Architecture of the Cutaneous Autonomic Nervous System

Patrick Glatte, Sylvia J Buchmann, Mido Max Hijazi, Ben Min-Woo Illigens, Timo Siepmann, Patrick Glatte, Sylvia J Buchmann, Mido Max Hijazi, Ben Min-Woo Illigens, Timo Siepmann

Abstract

The human skin is a highly specialized organ for receiving sensory information but also to preserve the body's homeostasis. These functions are mediated by cutaneous small nerve fibers which display a complex anatomical architecture and are commonly classified into cutaneous A-beta, A-delta and C-fibers based on their diameter, myelinization, and velocity of conduction of action potentials. Knowledge on structure and function of these nerve fibers is relevant as they are selectively targeted by various autonomic neuropathies such as diabetic neuropathy or Parkinson's disease. Functional integrity of autonomic skin nerve fibers can be assessed by quantitative analysis of cutaneous responses to local pharmacological induction of axon reflex responses which result in dilation of cutaneous vessels, sweating, or piloerection depending on the agent used to stimulate this neurogenic response. Sensory fibers can be assessed using quantitative sensory test. Complementing these functional assessments, immunohistochemical staining of superficial skin biopsies allow analysis of structural integrity of cutaneous nerve fibers, a technique which has gained attention due to its capacity of detecting pathogenic depositions of alpha-synuclein in patients with Parkinson's disease. Here, we reviewed the current literature on the anatomy and functional pathways of the cutaneous autonomic nervous system as well as diagnostic techniques to assess its functional and structural integrity.

Keywords: C-fiber; Parkinson's disease; autonomic (vegetative) nervous system; autonomic neuropathy; axon-reflex; diabetes; punch skin biopsy; skin.

Figures

Figure 1
Figure 1
A simplified illustration of the general anatomy of the skin with the focus on autonomic nerve fibers and their innervated organs. Sweat glands, blood vessels and the arrector pili muscle are innervated by sympathetic C-fibers in the dermis. Afferent intraepidermal nerve fibers of the class C and Aδ are found in the epidermis as free nerve endings. Axon collaterals of these afferent fibers also supply blood vessels with efferent antidromic control. Small sensory fibers branch off from thicker dermal nerve bundles to create thinner subepidermal nerve bundles that innervate the epidermis.
Figure 2
Figure 2
Illustration of skin organs innervated by the autonomic nervous system with an axon reflex mediated in sudomotor nerve fibers by iontophoretic application of acetylcholine to the skin. Following a direct sweat response in the area of acetylcholine application, an action potential travels antidromically and then orthodromically to a neighboring population of sweat glands where it evokes “indirect” sweating in a skin region adjacent to the region of iontophoresis. Similar responses can be induced in pilomotor and vasomotor fibers. Their magnitude is a surrogate measure of functional integrity of the autonomic nerve fiber mediating the axon reflex.
Figure 3
Figure 3
Illustration of a punch skin biopsy on eccrine sweat glands to quantify the cholinergic sudomotor nerve fibers. The specimen is fixed, sectioned, and stained with antibodies for PGP 9,5 (the pan axonal marker), tyrosine hydroxylase (a sweat gland neuroendocrine cell marker), and VIP (a marker for sympathetic nerve fibers) to highlight the sought-after tissue. Further various quantitation methods are applied to assess the sweat gland nerve fiber density. Based on this technique pilomotor and vasomotor autonomic nerve fibers can be quantified by using suitable staining methods. A comparison of the determined nerve fiber density to those of normative datasets gives information about the functionality and condition of the autonomic nervous system innervating skin organs.

References

    1. Peters MJ, Bakkers M, Merkies IS, Hoeijmakers JG, van Raak EP, Faber CG. Incidence and prevalence of small-fiber neuropathy: a survey in the Netherlands. Neurology. (2013) 81:1356–60. 10.1212/WNL.0b013e3182a8236e
    1. Chan AC, Wilder-Smith EP. Small fiber neuropathy: getting bigger! Muscle Nerve. (2016) 53:671–82. 10.1002/mus.25082
    1. Freeman R. Autonomic peripheral neuropathy. Lancet. (2005) 365:1259–70. 10.1016/S0140-6736(05)74815-7
    1. Donadio V, Incensi A, Giannoccaro MP, Cortelli P, Stasi VD, Pizza F, et al. . Peripheral autonomic neuropathy: diagnostic contribution of skin biopsy. J Neuropathol Exp Neurol. (2012) 71:1000–8. 10.1097/NEN.0b013e3182729fdc
    1. Frerichs KU, Feuerstein GZ. Laser-Doppler flowmetry. A review of its application for measuring cerebral and spinal cord blood flow. Mol Chem Neuropathol. (1990) 12:55–70. 10.1007/BF03160057
    1. Illigens BMW, Siepmann T, Roofeh J, Gibbons CH. Laser-doppler imaging in the detection of peripheral neuropathy. Auton Neurosci. (2013) 177:286–90. 10.1016/j.autneu.2013.06.006
    1. Siepmann T, Gibbons CH, Illigens BM, Lafo JA, Brown CM, Freeman R. Quantitative Pilomotor axon-reflex test – a novel test of pilomotor function. Arch Neurol. (2012) 69:1488–92. 10.1001/archneurol.2012.1092
    1. Illigens BMW, Gibbons CH. Sweat testing to evaluate autonomic function. Clin Auton Res. (2009) 19:79–87. 10.1007/s10286-008-0506-8
    1. Doppler K, Ebert S, Uceyler N, Trenkwalder C, Ebentheuer J, Volkmann J, et al. . Cutaneous neuropathy in Parkinson's disease: a window into brain pathology. Acta Neuropathol. (2014) 128:99–109. 10.1007/s00401-014-1284-0
    1. Nolano M, Provitera V, Caporaso G, Stancanelli A, Leandri M, Biasiotta A, et al. . Cutaneous innervation of the human face as assessed by skin biopsy. J Anat. (2013) 222:161–9. 10.1111/joa.12001
    1. Siemionow M, Gharb BB, Rampazzo A. The face as a sensory organ. Plastic Reconstr Surg. (2011) 127:652–62. 10.1097/PRS.0b013e3181fed6fd
    1. Abraira VE, Ginty DD. The sensory neurons of touch. Neuron. (2013) 79:618–39. 10.1016/j.neuron.2013.07.051
    1. Roosterman D, Goerge T, Schneider SW, Bunnett NW, Steinhoff M. Neuronal control of skin function: the skin as a neuroimmunoendocrine organ. Physiol Rev. (2006) 86:1309–79. 10.1152/physrev.00026.2005
    1. Djouhri L. Aδ-fiber low threshold mechanoreceptors innervating mammalian hairy skin: a review of their receptive, electrophysiological and cytochemical properties in relation to Aδ-fiber high threshold mechanoreceptors. Neurosci Biobehav Rev. (2016) 61:225–38. 10.1016/j.neubiorev.2015.12.009
    1. Fleming MS, Luo W. The anatomy, function, and development of mammalian Aβ low-threshold mechanoreceptors. Front Biol. (2013) 8:408–20. 10.1007/s11515-013-1271-1
    1. Li L, Rutlin M, Abraira Victoria E, Cassidy C, Kus L, Gong S, et al. . The functional organization of cutaneous low-threshold mechanosensory neurons. Cell. (2011) 147:1615–27. 10.1016/j.cell.2011.11.027
    1. Roudaut Y, Lonigro A, Coste B, Hao J, Delmas P, Crest M. Touch sense: Functional organization and molecular determinants of mechanosensitive receptors. Channels. (2012) 6:234–45. 10.4161/chan.22213
    1. Fang X, McMullan S, Lawson SN, Djouhri L. Electrophysiological differences between nociceptive and non-nociceptive dorsal root ganglion neurones in the rat in vivo. J Physiol. (2005) 565:927–43. 10.1113/jphysiol.2005.086199
    1. Lawson SN. Phenotype and function of somatic primary afferent nociceptive neurones with C-, Aδ- or Aα/β-Fibres. Exp Physiol. (2002) 87:239–44. 10.1113/eph8702350
    1. Al-Horani RA, Mohammad M. The contribution of noradrenergic nerves to the vasoconstrictor response during local cooling of leg and forearm skin in humans. Gen Physiol Biophys. (2018) 37:33–40. 10.4149/gpb_2017021
    1. Vetrugno R, Liguori R, Cortelli P, Montagna P. Sympathetic skin response: basic mechanisms and clinical applications. Clin Auton Res. (2003) 13:256–70. 10.1007/s10286-003-0107-5
    1. Jenkinson DM, Montgomery I, Elder HY. Studies on the nature of the peripheral sudomotor control mechanism. J Anat. (1978) 125:625–39.
    1. Low PA, Caskey PE, Tuck RR, Fealey RD, Dyck PJ. Quantitative sudomotor axon reflex test in normal and neuropathic subjects. Ann Neurol. (1983) 14:573–80. 10.1002/ana.410140513
    1. Siepmann T, Frenz E, Penzlin AI, Goelz S, Zago W, Friehs I, et al. . Pilomotor function is impaired in patients with Parkinson's disease: a study of the adrenergic axon-reflex response and autonomic functions. Parkinsonism Relat Disord. (2016) 31:129–34. 10.1016/j.parkreldis.2016.08.001
    1. Sternini C. Organization of the peripheral nervous system: autonomic and sensory ganglia. J Investig Dermatol Symp Proc. (1997) 2:1–7. 10.1038/jidsymp.1997.2
    1. Van Hees J, Gybels J. C nociceptor activity in human nerve during painful and non painful skin stimulation. J Neurol Neurosurg Psychiatry. (1981) 44:600–7.
    1. Alvarez FJ, Fyffe REW. Nociceptors for the 21st Century. Curr Rev Pain. (2000) 4:451–8. 10.1007/s11916-000-0069-4
    1. Schmelz M, Schmidt R, Weidner C, Hilliges M, Torebjork EH, Handwerker H, et al. . Chemical response pattern of different classes of C-nociceptors to pruritogens and algogens. J Neurophysiol. (2003) 89:2441–8. 10.1152/jn.01139.2002
    1. Campero M, Bostock H. Unmyelinated afferents in human skin and their responsiveness to low temperature. Neurosci Lett. (2010) 470:188–92. 10.1016/j.neulet.2009.06.089
    1. Liljencrantz J, Olausson H. Tactile C fibers and their contributions to pleasant sensations and to tactile allodynia. Front Behav Neurosci. (2014) 8:37. 10.3389/fnbeh.2014.00037
    1. Triscoli C, Olausson H, Sailer U, Ignell H, Croy I. CT-optimized skin stroking delivered by hand or robot is comparable. Front Behav Neurosci. (2013) 7:208 10.3389/fnbeh.2013.00208
    1. Habig K, Schänzer A, Schirner W, Lautenschläger G, Dassinger B, Olausson H, et al. . Low threshold unmyelinated mechanoafferents can modulate pain. BMC Neurol. (2017) 17:184. 10.1186/s12883-017-0963-6
    1. Schmelz M, Schmidt R, Bickel A, Torebjörk HE, Handwerker HO. Innervation territories of single sympathetic C fibers in human skin. J Neurophysiol. (1998) 79:1653–60. 10.1152/jn.1998.79.4.1653
    1. Ertekin C, Ertekin N, Karcioglu M. Conduction velocity along human nociceptive reflex afferent nerve fibres. J Neurol Neurosurg Psychiatry. (1975) 38:959–65. 10.1136/jnnp.38.10.959
    1. Collongues N, Samama B, Schmidt-Mutter C, Chamard-Witkowski L, Debouverie M, Chanson J-B, et al. . Quantitative and qualitative normative dataset for intraepidermal nerve fibers using skin biopsy. PLoS ONE. (2018) 13:e0191614. 10.1371/journal.pone.0191614
    1. Obi T, Takatsu M, Yamazaki K, Kuroda R, Terada T, Mizoguchi K. Conduction velocities of Adelta-fibers and C-fibers in human peripheral nerves and spinal cord after CO2 laser stimulation. J Clin Neurophysiol. (2007) 24:294–7. 10.1097/WNP.0b013e318038f45f
    1. Li CL, Bak A. Excitability characteristics of the A- and C-fibers in a peripheral nerve. Exp Neurol. (1976) 50:67–79. 10.1016/0014-4886(76)90236-3
    1. Nolano M, Provitera V, Caporaso G, Stancanelli A, Vitale DF, Santoro L. Quantification of pilomotor nerves: a new tool to evaluate autonomic involvement in diabetes. Neurology. (2010) 75:1089–97. 10.1212/WNL.0b013e3181f39cf4
    1. Gibbons CH, Illigens BMW, Wang N, Freeman R. Quantification of sweat gland innervation: a clinical–pathologic correlation. Neurology. (2009) 72:1479–86. 10.1212/WNL.0b013e3181a2e8b8
    1. Gibbons CH, Illigens BMW, Wang N, Freeman R. Quantification of sudomotor innervation: a comparison of 3 methods. Muscle Nerve. (2010) 42:112–9. 10.1002/mus.21626
    1. Bjorklund H, Dalsgaard CJ, Jonsson CE, Hermansson A. Sensory and autonomic innervation of non-hairy and hairy human skin. An immunohistochemical study. Cell Tissue Res. (1986) 243:51–7. 10.1007/BF00221851
    1. Wang N, Gibbons CH. Chapter 30: Skin biopsies in the assessment of the autonomic nervous system. In: Buijs RM, Swaab DF, editors. Handbook of Clinical Neurology Vol. 117. Elsevier (2013). p. 371–8. 10.1016/B978-0-444-53491-0.00030-4
    1. Pereira MP, Mühl S, Pogatzki-Zahn EM, Agelopoulos K, Ständer S. Intraepidermal nerve fiber density: diagnostic and therapeutic relevance in the management of chronic pruritus: a review. Dermatol Therap. (2016) 6:509–17. 10.1007/s13555-016-0146-1
    1. Lauria G, Bakkers M, Schmitz C, Lombardi R, Penza P, Devigili G, et al. . Intraepidermal nerve fiber density at the distal leg: a worldwide normative reference study. J Periph Nervous Syst. (2010) 15:202–7. 10.1111/j.1529-8027.2010.00271.x
    1. Low PA. Evaluation of sudomotor function. Clin Neurophysiol. (2004) 115:1506–13. 10.1016/j.clinph.2004.01.023
    1. Guttmann L, Silver J, Wyndham CH. Thermoregulation in spinal man. J Physiol. (1958) 142:406–19. 10.1113/jphysiol.1958.sp006026
    1. Namer B, Bickel A, Kramer H, Birklein F, Schmelz M. Chemically and electrically induced sweating and flare reaction. Auton Neurosci. (2004) 114:72–82. 10.1016/j.autneu.2004.06.007
    1. Kubasch ML, Kubasch AS, Torres Pacheco J, Buchmann SJ, Illigens BM-W, Barlinn K, et al. . Laser doppler assessment of vasomotor axon reflex responsiveness to evaluate neurovascular function. Front Neurol. (2017) 8:370. 10.3389/fneur.2017.00370
    1. Ochoa J, Yarnitsky D, Marchettini P, Dotson R, Cline M. Interactions between sympathetic vasoconstrictor outflow and C nociceptor-induced antidromic vasodilatation. Pain. (1993) 54:191–6. 10.1016/0304-3959(93)90208-7
    1. Berghoff M, Kathpal M, Kilo S, Hilz MJ, Freeman R. Vascular and neural mechanisms of ACh-mediated vasodilation in the forearm cutaneous microcirculation. J Appl Physiol. (2002) 92:780–8. 10.1152/japplphysiol.01167.2000
    1. Siepmann T, Pintér A, Buchmann SJ, Stibal L, Arndt M, Kubasch AS, et al. . Cutaneous Autonomic Pilomotor Testing to Unveil the Role of Neuropathy Progression in Early Parkinson's Disease (CAPTURE PD): protocol for a multicenter study. Front Neurol. (2017) 8:212. 10.3389/fneur.2017.00212
    1. Dalsgaard C-J, Rydh M, Hægerstrand A. Cutaneous innervation in man visualized with protein gene product 9.5 (PGP 9.5) antibodies. Histochemistry. (1989) 92:385–90. 10.1007/BF00492495
    1. Bossaller C, Reither K, Hehlert-Friedrich C, Auch-Schwelk W, Graf K, Grafe M, et al. . In vivo measurement of endothelium-dependent vasodilation with substance P in man. Herz. (1992) 17:284–90.
    1. Anand P, Bloom SR, McGregor GP. Topical capsaicin pretreatment inhibits axon reflex vasodilatation caused by somatostatin and vasoactive intestinal polypeptide in human skin. Br J Pharmacol. (1983) 78:665–9. 10.1111/j.1476-5381.1983.tb09418.x
    1. Wong BJ, Tublitz NJ, Minson CT. Neurokinin-1 receptor desensitization to consecutive microdialysis infusions of substance P in human skin. J Physiol. (2005) 568:1047–56. 10.1113/jphysiol.2005.095372
    1. Lotti T, Hautmann G, Panconesi E. Neuropeptides in skin. J Am Academy Dermatol. (1995) 33:482–96. 10.1016/0190-9622(95)91395-5
    1. Laverdet B, Danigo A, Girard D, Laurent M, Demiot C, Alexis D. Skin innervation: important roles during normal and pathological cutaneous repair. Histol Histopathol. (2015). 30:875–92.
    1. Ashrafi M, Baguneid M, Bayat A. The role of neuromediators and innervation in cutaneous wound healing. Acta Derm Venereol. (2016) 96:587–94. 10.2340/00015555-2321
    1. Baloh RH. Mitochondrial dynamics and peripheral neuropathy. Neuroscientist. (2008) 14:12–8. 10.1177/1073858407307354
    1. Misra UK, Kalita J, Nair PP. Diagnostic approach to peripheral neuropathy. Ann Indian Acad Neurol. (2008) 11:89–97. 10.4103/0972-2327.41875
    1. Chung T, Prasad K, Lloyd TE. Peripheral neuropathy: clinical and electrophysiological considerations. Neuroimaging Clin N Am. (2014) 24:49–65. 10.1016/j.nic.2013.03.023
    1. Myers MI, Peltier AC, Li J. Evaluating dermal myelinated nerve fibers in skin biopsy. Muscle Nerve. (2013) 47:1–11. 10.1002/mus.23510
    1. Siepmann T, Penzlin AI, Illigens BM-W, Reichmann H. Should skin biopsies be performed in patients suspected of having Parkinson's Disease? Parkinson's Dis. (2017) 2017:6064974. 10.1155/2017/6064974
    1. Wang N, Gibbons CH, Lafo J, Freeman R. α-Synuclein in cutaneous autonomic nerves. Neurology. (2013) 81:1604–10. 10.1212/WNL.0b013e3182a9f449
    1. Doppler K, Jentschke H-M, Schulmeyer L, Vadasz D, Janzen A, Luster M, et al. . Dermal phospho-alpha-synuclein deposits confirm REM sleep behaviour disorder as prodromal Parkinson's disease. Acta Neuropathol. (2017) 133:535–45. 10.1007/s00401-017-1684-z
    1. Siepmann T, Illigens BM-W, Barlinn K. Alpha-synuclein in cutaneous small nerve fibers. Neuropsychiatr Dis Treat. (2016) 12:2731–5. 10.2147/NDT.S117423
    1. Vinik AI, Erbas T, Casellini CM. Diabetic cardiac autonomic neuropathy, inflammation and cardiovascular disease. J Diabetes Investig. (2013) 4:4–18. 10.1111/jdi.12042
    1. Freeman R. Diabetic autonomic neuropathy. Handbook Clin. Neurol. (2014) 126:63–79. 10.1016/B978-0-444-53480-4.00006-0
    1. Pop-Busui R, Evans GW, Gerstein HC, Fonseca V, Fleg JL, Hoogwerf BJ, et al. . Effects of Cardiac Autonomic Dysfunction on Mortality Risk in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Trial. Diabetes Care. (2010) 33:1578–84. 10.2337/dc10-0125
    1. Verrotti A, Prezioso G, Scattoni R, Chiarelli F. Autonomic neuropathy in diabetes mellitus. Front Endocrinol. (2014) 5:205. 10.3389/fendo.2014.00205
    1. Rolim LC, de Souza JST, Dib SA. Tests for early diagnosis of cardiovascular autonomic neuropathy: critical analysis and relevance. Front Endocrinol. (2013) 4:173. 10.3389/fendo.2013.00173
    1. Krishnan ST, Rayman G. The LDIflare: a novel test of C-fiber function demonstrates early neuropathy in type 2 diabetes. Diabetes Care. (2004) 27:2930–5. 10.2337/diacare.27.12.2930
    1. Callaghan BC, Xia R, Reynolds E, Banerjee M, Rothberg AE, Burant CF, et al. . Association between metabolic syndrome components and polyneuropathy in an obese population. JAMA Neurol. (2016) 73:1468–76. 10.1001/jamaneurol.2016.3745

Source: PubMed

Sponsorer och medarbetare

Medicinska tillstånd

Läkemedelsinterventioner

3
Prenumerera