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Human Physiology

, Volume 45, Issue 5, pp 557–564 | Cite as

Serotonergic Mechanisms in Locomotor Effects of Electrical Spinal Cord Stimulation

  • I. A. Sukhotina
  • T. R. MoshonkinaEmail author
REVIEWS
  • 18 Downloads

Abstract

Electrical stimulation of the spinal cord (ESSC) is a method enabling researchers to confirm the existence of the stepping movement generator in humans. Currently, the ESSC-based technologies of motor rehabilitation of patients immobilized after spinal cord injury are actively developing. The impact of the serotonergic system in the organization of movement is intensively studied both at the systemic and the molecular–cellular level in a large number of researches. The aim of this review was to analyze the current experimental data on the participation of serotonergic system in the locomotor activity control at the spinal level with a focus on the processes related to electrical stimulation of spinal locomotor networks. Special interest is given to the serotonin-based regulation of human motor activity. The data on the use of serotonin-modulating pharmacotherapy for increasing the efficacy of the ESSC method in locomotor rehabilitation are presented in the final part of the review.

Keywords:

spinal cord 5-HT serotonergic system electrical stimulation rehabilitation 

Notes

ACKNOWLEDGMENTS

The authors thank Yu. P. Gerasimenko, Corresponding Member of the Russian Academy of Sciences (RAS), for recommendations in the selection of materials for the review and I. B. Kozlovskaya, Corresponding Member of the RAS, for advices and help in editing the text.

FUNDING

The study was supported by the Russian Foundation for Basic Research, project no. 16-29-08277.

CONFLICT OF INTERESTS

The authors declare the absence of obvious and potential conflicts of interests associated with the publication of this review.

REFERENCES

  1. 1.
    Hofstoetter, U.S., Krenn, M., Danner, S.M., et al., Augmentation of voluntary locomotor activity by transcutaneous spinal cord stimulation in motor-incomplete spinal cord-injured individuals, Artif. Organs, 2015, vol. 39, p. E176.PubMedCrossRefGoogle Scholar
  2. 2.
    Shah, P.K. and Gerasimenko, Y., Multi-site spinal stimulation strategies to enhance locomotion after paralysis, Neural Regener. Res., 2016, vol. 11, no. 12, p. 1926.CrossRefGoogle Scholar
  3. 3.
    Gad, P., Gerasimenko, Y., Zdunowski, S., et al., Weight bearing over-ground stepping in an exoskeleton with non-invasive spinal cord neuromodulation after motor complete paraplegia, Front. Neurosci., 2017, vol. 11, p. 333.PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Gill, M.L., Grahn, P.J., Calvert, J.S., et al., Neuromodulation of lumbosacral spinal networks enables independent stepping after complete paraplegia, Nat. Med., 2018, vol. 24, no. 11, p. 1677.PubMedCrossRefGoogle Scholar
  5. 5.
    Lobov, G.I., shccherbakova, N.A., Gorodnichev, R.M., et al., Effect of transcutaneous electrical spinal cord stimulation on the blood flow in the skin of lower limbs, Hum. Physiol., 2017, vol. 43, no. 5, p. 518.CrossRefGoogle Scholar
  6. 6.
    Minyaeva, A.V., Moiseev, S.A., Pukhov, A.M., et al., Dependence of respiratory reaction on the intensity of locomotor response to transcutaneous electrical stimulation of the spinal cord, Hum. Physiol., 2019, vol. 45, no. 3, p. 262.CrossRefGoogle Scholar
  7. 7.
    Gad, P., Kreydin, E., Zhong, H., et al., Non-invasive neuromodulation of spinal cord restores lower urinary tract function after paralysis, Front. Neurosci., 2018, vol. 12, p. 432.PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Ikoeva, G.A., Nikityuk, I.E., Kivoenko, O.I., et al., Clinical-neurological and neurophysiological assessment of the efficiency of locomotor rehabilitation in children with cerebral palsy using robotic mechanotherapy and transcutaneous electrical stimulation of the spinal cord, Ortop., Travmatol. Vosstanovittel’naya Khir. Detskogo Vozrasta, 2016, vol. 4, no. 4, p. 47.Google Scholar
  9. 9.
    Bogacheva, I.N., Moshonkina, T.R., Savokhin, A.A., et al., Effects of transcutaneous electrical spinal cord stimulation on stepping patterns during walking, Hum. Physiol., 2017, vol. 43, no. 5, p. 512.CrossRefGoogle Scholar
  10. 10.
    Solopova, I.A., Sukhotina, I.A., Zhvansky, D.S., et al., Effects of spinal cord stimulation on motor functions in children with cerebral palsy, Neurosci. Lett., 2017, vol. 639, no. 3, p. 192.PubMedCrossRefGoogle Scholar
  11. 11.
    Gerasimenko, Yu.P., Moshonkina, T.R., Pavlova, N.V., et al., Morphofunctional studies of the involvement of the serotoninergic system in the control of postural and locomotor functions, Neurosci. Behav. Physiol., 2014, vol. 44, no. 8, p. 967.CrossRefGoogle Scholar
  12. 12.
    Musienko, P., van den Brand, R., Maerzendorfer, O., et al., Controlling specific locomotor behaviors through multidimensional monoaminergic modulation of spinal circuitries, J. Neurosci., 2011, vol. 31, p. 9262.CrossRefGoogle Scholar
  13. 13.
    Moshonkina, T.R., Shapkova, E.Yu., Sukhotina, I.A., et al., Effect of combination of non-invasive spinal cord electrical stimulation and serotonin receptor activation in patients with chronic spinal cord lesion, Bull. Exp. Biol. Med., 2016, vol. 161, no. 6, p. 749.PubMedCrossRefGoogle Scholar
  14. 14.
    Perrier, J.F., Modulation of motoneuron activity by serotonin, Dan. Med. J., 2016, vol. 63, no. 2, p. B5204.PubMedGoogle Scholar
  15. 15.
    Hochman, S., Garraway, S.M., Machacek, D.W., and Shay, B.L., 5-HT receptors and the neuromodulatory control of spinal cord function, in Motor Neurobiology of the Spinal Cord, Cope, T.C., Ed., Boca Raton: CRC Press, 2001, p. 47.Google Scholar
  16. 16.
    Ghosh, M. and Pearse, D.D., The role of the serotonergic system in locomotor recovery after spinal cord injury, Front. Neural Circ., 2015, vol. 8, p. 151.Google Scholar
  17. 17.
    Hornung, J.P., The human raphe nuclei and the serotonergic system, J. Chem. Neuroanat., 2003, vol. 26, no. 4, p. 331.PubMedCrossRefGoogle Scholar
  18. 18.
    Beliveau, V., Svarer, C., Frokjaer, V.G., et al., Functional connectivity of the dorsal and median raphe nuclei at rest, NeuroImage, 2015, vol. 116, no. 1, p. 187.PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Branchereau, P., Chapron, J., and Meyrand, P., Descending 5-hydroxytryptamine raphe inputs repress the expression of serotonergic neurons and slow the maturation of inhibitory systems in mouse embryonic spinal cord, J. Neurosci., 2002, vol. 22, no. 7, p. 2598.PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Wienecke, J., Ren, L.Q., Hultborn, H., et al., Spinal cord injury enables aromatic L-amino acid decarboxylase cells to synthesize monoamines, J. Neurosci., 2014, vol. 34, no. 36, p. 11984.PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Pavlova, N.V., Moshonkina, T.R., Gilerovich, E.G., and Gerasimenko, Yu.P., Histological study of serotonergic structures in the rat spinal cord in normal and after complete transection, Trudy VII Vserossiiskoi Shkoly-konferentsii s mezhdunarodnym uchastiem po fiziologii myshts i myshechnoi deyatel’nosti “Novye podkhody k izucheniyu klassicheskikh problem,” Moskva, 29 yanvarya–1 fevralya 2013 g. (Proc. VII All-Russ. School-Conf. with Int. Participation on Physiology of Muscles and Muscular Activity “New Approaches to the Study of Traditional Problems,” Moscow, January 29–February 1, 2013), Moscow, 2013, p. 59.Google Scholar
  22. 22.
    Perrin, F.E., Gerber, Y.N., Teigell, M., et al., Anatomical study of serotonergic innervation and 5-HT1A receptor in the human spinal cord, Cell Death Dis., 2011, vol. 13, no. 2, p. e218.CrossRefGoogle Scholar
  23. 23.
    García-Ramírez, D.L., Calvo, J.R., Hochman, S., and Quevedo, J.N., Serotonin, dopamine and noradrenaline adjust actions of myelinated afferents via modulation of presynaptic inhibition in the mouse spinal cord, PLoS One, 2014, vol. 9, no. 2, p. e89999.PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Tomilovskaya, E.S., Moshonkina, T.R., Gorodnichev, R.M., et al., Mechanical stimulation of the support zones of soles: the method of noninvasive activation of the stepping movement generators in humans, Hum. Physiol., 2013, vol. 39, no. 5, p. 480.CrossRefGoogle Scholar
  25. 25.
    Shcherbakova, N.A., Moshonkina, T.R., Savohin, A.A., et al., Noninvasive method to control the human spinal locomotor systems, Hum. Physiol., 2016, vol. 42, no. 1, p. 61.CrossRefGoogle Scholar
  26. 26.
    Gerasimenko, Y.P., McKinney, Z., Sayenko, D.G., et al., Spinal and sensory neuromodulation of spinal neuronal networks in humans, Hum. Physiol., 2017, vol. 43, no. 5, p. 492.CrossRefGoogle Scholar
  27. 27.
    Gerasimenko, Y., Gorodnichev, R., Moshonkina, T., et al., Transcutaneous electrical spinal-cord stimulation in humans, Ann. Phys. Rehabil. Med., 2015, vol. 58, p. 225.PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    D’Amico, J.M., Butler, A.A., Héroux, M.E., et al., Human motoneurone excitability is depressed by activation of serotonin 1A receptors with buspirone, J. Physiol., 2017, vol. 595, no. 5, p. 1763.PubMedCrossRefGoogle Scholar
  29. 29.
    Zuchner, M., Kondratskaya, E., Sylte, C.B., et al., Rapid recovery and altered neurochemical dependence of locomotor central pattern generation following lumbar neonatal spinal cord injury, J. Physiol., 2018, vol. 596, no. 2, p. 281.PubMedCrossRefGoogle Scholar
  30. 30.
    Jacobs, B.L. and Fornal, C.A., 5-HT and motor control: a hypothesis, Trends Neurosci., 1993, vol. 16, p. 346.PubMedCrossRefGoogle Scholar
  31. 31.
    Cervantes-Durán, C., Rocha-González, H.I., and Granados-Soto, V., Peripheral and spinal 5-HT receptors participate in the pronociceptive and antinociceptive effects of fluoxetine in rats, Neuroscience, 2013, vol. 252, p. 396.PubMedCrossRefGoogle Scholar
  32. 32.
    D’Amico, J.M., Condliffe, E.G., Martins, K.J.B., et al., Recovery of neuronal and network excitability after spinal cord injury and implications for spasticity, Front. Integr. Neurosci., 2014, vol. 8, p. 36.PubMedPubMedCentralGoogle Scholar
  33. 33.
    Perrier, J.F., If serotonin does not exhaust you, it makes you stronger, J. Physiol., 2019, vol. 597, no. 1 P. 5.PubMedCrossRefGoogle Scholar
  34. 34.
    Kavanagh, J.J., McFarland, A.J., and Taylor, J.L., Enhanced availability of serotonin increases activation of unfatigued muscle but exacerbates central fatigue during prolonged sustained contractions, J. Physiol., 2019, vol. 597, no. 1. P. 319.PubMedCrossRefGoogle Scholar
  35. 35.
    Alvarez, F.J., Pearson, J.C., Harrington, D., et al., Distribution of 5-hydroxytryptamine-immunoreactive boutons on alpha-motoneurons in the lumbar spinal cord of adult cats, J. Comp. Neurol., 1998, vol. 393, no. 1, p. 69.PubMedCrossRefGoogle Scholar
  36. 36.
    McCorvy, J.D. and Roth, B.L., Structure and function of serotonin G protein-coupled receptors, Pharmacol. Ther., 2015, vol. 150, p. 129.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Maroteaux, L., Ayme-Dietrich, E., Aubertin-Kirch, G., et al., New therapeutic opportunities for 5‑HT2 receptor ligands, Pharmacol. Ther., 2017, vol. 170, p. 14.PubMedCrossRefGoogle Scholar
  38. 38.
    Mosesso, R. and Dougherty, D.A., A triad of residues is functionally transferable between 5-HT3 serotonin receptors and nicotinic acetylcholine receptors, J. Biol. Chem., 2018, vol. 293, no. 8, p. 2903.PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Giulietti, M., Vivenzio, V., Piva, F., et al., How much do we know about the coupling of G-proteins to serotonin receptors, Mol. Brain, 2014, vol. 7, p. 49.PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Palacios, J.M., Pazos, A., and Hoyer, D., A short history of the 5-HT2C receptor: from the choroid plexus to depression, obesity and addiction treatment, Psychopharmacology, 2017, vol. 234, no. 9–10, p. 1395.PubMedCrossRefGoogle Scholar
  41. 41.
    Palacios, J.M., Serotonin receptors in brain revisited, Brain Res., 2016, vol. 1645, p. 46.PubMedCrossRefGoogle Scholar
  42. 42.
    Chagraoui, A., Thibaut, F., Skiba, M., et al., 5-HT2C receptors in psychiatric disorders, Prog. Neuro-Psychopharmacol. Biol. Psychiatry, 2016, vol. 66, p. 120.CrossRefGoogle Scholar
  43. 43.
    Beliveau, V., Ganz, M., Feng, L., et al., A high-resolution in vivo atlas of the human brain’s serotonin system, J. Neurosci., 2017, vol. 37, no. 1, p. 120.PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Perrier, J.F., Rasmussen, H.B., Jorgensen, L.K., and Berg, R.W., Intense activity of the raphe spinal pathway depresses motor activity via a serotonin dependent mechanism, Front. Neural Circ., 2018, vol. 11, p. 111.CrossRefGoogle Scholar
  45. 45.
    Miazga, K., Fabczak, H., Joachimiak, E., et al., Intraspinal grafting of serotonergic neurons modifies expression of genes important for functional recovery in paraplegic rats, Neural Plast., 2018, vol. 2018, art. ID 4232706.PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Castro, M.E., Pascual, J., Romón, T., et al., Differential distribution of [3H] sumatriptan binding sites (5-HT1B, 5-HT1D and 5-HT1F receptors) in human brain: focus on brainstem and spinal cord, Neuropharmacology, 1997, vol. 36, p. 535.PubMedCrossRefGoogle Scholar
  47. 47.
    Schmidt, B.J. and Jordan, L.M., The role of serotonin in reflex modulation and locomotor rhythm production in the mammalian spinal cord, Brain Res. Bull., 2000, vol. 53, p. 689.PubMedCrossRefGoogle Scholar
  48. 48.
    Sławińska, U. and Jordan, L.M., Serotonergic influences on locomotor circuits, Curr. Opin. Physiol., 2019, vol. 8, p. 63.CrossRefGoogle Scholar
  49. 49.
    Gerasimenko, Y., Musienko, P., Bogacheva, I., et al., Propriospinal bypass of the serotonergic system that can facilitate stepping, J. Neurosci., 2009, vol. 29, no. 17, p. 5681.PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Sławińska, U., Miazga, K., and Jordan, L.M., 5-HT2 and 5-HT7 receptor agonists facilitate plantar stepping in chronic spinal rats through actions on different populations of spinal neurons, Front. Neural Circ., 2014, vol. 8, p. 95.Google Scholar
  51. 51.
    Sławińska, U., Miazga, K., and Jordan, L.M., The role of serotonin in the control of locomotor movements and strategies for restoring locomotion after spinal cord injury, Acta Neurobiol. Exp., 2014, vol. 74, no. 2, p. 172.Google Scholar
  52. 52.
    D’Amico, J.M., Murray, K.C., Li, Y., et al., Constitutively active 5-HT2/α1 receptors facilitate muscle spasms after human spinal cord injury, J. Neurophysiol., 2013, vol. 109, p. 1473.PubMedCrossRefGoogle Scholar
  53. 53.
    Perrier, J.F. and Cotel, F., Serotonergic modulation of spinal motor control, Curr. Opin. Neurobiol., 2015, vol. 33, p. 1.PubMedCrossRefGoogle Scholar
  54. 54.
    Cabaj, A.M., Majczyński, H., Couto, E., et al., Serotonin controls initiation of locomotion and afferent modulation of coordination via 5-HT7 receptors in adult rats, J. Physiol., 2017, vol. 595, no. 1, p. 301.PubMedCrossRefGoogle Scholar
  55. 55.
    Dimitrijevic, M.R., Gerasimenko, Y., and Pinter, M.M., Evidence for a spinal central pattern generator in humansa, Ann. N. Y. Acad. Sci., 1998, vol. 860, no. 1, p. 360.PubMedCrossRefGoogle Scholar
  56. 56.
    Gorodnichev, R.M., Pivovarova, E.A., Puhov, A., et al., Transcutaneous electrical stimulation of the spinal cord: a noninvasive tool for the activation of stepping pattern generators in humans, Hum. Physiol., 2012, vol. 38, no. 2, p. 158.CrossRefGoogle Scholar
  57. 57.
    Gerasimenko, Y.P., Lu, D.C., Modaber, M., et al., Noninvasive reactivation of motor descending control after paralysis, J. Neurotrauma, 2015, vol. 32, no. 24, p. 1968.PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Wagner, F.B., Mignardot, J.B., Le Goff-Mignardot, C.G., et al., Targeted neurotechnology restores walking in humans with spinal cord injury, Nature, 2018, vol. 563, no. 7729, p. 65.PubMedCrossRefGoogle Scholar
  59. 59.
    Gerasimenko, Y.P., Ichiyama, R.M., Lavrov, I.A., et al., Epidural spinal cord stimulation plus quipazine administration enable stepping in complete spinal adult rats, J. Neurophysiol., 2007, vol. 98, no. 5, p. 2525.PubMedCrossRefGoogle Scholar
  60. 60.
    Musienko, P.E., Spinal-stem mechanisms of integrative control of posture and locomotion, Extended Abstract of Doctoral (Med.) Dissertation, Moscow: Pavlov Inst. Physiol., Russ. Acad. Sci., 2014.Google Scholar
  61. 61.
    Jeffrey-Gauthier, R., Josset, N., Bretzner, F., and Leblond, H., Facilitation of locomotor spinal networks activity by buspirone after a complete spinal cord lesion in mice, J. Neurotrauma, 2018, vol. 35, no. 18, p. 2208.PubMedCrossRefGoogle Scholar
  62. 62.
    Guertin, P.A., Rationale for assessing safety and efficacy of drug candidates alone and in combination with medical devices: the case study of SpinalonTM, Curr. Pharm. Des., 2017, vol. 23, no. 12, p. 1778.PubMedCrossRefGoogle Scholar
  63. 63.
    Radhakrishna, M., Steuer, I., Prince, F., et al., Double-blind, placebo-controlled, randomized phase I/IIa study (safety and efficacy) with buspirone/levodopa/carbidopa (SpinalonTM) in subjects with complete AIS A or motor-complete AIS B spinal cord injury, Curr. Pharm. Des., 2017, vol. 23, no. 12, p. 1789.PubMedCrossRefGoogle Scholar
  64. 64.
    Minev, I.R., Musienko, P., Hirsch, A., et al., Electronic dura mater for long-term multimodal neural interfaces, Science, 2015, vol. 347, no. 6218, p. 159.PubMedCrossRefGoogle Scholar
  65. 65.
    Bloch, J., Lacour, S.P., and Courtine, G., Electronic dura mater meddling in the central nervous system, J.A.M.A. Neurol., 2017, vol. 74, no. 4, p. 470.Google Scholar
  66. 66.
    Capogrosso, M., Gandar, J., Greiner, N., et al., Advantages of soft subdural implants for the delivery of electrochemical neuromodulation therapies to the spinal cord, J. Neural. Eng., 2018, vol. 15, no. 2, p. 026024.PubMedCrossRefGoogle Scholar
  67. 67.
    Nagel, S.J., Reddy, C.G., Frizon, L.A., et al., Spinal dura mater: biophysical characteristics relevant to medical device development, J. Med. Eng. Technol., 2018, vol. 42, no. 2, p. 128.PubMedCrossRefGoogle Scholar

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© Pleiades Publishing, Inc. 2019

Authors and Affiliations

  1. 1.Pavlov First State Medical UniversitySt. PetersburgRussia
  2. 2.Pavlov Institute of Physiology, Russian Academy of SciencesSt. PetersburgRussia

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