Repeated transspinal stimulation decreases soleus H-reflex excitability and restores spinal inhibition in human spinal cord injury
Maria Knikou, Lynda M Murray, Maria Knikou, Lynda M Murray
Abstract
Transcutaneous spinal cord or transspinal stimulation over the thoracolumbar enlargement, the spinal location of motoneurons innervating leg muscles, modulates neural circuits engaged in the control of movement. The extent to which daily sessions (e.g. repeated) of transspinal stimulation affects soleus H-reflex excitability in individuals with chronic spinal cord injury (SCI) remains largely unknown. In this study, we established the effects of repeated cathodal transspinal stimulation on soleus H-reflex excitability and spinal inhibition in individuals with and without chronic SCI. Ten SCI and 10 healthy control subjects received monophasic transspinal stimuli of 1-ms duration at 0.2 Hz at subthreshold and suprathreshold intensities of the right soleus transspinal evoked potential (TEP). SCI subjects received an average of 16 stimulation sessions, while healthy control subjects received an average of 10 stimulation sessions. Before and one or two days post intervention, we used the soleus H reflex to assess changes in motoneuron recruitment, homosynaptic depression following single tibial nerve stimuli delivered at 0.1, 0.125, 0.2, 0.33 and 1.0 Hz, and postactivation depression following paired tibial nerve stimuli at the interstimulus intervals of 60, 100, 300, and 500 ms. Soleus H-reflex excitability was decreased in both legs in motor incomplete and complete SCI but not in healthy control subjects. Soleus H-reflex homosynaptic and postactivation depression was present in motor incomplete and complete SCI but was of lesser strength to that observed in healthy control subjects. Repeated transspinal stimulation increased homosynaptic depression in all SCI subjects and remained unaltered in healthy controls. Postactivation depression remained unaltered in all subject groups. Lastly, transspinal stimulation decreased the severity of spasms and ankle clonus. The results indicate decreased reflex hyperexcitability and recovery of spinal inhibitory control in the injured human spinal cord with repeated transspinal stimulation. Transspinal stimulation is a noninvasive neuromodulation method for restoring spinally-mediated afferent reflex actions after SCI in humans.
Conflict of interest statement
The authors have declared that no competing interests exist.
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References
- Knikou M, Conway BA. Reflex effects of induced muscle contraction in normal and spinal cord injured subjects. Muscle Nerve 2002; 26: 374–382. 10.1002/mus.10206
- Knikou M, Conway BA. Effects of electrically induced muscle contraction on flexion reflex in human spinal cord injury. Spinal Cord 2005; 43: 640–648. 10.1038/sj.sc.3101772
- Christiansen L, Perez MA. Targeted-plasticity in the corticospinal tract after human spinal cord injury. Neurotherapeutics 2018; 15: 618–627. 10.1007/s13311-018-0639-y
- Dimitrijevic MR, Gerasimenko Y, Pinter MM. Evidence for a spinal central pattern generator in humans. Ann N Y Acad Sci. 1998; 860: 360–376. 10.1111/j.1749-6632.1998.tb09062.x
- Harkema S, Gerasimenko Y, Hodes J, Burdick J, Angeli C, Chen Y. et al. Effect of epidural stimulation of the lumbosacral spinal cord on voluntary movement, standing, and assisted stepping after motor complete paraplegia: a case study. Lancet. 2011; 377: 1938–1947. 10.1016/S0140-6736(11)60547-3
- Hofstoetter US, Knikou M, Guertin PA, Minassian K. Probing the human spinal locomotor circuits by phasic step-induced feedback and by tonic electrical and pharmacological neuromodulation. Curr Pharm Des. 2017; 23: 1805–1820. 10.2174/1381612822666161214144655
- Knikou M. Neurophysiological characterization of transpinal evoked potentials in human leg muscles. Bioelectromagnetics. 2013; 34: 630–640. 10.1002/bem.21808
- Knikou M, Dixon L, Santora D, Ibrahim MM. Transspinal constant-current long-lasting stimulation: a new method to induce cortical and corticospinal plasticity. J Neurophysiol. 2015; 114: 1486–1499. 10.1152/jn.00449.2015
- Sayenko DG, Atkinson DA, Dy CJ, Gurley KM, Smith VL, Angeli C, et al. Spinal segment-specific transcutaneous stimulation differentially shapes activation pattern among motor pools in humans. J Appl Physiol. 2015; 118: 1364–1374. 10.1152/japplphysiol.01128.2014
- Murray LM, Knikou M. Transspinal stimulation increases motoneuron output of multiple segments in human spinal cord injury. PLoS One. 2019; 14(3): e0213696 10.1371/journal.pone.0213696
- Knikou M, Murray LM. Neural interactions between transspinal evoked potentials and muscle spindle afferents in humans. J Electromyogr Kinesiol. 2018; 43: 174–183. 10.1016/j.jelekin.2018.10.005
- Hofstoetter US, Krenn M, Danner SM, Hofer C, Kern H, McKay WB, et al. Augmentation of voluntary locomotor activity by transcutaneous spinal cord stimulation in motor-incomplete spinal cord-injured individuals. Artif Organs. 2015; 39: 176–186.
- Hofstoetter US, McKay WB, Tansey KE, Mayr W, Kern H, Minassian K. Modification of spasticity by transcutaneous spinal cord stimulation in individuals with incomplete spinal cord injury. J Spinal Cord Med. 2014; 37: 202–211. 10.1179/2045772313Y.0000000149
- Minassian K, Jilge B, Rattay F, Pinter MM, Binder H, Gerstenbrand F, et al. Stepping-like movements in humans with complete spinal cord injury induced by epidural stimulation of the lumbar cord: electromyographic study of compound muscle action potentials. Spinal Cord 2004; 42: 401–416. 10.1038/sj.sc.3101615
- Elbasiouny SM, Mushahwar VK. Modulation of motoneuronal firing behavior after spinal cord injury using intraspinal microstimulation current pulses: a modeling study. J Appl Physiol. 2007; 103: 276–286. 10.1152/japplphysiol.01222.2006
- Elbasiouny SM, Mushahwar VK. Suppressing the excitability of spinal motoneurons by extracellularly applied electrical fields: insights from computer simulations. J Appl Physiol. 2007; 103: 1824–1836. 10.1152/japplphysiol.00362.2007
- Murray LM, Knikou M. Remodeling brain activity by repetitive cervicothoracic transspinal stimulation after human spinal cord injury. Front Neurol. 2017; 8: 50 10.3389/fneur.2017.00050
- Knikou M. Transpinal and transcortical stimulation alter corticospinal excitability and increase spinal output. PLoS One. 2014; 9(7): e102313 10.1371/journal.pone.0102313
- Knikou M. Plantar cutaneous input modulates differently spinal reflexes in subjects with intact and injured spinal cord. Spinal Cord. 2007; 45: 69–77. 10.1038/sj.sc.3101917
- Knikou M. The H-reflex as a probe: pathways and pitfalls. J Neurosci Methods. 2008; 171: 1–12. 10.1016/j.jneumeth.2008.02.012
- Adams MM, Ginis KA, Hicks AL. The spinal cord injury spasticity evaluation tool: development and evaluation. Arch Phys Med Rehab. 2007; 88: 1185–1192. 10.1016/j.apmr.2007.06.012
- Savic G, Bergstrom EMK, Frankel HL, Jamous MA, Jones PW. Inter-rater reliability of motor and sensory examinations performed according to American Spinal Injury Association standards. Spinal Cord. 2007; 45: 444–451. 10.1038/sj.sc.3102044
- Klimstra M, Zehr EP. A sigmoid function is the best fit for the ascending limb of the Hoffmann reflex recruitment curve. Exp Brain Res. 2008; 186: 93–105. 10.1007/s00221-007-1207-6
- Smith AC, Rymer WZ, Knikou M. Locomotor training modifies soleus monosynaptic motoneuron responses in human spinal cord injury. Exp Brain Res. 2015; 233: 89–103. 10.1007/s00221-014-4094-7
- Grey MJ, Klinge K, Crone C, Lorentzen J, Biering-Sørensen F, Ravnborg M, et al. Post-activation depression of soleus stretch reflexes in healthy and spastic humans. Exp Brain Res. 2008; 185: 189–197. 10.1007/s00221-007-1142-6
- Eccles JC, Rall W. Effects induced in a monosynaptic reflex path by its activation. J Neurophysiol. 1951; 14: 353–376. 10.1152/jn.1951.14.5.353
- Crone C, Nielsen J. Methodological implications of the post activation depression of the soleus H-reflex in man. Exp Brain Res. 1989; 78: 28–32. 10.1007/bf00230683
- Hultborn H, Illert M, Nielsen J, Paul A, Ballegaard M, Wiese H. On the mechanism of the post-activation depression of the H-reflex in human subjects. Exp Brain Res. 1996; 108: 450–462. 10.1007/bf00227268
- Katz R, Morin C, Pierrot-Deseilligny E, Hibino R. Conditioning of H reflex by a preceding subthreshold tendon reflex stimulus. J Neurol Neurosurg Psychiatry. 1977; 40: 575–580. 10.1136/jnnp.40.6.575
- Lamy JC, Wargon I, Baret M, Ben Smail D, Milani P, Raoul S, et al. Post-activation depression in various group I spinal pathways in humans. Exp Brain Res. 2005; 166: 248–262. 10.1007/s00221-005-2360-4
- Côté MP, Murray LM, Knikou M. Spinal control of locomotion: individual neurons, their circuits and functions. Front Physiol. 2018; 9: 784 10.3389/fphys.2018.00784
- Lin S, Li Y, Lucas-Osma AM, Hari K, Stephens MJ, Singla R, et al. Locomotor-related V3 interneurons initiate and coordinate muscles spasms after spinal cord injury. J Neurophysiol. 2019; 121: 1352–1367. 10.1152/jn.00776.2018
- Aymard C, Katz R, Lafitte C, Lo E, Pénicaud A, Pradat-Diehl P, et al. Presynaptic inhibition and homosynaptic depression: a comparison between lower and upper limbs in normal human subjects and patients with hemiplegia. Brain. 2000; 123: 1688–1702. 10.1093/brain/123.8.1688
- Schindler-Ivens S, Shields RK. Low frequency depression of H-reflexes in humans with acute and chronic spinal-cord injury. Exp Brain Res. 2000; 133: 233–241. 10.1007/s002210000377
- Knikou M. Hip-phase-dependent flexion reflex modulation and expression of spasms in patients with spinal cord injury. Exp Neurol. 2007; 204: 171–181. 10.1016/j.expneurol.2006.10.006
- Norton JA, Bennett DJ, Knash ME, Murray KC, Gorassini MA. Changes in sensory-evoked synaptic activation of motoneurons after spinal cord injury in man. Brain. 2008; 131: 1478–1491. 10.1093/brain/awn050
- D’Amico JM, Murray KC, Li Y, Chan KM, Finlay MG, Bennett DJ, et al. Constitutively active 5-HT2/α1 receptors facilitate muscle spasms after human spinal cord injury. J Neurophysiol. 2013; 109:1473–1484. 10.1152/jn.00821.2012
- ElBasiouny SM, Schuster JE, Heckman CJ. Persistent inward currents in spinal motoneurons: important for normal function but potentially harmful after spinal cord injury and in amyotrophic lateral sclerosis. Clin Neurophysiol. 2010; 121: 1669–1679. 10.1016/j.clinph.2009.12.041
- Kim H. Impact of the localization of dendritic calcium persistent inward current on the input-output properties of spinal motoneuron pool: a computational study. J Appl Physiol. 2017; 123: 1166–1187. 10.1152/japplphysiol.00034.2017
- Hunter JP, Ashby P. Segmental effects of epidural spinal cord stimulation in humans. J Physiol. 1994; 474: 407–419. 10.1113/jphysiol.1994.sp020032
- Tsentsevitsky A, Nurullin L, Nikolsky E, Malomouzh A. Metabotropic and ionotropic glutamate receptors mediate the modulation of acetylcholine release at the frog neuromuscular junction. J Neurosci Res. 2017; 95: 1391–1401. 10.1002/jnr.23977
- Trussell LO, Zhang S, Raman IM. Desensitization of AMPA receptors upon multiquantal neurotransmitter release. Neuron. 1993; 10: 1185–1196. 10.1016/0896-6273(93)90066-z
- Frischknecht R, Heine M, Perrais D, Seidenbecher CI, Choquet D, Gundelfinger ED. Brain extracellular matrix affects AMPA receptor lateral mobility and short-term synaptic plasticity. Nat Neurosci. 2009; 12: 897–904. 10.1038/nn.2338
- Eccles JC, O’Connor WJ. Abortive impulses at the neuro-muscular junction. J Physiol Lond. 1941; 100: 318–328. 10.1113/jphysiol.1941.sp003945
- Bergmans J. Spontaneous activity of single nerve fibres induced by repetitive activation. Arch Int Physiol Biochim. 1969; 77: 354–356.
- Táboriková H, Sax DS. Conditioning of H-reflexes by a preceding subthreshold H-reflex stimulus. Brain. 1969; 92: 203–212. 10.1093/brain/92.1.203
- Eccles JC, Sasaki K, Strata P. Interpretation of the potential fields generated in the cerebellar cortex by a mossy fibre volley. Exp Brain Res. 1967; 3: 58–80. 10.1007/bf00234470
- Chofflon M, Lachat JM, Rüegg DG. A transcortical loop demonstrated by stimulation of low-threshold muscle afferents in the awake monkey. J Physiol Lond. 1982; 323: 393–402. 10.1113/jphysiol.1982.sp014079
- Knikou M, Mummidisetty CK. Locomotor training improves premotoneuronal control after chronic spinal cord injury. J Neurophysiol. 2014; 111: 2264–2275. 10.1152/jn.00871.2013
- Knikou M. Functional reorganization of soleus H-reflex modulation during stepping after robotic-assisted step training in people with complete and incomplete spinal cord injury. Exp Brain Res. 2013; 228: 279–296. 10.1007/s00221-013-3560-y
- Knikou M. Neural control of locomotion and training-induced plasticity after spinal and cerebral lesions. Clin Neurophysiol. 2010; 121: 1655–1668. 10.1016/j.clinph.2010.01.039
- Côté MP, Azzam GA, Lemay MA, Zhukareva V, Houlé JD. Activity-dependent increase in neurotrophic factors is associated with an enhanced modulation of spinal reflexes after spinal cord injury. J Neurotrauma. 2011; 28: 299–309. 10.1089/neu.2010.1594
- Côté MP, Gandhi S, Zambrotta M, Houlé JD. Exercise modulates chloride homeostasis after spinal cord injury. J Neurosci. 2014; 34: 8976–8987. 10.1523/JNEUROSCI.0678-14.2014
- Wang Y, Pillai S, Wolpaw JR, Chen XY. Motor learning changes GABAergic terminals on spinal motoneurons in normal rats. Eur J Neurosci. 2006; 23: 141–150. 10.1111/j.1460-9568.2005.04547.x
- Wang Y, Pillai S, Wolpaw JR, Chen XY. H-reflex down-conditioning greatly increases the number of identifiable GABAergic interneurons in rat ventral horn. Neurosci Lett. 2009; 452: 124–129. 10.1016/j.neulet.2009.01.054
- Thompson AK, Pomerantz FR, Wolpaw JR. Operant conditioning of a spinal reflex can improve locomotion after spinal cord injury in humans. J Neurosci. 2013; 33: 2365–2375. 10.1523/JNEUROSCI.3968-12.2013
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