Neurophysiological Assessments in Small Fiber Neuropathy: Evoked Potentials

  • Rosario Privitera
  • Praveen AnandEmail author


The syndromes of small fiber neuropathies (SFN) affect thinly myelinated Aδ-fibers and unmyelinated C-fibers, which are assessed by a range of techniques including cerebral potentials evoked by noxious electrical, laser, or contact heat stimuli. These specialized neurophysiological techniques contribute to the diagnosis, monitoring, and evaluation of treatment effects in SFN and understanding their pathophysiology. The standard clinical neurophysiological tests (nerve conduction studies, NCS, and somatosensory-evoked potentials, SSEPs) assess large myelinated Aβ-nerve fibers and their associated pathways in the central nervous system (CNS), hence may be normal in SFN. Nociceptor dysfunction assessment with electrical stimuli has been used in organs such as tooth pulp, which are exclusively innervated by small fibers, mainly to investigate the efficacy of analgesic agents in acute experimental pain. Laser-evoked potentials (LEPs) are obtained after rapid heating of the skin with laser pulses, can help to identify lesions of small sensory nerve fibers and/or their CNS pathways, and represent a sensitive, objective, and noninvasive method for the assessment of SFN. Contact heat-evoked potentials (CHEPs) are similar to LEPs with some practical advantages for clinical use, particularly when the region affected precludes skin biopsy, as it has been correlated with other techniques for assessing SFN including intraepidermal nerve fiber density (IENFD) in skin biopsies. They help in assessing patients unable to perform quantitative sensory testing (QST). However, LEPs/CHEPs may be reduced or absent in patients with CNS pain conditions and do not localize the abnormality to peripheral nerves. They can be helpful in distinguishing SFN from other conditions such as nonorganic pain or non-neuropathic hypersensitivity disorders, in which LEPs/CHEPs are preserved or even enhanced. Pain-evoked potentials are a useful tool for studying endogenous processing of emotional-motivational responses related to pain. They have been recommended in guidelines for the assessment of neuropathic pain.


Pain-evoked potential Laser-evoked potential (LEP) Contact heat-evoked potential (CHEP) Tooth pulp-evoked potential (TPEP) 


  1. 1.
    Cruccu G, Aminoff MJ, Curio G, Guerit JM, Kakigi R, Mauguiere F, et al. Recommendations for the clinical use of somatosensory-evoked potentials. Clin Neurophysiol. 2008;119:1705–19.PubMedCrossRefPubMedCentralGoogle Scholar
  2. 2.
    Haanpää M, Attal N, Backonja M, Baron R, Bennett M, Bouhassira D, et al. NeuPSIG guidelines on neuropathic pain assessment. Pain. 2011;152:14–27.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Lagerburg V, Bakkers M, Bouwhuis A, Hoeijmakers JGJ, Smit AM, Van Den Berg SJM, et al. Contact heat evoked potentials: normal values and use in small-fiber neuropathy. Muscle Nerve. 2015;51:743–9.PubMedCrossRefGoogle Scholar
  4. 4.
    Madsen CS, Finnerup NB, Baumgärtner U. Assessment of small fibers using evoked potentials. Scand J Pain. 2014;5:111–8.PubMedCrossRefPubMedCentralGoogle Scholar
  5. 5.
    Truini A, Haanpaa M, Zucchi R, Galeotti F, Iannetti GD, Romaniello A, et al. Laser-evoked potentials in post-herpetic neuralgia. Clin Neurophysiol. 2003;114:702–9.PubMedCrossRefPubMedCentralGoogle Scholar
  6. 6.
    Cruccu G, Leandri M, Iannetti GD, Mascia A, Romaniello A, Truini A, et al. Small-fiber dysfunction in trigeminal neuralgia: carbamazepine effect on laser-evoked potentials. Neurology. 2001;56:1722–6.PubMedCrossRefPubMedCentralGoogle Scholar
  7. 7.
    Truini A, Galeotti F, Pennisi E, Casa F, Biasiotta A, Cruccu G. Trigeminal small-fibre function assessed with contact heat evoked potentials in humans. Pain. 2007;132:102–7.PubMedCrossRefPubMedCentralGoogle Scholar
  8. 8.
    Chao CC, Tseng MT, Lin YJ, Yang WS, Hsieh SC, Lin YH, et al. Pathophysiology of neuropathic pain in type 2 diabetes: skin denervation and contact heat-evoked potentials. Diabetes Care. 2010;33:2654–9.PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Mueller D, Obermann M, Koeppen S, Kavuk I, Yoon MS, Sack F, et al. Electrically evoked nociceptive potentials for early detection of diabetic small-fiber neuropathy. Eur J Neurol. 2010;17:834–41.PubMedCrossRefPubMedCentralGoogle Scholar
  10. 10.
    Chao CC, Hsieh SC, Tseng MT, Chang YC, Hsieh ST. Patterns of contact heat evoked potentials (CHEP) in neuropathy with skin denervation: correlation of CHEP amplitude with intraepidermal nerve fiber density. Clin Neurophysiol. 2008;119:653–61.CrossRefGoogle Scholar
  11. 11.
    Pazzaglia C, Valeriani M. Brain-evoked potentials as a tool for diagnosing neuropathic pain. Expert Rev Neurother. 2009;9:759–71.PubMedCrossRefPubMedCentralGoogle Scholar
  12. 12.
    Wong MC, Chung JWY. Feasibility of contact heat evoked potentials for detection of diabetic neuropathy. Muscle Nerve. 2011;44:902–6.PubMedCrossRefPubMedCentralGoogle Scholar
  13. 13.
    Pluijms WA, Slangen R, Joosten EA, Kessels AG, Merkies IS, Schaper NC, et al. Electrical spinal cord stimulation in painful diabetic polyneuropathy, a systematic review on treatment efficacy and safety. Eur J Pain. 2011;15:783–8.PubMedCrossRefPubMedCentralGoogle Scholar
  14. 14.
    Atherton DD, Facer P, Roberts KM, Misra VP, Chizh BA, Bountra C, et al. Use of the novel Contact Heat Evoked Potential Stimulator (CHEPS) for the assessment of small fibre neuropathy: correlations with skin flare responses and intra-epidermal nerve fibre counts. BMC Neurol. 2007;7:21.PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Kodaira M, Inui K, Kakigi R. Evaluation of nociceptive Aδ- and C-fiber dysfunction with lidocaine using intraepidermal electrical stimulation. Clin Neurophysiol. 2014;125:1870–7.PubMedCrossRefPubMedCentralGoogle Scholar
  16. 16.
    Treede RD, Apkarian AV, Bromm B, Greenspan JD, Lenz FA. Cortical representation of pain: functional characterization of nociceptive areas near the lateral sulcus. Pain. 2000;87:113–9.PubMedCrossRefPubMedCentralGoogle Scholar
  17. 17.
    Brennum J, Jensen TS. Relationship between vertex potentials and magnitude of pre-pain and pain sensations evoked by electrical skin stimuli. Electroencephalogr Clin Neurophysiol. 1992;82:387–90.PubMedCrossRefPubMedCentralGoogle Scholar
  18. 18.
    Boor R, Li L, Goebel B, Reitter B. Subcortical somatosensory evoked potentials after posterior tibial nerve stimulation in children. Brain Dev. 2008;30:493–8.PubMedCrossRefPubMedCentralGoogle Scholar
  19. 19.
    Prestor B, Gnidovec B, Golob P. Long sensory tracts (cuneate fascicle) in cervical somatosensory evoked potential after median nerve stimulation. Electroencephalogr Clin Neurophysiol. 1997;104:470–9.PubMedCrossRefPubMedCentralGoogle Scholar
  20. 20.
    Restuccia D, Valeriani M, Di Lazzaro V, Tonali P, Mauguiere F. Somatosensory evoked potentials after multisegmental upper limb stimulation in diagnosis of cervical spondylotic myelopathy. J Neurol Neurosurg Psychiatry. 1994;57:301–8.PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Restuccia D, Insola A, Valeriani M, Santilli V, Bedini L, Le Pera D, et al. Somatosensory evoked potentials after multisegmental lower limb stimulation in focal lesions of the lumbosacral spinal cord. J Neurol Neurosurg Psychiatry. 2000;69:91–5.PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Yamada T, Machida M, Kimura J. Far-field somatosensory evoked potentials after stimulation of the tibial nerve. Neurology. 1982;32:1151–8.PubMedCrossRefPubMedCentralGoogle Scholar
  23. 23.
    Naguszewski WK, Naguszewski RK, Gose EE. Dermatomal somatosensory evoked potential demonstration of nerve root decompression after VAX-D therapy. Neurol Res. 2001;23:706–14.PubMedCrossRefPubMedCentralGoogle Scholar
  24. 24.
    Nakamura R, Noritake M, Hosoda Y, Kamakura K, Nagata N, Shibasaki H. Somatosensory conduction delay in central and peripheral nervous system of diabetic patients. Diabetes Care. 1992;15:532–5.PubMedCrossRefPubMedCentralGoogle Scholar
  25. 25.
    Soininen K, Järvilehto T. Somatosensory evoked potentials associated with tactile stimulation at detection threshold in man. Electroencephalogr Clin Neurophysiol. 1983;56:494–500.PubMedCrossRefPubMedCentralGoogle Scholar
  26. 26.
    Kakigi R, Shibasaki H, Neshige R, Ikeda A, Mamiya K, Kuroda Y. Pain-related somatosensory evoked potentials in cortical reflex myoclonus. J Neurol Neurosurg Psychiatry. 1990;53:44–8.PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Yamauchi N, Fujitani Y, Oikawa T. Somatosensory evoked potentials elicited by mechanical and electrical stimulation of each single pain or tactile spot of the skin. Tohoku J Exp Med. 1981;133:81–92.PubMedCrossRefPubMedCentralGoogle Scholar
  28. 28.
    Inui K, Tran TD, Hoshiyama M, Kakigi R. Preferential stimulation of Adelta fibers by intra-epidermal needle electrode in humans. Pain. 2002;96:247–52.PubMedCrossRefPubMedCentralGoogle Scholar
  29. 29.
    Treede RD, Lorenz J, Baumgärtner U. Clinical usefulness of laser-evoked potentials. Neurophysiol Clin. 2003;33:303–14.PubMedCrossRefPubMedCentralGoogle Scholar
  30. 30.
    Katsarava Z, Ayzenberg I, Sack F, Limmroth V, Diener HC, Kaube H. A novel method of eliciting pain-related potentials by transcutaneous electrical stimulation. Headache. 2006;46:1511–7.PubMedCrossRefPubMedCentralGoogle Scholar
  31. 31.
    Bromm B, Jahnke MT, Treede RD. Responses of human cutaneous afferents to CO2 laser stimuli causing pain. Exp Brain Res. 1984;55:158–66.PubMedCrossRefPubMedCentralGoogle Scholar
  32. 32.
    Bromm B, Lorenz J. Neurophysiological evaluation of pain. Electroencephalogr Clin Neurophysiol. 1998;107:227–53.PubMedCrossRefPubMedCentralGoogle Scholar
  33. 33.
    Chen AC, Niddam DM, Arendt-Nielsen L. Contact heat evoked potentials as a valid means to study nociceptive pathways in human subjects. Neurosci Lett. 2001;316:79–82.PubMedCrossRefPubMedCentralGoogle Scholar
  34. 34.
    Treede RD. Neurophysiological studies of pain pathways in peripheral and central nervous system disorders. J Neurol. 2003;250:1152–61.PubMedCrossRefPubMedCentralGoogle Scholar
  35. 35.
    Valeriani M, Le Pera D, Niddam D, Chen AC, Arendt-Nielsen L. Dipolar modelling of the scalp evoked potentials to painful contact heat stimulation of the human skin. Neurosci Lett. 2002;318:44–8.PubMedCrossRefPubMedCentralGoogle Scholar
  36. 36.
    Casanova-Molla J, Grau-Junyent JM, Morales M, Valls-Solé J. On the relationship between nociceptive evoked potentials and intraepidermal nerve fiber density in painful sensory polyneuropathies. Pain. 2011;152:410–8.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Garcia-Larrea L. Objective pain diagnostics: clinical neurophysiology. Neurophysiol Clin. 2012;42:187–97.PubMedCrossRefPubMedCentralGoogle Scholar
  38. 38.
    Passmore SR, Murphy B, Lee TD. The origin and application of somatosensory evoked potentials as a neurophysiological technique to investigate neuroplasticity. J Can Chiropr Assoc. 2014;58:170–83.PubMedPubMedCentralGoogle Scholar
  39. 39.
    Parhizgar SE, Ekhtiari H. A review on experimental assessments of pain threshold in healthy human subjects. Basic Clin Neurosci. 2010;1:62–7.Google Scholar
  40. 40.
    Hansen N, Kahn AK, Zeller D, Katsarava Z, Sommer C, Üçeyler N. Amplitudes of pain-related evoked potentials are useful to detect small fiber involvement in painful mixed fiber neuropathies in addition to quantitative sensory testing – an electrophysiological study. Front Neurol. 2015;6:244.PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Üçeyler N, Kahn AK, Kramer D, Zeller D, Casanova-Molla J, Wanner C, et al. Impaired small fiber conduction in patients with Fabry disease: a neurophysiological case-control study. BMC Neurol. 2013;13:47.PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Hansen N, Obermann M, Üçeyler N, Zeller D, Mueller D, Yoon MS, et al. [Clinical application of pain-related evoked potentials]. Schmerz. 2012;26:8–15.Google Scholar
  43. 43.
    Obermann M, Katsarava Z, Esser S, Sommer C, He L, Selter L, et al. Correlation of epidermal nerve fiber density with pain-related evoked potentials in HIV neuropathy. Pain. 2008;138:79–86.PubMedCrossRefPubMedCentralGoogle Scholar
  44. 44.
    Chatrian GE, Canfield RC, Knauss TA, Eegt EL. Cerebral responses to electrical tooth pulp stimulation in man. An objective correlate of acute experimental pain. Neurology. 1975;25:745–57.PubMedCrossRefPubMedCentralGoogle Scholar
  45. 45.
    Bromm B, Meier W. The intracutaneous stimulus: a new pain model for algesimetric studies. Methods Find Exp Clin Pharmacol. 1984;6:405–10.PubMedPubMedCentralGoogle Scholar
  46. 46.
    Chen AC, Chapman CR, Harkins SW. Brain evoked potentials are functional correlates of induced pain in man. Pain. 1979;6:365–74.PubMedCrossRefPubMedCentralGoogle Scholar
  47. 47.
    Fernandes de Lima VM, Chatrian GE, Lettich E, Canfield RC, Miller RC, Soso MJ. Electrical stimulation of tooth pulp in humans. I. Relationships among physical stimulus intensities, psychological magnitude estimates and cerebral evoked potentials. Pain. 1982;14:207–32.PubMedCrossRefPubMedCentralGoogle Scholar
  48. 48.
    Harkins SW, Chapman CR. Cerebral evoked potentials to noxious dental stimulation: relationship to subjective pain report. Psychophysiology. 1978;15:248–52.PubMedCrossRefPubMedCentralGoogle Scholar
  49. 49.
    Klement W, Medert HA, Arndt JO. Nalbuphine does not act analgetically in electrical painful tooth pulp stimulation in man. Pain. 1992;48:269–74.PubMedCrossRefPubMedCentralGoogle Scholar
  50. 50.
    Chen AC, Chapman CR. Aspirin analgesia evaluated by event-related potentials in man: possible central action in brain. Exp Brain Res. 1980;39:359–64.PubMedCrossRefPubMedCentralGoogle Scholar
  51. 51.
    Gehrig JD, Colpitts YH, Chapman CR. Effects of local anesthetic infiltration on brain potentials evoked by painful dental stimulation. Anesth Analg. 1981;60:779–82.PubMedCrossRefPubMedCentralGoogle Scholar
  52. 52.
    Rohdewald P, Granitzki HW, Neddermann E. Comparison of the analgesic efficacy of metamizole and tramadol in experimental pain. Pharmacology. 1988;37:209–17.PubMedCrossRefPubMedCentralGoogle Scholar
  53. 53.
    Suri A, Kaltenbach ML, Grundy BL, Derendorf H. Pharmacodynamic evaluation of codeine using tooth pulp evoked potentials. J Clin Pharmacol. 1996;36:1126–31.PubMedCrossRefPubMedCentralGoogle Scholar
  54. 54.
    Coda B, Tanaka A, Jacobson RC, Donaldson G, Chapman CR. Hydromorphone analgesia after intravenous bolus administration. Pain. 1997;71:41–8.PubMedCrossRefPubMedCentralGoogle Scholar
  55. 55.
    Hill H, Walter MH, Saeger L, Sargur M, Sizemore W, Chapman CR. Dose effects of alfentanil in human analgesia. Clin Pharmacol Ther. 1986;40:178–86.PubMedCrossRefPubMedCentralGoogle Scholar
  56. 56.
    Chapman CR, Hill HF, Saeger L, Gavrin J. Profiles of opioid analgesia in humans after intravenous bolus administration: alfentanil, fentanyl and morphine compared on experimental pain. Pain. 1990;43:47–55.PubMedCrossRefPubMedCentralGoogle Scholar
  57. 57.
    Katsarava Z, Yaldizli O, Voulkoudis C, Diener HC, Kaube H, Maschke M. Pain related potentials by electrical stimulation of skin for detection of small-fiber neuropathy in HIV. J Neurol. 2006;253:1581–4.PubMedCrossRefPubMedCentralGoogle Scholar
  58. 58.
    Inui K, Kakigi R. Pain perception in humans: use of intraepidermal electrical stimulation. J Neurol Neurosurg Psychiatry. 2012;83:551–6.PubMedCrossRefPubMedCentralGoogle Scholar
  59. 59.
    Otsuru N, Inui K, Yamashiro K, Miyazaki T, Takeshima Y, Kakigi R. Assessing Aδ fiber function with lidocaine using intraepidermal electrical stimulation. J Pain. 2010;11:621–7.PubMedCrossRefPubMedCentralGoogle Scholar
  60. 60.
    Obayashi K, Yamashita T, Tasaki M, Ueda M, Shono M, Jono H, et al. Amyloid neuropathy in a younger domino liver transplanted recipient. Muscle Nerve. 2011;43:449–50.PubMedCrossRefPubMedCentralGoogle Scholar
  61. 61.
    Kukidome D, Nishikawa T, Sato M, Igata M, Kawashima J, Shimoda S, et al. Measurement of small fibre pain threshold values for the early detection of diabetic polyneuropathy. Diabet Med. 2016;33:62–9.PubMedCrossRefPubMedCentralGoogle Scholar
  62. 62.
    Suzuki C, Kon T, Funamizu Y, Ueno T, Haga R, Nishijima H, et al. Elevated pain threshold in patients with asymptomatic diabetic neuropathy: an intraepidermal electrical stimulation study. Muscle Nerve. 2016;54:146–9.PubMedCrossRefPubMedCentralGoogle Scholar
  63. 63.
    Carmon A, Mor J, Goldberg J. Evoked cerebral responses to noxious thermal stimuli in humans. Exp Brain Res. 1976;25:103–7.PubMedCrossRefPubMedCentralGoogle Scholar
  64. 64.
    Plaghki L, Delisle D, Godfraind JM. Heterotopic nociceptive conditioning stimuli and mental task modulate differently the perception and physiological correlates of short CO2 laser stimuli. Pain. 1994;57:181–92.PubMedCrossRefPubMedCentralGoogle Scholar
  65. 65.
    Arendt-Nielsen L, Bjerring P. Sensory and pain threshold characteristics to laser stimuli. J Neurol Neurosurg Psychiatry. 1988;51:35–42.PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Ng Wing Tin S, Plante-Bordeneuve V, Salhi H, Goujon C, Damy T, Lefaucheur JP. Characterization of pain in familial amyloid polyneuropathy. J Pain. 2015;16:1106–14.PubMedCrossRefPubMedCentralGoogle Scholar
  67. 67.
    Pazzaglia C, Vollono C, Ferraro D, Virdis D, Lupi V, Le Pera D, et al. Mechanisms of neuropathic pain in patients with Charcot-Marie-Tooth 1 A: a laser-evoked potential study. Pain. 2010;149:379–85.PubMedCrossRefPubMedCentralGoogle Scholar
  68. 68.
    Valeriani M, Mariotti P, Le Pera D, Restuccia D, De Armas L, Maiese T, et al. Functional assessment of A delta and C fibers in patients with Fabry’s disease. Muscle Nerve. 2004;30:708–13.PubMedCrossRefPubMedCentralGoogle Scholar
  69. 69.
    Agostino R, Cruccu G, Romaniello A, Innocenti P, Inghilleri M. Dysfunction of small myelinated afferents in diabetic polyneuropathy, as assessed by laser evoked potentials. Clin Neurophysiol. 2000;111:270–6.PubMedCrossRefPubMedCentralGoogle Scholar
  70. 70.
    Agostino R, Cruccu G, Iannetti GD, Innocenti P, Romaniello A, Truini A, et al. Trigeminal small-fibre dysfunction in patients with diabetes mellitus: a study with laser evoked potentials and corneal reflex. Clin Neurophysiol. 2000;111:2264–7.PubMedCrossRefPubMedCentralGoogle Scholar
  71. 71.
    Kakigi R, Shibasaki H, Tanaka K, Ikeda T, Oda K, Endo C, et al. CO2 laser-induced pain-related somatosensory evoked potentials in peripheral neuropathies: correlation between electrophysiological and histopathological findings. Muscle Nerve. 1991;14:441–50.PubMedCrossRefPubMedCentralGoogle Scholar
  72. 72.
    Lorenz J, Hansen HC, Kunze K, Bromm B. Sensory deficits of a nerve root lesion can be objectively documented by somatosensory evoked potentials elicited by painful infrared laser stimulations: a case study. J Neurol Neurosurg Psychiatry. 1996;61:107–10.PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Arendt-Nielsen L, Gregersen H, Toft E, Bjerring P. Involvement of thin afferents in carpal tunnel syndrome: evaluated quantitatively by argon laser stimulation. Muscle Nerve. 1991;14:508–14.PubMedCrossRefPubMedCentralGoogle Scholar
  74. 74.
    Wu Q, Garcia-Larrea L, Mertens P, Beschet A, Sindou M, Mauguiere F. Hyperalgesia with reduced laser evoked potentials in neuropathic pain. Pain. 1999;80:209–14.PubMedCrossRefPubMedCentralGoogle Scholar
  75. 75.
    Garcia-Larrea L, Convers P, Magnin M, Andre-Obadia N, Peyron R, Laurent B, et al. Laser-evoked potential abnormalities in central pain patients: the influence of spontaneous and provoked pain. Brain. 2002;125:2766–81.PubMedCrossRefPubMedCentralGoogle Scholar
  76. 76.
    Gibson SJ, Littlejohn GO, Gorman MM, Helme RD, Granges G. Altered heat pain thresholds and cerebral event-related potentials following painful CO2 laser stimulation in subjects with fibromyalgia syndrome. Pain. 1994;58:185–93.PubMedCrossRefPubMedCentralGoogle Scholar
  77. 77.
    Lorenz J, Grasedyck K, Bromm B. Middle and long latency somatosensory evoked potentials after painful laser stimulation in patients with fibromyalgia syndrome. Electroencephalogr Clin Neurophysiol. 1996;100:165–8.PubMedCrossRefPubMedCentralGoogle Scholar
  78. 78.
    Valeriani M, de Tommaso M, Restuccia D, Le Pera D, Guido M, Iannetti GD, et al. Reduced habituation to experimental pain in migraine patients: a CO2 laser evoked potential study. Pain. 2003;105(1–2):57–64.PubMedCrossRefPubMedCentralGoogle Scholar
  79. 79.
    Nolano M, Simone DA, Wendelschafer-Crabb G, Johnson T, Hazen E, Kennedy WR. Topical capsaicin in humans: parallel loss of epidermal nerve fibers and pain sensation. Pain. 1999;81:135–45.PubMedCrossRefPubMedCentralGoogle Scholar
  80. 80.
    Polydefkis M, Hauer P, Sheth S, Sirdofsky M, Griffin JW, McArthur JC. The time course of epidermal nerve fibre regeneration: studies in normal controls and in people with diabetes, with and without neuropathy. Brain. 2004;127:1606–15.PubMedCrossRefPubMedCentralGoogle Scholar
  81. 81.
    Carpenter SE, Lynn B. Vascular and sensory responses of human skin to mild injury after topical treatment with capsaicin. Br J Pharmacol. 1981;73:755–8.PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Lynn B. Capsaicin: actions on nociceptive C-fibres and therapeutic potential. Pain. 1990;41:61–9.PubMedCrossRefPubMedCentralGoogle Scholar
  83. 83.
    Simone DA, Ochoa J. Early and late effects of prolonged topical capsaicin on cutaneous sensibility and neurogenic vasodilatation in humans. Pain. 1991;47:285–94.PubMedCrossRefPubMedCentralGoogle Scholar
  84. 84.
    Beydoun A, Dyke DBS, Morrow TJ, Casey KL. Topical capsaicin selectively attenuates heat pain and Aδ fiber-mediated laser-evoked potentials. Pain. 1996;65:189–96.PubMedCrossRefPubMedCentralGoogle Scholar
  85. 85.
    Rage M, Van Acker N, Facer P, Shenoy R, Knaapen MW, Timmers M, et al. The time course of CO2 laser-evoked responses and of skin nerve fibre markers after topical capsaicin in human volunteers. Clin Neurophysiol. 2010;121:1256–66.PubMedCrossRefPubMedCentralGoogle Scholar
  86. 86.
    Granovsky Y, Matre D, Sokolik A, Lorenz J, Casey KL. Thermoreceptive innervation of human glabrous and hairy skin: a contact heat evoked potential analysis. Pain. 2005;115:238–47.PubMedCrossRefPubMedCentralGoogle Scholar
  87. 87.
    Itskovich VV, Fei DY, Harkins SW. Psychophysiological and psychophysical responses to experimental pain induced by two types of cutaneous thermal stimuli. Int J Neurosci. 2000;105:63–75.PubMedCrossRefPubMedCentralGoogle Scholar
  88. 88.
    Granovsky Y, Anand P, Nakae A, Nascimento O, Smith B, Sprecher E, et al. Normative data for Aδ contact heat evoked potentials in adult population: a multicenter study. Pain. 2016;157:1156–63.PubMedCrossRefPubMedCentralGoogle Scholar
  89. 89.
    Le Pera D, Valeriani M, Niddam D, Chen AC, Arendt-Nielsen L. Contact heat evoked potentials to painful and non-painful stimuli: effect of attention towards stimulus properties. Brain Topogr. 2002;15:115–23.PubMedCrossRefPubMedCentralGoogle Scholar
  90. 90.
    Howard MA, Coen SJ, Buchanan TJ, Smart TS, Gregory SL, Huggins JP, et al. Test-retest reproducibility of cerebral and subjective responses to painful and non-painful contact-heat evoked potential stimulation (CHEPS). Eur J Pain. 2006;10:S82–S82.CrossRefGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  1. 1.Peripheral Neuropathy Unit, Centre for Clinical Translation, Division of Brain SciencesImperial College London, Hammersmith HospitalLondonUK

Personalised recommendations