Effect of epidural spinal cord stimulation after chronic spinal cord injury on volitional movement and cardiovascular function: study protocol for the phase II open label controlled E-STAND trial

David P Darrow, David Young Balser, David Freeman, Eliza Pelrine, Andrei Krassioukov, Aaron Phillips, Theoden Netoff, Ann Parr, Uzma Samadani, David P Darrow, David Young Balser, David Freeman, Eliza Pelrine, Andrei Krassioukov, Aaron Phillips, Theoden Netoff, Ann Parr, Uzma Samadani

Abstract

Introduction: Spinal cord injury (SCI) leads to significant changes in morbidity, mortality and quality of life (QOL). Currently, there are no effective therapies to restore function after chronic SCI. Preliminary studies have indicated that epidural spinal cord stimulation (eSCS) is a promising therapy to improve motor control and autonomic function for patients with chronic SCI. The aim of this study is to assess the effects of tonic eSCS after chronic SCI on quantitative outcomes of volitional movement and cardiovascular function. Our secondary objective is to optimise spinal cord stimulation parameters for volitional movement.

Methods and analysis: The Epidural Stimulation After Neurologic Damage (ESTAND) trial is a phase II single-site self-controlled trial of epidural stimulation with the goal of restoring volitional movement and autonomic function after motor complete SCI. Participants undergo epidural stimulator implantation and are followed up over 15 months while completing at-home, mobile application-based movement testing. The primary outcome measure integrates quantity of volitional movement and similarity to normal controls using the volitional response index (VRI) and the modified Brain Motor Control Assessment. The mobile application is a custom-designed platform to support participant response and a kinematic task to optimise the settings for each participant. The application optimises stimulation settings by evaluating the parameter space using movement data collected from the tablet application and accelerometers. A subgroup of participants with cardiovascular dysautonomia are included for optimisation of blood pressure stabilisation. Indirect effects of stimulation on cardiovascular function, pain, sexual function, bowel/bladder, QOL and psychiatric measures are analysed to assess generalisability of this targeted intervention.

Ethics and dissemination: This study has been approved after full review by the Minneapolis Medical Research Foundation Institutional Review Board and by the Minneapolis VA Health Care System. This project has received Food and Drug Administration investigational device exemption approval. Trial results will be disseminated through peer-reviewed publications, conference presentations and seminars.

Trial registration number: NCT03026816.

Keywords: neurological injury; neurosurgery; rehabilitation medicine.

Conflict of interest statement

Competing interests: This study has received a contribution of epidural stimulation devices from St. Jude Medical/Abbott managed by the University of Minnesota. DPD has provisional patents for optimisation methods spinal cord stimulation and is also the CMO and owner of Stimsherpa Neuromodulation. US’s lab has received donations from Abbott through the J. Aron Allen Foundation. AK has received research grants from the Praxis Spinal Cord Institute through the University of British Columbia. He is also on the Coloplast and Convatech advisory boards and is the president of the American Spinal Cord Injury Association.

© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1
Figure 1
Study schema. Participants are assigned a study group (autonomic+movement vs movement only) and followed for a total of 15 months including the screening and implantation periods.
Figure 2
Figure 2
Example preference response surface over frequency and pulse width. Black crosses denote settings evaluated and red crosses denote setting suggested by Bayesian optimisation.

References

    1. Sezer N, Akkuş S, Uğurlu FG. Chronic complications of spinal cord injury. World J Orthop 2015;6:24–33. 10.5312/wjo.v6.i1.24
    1. Consortium for Spinal Cord Medicine . Bladder management for adults with spinal cord injury: a clinical practice guideline for health-care providers. J Spinal Cord Med 2006;29:527–73.
    1. Consortium for Spinal Cord Medicine . Acute management of autonomic dysreflexia: individuals with spinal cord injury presenting to health-care facilities. J Spinal Cord Med 2002;25 Suppl 1:S67–88.
    1. Consortium for Spinal Cord Medicine . Neurogenic bowel management in adults with spinal cord injury. Paralyzed Veterans of America, 1998. Available:
    1. Consortium for Spinal Cord Medicine . Pressure ulcer prevention and treatment following spinal cord injury: a clinical practice guideline for health-care professionals second edition. Paralyzed veterans of America, 2014. Available:
    1. Oh SK, Choi KH, Yoo JY, et al. . A phase III clinical trial showing limited efficacy of autologous mesenchymal stem cell therapy for spinal cord injury. Neurosurgery 2016;78:436–47. 10.1227/NEU.0000000000001056
    1. Shin JC, Kim KN, Yoo J, et al. . Clinical trial of human fetal brain-derived neural stem/progenitor cell transplantation in patients with traumatic cervical spinal cord injury. Neural Plast 2015;2015:630932. 10.1155/2015/630932
    1. de Leon RD, Hodgson JA, Roy RR, et al. . Locomotor capacity attributable to step training versus spontaneous recovery after spinalization in adult cats. J Neurophysiol 1998;79:1329–40. 10.1152/jn.1998.79.3.1329
    1. Grillner S, Wallén P. Central pattern generators for locomotion, with special reference to vertebrates. Annu Rev Neurosci 1985;8:233–61. 10.1146/annurev.ne.08.030185.001313
    1. Gad P, Choe J, Nandra MS, et al. . Development of a multi-electrode array for spinal cord epidural stimulation to facilitate stepping and standing after a complete spinal cord injury in adult rats. J Neuroeng Rehabil 2013;10:2. 10.1186/1743-0003-10-2
    1. Lavrov I, Musienko PE, Selionov VA, et al. . Activation of spinal locomotor circuits in the decerebrated cat by spinal epidural and/or intraspinal electrical stimulation. Brain Res 2015;1600:84–92. 10.1016/j.brainres.2014.11.003
    1. Harkema S, Gerasimenko Y, Hodes J, 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;377:1938–47. 10.1016/S0140-6736(11)60547-3
    1. Kirshblum SC, Burns SP, Biering-Sorensen F, et al. . International standards for neurological classification of spinal cord injury (revised 2011). J Spinal Cord Med 2011;34:535–46. 10.1179/204577211X13207446293695
    1. Angeli CA, Edgerton VR, Gerasimenko YP, et al. . Altering spinal cord excitability enables voluntary movements after chronic complete paralysis in humans. Brain 2014;137:1394–409. 10.1093/brain/awu038
    1. Angeli CA, Boakye M, Morton RA, et al. . Recovery of over-ground walking after chronic motor complete spinal cord injury. N Engl J Med 2018;379:1244–50. 10.1056/NEJMoa1803588
    1. Harkema SJ, Legg Ditterline B, Wang S, et al. . Epidural spinal cord stimulation training and sustained recovery of cardiovascular function in individuals with chronic cervical spinal cord injury. JAMA Neurol 2018;75:1569–71. 10.1001/jamaneurol.2018.2617
    1. Rejc E, Angeli CA, Atkinson D, et al. . Motor recovery after activity-based training with spinal cord epidural stimulation in a chronic motor complete paraplegic. Sci Rep 2017;7:13476. 10.1038/s41598-017-14003-w
    1. Rejc E, Angeli CA, Bryant N, et al. . Effects of stand and step training with epidural stimulation on motor function for standing in chronic complete paraplegics. J Neurotrauma 2017;34:1787–802. 10.1089/neu.2016.4516
    1. Grahn PJ, Lavrov IA, Sayenko DG, et al. . Enabling task-specific volitional motor functions via spinal cord neuromodulation in a human with paraplegia. Mayo Clin Proc 2017;92:544–54. 10.1016/j.mayocp.2017.02.014
    1. Sherwood AM, McKay WB, Dimitrijević MR. Motor control after spinal cord injury: assessment using surface EMG. Muscle Nerve 1996;19:966–79. 10.1002/(SICI)1097-4598(199608)19:8<966::AID-MUS5>;2-6
    1. Aslan SC, Legg Ditterline BE, Park MC, et al. . Epidural spinal cord stimulation of lumbosacral networks modulates arterial blood pressure in individuals with spinal cord injury-induced cardiovascular deficits. Front Physiol 2018;9:565. 10.3389/fphys.2018.00565
    1. Legg Ditterline BE, Wade S, Ugiliweneza B, et al. . Beneficial cardiac structural and functional adaptations after lumbosacral spinal cord epidural stimulation and task-specific interventions: a pilot study. Front Neurosci 2020;14:554018. 10.3389/fnins.2020.554018
    1. Walter M, Lee AHX, Kavanagh A, et al. . Epidural spinal cord stimulation acutely modulates lower urinary tract and bowel function following spinal cord injury: a case report. Front Physiol 2018;9:9. 10.3389/fphys.2018.01816
    1. Herrity AN, Aslan SC, Ugiliweneza B, et al. . Improvements in bladder function following activity-based recovery training with epidural stimulation after chronic spinal cord injury. Front Syst Neurosci 2020;14:614691. 10.3389/fnsys.2020.614691
    1. Kuncel AM, Grill WM. Selection of stimulus parameters for deep brain stimulation. Clin Neurophysiol 2004;115:2431–41. 10.1016/j.clinph.2004.05.031
    1. Chan A-W, Tetzlaff JM, Altman DG, et al. . SPIRIT 2013 statement: defining standard protocol items for clinical trials. Ann Intern Med 2013;158:200–7. 10.7326/0003-4819-158-3-201302050-00583
    1. Mckay WB, Sherwood A, Tang SFT. Manual for performing brain motor control assessment (BMCA) 2012.
    1. Grinnon ST, Miller K, Marler JR, et al. . National Institute of Neurological Disorders and Stroke Common Data Element Project - approach and methods. Clin Trials 2012;9:322–9. 10.1177/1740774512438980
    1. Anderson KD. Targeting recovery: priorities of the spinal cord-injured population. J Neurotrauma 2004;21:1371–83. 10.1089/neu.2004.21.1371
    1. van Middendorp JJ, Allison H, Cowan K, et al. . Top ten research priorities for spinal cord injury. Lancet Neurol 2014;13:1167. 10.1016/S1474-4422(14)70253-4
    1. Barolat G, North RB. Spinal cord stimulation: equipment and implantation technique. In: Burchiel K, ed. Surgical management of pain. New York, NY: Thieme, 2002: 535–48.
    1. Kumar K, Taylor RS, Jacques L, et al. . Spinal cord stimulation versus conventional medical management for neuropathic pain: a multicentre randomised controlled trial in patients with failed back surgery syndrome. Pain 2007;132:179–88. 10.1016/j.pain.2007.07.028
    1. Lee DC, Lim HK, McKay WB, et al. . Toward an objective interpretation of surface EMG patterns: a voluntary response index (VRI). J Electromyogr Kinesiol 2004;14:379–88. 10.1016/j.jelekin.2003.10.006
    1. Zhao Z, Ahmadi A, Hoover C, et al. . Optimization of spinal cord stimulation using Bayesian preference learning and its validation. IEEE Trans Neural Syst Rehabil Eng 2021;29:1987–97. 10.1109/TNSRE.2021.3113636
    1. Bench CJ, Frith CD, Grasby PM, et al. . Investigations of the functional anatomy of attention using the Stroop test. Neuropsychologia 1993;31:907–22. 10.1016/0028-3932(93)90147-r
    1. Baker LD, Frank LL, Foster-Schubert K, et al. . Effects of aerobic exercise on mild cognitive impairment: a controlled trial. Arch Neurol 2010;67:71–9. 10.1001/archneurol.2009.307
    1. Hubli M, Krassioukov AV. Ambulatory blood pressure monitoring in spinal cord injury: clinical practicability. J Neurotrauma 2014;31:789–97. 10.1089/neu.2013.3148
    1. Paton CD, Hopkins WG. Tests of cycling performance. Sports Med 2001;31:489–96. 10.2165/00007256-200131070-00004
    1. Skevington SM, Lotfy M, O'Connell KA, et al. . The world Health organization's WHOQOL-BREF quality of life assessment: psychometric properties and results of the International field trial. A report from the WHOQOL group. Qual Life Res 2004;13:299–310. 10.1023/B:QURE.0000018486.91360.00
    1. Development of the world Health organization WHOQOL-BREF quality of life assessment. The WHOQOL group. Psychol Med 1998;28:551–8. 10.1017/S0033291798006667
    1. Biering-Sørensen F, Charlifue S, DeVivo M, et al. . International spinal cord injury data sets. Spinal Cord 2006;44:530–4. 10.1038/sj.sc.3101930
    1. Johns MW. Reliability and factor analysis of the Epworth Sleepiness scale. Sleep 1992;15:376–81. 10.1093/sleep/15.4.376
    1. Johns MW. A new method for measuring daytime sleepiness: the Epworth Sleepiness scale. Sleep 1991;14:540–5. 10.1093/sleep/14.6.540
    1. Sankari A, Bascom A, Oomman S, et al. . Sleep disordered breathing in chronic spinal cord injury. J Clin Sleep Med 2014;10:65–72. 10.5664/jcsm.3362
    1. Krogh K, Christensen P, Sabroe S, et al. . Neurogenic bowel dysfunction score. Spinal Cord 2006;44:625–31. 10.1038/sj.sc.3101887
    1. Welk B, Morrow S, Madarasz W, et al. . The validity and reliability of the neurogenic bladder symptom score. J Urol 2014;192:452–7. 10.1016/j.juro.2014.01.027
    1. Schurch B, Denys P, Kozma CM, et al. . Reliability and validity of the incontinence quality of life questionnaire in patients with neurogenic urinary incontinence. Arch Phys Med Rehabil 2007;88:646–52. 10.1016/j.apmr.2007.02.009
    1. Bonniaud V, Parratte B, Amarenco G, et al. . Measuring quality of life in multiple sclerosis patients with urinary disorders using the Qualiveen questionnaire. Arch Phys Med Rehabil 2004;85:1317–23. 10.1016/j.apmr.2003.09.029
    1. Rosen RC, Riley A, Wagner G, et al. . The International index of erectile function (IIEF): a multidimensional scale for assessment of erectile dysfunction. Urology 1997;49:822–30. 10.1016/s0090-4295(97)00238-0
    1. Derogatis LR, Rosen R, Leiblum S, et al. . The female sexual distress scale (FSDS): initial validation of a standardized scale for assessment of sexually related personal distress in women. J Sex Marital Ther 2002;28:317–30. 10.1080/00926230290001448
    1. ter Kuile MM, Brauer M, Laan E. The female sexual function index (FSFI) and the female sexual distress scale (FSDS): psychometric properties within a Dutch population. J Sex Marital Ther 2006;32:289–304. 10.1080/00926230600666261
    1. Derogatis L, Clayton A, Lewis-D'Agostino D, et al. . Validation of the female sexual distress scale-revised for assessing distress in women with hypoactive sexual desire disorder. J Sex Med 2008;5:357–64. 10.1111/j.1743-6109.2007.00672.x
    1. Meston CM. Validation of the female sexual function index (FSFI) in women with female orgasmic disorder and in women with hypoactive sexual desire disorder. J Sex Marital Ther 2003;29:39–46. 10.1080/713847100
    1. Rosen R, Brown C, Heiman J, et al. . The female sexual function index (FSFI): a multidimensional self-report instrument for the assessment of female sexual function. J Sex Marital Ther 2000;26:191–208. 10.1080/009262300278597
    1. Wiegel M, Meston C, Rosen R. The female sexual function index (FSFI): cross-validation and development of clinical cutoff scores. J Sex Marital Ther 2005;31:1–20. 10.1080/00926230590475206
    1. Widerström-Noga E, Biering-Sørensen F, Bryce TN, et al. . The International spinal cord injury pain basic data set (version 2.0). Spinal Cord 2014;52:282–6. 10.1038/sc.2014.4
    1. Penn RD, Savoy SM, Corcos D, et al. . Intrathecal baclofen for severe spinal spasticity. N Engl J Med 1989;320:1517–21. 10.1056/NEJM198906083202303
    1. Priebe MM, Sherwood AM, Thornby JI, et al. . Clinical assessment of spasticity in spinal cord injury: a multidimensional problem. Arch Phys Med Rehabil 1996;77:713–6. 10.1016/s0003-9993(96)90014-3
    1. Naghdi S, Ebrahimi I, Asgari A, et al. . A preliminary study into the criterion validity of the modified modified Ashworth scale using the new measure of the alpha motoneuron excitability in spastic hemiplegia. Electromyogr Clin Neurophysiol 2007;47:187–92.

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