Harnessing Neuroplasticity of Postural Sensorimotor Networks Using Non-Invasive Spinal Neuromodulation to Maximize Functional Recovery After Spinal Cord Injury

Обзор

It has been demonstrated that the human lumbosacral spinal cord can be neuromodulated with epidural (ESS) and transcutaneous (TSS) spinal cord stimulation to enable recovery of standing and volitional control of the lower limbs after complete motor paralysis due to spinal cord injury (SCI). The work proposed herein will examine and identify distinct electrophysiological mechanisms underlying transcutaneous spinal stimulation (TSS) and epidural spinal stimulation (ESS) to define how these approaches determine the ability to maintain self-assisted standing after SCI.

Подробное описание

Spinal circuitries below a paralyzing injury have a functional potential that far exceeds what has been thought possible. It has been demonstrated that task-specific motor therapy combined with epidural spinal cord stimulation (ESS) can promote improved motor function during postural, locomotor, and voluntary movement tasks, resulting in dramatic effects on the wellbeing of individuals with spinal cord injury (SCI). While these findings indicate a substantial promise for restoring mobility even after motor complete paralysis, chronic ESS is based on a high-cost implantable device, as well as an expensive and invasive surgical procedure. The investigators have developed a cost-effective alternative to ESS - non-invasive, transcutaneous electrical stimulation of the spinal cord (TSS). Preliminary works demonstrate that this neuromodulatory strategy provides sufficient specificity to selectively stimulate multisegmental dorsal nerve roots, enable stepping movements, and improve postural control during sitting and standing in individuals with motor complete SCI. The similarities between the effects of ESS and TSS are of critical importance in guiding more individually-specific neuromodulatory approaches to improve motor function and mobility after SCI, but have not been compared directly in the same subjects.

This study is focused on investigation the effects and mechanisms of each spinal neuromodulation strategy in regaining self-assisted standing. Not only is the recovery of balance control one of the most desired goals of people with paralysis, it provides the foundation necessary for regaining the ability to walk, and is critical to future therapies, involving robotic (e.g. exoskeleton) technologies. The objectives of this study are (1) to define the therapeutic potential of TSS during standing in individuals with motor complete SCI, and (2) to identify the neurophysiological and functional signatures of TSS and ESS. The central hypothesis is that each of the neuromodulatory strategies, when individually tailored, can result in significant motor recovery in individuals with chronic paralysis by reactivation and integration of networks that were clinically dormant prior to the intervention. The investigators predict that this proposal will have a high impact given that it encompasses multiple functional systems that contribute to the independence and quality of life in a broad population of individuals with SCI, and provides the first direct comparison of the invasive and non-invasive approaches. The investigators propose a progressive, mechanistic, and translational study to validate the effects of each approach, examine the neuroplastic capacity caused by activity-based training in the presence of TSS, and evaluate TSS and ESS stimulation paradigms as rehabilitative modalities after SCI.

Вмешательства

• Устройство Transcutaneous Spinal cord Stimulation
  Delivered using a constant-current stimulator
• Устройство Epidural Spinal Stimulation (ESS)
  The device used for ESS, the CoverEdgeX 32 Surgical Lead system (Boston Scientific, USA), is a device approved by the FDA used in the treatment of severe pain and is approved for individuals to manage chronic pain when other treatments have not been effective. If you are in the ESS group, you will have surgery to have the stimulator placed and the stimulator will be removed at an office visit towards the end of the study.

Первичные конечные точки

• Assessment of force generation by lower limbs [Срок оценки: Baseline 1(week 1), baseline 2(week 6), post interventions (week 11), and follow up (week 16)]

Вторичные конечные точки (2)

• Assessment of neurological status [Срок оценки: Baseline 1(week 1), baseline 2(week 6), post interventions (week 11), and follow up (week 16)]
• Assessment of Independence [Срок оценки: Baseline 1(week 1), baseline 2(week 6), post interventions (week 11), and follow up (week 16)]

Критерии участия

Критерии включения

• All participants must be able to provide a provision of a signed and dated informed consent form.
• Stated willingness to comply with all study procedures and availability for the duration of the study.
• Male or female, aged 22-75 years old.
• Documentation from the participant's primary treating physician confirming a stable medical condition.
• Inability to maintain standing independently without external support due to SCI AIS A-C.
• Ability to tolerate at least 15 minutes in an upright (supported) position.
• Able to self-transfer from the wheelchair and demonstrate active range of motion of bilateral upper extremities in gravity dependent plane.
• Able to passively range bilateral lower extremities within normal mobility parameters including:

• greater than 90 degrees of hip flexion and 165 degrees of hip extension;
• greater than 90 degrees of knee flexion and reach neutral knee extension of 180 degrees;
• neutral ankle position reaching a minimum of 90 degrees of dorsiflexion.
• Participants should be on a stable intrathecal baclofen or oral anti-spasticity regimen/dose for the period of the study unless advised otherwise by their physician.
• 1 to 30 years post spinal cord injury.
• Non-progressive spinal cord injury.
• Neurological level of injury below C4 and above T12 (excluding conus injury and/or indications of lower motor neuron injury).
• Eligible for fMRI per safety questionnaire.
• Women of childbearing potential must agree to the use of an effective means of avoiding pregnancy for the duration of the study.
• Able to commit to the full study.

Критерии исключения

• Ability to maintain standing independently without external support.
• Currently involved in another rehabilitation training of the lower extremities.
• Active pressure sores, unhealed bone fractures, peripheral neuropathies, or painful musculoskeletal dysfunction (including but not limited to contractures in the upper and lower extremities).
• Any ongoing medical condition which would preclude participant from regular physical activity (including but not limited to: cardiopulmonary disease, uncontrollable autonomic dysreflexia or orthostatic hypotension, active urinary tract infections, pregnant or nursing).
• Intrathecal baclofen pump therapy for spasticity not compatible with 3T MRI.
• Must not have received Botox injections to primary lower extremity and trunk musculature within the past 3 months, resulting in absence of muscle tone and precluding response to electrical stimulation therapy.
• Current or history of neuromuscular conditions (including but not limited to: unhealed ligament of muscular tears in the upper or lower extremities, pain in weight bearing positions for upper and lower extremities).
• Clinically significant depression, psychiatric disorders, or ongoing drug abuse, including heavy alcohol use.
• Any reason the PI or treating physician may deem as harmful to the participant to enroll or continue in the study.
• Body Mass Index (BMI) over 30.
• Pregnancy.
• Use a ventilator or diaphragmatic pacer.
• Participants with the following conditions will be excluded from TMS, but may take part in the overall study:

• Personal or first-degree family history of seizures or epilepsy.
• Metal in the head, except mouth implants.
• History of suicide attempts.
• History of intracranial lesions, increased intracranial pressure, or stroke.
• Current use of tricyclic anti-depressants, selective serotonin reuptake inhibitors (SSRIs), serotonin nor-epinephrine reuptake inhibitors (SNRIs), buproprion (Wellbutrin), or tramadol.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Простое слепое

Основная цель

Лечение

Центры проведения

США · 1 центр

• Houston Methodist Hospital — Houston

Публикации

• Biering-Sorensen F, Hansen B, Lee BS. Non-pharmacological treatment and prevention of bone loss after spinal cord injury: a systematic review. Spinal Cord. 2009 Jul;47(7):508-18. doi: 10.1038/sc.2008.177. Epub 2009 Jan 27. PMID 19172152
• Harkema SJ, Ferreira CK, van den Brand RJ, Krassioukov AV. Improvements in orthostatic instability with stand locomotor training in individuals with spinal cord injury. J Neurotrauma. 2008 Dec;25(12):1467-75. doi: 10.1089/neu.2008.0572. PMID 19118454
• Agarwal S, Triolo RJ, Kobetic R, Miller M, Bieri C, Kukke S, Rohde L, Davis JA Jr. Long-term user perceptions of an implanted neuroprosthesis for exercise, standing, and transfers after spinal cord injury. J Rehabil Res Dev. 2003 May-Jun;40(3):241-52. PMID 14582528
• Walter JS, Sola PG, Sacks J, Lucero Y, Langbein E, Weaver F. Indications for a home standing program for individuals with spinal cord injury. J Spinal Cord Med. 1999 Fall;22(3):152-8. doi: 10.1080/10790268.1999.11719564. PMID 10685379
• Fernhall B, Heffernan K, Jae SY, Hedrick B. Health implications of physical activity in individuals with spinal cord injury: a literature review. J Health Hum Serv Adm. 2008 Spring;30(4):468-502. PMID 18236700
• Anneken V, Hanssen-Doose A, Hirschfeld S, Scheuer T, Thietje R. Influence of physical exercise on quality of life in individuals with spinal cord injury. Spinal Cord. 2010 May;48(5):393-9. doi: 10.1038/sc.2009.137. Epub 2009 Oct 20. PMID 19841634
• Snoek GJ, IJzerman MJ, Hermens HJ, Maxwell D, Biering-Sorensen F. Survey of the needs of patients with spinal cord injury: impact and priority for improvement in hand function in tetraplegics. Spinal Cord. 2004 Sep;42(9):526-32. doi: 10.1038/sj.sc.3101638. PMID 15224087
• Sayenko DG, Rath M, Ferguson AR, Burdick JW, Havton LA, Edgerton VR, Gerasimenko YP. Self-Assisted Standing Enabled by Non-Invasive Spinal Stimulation after Spinal Cord Injury. J Neurotrauma. 2019 May 1;36(9):1435-1450. doi: 10.1089/neu.2018.5956. Epub 2018 Dec 15. PMID 30362876

Идентификаторы

NCT: NCT06213012 · PRO00037483 · 5R01NS119587-02

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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