Safety, Feasibility, and Efficacy of Vagus Nerve Stimulation Paired With Upper-Limb Rehabilitation After Ischemic Stroke

Jesse Dawson, David Pierce, Anand Dixit, Teresa J Kimberley, Michele Robertson, Brent Tarver, Omar Hilmi, John McLean, Kirsten Forbes, Michael P Kilgard, Robert L Rennaker, Steven C Cramer, Matthew Walters, Navzer Engineer, Jesse Dawson, David Pierce, Anand Dixit, Teresa J Kimberley, Michele Robertson, Brent Tarver, Omar Hilmi, John McLean, Kirsten Forbes, Michael P Kilgard, Robert L Rennaker, Steven C Cramer, Matthew Walters, Navzer Engineer

Abstract

Background and purpose: Recent animal studies demonstrate that vagus nerve stimulation (VNS) paired with movement induces movement-specific plasticity in motor cortex and improves forelimb function after stroke. We conducted a randomized controlled clinical pilot study of VNS paired with rehabilitation on upper-limb function after ischemic stroke.

Methods: Twenty-one participants with ischemic stroke >6 months before and moderate to severe upper-limb impairment were randomized to VNS plus rehabilitation or rehabilitation alone. Rehabilitation consisted of three 2-hour sessions per week for 6 weeks, each involving >400 movement trials. In the VNS group, movements were paired with 0.5-second VNS. The primary objective was to assess safety and feasibility. Secondary end points included change in upper-limb measures (including the Fugl-Meyer Assessment-Upper Extremity).

Results: Nine participants were randomized to VNS plus rehabilitation and 11 to rehabilitation alone. There were no serious adverse device effects. One patient had transient vocal cord palsy and dysphagia after implantation. Five had minor adverse device effects including nausea and taste disturbance on the evening of therapy. In the intention-to-treat analysis, the change in Fugl-Meyer Assessment-Upper Extremity scores was not significantly different (between-group difference, 5.7 points; 95% confidence interval, -0.4 to 11.8). In the per-protocol analysis, there was a significant difference in change in Fugl-Meyer Assessment-Upper Extremity score (between-group difference, 6.5 points; 95% confidence interval, 0.4 to 12.6).

Conclusions: This study suggests that VNS paired with rehabilitation is feasible and has not raised safety concerns. Additional studies of VNS in adults with chronic stroke will now be performed.

Clinical trial registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01669161.

Keywords: deglutition disorders; intention to treat analysis; rehabilitation; stroke; vagus nerve.

© 2015 The Authors.

Figures

Figure 1.
Figure 1.
Schematic of vagus nerve stimulation device use in a typical therapy session.
Figure 2.
Figure 2.
Consort diagram. VNS indicates vagus nerve stimulation.
Figure 3.
Figure 3.
Change in upper extremity Fugl–Meyer assessment (FMA-UE) score and baseline magnetic resonance imaging variables. These figures show change in FMA-UE score plotted against the baseline infarct volume (A) and the baseline corticospinal tract fractional anisotropy (FA) ratio (B). Vagus nerve stimulation (VNS)–treated patients are shown in gray circles, and rehabilitation-only treated participants in black diamonds. Responders lie to the right of the vertical line.

References

    1. Pollock A, St George B, Fenton M, Firkins L. Top ten research priorities relating to life after stroke. Lancet Neurol. 2012;11:209. doi: 10.1016/S1474-4422(12)70029-7.
    1. Nakayama H, Jørgensen HS, Raaschou HO, Olsen TS. Recovery of upper extremity function in stroke patients: the Copenhagen Stroke Study. Arch Phys Med Rehabil. 1994;75:394–398.
    1. Wade DT, Langton-Hewer R, Wood VA, Skilbeck CE, Ismail HM. The hemiplegic arm after stroke: measurement and recovery. J Neurol Neurosurg Psychiatry. 1983;46:521–524.
    1. National Institute for Health Care and Clinical Excellence, Stroke Rehabilitation. Long term rehabilitation after stroke. CG162, London: National Institute for Health Care and Clinical Excellence; 2013.
    1. Langhorne P, Coupar F, Pollock A. Motor recovery after stroke: a systematic review. Lancet Neurol. 2009;8:741–754. doi: 10.1016/S1474-4422(09)70150-4.
    1. Lo AC, Guarino PD, Richards LG, Haselkorn JK, Wittenberg GF, Federman DG, et al. Robot-assisted therapy for long-term upper-limb impairment after stroke. N Engl J Med. 2010;362:1772–1783. doi: 10.1056/NEJMoa0911341.
    1. Wagner TH, Lo AC, Peduzzi P, Bravata DM, Huang GD, Krebs HI, et al. An economic analysis of robot-assisted therapy for long-term upper-limb impairment after stroke. Stroke. 2011;42:2630–2632. doi: 10.1161/STROKEAHA.110.606442.
    1. Buma FE, Lindeman E, Ramsey NF, Kwakkel G. Functional neuroimaging studies of early upper limb recovery after stroke: a systematic review of the literature. Neurorehabil Neural Repair. 2010;24:589–608. doi: 10.1177/1545968310364058.
    1. Cramer SC, Sur M, Dobkin BH, O’Brien C, Sanger TD, Trojanowski JQ, et al. Harnessing neuroplasticity for clinical applications. Brain. 2011;134(pt 6):1591–1609. doi: 10.1093/brain/awr039.
    1. Hays SA, Rennaker RL, Kilgard MP. Targeting plasticity with vagus nerve stimulation to treat neurological disease. Prog Brain Res. 2013;207:275–299. doi: 10.1016/B978-0-444-63327-9.00010-2.
    1. Porter BA, Khodaparast N, Fayyaz T, Cheung RJ, Ahmed SS, Vrana WA, et al. Repeatedly pairing vagus nerve stimulation with a movement reorganizes primary motor cortex. Cereb Cortex. 2012;22:2365–2374. doi: 10.1093/cercor/bhr316.
    1. Engineer ND, Riley JR, Seale JD, Vrana WA, Shetake JA, Sudanagunta SP, et al. Reversing pathological neural activity using targeted plasticity. Nature. 2011;470:101–104. doi: 10.1038/nature09656.
    1. Nichols JA, Nichols AR, Smirnakis SM, Engineer ND, Kilgard MP, Atzori M. Vagus nerve stimulation modulates cortical synchrony and excitability through the activation of muscarinic receptors. Neuroscience. 2011;189:207–214. doi: 10.1016/j.neuroscience.2011.05.024.
    1. Khodaparast N, Hays SA, Sloan AM, Hulsey DR, Ruiz A, Pantoja M, et al. Vagus nerve stimulation during rehabilitative training improves forelimb strength following ischemic stroke. Neurobiol Dis. 2013;60:80–88. doi: 10.1016/j.nbd.2013.08.002.
    1. Khodaparast N, Hays SA, Sloan AM, Fayyaz T, Hulsey DR, Rennaker RL, II, et al. Vagus nerve stimulation delivered during motor rehabilitation improves recovery in a rat model of stroke. Neurorehabil Neural Repair. 2014;28:698–706. doi: 10.1177/1545968314521006.
    1. Hays SA, Khodaparast N, Hulsey DR, Ruiz A, Sloan AM, Rennaker RL, II, et al. Vagus nerve stimulation during rehabilitative training improves functional recovery after intracerebral hemorrhage. Stroke. 2014;45:3097–3100. doi: 10.1161/STROKEAHA.114.006654.
    1. Hays SA, Khodaparast N, Ruiz A, Sloan AM, Hulsey DR, Rennaker RL, II, et al. The timing and amount of vagus nerve stimulation during rehabilitative training affect poststroke recovery of forelimb strength. Neuroreport. 2014;25:676–682. doi: 10.1097/WNR.0000000000000154.
    1. See J, Dodakian L, Chou C, Chan V, McKenzie A, Reinkensmeyer DJ, et al. A standardized approach to the Fugl-Meyer assessment and its implications for clinical trials. Neurorehabil Neural Repair. 2013;27:732–741. doi: 10.1177/1545968313491000.
    1. Van der Lee JH, De Groot V, Beckerman H, Wagenaar RC, Lankhorst GJ, Bouter LM. The intra- and interrater reliability of the action research arm test: a practical test of upper extremity function in patients with stroke. Arch Phys Med Rehabil. 2001;82:14–19. doi: 10.1053/apmr.2001.18668.
    1. Schmidt RT, Toews JV. Grip strength as measured by the Jamar dynamometer. Arch Phys Med Rehabil. 1970;51:321–327.
    1. Mathiowetz V, Volland G, Kashman N, Weber K. Adult norms for the Box and Block Test of manual dexterity. Am J Occup Ther. 1985;39:386–391.
    1. Sharpless JW. The nine-hold peg test of finger hand coordination for the hemiplegic patient. In: Sharpless JW, editor. In: Mossman’s A Problem Oriented Approach to Stroke Rehabilitation. 2nd ed. Springfield, IL: Charles C Thomas Publishing; 1982. pp. 420–423.
    1. Krebs HI, Krams M, Agrafiotis DK, DiBernardo A, Chavez JC, Littman GS, et al. Robotic measurement of arm movements after stroke establishes biomarkers of motor recovery. Stroke. 2014;45:200–204. doi: 10.1161/STROKEAHA.113.002296.
    1. Duncan PW, Bode RK, Min Lai S, Perera S Glycine Antagonist in Neuroprotection Americans Investigators. Rasch analysis of a new stroke-specific outcome scale: the Stroke Impact Scale. Arch Phys Med Rehabil. 2003;84:950–963.
    1. Burke Quinlan E, Dodakian L, See J, McKenzie A, Le V, Wojnowicz M, et al. Neural function, injury, and stroke subtype predict treatment gains after stroke. Ann Neurol. 2015;77:132–145. doi: 10.1002/ana.24309.
    1. De Ridder D, Vanneste S, Engineer ND, Kilgard MP. Safety and efficacy of vagus nerve stimulation paired with tones for the treatment of tinnitus: a case series. Neuromodulation. 2014;17:170–179. doi: 10.1111/ner.12127.
    1. Borland MS, Vrana WA, Moreno NA, Fogarty EA, Buell EP, Sharma P, et al. Cortical Map Plasticity as a Function of Vagus Nerve Stimulation Intensity. Brain Stimul. . Accessed October 15, 2015.
    1. Clark KB, Naritoku DK, Smith DC, Browning RA, Jensen RA. Enhanced recognition memory following vagus nerve stimulation in human subjects. Nat Neurosci. 1999;2:94–98. doi: 10.1038/4600.
    1. Sara SJ, Devauges V. Priming stimulation of locus coeruleus facilitates memory retrieval in the rat. Brain Res. 1988;438:299–303.
    1. Ben-Menachem E, Revesz D, Simon BJ, Silberstein S. Surgically implanted and non-invasive vagus nerve stimulation: a review of efficacy, safety and tolerability. Eur J Neurol. 2015;22:1260–1268. doi: 10.1111/ene.12629.
    1. Landercasper J, Merz BJ, Cogbill TH, Strutt PJ, Cochrane RH, Olson RA, et al. Perioperative stroke risk in 173 consecutive patients with a past history of stroke. Arch Surg. 1990;125:986–989.
    1. Kwakkel G, Veerbeek JM, van Wegen EE, Wolf SL. Constraint-induced movement therapy after stroke. Lancet Neurol. 2015;14:224–234. doi: 10.1016/S1474-4422(14)70160-7.
    1. Puig J, Blasco G, Daunis-I-Estadella J, Thomalla G, Castellanos M, Figueras J, et al. Decreased corticospinal tract fractional anisotropy predicts long-term motor outcome after stroke. Stroke. 2013;44:2016–2018. doi: 10.1161/STROKEAHA.111.000382.

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