article  PubMed  Google Scholar 

  56. Nieoullon, A., Cheramy, A. & Glowinski, J. Release of dopamine evoked by electrical stimulation of the motor and visual areas of the cerebral cortex in both caudate nuclei and in the substantia nigra in the cat. Brain Res. 145, 69–83 (1978).

    Article  PubMed  Google Scholar 

  57. Lamusuo, S. et al. Neurotransmitters behind pain relief with transcranial magnetic stimulation—positron emission tomography evidence for release of endogenous opioids. Eur. J. Pain 21, 1505–1515 (2017).

    Article  PubMed  Google Scholar 

  58. Strafella, A. P., Paus, T., Fraraccio, M. & Dagher, A. Striatal dopamine release induced by repetitive transcranial magnetic stimulation of the human motor cortex. Brain 126, 2609–2615 (2003).

    Article  PubMed  Google Scholar 

  59. Ojala, J. et al. A randomized, sham-controlled trial of repetitive transcranial magnetic stimulation targeting M1 and S2 in central poststroke pain: a pilot trial. Neuromodulation 25, 538–548 (2021).

    Article  Google Scholar 

  60. Cilia, R. et al. Cerebral activity modulation by extradural motor cortex stimulation in Parkinson’s disease: a perfusion SPECT study. Eur. J. Neurol. 15, 22–28 (2008).

    Article  PubMed  Google Scholar 

  61. Morari, M. et al. Reciprocal dopamine-glutamate modulation of release in the basal ganglia. Neurochem. Int. 33, 383–397 (1998).

    Article  PubMed  Google Scholar 

  62. Kuner, R. & Kuner, T. Cellular circuits in the brain and their modulation in acute and chronic pain. Physiol. Rev. 101, 213–258 (2021).

    Article  PubMed  Google Scholar 

  63. Cummiford, C. M. et al. Changes in resting state functional connectivity after repetitive transcranial direct current stimulation applied to motor cortex in fibromyalgia patients. Arthritis Res. Ther. 18, 40 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  64. Sankarasubramanian, V. et al. Transcranial direct current stimulation targeting primary motor versus dorsolateral prefrontal cortices: proof-of-concept study investigating functional connectivity of thalamocortical networks specific to sensory-affective information processing. Brain Connect. 7, 182–196 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  65. Ohn, S. H. et al. Neural correlates of the antinociceptive effects of repetitive transcranial magnetic stimulation on central pain after stroke. Neurorehabil. Neural Repair 26, 344–352 (2012).

    Article  PubMed  Google Scholar 

  66. Garcia-Larrea, L. et al. On the relation between sensory deafferentation, pain and thalamic activity in Wallenberg’s syndrome: a PET-scan study before and after motor cortex stimulation. Eur. J. Pain 10, 677–688 (2006).

    Article  PubMed  Google Scholar 

  67. Tsubokawa, T., Katayama, Y., Yamamoto, T., Hirayama, T. & Koyama, S. Chronic motor cortex stimulation in patients with thalamic pain. J. Neurosurg. 78, 393–401 (1993).

    Article  PubMed  Google Scholar 

  68. Brown, J. A. & Pilitsis, J. G. Motor cortex stimulation for central and neuropathic facial pain: a prospective study of 10 patients and observations of enhanced sensory and motor function during stimulation. Neurosurgery 56, 290–297 (2005).

    Article  PubMed  Google Scholar 

  69. Masri, R. et al. Zona incerta: a role in central pain. J. Neurophysiol. 102, 181–191 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  70. Rinaldi, P. C., Young, R. F., Albe-Fessard, D. & Chodakiewitz, J. Spontaneous neuronal hyperactivity in the medial and intralaminar thalamic nuclei of patients with deafferentation pain. J. Neurosurg. 74, 415–421 (1991).

    Article  PubMed  Google Scholar 

  71. Syré, P. P., Weisshaar, C. L. & Winkelstein, B. A. Sustained neuronal hyperexcitability is evident in the thalamus after a transient cervical radicular injury. Spine 39, E870–E877 (2014).

    Article  PubMed  Google Scholar 

  72. Garcia-Larrea, L. & Peyron, R. Pain matrices and neuropathic pain matrices: a review. Pain 154, S29–S43 (2013).

    Article  PubMed  Google Scholar 

  73. Jung, H. H. & Shin, J. Rostral agranular insular cortex lesion with motor cortex stimulation enhances pain modulation effect on neuropathic pain model. Neural Plast. 2016, 3898924 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  74. Cha, M., Ji, Y. & Masri, R. Motor cortex stimulation activates the incertothalamic pathway in an animal model of spinal cord injury. J. Pain 14, 260–269 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  75. Islam, J. et al. Optogenetic stimulation of the motor cortex alleviates neuropathic pain in rats of infraorbital nerve injury with/without CGRP knock-down. J. Headache Pain 21, 106 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  76. Halassa, M. M. & Acsády, L. Thalamic inhibition: diverse sources, diverse scales. Trends Neurosci. 39, 680–693 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  77. Arcelli, P., Frassoni, C., Regondi, M. C., De Biasi, S. & Spreafico, R. GABAergic neurons in mammalian thalamus: a marker of thalamic complexity? Brain Res. Bull. 42, 27–37 (1997).

    Article  PubMed  Google Scholar 

  78. Wang, X., Chou, X. L., Zhang, L. I. & Tao, H. W. Zona incerta: an integrative node for global behavioral modulation. Trends Neurosci. 43, 82–87 (2020).

    Article  PubMed  Google Scholar 

  79. Lucas, J. M., Ji, Y. & Masri, R. Motor cortex stimulation reduces hyperalgesia in an animal model of central pain. Pain 152, 1398–1407 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  80. Wang, H. et al. Incerta-thalamic circuit controls nocifensive behavior via cannabinoid type 1 receptors. Neuron 107, 538–551.e537 (2020).

    Article  PubMed  Google Scholar 

  81. Urbain, N. & Deschênes, M. Motor cortex gates vibrissal responses in a thalamocortical projection pathway. Neuron 56, 714–725 (2007).

    Article  PubMed  Google Scholar 

  82. Pinault, D. The thalamic reticular nucleus: structure, function and concept. Brain Res. Rev. 46, 1–31 (2004).

    Article  PubMed  Google Scholar 

  83. Zhang, C. et al. Reduced GABAergic transmission in the ventrobasal thalamus contributes to thermal hyperalgesia in chronic inflammatory pain. Sci. Rep. 7, 41439 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  84. Alipour, M., Chen, Y. & Jürgens, U. Anterograde projections of the motorcortical tongue area in the saddle-back tamarin (Saguinus fuscicollis). Brain Behav. Evol. 60, 101–116 (2002).

    Article  PubMed  Google Scholar 

  85. Kobaïter-Maarrawi, S., Maarrawi, J., Saadé, N., Garcia-Larrea, L. & Magnin, M. Differential effect of motor cortex stimulation on unit activities in the ventral posterior lateral thalamus in cats. Pain 159, 157–167 (2018).

    Article  PubMed  Google Scholar 

  86. Ralston, H. J. 3rd & Ralston, D. D. Medial lemniscal and spinal projections to the macaque thalamus: an electron microscopic study of differing GABAergic circuitry serving thalamic somatosensory mechanisms. J. Neurosci.14, 2485–2502 (1994).

    Article  PubMed  PubMed Central  Google Scholar 

  87. Peyron, R., Laurent, B. & García-Larrea, L. Functional imaging of brain responses to pain. A review and meta-analysis (2000). Neurophysiol. Clin. 30, 263–288 (2000).

    Article  PubMed  Google Scholar 

  88. Cichon, J., Blanck, T. J. J., Gan, W. B. & Yang, G. Activation of cortical somatostatin interneurons prevents the development of neuropathic pain. Nat. Neurosci. 20, 1122–1132 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  89. Eto, K. et al. Enhanced GABAergic activity in the mouse primary somatosensory cortex is insufficient to alleviate chronic pain behavior with reduced expression of neuronal potassium-chloride cotransporter. J. Neurosci. 32, 16552–16559 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  90. Ziegler, K. et al. Primary somatosensory cortex bidirectionally modulates sensory gain and nociceptive behavior in a layer-specific manner. Nat. Commun. 14, 2999 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  91. Tan, L. L. & Kuner, R. Neocortical circuits in pain and pain relief. Nat. Rev. Neurosci. 22, 458–471 (2021).

    Article  PubMed  Google Scholar 

  92. Tasker, R. R. & Dostrovsky, J. O. in Textbook of Pain 2nd edn. (eds. Wall, P. D. & Melzack, R.) 154–180 (Churchill Livingstone, 1989).

  93. Mountcastle, V. B. & Powell, T. P. Neural mechanisms subserving cutaneous sensibility, with special reference to the role of afferent inhibition in sensory perception and discrimination. Bull. Johns Hopkins Hosp. 105, 201–232 (1959).

    PubMed  Google Scholar 

  94. Kinnischtzke, A. K., Simons, D. J. & Fanselow, E. E. Motor cortex broadly engages excitatory and inhibitory neurons in somatosensory barrel cortex. Cereb. Cortex 24, 2237–2248 (2014).

    Article  PubMed  Google Scholar 

  95. Lee, S., Kruglikov, I., Huang, Z. J., Fishell, G. & Rudy, B. A disinhibitory circuit mediates motor integration in the somatosensory cortex. Nat. Neurosci. 16, 1662–1670 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  96. Houzé, B., Bradley, C., Magnin, M. & Garcia-Larrea, L. Changes in sensory hand representation and pain thresholds induced by motor cortex stimulation in humans. Cereb. Cortex 23, 2667–2676 (2013).

    Article  PubMed  Google Scholar 

  97. Delon-Martin, C. et al. Neural correlates of pain-autonomic coupling in patients with complex regional pain syndrome treated by repetitive transcranial magnetic stimulation of the motor cortex. Neuromodulation 27, 188–199 (2023).

    Article  PubMed  Google Scholar 

  98. Jiang, L. et al. Motor cortex stimulation suppresses cortical responses to noxious hindpaw stimulation after spinal cord lesion in rats. Brain Stimul. 7, 182–189 (2014).

    Article  PubMed  Google Scholar 

  99. Chiou, R. J., Lee, H. Y., Chang, C. W., Lin, K. H. & Kuo, C. C. Epidural motor cortex stimulation suppresses somatosensory evoked potentials in the primary somatosensory cortex of the rat. Brain Res. 1463, 42–50 (2012).

    Article  PubMed  Google Scholar 

  100. Drouot, X., Nguyen, J. P., Peschanski, M. & Lefaucheur, J. P. The antalgic efficacy of chronic motor cortex stimulation is related to sensory changes in the painful zone. Brain 125, 1660–1664 (2002).

    Article  PubMed  Google Scholar 

  101. Lefaucheur, J. P., Drouot, X., Ménard-Lefaucheur, I., Keravel, Y. & Nguyen, J. P. Motor cortex rTMS in chronic neuropathic pain: pain relief is associated with thermal sensory perception improvement. J. Neurol. Neurosurg. Psychiatry 79, 1044–1049 (2008).

    Article  PubMed  Google Scholar 

  102. Hasan, M. et al. Somatosensory change and pain relief induced by repetitive transcranial magnetic stimulation in patients with central poststroke pain. Neuromodulation 17, 731–736 (2014).

  103. Fontaine, D., Bruneto, J. L., El Fakir, H., Paquis, P. & Lanteri-Minet, M. Short-term restoration of facial sensory loss by motor cortex stimulation in peripheral post-traumatic neuropathic pain. J. Headache Pain 10, 203–206 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  104. Reyns, N. et al. Motor cortex stimulation modulates defective central beta rhythms in patients with neuropathic pain. Clin. Neurophysiol. 124, 761–769 (2013).

    Article  PubMed  Google Scholar 

  105. Brasil-Neto, J. P. Motor cortex stimulation for pain relief: do corollary discharges play a role? Front. Hum. Neurosci. 10, 323 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  106. Palmeri, A., Bellomo, M., Giuffrida, R. & Sapienza, S. Motor cortex modulation of exteroceptive information at bulbar and thalamic lemniscal relays in the cat. Neuroscience 88, 135–150 (1999).

    Article  PubMed  Google Scholar 

  107. Kudo, K., Takahashi, T. & Suzuki, S. The changes of c-Fos expression by motor cortex stimulation in the deafferentation pain model. Neurol. Med. Chir. 54, 537–544 (2014).

    Article  Google Scholar 

  108. Cha, M., Um, S. W., Kwon, M., Nam, T. S. & Lee, B. H. Repetitive motor cortex stimulation reinforces the pain modulation circuits of peripheral neuropathic pain. Sci. Rep. 7, 7986 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  109. Hodkinson, D. J., Bungert, A., Bowtell, R., Jackson, S. R. & Jung, J. Operculo-insular and anterior cingulate plasticity induced by transcranial magnetic stimulation in the human motor cortex: a dynamic casual modeling study. J. Neurophysiol. 125, 1180–1190 (2021).

    Article  PubMed  Google Scholar 

  110. Maarrawi, J. et al. Brain opioid receptor density predicts motor cortex stimulation efficacy for chronic pain. Pain 154, 2563–2568 (2013).

    Article  PubMed  Google Scholar 

  111. Maarrawi, J. et al. Motor cortex stimulation for pain control induces changes in the endogenous opioid system. Neurology 69, 827–834 (2007).

    Article  PubMed  Google Scholar 

  112. DaSilva, A. F. et al. Effect of high-definition transcranial direct current stimulation on headache severity and central µ-opioid receptor availability in episodic migraine. J. Pain Res. 16, 2509–2523 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  113. Gonçalves, F. T. et al. Association of mu opioid receptor (A118G) and BDNF (G196A) polymorphisms with rehabilitation-induced cortical inhibition and analgesic response in chronic osteoarthritis pain. Int. J. Clin. Health Psychol. 23, 100330 (2023).

    Article  PubMed  Google Scholar 

  114. Khedr, E. M. et al. Effects of transcranial direct current stimulation on pain, mood and serum endorphin level in the treatment of fibromyalgia: a double blinded, randomized clinical trial. Brain Stimul. 10, 893–901 (2017).

    Article  PubMed  Google Scholar 

  115. Ahmed, M. A., Mohamed, S. A. & Sayed, D. Long-term antalgic effects of repetitive transcranial magnetic stimulation of motor cortex and serum beta-endorphin in patients with phantom pain. Neurol. Res. 33, 953–958 (2011).

    Article  PubMed  Google Scholar 

  116. Misra, U. K., Kalita, J., Tripathi, G. & Bhoi, S. K. Role of β endorphin in pain relief following high rate repetitive transcranial magnetic stimulation in migraine. Brain Stimul. 10, 618–623 (2017).

    Article  PubMed  Google Scholar 

  117. Misra, U. K., Kalita, J., Tripathi, G. M. & Bhoi, S. K. Is β endorphin related to migraine headache and its relief? Cephalalgia 33, 316–322 (2013).

    Article  PubMed  Google Scholar 

  118. Assis, D. V. et al. Systemic and peripheral mechanisms of cortical stimulation-induced analgesia and refractoriness in a rat model of neuropathic pain. Int. J. Mol. Sci. 24, 7796 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  119. Fonoff, E. T. et al. Antinociception induced by epidural motor cortex stimulation in naive conscious rats is mediated by the opioid system. Behav. Brain Res. 196, 63–70 (2009).

    Article  PubMed  Google Scholar 

  120. de Andrade, D. C., Mhalla, A., Adam, F., Texeira, M. J. & Bouhassira, D. Neuropharmacological basis of rTMS-induced analgesia: the role of endogenous opioids. Pain 152, 320–326 (2011).

    Article  PubMed  Google Scholar 

  121. Chiou, R. J., Chang, C. W. & Kuo, C. C. Involvement of the periaqueductal gray in the effect of motor cortex stimulation. Brain Res. 1500, 28–35 (2013).

    Article  PubMed  Google Scholar 

  122. Schafer, S. M., Geuter, S. & Wager, T. D. Mechanisms of placebo analgesia: a dual-process model informed by insights from cross-species comparisons. Prog. Neurobiol. 160, 101–122 (2018).

    Article  PubMed  Google Scholar 

  123. Wager, T. D. & Atlas, L. Y. The neuroscience of placebo effects: connecting context, learning and health. Nat. Rev. Neurosci. 16, 403–418 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  124. Peciña, M. & Zubieta, J. K. Molecular mechanisms of placebo responses in humans. Mol. Psychiatry 20, 416–423 (2015).

    Article  PubMed  Google Scholar 

  125. Atlas, L. Y. A social affective neuroscience lens on placebo analgesia. Trends Cogn. Sci. 25, 992–1005 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  126. André-Obadia, N. et al. Transcranial magnetic stimulation for pain control. Double-blind study of different frequencies against placebo, and correlation with motor cortex stimulation efficacy. Clin. Neurophysiol. 117, 1536–1544 (2006).

    Article  PubMed  Google Scholar 

  127. André-Obadia, N., Magnin, M. & Garcia-Larrea, L. On the importance of placebo timing in rTMS studies for pain relief. Pain 152, 1233–1237 (2011).

    Article  PubMed  Google Scholar 

  128. DosSantos, M. F. et al. Building up analgesia in humans via the endogenous μ-opioid system by combining placebo and active tDCS: a preliminary report. PLoS ONE 9, e102350 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  129. Lim, M. et al. Functional magnetic resonance imaging signal variability is associated with neuromodulation in fibromyalgia. Neuromodulation 26, 999–1008 (2021).

    Article  Google Scholar 

  130. Schambra, H. M., Bikson, M., Wager, T. D., DosSantos, M. F. & DaSilva, A. F. It’s all in your head: reinforcing the placebo response with tDCS. Brain Stimul. 7, 623–624 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  Google Scholar 

  132. Boyer, L. et al. rTMS in fibromyalgia: a randomized trial evaluating QoL and its brain metabolic substrate. Neurology 82, 1231–1238 (2014).

    Article  PubMed  Google Scholar 

  133. Fonoff, E. T. et al. Pain relief and functional recovery in patients with complex regional pain syndrome after motor cortex stimulation. Stereotact. Funct. Neurosurg. 89, 167–172 (2011).

    Article  PubMed  Google Scholar 

  134. Kadono, Y. et al. Repetitive transcranial magnetic stimulation restores altered functional connectivity of central poststroke pain model monkeys. Sci. Rep. 11, 6126 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  135. Timbie, C. & Barbas, H. Pathways for emotions: specializations in the amygdalar, mediodorsal thalamic, and posterior orbitofrontal network. J. Neurosci. 35, 11976–11987 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  136. Riedl, V. et al. Metabolic connectivity mapping reveals effective connectivity in the resting human brain. Proc. Natl Acad. Sci. USA 113, 428–433 (2016).

    Article  PubMed  Google Scholar 

  137. Ashkan, K., Rogers, P., Bergman, H. & Ughratdar, I. Insights into the mechanisms of deep brain stimulation. Nat. Rev. Neurol. 13, 548–554 (2017).

    Article  PubMed  Google Scholar 

  138. Mylius, V., Borckardt, J. J. & Lefaucheur, J. P. Noninvasive cortical modulation of experimental pain. Pain 153, 1350–1363 (2012).

    Article  PubMed  Google Scholar 

  139. Basbaum, A. I., Bautista, D. M., Scherrer, G. & Julius, D. Cellular and molecular mechanisms of pain. Cell 139, 267–284 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  140. Silva, G. D., Lopes, P. S., Fonoff, E. T. & Pagano, R. L. The spinal anti-inflammatory mechanism of motor cortex stimulation: cause of success and refractoriness in neuropathic pain? J. Neuroinflammation 12, 10 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  141. Farina, S., Tinazzi, M., Le Pera, D. & Valeriani, M. Pain-related modulation of the human motor cortex. Neurol. Res. 25, 130–142 (2003).

    Article  PubMed  Google Scholar 

  142. Braz, J., Solorzano, C., Wang, X. & Basbaum, A. I. Transmitting pain and itch messages: a contemporary view of the spinal cord circuits that generate gate control. Neuron 82, 522–536 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  143. Todd, A. J. Neuronal circuitry for pain processing in the dorsal horn. Nat. Rev. Neurosci. 11, 823–836 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  144. Meda, K. S. et al. Microcircuit mechanisms through which mediodorsal thalamic input to anterior cingulate cortex exacerbates pain-related aversion. Neuron 102, 944–959.e943 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  145. Yen, C. T. & Lu, P. L. Thalamus and pain. Acta Anaesthesiol. Taiwan. 51, 73–80 (2013).

    Article  PubMed  Google Scholar 

  146. Ma, Q. A functional subdivision within the somatosensory system and its implications for pain research. Neuron 110, 749–769 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  147. Moriarty, O., McGuire, B. E. & Finn, D. P. The effect of pain on cognitive function: a review of clinical and preclinical research. Prog. Neurobiol. 93, 385–404 (2011).

    Article  PubMed  Google Scholar 

  148. Tracey, I. & Mantyh, P. W. The cerebral signature for pain perception and its modulation. Neuron 55, 377–391 (2007).

    Article  PubMed  Google Scholar 

  149. Ossipov, M. H. The perception and endogenous modulation of pain. Scientifica 2012, 561761 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  150. Bushnell, M. C., Ceko, M. & Low, L. A. Cognitive and emotional control of pain and its disruption in chronic pain. Nat. Rev. Neurosci. 14, 502–511 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  151. Ghimire, P. et al. Intraoperative mapping of pre-central motor cortex and subcortex: a proposal for supplemental cortical and novel subcortical maps to Penfield’s motor homunculus. Brain Struct. Funct. 226, 1601–1611 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  152. Lefaucheur, J. P., Ménard-Lefaucheur, I., Goujon, C., Keravel, Y. & Nguyen, J. P. Predictive value of rTMS in the identification of responders to epidural motor cortex stimulation therapy for pain. J. Pain 12, 1102–1111 (2011).

    Article  PubMed  Google Scholar 

  153. Leung, A. et al. Transcranial magnetic stimulation for pain, headache, and comorbid depression: INS-NANS expert consensus panel review and recommendation. Neuromodulation 23, 267–290 (2020).

    Article  PubMed  Google Scholar 

  154. Gordon, E. M. et al. A somato-cognitive action network alternates with effector regions in motor cortex. Nature 617, 351–359 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  155. Borutta, M. C. et al. The impact of burst motor cortex stimulation on cardiovascular autonomic modulation in chronic pain: a feasibility study for a new approach to objectively monitor therapeutic effects. Pain Ther. 12, 1235–1251 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  156. Baudic, S. et al. Unilateral repetitive transcranial magnetic stimulation of the motor cortex does not affect cognition in patients with fibromyalgia. J. Psychiatric Res. 47, 72–77 (2013).

    Article  Google Scholar 

  157. Montes, C. et al. Cognitive effects of precentral cortical stimulation for pain control: an ERP study. Neurophysiol. Clin. 32, 313–325 (2002).

    Article  PubMed  Google Scholar 

  158. Shepherd, G. M. Corticostriatal connectivity and its role in disease. Nat. Rev. Neurosci. 14, 278–291 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  159. McColgan, P., Joubert, J., Tabrizi, S. J. & Rees, G. The human motor cortex microcircuit: insights for neurodegenerative disease. Nat. Rev. Neurosci. 21, 401–415 (2020).

    Article  PubMed  Google Scholar 

  160. Lindenbach, D. & Bishop, C. Critical involvement of the motor cortex in the pathophysiology and treatment of Parkinson’s disease. Neuroscience and biobehavioral reviews 37, 2737–2750 (2013).

    Article  PubMed  Google Scholar 

  161. Chu, H. Y. Synaptic and cellular plasticity in Parkinson’s disease. Acta Pharmacol. Sin. 41, 447–452 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  162. Koch, C. The action of the corticofugal pathway on sensory thalamic nuclei: a hypothesis. Neuroscience 23, 399–406 (1987).

    Article  PubMed  Google Scholar 

  163. Nguyen, J. P. et al. Chronic motor cortex stimulation in the treatment of central and neuropathic pain. Correlations between clinical, electrophysiological and anatomical data. Pain 82, 245–251 (1999).

    Article  PubMed  Google Scholar 

  164. Vaculín, S., Franek, M., Yamamotová, A. & Rokyta, R. Motor cortex stimulation in rats with chronic constriction injury. Exp. Brain Res. 185, 331–335 (2008).

    Article  PubMed  Google Scholar 

  165. Nahmias, F., Debes, C., de Andrade, D. C., Mhalla, A. & Bouhassira, D. Diffuse analgesic effects of unilateral repetitive transcranial magnetic stimulation (rTMS) in healthy volunteers. Pain 147, 224–232 (2009).

    Article  PubMed  Google Scholar 

  166. Passard, A. et al. Effects of unilateral repetitive transcranial magnetic stimulation of the motor cortex on chronic widespread pain in fibromyalgia. Brain 130, 2661–2670 (2007).

    Article  PubMed  Google Scholar 

  167. Luo, L. Q. Principles of Neurobiology Ch. 6 (Garland Science, 2016).

  168. Harding, E. K., Fung, S. W. & Bonin, R. P. Insights into spinal dorsal horn circuit function and dysfunction using optical approaches. Front. Neural Circuits 14, 31 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  169. Prescott, S. A., Ma, Q. & De Koninck, Y. Normal and abnormal coding of somatosensory stimuli causing pain. Nat. Neurosci. 17, 183–191 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  170. Hosomi, K., Seymour, B. & Saitoh, Y. Modulating the pain network–neurostimulation for central poststroke pain. Nat. Rev. Neurol. 11, 290–299 (2015).

    Article  PubMed  Google Scholar 

  171. Duncan, G. H., Bushnell, C. M. & Marchand, S. Deep brain stimulation: a review of basic research and clinical studies. Pain 45, 49–59 (1991).

    Article  PubMed  Google Scholar 

  172. Lu, C. et al. Insular cortex is critical for the perception, modulation, and chronification of pain. Neurosci. Bull. 32, 191–201 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  173. Lu, J. et al. Somatosensory cortical signature of facial nociception and vibrotactile touch-induced analgesia. Sci. Adv. 8, eabn6530 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  174. Cruz-Almeida, Y., Felix, E. R., Martinez-Arizala, A. & Widerström-Noga, E. G. Decreased spinothalamic and dorsal column medial lemniscus-mediated function is associated with neuropathic pain after spinal cord injury. J. Neurotrauma 29, 2706–2715 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  175. Hollins, M. Somesthetic senses. Annual Rev. Psychol. 61, 243–271 (2010).

    Article  PubMed  Google Scholar 

  176. Villanueva, L., Bouhassira, D. & Le Bars, D. The medullary subnucleus reticularis dorsalis (SRD) as a key link in both the transmission and modulation of pain signals. Pain 67, 231–240 (1996).

    Article  PubMed  Google Scholar 

  177. Martins, I. & Tavares, I. Reticular formation and pain: the past and the future. Front. Neuroanat. 11, 51 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  178. Kucharczyk, M. W., Valiente, D. & Bannister, K. Developments in understanding diffuse noxious inhibitory controls: pharmacological evidence from pre-clinical research. J. Pain Res. 14, 1083–1095 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  179. Takata, N. Thalamic reticular nucleus in the thalamocortical loop. Neurosci. Res. 156, 32–40 (2020).

    Article  PubMed  Google Scholar 

  180. Hagelberg, N. et al. Dopamine D2 receptor binding in the human brain is associated with the response to painful stimulation and pain modulatory capacity. Pain 99, 273–279 (2002).

    Article  PubMed  Google Scholar 

  181. Barceló, A. C., Fillipini, B. & Pazo, J. H. Study of the neural basis of striatal modulation of the jaw-opening reflex. J. Neural Transm. 117, 171–181 (2010).

    Article  PubMed  Google Scholar 

  182. Ansah, O. B., Leite-Almeida, H., Wei, H. & Pertovaara, A. Striatal dopamine D2 receptors attenuate neuropathic hypersensitivity in the rat. Exp. Neurol. 205, 536–546 (2007).

    Article  PubMed  Google Scholar 

  183. Luan, Y. et al. Reversal of hyperactive subthalamic circuits differentially mitigates pain hypersensitivity phenotypes in parkinsonian mice. Proc. Natl Acad. Sci. USA 117, 10045–10054 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  184. Pautrat, A. et al. Revealing a novel nociceptive network that links the subthalamic nucleus to pain processing. eLife 7, e36607 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  185. Mostofi, A., Morgante, F., Edwards, M. J., Brown, P. & Pereira, E. A. C. Pain in Parkinson’s disease and the role of the subthalamic nucleus. Brain 144, 1342–1350 (2021).

    Article  PubMed  Google Scholar 

  186. Jia, T. et al. A nigro-subthalamo-parabrachial pathway modulates pain-like behaviors. Nat. Commun. 13, 7756 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  187. Zubieta, J. K. & Stohler, C. S. Neurobiological mechanisms of placebo responses. Ann. N.Y. Acad. Sci. 1156, 198–210 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  188. Mansour, A., Fox, C. A., Akil, H. & Watson, S. J. Opioid-receptor mRNA expression in the rat CNS: anatomical and functional implications. Trends Neurosci. 18, 22–29 (1995).

    Article  PubMed  Google Scholar 

  189. Corder, G., Castro, D. C., Bruchas, M. R. & Scherrer, G. Endogenous and exogenous opioids in pain. Annu. Rev. Neurosci. 41, 453–473 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  190. Fichna, J., Janecka, A., Costentin, J. & Do Rego, J. C. The endomorphin system and its evolving neurophysiological role. Pharmacol. Rev. 59, 88–123 (2007).

    Article  PubMed  Google Scholar 

  191. Bach, F. W. Beta-endorphin in the brain. A role in nociception. Acta Anaesthesiol. Scand. 41, 133–140 (1997).

    Article  PubMed  Google Scholar 

  192. Tang, J. S., Qu, C. L. & Huo, F. Q. The thalamic nucleus submedius and ventrolateral orbital cortex are involved in nociceptive modulation: a novel pain modulation pathway. Prog. Neurobiol. 89, 383–389 (2009).

    Article  PubMed  Google Scholar 

  193. Oliva, V. et al. Parallel cortical-brainstem pathways to attentional analgesia. NeuroImage 226, 117548 (2021).

    Article  PubMed  Google Scholar 

  194. Neugebauer, V. et al. Pain-related cortico-limbic plasticity and opioid signaling. Neuropharmacology 231, 109510 (2023).

    Article  PubMed  Google Scholar 

  195. Bai, Y. et al. Anterior insular cortex mediates hyperalgesia induced by chronic pancreatitis in rats. Mol. Brain 12, 76 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  196. Yokota, E. et al. Opioid subtype- and cell-type-dependent regulation of inhibitory synaptic transmission in the rat insular cortex. Neuroscience 339, 478–490 (2016).

    Article  PubMed  Google Scholar 

  197. Burkey, A. R., Carstens, E., Wenniger, J. J., Tang, J. & Jasmin, L. An opioidergic cortical antinociception triggering site in the agranular insular cortex of the rat that contributes to morphine antinociception. J. Neurosci. 16, 6612–6623 (1996).

    Article  PubMed  PubMed Central  Google Scholar 

  198. Huang, J., Zhang, Z., Gambeta, E., Chen, L. & Zamponi, G. W. An orbitofrontal cortex to midbrain projection modulates hypersensitivity after peripheral nerve injury. Cell Rep. 35, 109033 (2021).

    Article  PubMed  Google Scholar 

  199. Sheng, H. Y. et al. Activation of ventrolateral orbital cortex improves mouse neuropathic pain-induced anxiodepression. JCI Insight 5, e133625 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  200. Fields, H. State-dependent opioid control of pain. Nat. Rev. Neurosci. 5, 565–575 (2004).

    Article  PubMed  Google Scholar 

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Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China under grant numbers 82101318 (to Y.B.) and 81971133 (to G.L.) and the US National Institutes of Health under grant number R01AT009491 (to F.F.). We are grateful to A. Qin (Shanghai Glossop Biotech) for help with the illustrations.

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  1. These authors contributed equally: Yang Bai, Kevin Pacheco-Barrios.

Authors and Affiliations

  1. Department of Neurosurgery, General Hospital of Northern Theater Command, Shenyang, China

    Yang Bai & Guobiao Liang

  2. Neuromodulation Center and Center for Clinical Research Learning, Spaulding Rehabilitation Hospital and Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    Kevin Pacheco-Barrios & Felipe Fregni

  3. Universidad San Ignacio de Loyola, Vicerrectorado de Investigación, Unidad de Investigación para la Generación y Síntesis de Evidencias en Salud, Lima, Peru

    Kevin Pacheco-Barrios

  4. Facultad de Medicina, Universidad Peruana Cayetano Heredia, Lima, Peru

    Niels Pacheco-Barrios

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Contributions

Y.B. and K.P.-B. wrote the first draft of the paper. Y.B. and N.P.-B. prepared the figures. F.F. and G.L. developed the conceptual framework of the paper. All authors edited, reviewed and refined all versions of the paper.

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Correspondence to Guobiao Liang or Felipe Fregni.

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Bai, Y., Pacheco-Barrios, K., Pacheco-Barrios, N. et al. Neurocircuitry basis of motor cortex-related analgesia as an emerging approach for chronic pain management. Nat. Mental Health 2, 496–513 (2024). https://doi.org/10.1038/s44220-024-00235-z

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