[Abstract + References] Improving Stroke Rehabilitation with Vagus Nerve Stimulation

Abstract

Stroke is a leading cause of neurological damage, with an estimated 795,000 cases reported in the United States each year. A large percentage of patients who suffer a stroke exhibit long-term impairments in motor function. Poststroke rehabilitation in part aims to promote adaptive changes in neural circuits to support recovery of function, but insufficient or maladaptive plasticity often limits benefits. Adjunctive strategies that support plasticity in conjunction with rehabilitation represent a potential means to improve recovery after stroke. Vagus nerve stimulation (VNS) has emerged as one such targeted plasticity strategy, providing phasic activation of neuromodulatory nuclei associated with plasticity. Repeatedly pairing brief bursts of VNS with motor training drives robust, specific plasticity in neural circuits. A number of studies in animal models of stroke and neurological injury demonstrate that VNS paired with rehabilitative training improves recovery of motor function. Moreover, emerging evidence from clinical trials indicates that VNS delivered during rehabilitation promotes functional recovery in stroke patients. Here, we provide a discussion of the existing literature of VNS-based targeted plasticity therapies in the context of stroke and outline challenges for clinical implementation.

References

1. 1.
   Benjamin EJ, Blaha MJ, Chiuve SE, Cushman M, Das SR, Deo R, de Ferranti SD, Floyd J, Fornage M, Gillespie C, Isasi CR, Jimenez MC, Jordan LC, Judd SE, Lackland D, Lichtman JH, Lisabeth L, Liu S, Longenecker CT, Mackey RH, Matsushita K, Mozaffarian D, Mussolino ME, Nasir K, Neumar RW, Palaniappan L, Pandey DK, Thiagarajan RR, Reeves MJ, Ritchey M, Rodriguez CJ, Roth GA, Rosamond WD, Sasson C, Towfighi A, Tsao CW, Turner MB, Virani SS, Voeks JH, Willey JZ, Wilkins JT, Wu JH, Alger HM, Wong SS, Muntner P, American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics-2017 update: a report from the American Heart Association. Circulation. 2017;135:e146–603.CrossRefPubMedPubMedCentralGoogle Scholar
2. 2.
   Dobkin BH. Strategies for stroke rehabilitation. Lancet Neurol. 2004;3:528–36.CrossRefPubMedPubMedCentralGoogle Scholar
3. 3.
   Dobkin BH. Rehabilitation after stroke. N Engl J Med. 2005;352:1677–84.CrossRefPubMedPubMedCentralGoogle Scholar
4. 4.
   Lai S, Studenski S, Duncan PW, Perera S. Persisting consequences of stroke measured by the stroke impact scale. Stroke. 2002;33:1840–4.CrossRefPubMedGoogle Scholar
5. 5.
   Calautti C, Baron J. Functional neuroimaging studies of motor recovery after stroke in adults a review. Stroke. 2003;34:1553–66.CrossRefPubMedGoogle Scholar
6. 6.
   Nudo R, Friel K. Cortical plasticity after stroke: implications for rehabilitation. Rev Neurol. 1999;155:713.PubMedGoogle Scholar
7. 7.
   Zhang J, Meng L, Qin W, Liu N, Shi FD, Yu C. Structural damage and functional reorganization in ipsilesional m1 in well-recovered patients with subcortical stroke. Stroke. 2014;45:788–93.CrossRefPubMedGoogle Scholar
8. 8.
   Liepert J, Miltner W, Bauder H, Sommer M, Dettmers C, Taub E, Weiller C. Motor cortex plasticity during constraint-induced movement therapy in stroke patients. Neurosci Lett. 1998;250:5–8.CrossRefPubMedGoogle Scholar
9. 9.
   Hallett M. Plasticity of the human motor cortex and recovery from stroke. Brain Res Rev. 2001;36:169–74.CrossRefPubMedGoogle Scholar
10. 10.
    Englot DJ, Rolston JD, Wright CW, Hassnain KH, Chang EF. Rates and predictors of seizure freedom with vagus nerve stimulation for intractable epilepsy. Neurosurgery. 2016;79:345–53.CrossRefPubMedGoogle Scholar
11. 11.
    Heck C, Helmers SL, DeGiorgio CM. Vagus nerve stimulation therapy, epilepsy, and device parameters scientific basis and recommendations for use. Neurology. 2002;59:S31–7.CrossRefPubMedGoogle Scholar
12. 12.
    Hays SA. Enhancing rehabilitative therapies with vagus nerve stimulation. Neurotherapeutics. 2016;13(2):382–94.CrossRefPubMedGoogle Scholar
13. 13.
    Hulsey DR, Riley JR, Loerwald KW, Rennaker RL, Kilgard MP, Hays SA. Parametric characterization of neural activity in the locus coeruleus in response to vagus nerve stimulation. Exp Neurol. 2016;Google Scholar
14. 14.
    Hulsey DR, Hays SA, Khodaparast N, Ruiz A, Das P, Rennaker RL, Kilgard MP. Reorganization of motor cortex by vagus nerve stimulation requires cholinergic innervation. Brain Stimul. 2016;9(2):174–81.CrossRefPubMedPubMedCentralGoogle Scholar
15. 15.
    Nichols J, Nichols A, Smirnakis S, Engineer N, Kilgard M, Atzori M. Vagus nerve stimulation modulates cortical synchrony and excitability through the activation of muscarinic receptors. Neuroscience. 2011;189:207–14.CrossRefPubMedGoogle Scholar
16. 16.
    Seol GH, Ziburkus J, Huang SY, Song L, Kim IT, Takamiya K, Huganir RL, Lee HK, Kirkwood A. Neuromodulators control the polarity of spike-timing-dependent synaptic plasticity. Neuron. 2007;55:919–29.CrossRefPubMedPubMedCentralGoogle Scholar
17. 17.
    He K, Huertas M, Hong S, Tie X, Hell J, Shouval H, Kirkwood A. Distinct eligibility traces for LTP and LTD in cortical synapses. Neuron. 2015;88:528–38.CrossRefPubMedPubMedCentralGoogle Scholar
18. 18.
    Flood JF, Smith GE, Morley JE. Modulation of memory processing by cholecystokinin: dependence on the vagus nerve. Science. 1987;236:832–4.CrossRefPubMedGoogle Scholar
19. 19.
    Flood JF, Morley JE. Effects of bombesin and gastrin-releasing peptide on memory processing. Brain Res. 1988;460:314–22.CrossRefPubMedGoogle Scholar
20. 20.
    Williams C, Jensen RA. Effects of vagotomy on Leu-enkephalin-induced changes in memory storage processes. Physiol Behav. 1993;54:659–63.CrossRefPubMedGoogle Scholar
21. 21.
    Jensen RA. Modulation of memory storage processes by peripherally acting pharmacological agents. Proc West Pharmacol Soc. 1996;39:85–9.PubMedGoogle Scholar
22. 22.
    Talley CP, Clayborn H, Jewel E, McCarty R, Gold PE. Vagotomy attenuates effects of L-glucose but not of D-glucose on spontaneous alternation performance. Physiol Behav. 2002;77:243–9.CrossRefPubMedGoogle Scholar
23. 23.
    Nogueira PJ, Tomaz C, Williams CL. Contribution of the vagus nerve in mediating the memory-facilitating effects of substance P. Behav Brain Res. 1994;62:165–9.CrossRefPubMedGoogle Scholar
24. 24.
    Clark K, Krahl S, Smith D, Jensen R. Post-training unilateral vagal stimulation enhances retention performance in the rat. Neurobiol Learn Mem. 1995;63:213–6.CrossRefPubMedGoogle Scholar
25. 25.
    Clark KB, Naritoku DK, Smith DC, Browning RA, Jensen RA. Enhanced recognition memory following vagus nerve stimulation in human subjects. Nat Neurosci. 1999;2:94–8.CrossRefPubMedGoogle Scholar
26. 26.
    Engineer ND, Riley JR, Seale JD, Vrana WA, Shetake JA, Sudanagunta SP, Borland MS, Kilgard MP. Reversing pathological neural activity using targeted plasticity. Nature. 2011;470:101–4.CrossRefPubMedPubMedCentralGoogle Scholar
27. 27.
    Shetake JA, Engineer ND, Vrana WA, Wolf JT, Kilgard MP. Pairing tone trains with vagus nerve stimulation induces temporal plasticity in auditory cortex. Exp Neurol. 2011;233:342–9.CrossRefPubMedGoogle Scholar
28. 28.
    Engineer CT, Engineer ND, Riley JR, Seale JD, Kilgard MP. Pairing speech sounds with vagus nerve stimulation drives stimulus-specific cortical plasticity. Brain Stimul. 2015;8(3):637–44.CrossRefPubMedPubMedCentralGoogle Scholar
29. 29.
    Borland MS, Vrana WA, Moreno NA, Fogarty EA, Buell EP, Sharma P, Engineer CT, Kilgard MP. Cortical map plasticity as a function of vagus nerve stimulation intensity. Brain Stimul. 2016;9:117–23.CrossRefPubMedGoogle Scholar
30. 30.
    Porter BA, Khodaparast N, Fayyaz T, Cheung RJ, Ahmed SS, Vrana WA, Rennaker RL II, Kilgard MP. Repeatedly pairing vagus nerve stimulation with a movement reorganizes primary motor cortex. Cereb Cortex. 2011;22:2365–74.CrossRefPubMedGoogle Scholar
31. 31.
    Khodaparast N, Hays SA, Sloan AM, Fayyaz T, Hulsey DR, Rennaker RL II, Kilgard MP. Vagus nerve stimulation delivered during motor rehabilitation improves recovery in a rat model of stroke. Neurorehabil Neural Repair. 2014;28:698–706.CrossRefPubMedPubMedCentralGoogle Scholar
32. 32.
    Hays SA, Khodaparast N, Sloan AM, Fayyaz T, Hulsey DR, Ruiz AD, Pantoja M, Kilgard MP, Rennaker RL II. The bradykinesia assessment task: an automated method to measure forelimb speed in rodents. J Neurosci Methods. 2013;214:52–61.CrossRefPubMedGoogle Scholar
33. 33.
    Khodaparast N, Hays SA, Sloan AM, Hulsey DR, Ruiz A, Pantoja M, Rennaker RL II, Kilgard MP. Vagus nerve stimulation during rehabilitative training improves forelimb strength following ischemic stroke. Neurobiol Dis. 2013;60:80–8.CrossRefPubMedGoogle Scholar
34. 34.
    Canning CG, Ada L, Adams R, O’Dwyer NJ. Loss of strength contributes more to physical disability after stroke than loss of dexterity. Clin Rehabil. 2004;18:300–8.CrossRefPubMedGoogle Scholar
35. 35.
    Harris JE, Eng JJ. Paretic upper-limb strength best explains arm activity in people with stroke. Phys Ther. 2007;87:88–97.CrossRefPubMedGoogle Scholar
36. 36.
    Hays SA, Khodaparast N, Ruiz A, Sloan AM, Hulsey DR, Rennaker RL, Kilgard MP. The timing and amount of vagus nerve stimulation during rehabilitative training affect post-stroke recovery of forelimb strength. Neuroreport. 2014;25(9):676–82.CrossRefPubMedGoogle Scholar
37. 37.
    Kelly-Hayes M, Beiser A, Kase CS, Scaramucci A, D’Agostino RB, Wolf PA. The influence of gender and age on disability following ischemic stroke: the Framingham study. J Stroke Cerebrovasc Dis. 2003;12:119–26.CrossRefPubMedGoogle Scholar
38. 38.
    Freitas C, Perez J, Knobel M, Tormos JM, Oberman L, Eldaief M, Bashir S, Vernet M, Peña-Gómez C, Pascual-Leone A. Changes in cortical plasticity across the lifespan. Front Aging Neurosci. 2011;3Google Scholar
39. 39.
    Pascual-Leone A, Freitas C, Oberman L, Horvath JC, Halko M, Eldaief M, Bashir S, Vernet M, Shafi M, Westover B. Characterizing brain cortical plasticity and network dynamics across the age-span in health and disease with TMS-EEG and TMS-fMRI. Brain Topogr. 2011;24:302–15.CrossRefPubMedPubMedCentralGoogle Scholar
40. 40.
    Hays SA, Ruiz A, Bethea T, Khodaparast N, Carmel JB, Rennaker RL, Kilgard MP. Vagus nerve stimulation during rehabilitative training enhances recovery of forelimb function after ischemic stroke in aged rats. Neurobiol Aging. 2016;43:111–8.CrossRefPubMedPubMedCentralGoogle Scholar
41. 41.
    Bagg S, Pombo AP, Hopman W. Effect of age on functional outcomes after stroke rehabilitation. Stroke. 2002;33:179–85.CrossRefPubMedGoogle Scholar
42. 42.
    Kwakkel G, Kollen BJ, van der Grond J, Prevo AJH. Probability of regaining dexterity in the flaccid upper limb impact of severity of paresis and time since onset in acute stroke. Stroke. 2003;34:2181–6.CrossRefPubMedGoogle Scholar
43. 43.
    Biernaskie J, Chernenko G, Corbett D. Efficacy of rehabilitative experience declines with time after focal ischemic brain injury. J Neurosci. 2004;24:1245–54.CrossRefPubMedGoogle Scholar
44. 44.
    Teasell R, Bitensky J, Salter K, Bayona NA. The role of timing and intensity of rehabilitation therapies. Top Stroke Rehabil. 2005;12:46.CrossRefPubMedGoogle Scholar
45. 45.
    Salter BK, Hartley BM, Foley BN. Impact of early vs delayed admission to rehabilitation on functional outcomes in persons with stroke. J Rehabil Med. 38, 2006;Google Scholar
46. 46.
    Khodaparast N, Kilgard MP, Casavant R, Ruiz A, Qureshi I, Ganzer PD, Rennaker RL 2nd, Hays SA. Vagus nerve stimulation during rehabilitative training improves forelimb recovery after chronic ischemic stroke in rats. Neurorehabil Neural Repair. 2016;30(7):676–84.CrossRefPubMedGoogle Scholar
47. 47.
    Qureshi AI, Tuhrim S, Broderick JP, Batjer HH, Hondo H, Hanley DF. Spontaneous intracerebral hemorrhage. N Engl J Med. 2001;344:1450–60.CrossRefPubMedGoogle Scholar
48. 48.
    Xi G, Keep RF, Hoff JT. Mechanisms of brain injury after intracerebral haemorrhage. Lancet Neurol. 2006;5:53–63.CrossRefPubMedGoogle Scholar
49. 49.
    Krishnamurthi RV, Feigin VL, Forouzanfar MH, Mensah GA, Connor M, Bennett DA, Moran AE, Sacco RL, Anderson LM, Truelsen T. Global and regional burden of first-ever ischaemic and haemorrhagic stroke during 1990–2010: findings from the global burden of disease study 2010. Lancet Glob Health. 2013;1:e259–81.CrossRefPubMedPubMedCentralGoogle Scholar
50. 50.
    Auriat AM, Wowk S, Colbourne F. Rehabilitation after intracerebral hemorrhage in rats improves recovery with enhanced dendritic complexity but no effect on cell proliferation. Behav Brain Res. 2010;214:42–7.CrossRefPubMedGoogle Scholar
51. 51.
    M. Santos, A. Pagnussat, R. Mestriner, C. Netto. Motor skill training promotes sensorimotor recovery and increases microtubule-associated protein-2 (MAP-2) immunoreactivity in the motor cortex after intracerebral hemorrhage in the rat. ISRN Neurol 2013. (2013).Google Scholar
52. 52.
    Liang H, Yin Y, Lin T, Guan D, Ma B, Li C, Wang Y, Zhang X. Transplantation of bone marrow stromal cells enhances nerve regeneration of the corticospinal tract and improves recovery of neurological functions in a collagenase-induced rat model of intracerebral hemorrhage. Mol Cells. 2013;36:17–24.CrossRefPubMedPubMedCentralGoogle Scholar
53. 53.
    Hays SA, Khodaparast N, Hulsey DR, Ruiz A, Sloan AM, Rennaker RL II, Kilgard MP. Vagus nerve stimulation during rehabilitative training improves functional recovery after intracerebral hemorrhage. Stroke. 2014;45(10):3097–30100.CrossRefPubMedPubMedCentralGoogle Scholar
54. 54.
    Pruitt D, Schmid A, Kim L, Abe C, Trieu J, Choua C, Hays S, Kilgard M, Rennaker RL II. Vagus nerve stimulation delivered with motor training enhances recovery of function after traumatic brain injury. J Neurotrauma. 2016;33(9):871–9.CrossRefPubMedPubMedCentralGoogle Scholar
55. 55.
    Dawson J, Pierce D, Dixit A, Kimberley TJ, Robertson M, Tarver B, Hilmi O, McLean J, Forbes K, Kilgard MP, Rennaker RL, Cramer SC, Walters M, Engineer N. Safety, feasibility, and efficacy of vagus nerve stimulation paired with upper-limb rehabilitation after ischemic stroke. Stroke. 2016;47:143–50.CrossRefPubMedGoogle Scholar
56. 56.
    Clinical Trials Identifier: NCT01669161, Paired vagus nerve stimulation (VNS) with rehabilitation for upper limb function improvement after stroke. ClinicalTrials. gov. Bethesda: National Library of Medicine (US). https://clinicaltrials.gov/ct2/show/NCT01669161 (2014).
57. 57.
    Dawson J, McGrane F. Vagus nerve stimulation and upper limb rehabilitation. Curr Phys Med Rehabil Rep. 2016;4:186–9.CrossRefGoogle Scholar
58. 58.
    Clinical Trials Identifier: NCT02243020, .VNS during rehabilitation for improved upper limb motor function after stroke. ClinicalTrials. gov. Bethesda: National Library of Medicine (US). https://clinicaltrials.gov/ct2/show/study/NCT02243020 (2014).
59. 59.
    Krahl SE, Senanayake SS, Handforth A. Destruction of peripheral C-fibers does not Alter subsequent vagus nerve stimulation-induced seizure suppression in rats. Epilepsia. 2001;42:586–9.CrossRefPubMedGoogle Scholar
60. 60.
    Ruffoli R, Giorgi FS, Pizzanelli C, Murri L, Paparelli A, Fornai F. The chemical neuroanatomy of vagus nerve stimulation. J Chem Neuroanat. 2011;42:288–96.CrossRefPubMedGoogle Scholar
61. 61.
    Evans M, Verma-Ahuja S, Naritoku D, Espinosa J. Intraoperative human vagus nerve compound action potentials. Acta Neurol Scand. 2004;110:232–8.CrossRefPubMedGoogle Scholar
62. 62.
    T. Verlinden, K. Rijkers, G. Hoogland, A. Herrler. Morphology of the human cervical vagus nerve: implications for vagus nerve stimulation treatment. Acta Neurol Scand. (2015).Google Scholar
63. 63.
    Hammer N, Glätzner J, Feja C, Kühne C, Meixensberger J, Planitzer U, Schleifenbaum S, Tillmann BN, Winkler D. Human vagus nerve branching in the cervical region. PLoS One. 2015;10:e0118006.CrossRefPubMedPubMedCentralGoogle Scholar
64. 64.
    U. Planitzer, N. Hammer, I. Bechmann, J. Glätzner, S. Löffler, R. Möbius, B. N. Tillmann, D. Weise, D. Winkler. Positional relations of the cervical vagus nerve revisited. In: Neuromodulation: technology at the neural interface. (2017).Google Scholar
65. 65.
    Roosevelt RW, Smith DC, Clough RW, Jensen RA, Browning RA. Increased extracellular concentrations of norepinephrine in cortex and hippocampus following vagus nerve stimulation in the rat. Brain Res. 2006;1119:124–32.CrossRefPubMedPubMedCentralGoogle Scholar
66. 66.
    Castoro MA, Yoo PB, Hincapie JG, Hamann JJ, Ruble SB, Wolf PD, Grill WM. Excitation properties of the right cervical vagus nerve in adult dogs. Exp Neurol. 2011;227:62–8.CrossRefPubMedGoogle Scholar
67. 67.
    Mollet L, Raedt R, Delbeke J, El Tahry R, Grimonprez A, Dauwe I, De Herdt V, Meurs A, Wadman W, Boon P. Electrophysiological responses from vagus nerve stimulation in rats. Int J Neural Syst. 2013;23:1350027.CrossRefPubMedGoogle Scholar
68. 68.
    Clark K, Smith D, Hassert D, Browning R, Naritoku D, Jensen R. Posttraining electrical stimulation of vagal afferents with concomitant vagal efferent inactivation enhances memory storage processes in the rat. Neurobiol Learn Mem. 1998;70:364–73.CrossRefPubMedGoogle Scholar
69. 69.
    Follesa P, Biggio F, Gorini G, Caria S, Talani G, Dazzi L, Puligheddu M, Marrosu F, Biggio G. Vagus nerve stimulation increases norepinephrine concentration and the gene expression of BDNF and bFGF in the rat brain. Brain Res. 2007;1179:28–34.CrossRefPubMedGoogle Scholar
70. 70.
    Ploughman M, Windle V, MacLellan CL, White N, Doré JJ, Corbett D. Brain-derived neurotrophic factor contributes to recovery of skilled reaching after focal ischemia in rats. Stroke. 2009;40:1490–5.CrossRefPubMedGoogle Scholar
71. 71.
    Schäbitz W, Berger C, Kollmar R, Seitz M, Tanay E, Kiessling M, Schwab S, Sommer C. Effect of brain-derived neurotrophic factor treatment and forced arm use on functional motor recovery after small cortical ischemia. Stroke. 2004;35:992–7.CrossRefPubMedGoogle Scholar
72. 72.
    Dan Y, Poo M. Spike timing-dependent plasticity of neural circuits. Neuron. 2004;44:23–30.CrossRefPubMedGoogle Scholar
73. 73.
    Alvarez-Dieppa AC, Griffin K, Cavalier S, McIntyre CK. Vagus nerve stimulation enhances extinction of conditioned fear in rats and modulates arc protein, CaMKII, and GluN2B-containing NMDA receptors in the basolateral amygdala. Neural Plast. 2016;2016Google Scholar
74. 74.
    Xu T, Yu X, Perlik AJ, Tobin WF, Zweig JA, Tennant K, Jones T, Zuo Y. Rapid formation and selective stabilization of synapses for enduring motor memories. Nature. 2009;462:915–9.CrossRefPubMedPubMedCentralGoogle Scholar
75. 75.
    Ay I, Lu J, Ay H, Gregory Sorensen A. Vagus nerve stimulation reduces infarct size in rat focal cerebral ischemia. Neurosci Lett. 2009;459:147–51.CrossRefPubMedGoogle Scholar
76. 76.
    Ay I, Ay H. Ablation of the sphenopalatine ganglion does not attenuate the infarct reducing effect of vagus nerve stimulation. Auton Neurosci. 2013;174:31–5.CrossRefPubMedGoogle Scholar
77. 77.
    Ay I, Nasser R, Simon B, Ay H. Transcutaneous cervical vagus nerve stimulation ameliorates acute ischemic injury in rats. Brain Stimul. 2015;9(2):166–73.CrossRefPubMedPubMedCentralGoogle Scholar

via Improving Stroke Rehabilitation with Vagus Nerve Stimulation | SpringerLink