Enhancing Recovery after Chronic Bilateral Cervical Spinal Cord Injury with Targeted Plasticity Therapy

通过靶向可塑性治疗促进慢性双侧颈脊髓损伤后的恢复

• 批准号: 10413146
• 负责人: MICHAEL P KILGARD
• 金额: $ 33.47万
• 依托单位: UNIVERSITY OF TEXAS DALLAS
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10413146
• 关键词: Affect; Anatomy; Animal Model; Basal Nucleus of Meynert; Bilateral; Brain; Brain hemorrhage; Cervical; Cervical spinal cord injury; Cervical spinal cord structure; Chronic; Clinical; Clinical Research; Clinical Trials; Contusions; Development; Enrollment; Evaluation; Forelimb; Goals; Impairment; Individual; Ischemic Stroke; Lead; Lesion; Modeling; Motor; Motor Cortex; Movement; Neuromodulator; Neuronal Plasticity; Pathway interactions; Patient-Focused Outcomes; Patients; Pharmacology; Physical Rehabilitation; Population; Rattus; Recovery; Recovery Support; Recovery of Function; Rehabilitation therapy; Role; Spinal; Spinal Cord; Spinal cord damage; Spinal cord injury; Spinal cord injury patients; Synapses; System; Techniques; Testing; Training; Translations; Traumatic Brain Injury; Upper Extremity; Ursidae Family; Viral; base; cholinergic; chronic stroke; clinical translation; clinically relevant; clinically significant; comorbidity; disability; effectiveness evaluation; experimental study; first-in-human; human study; improved; locus ceruleus structure; microstimulation; motor function recovery; motor recovery; neuroregulation; noradrenergic; novel therapeutic intervention; patient population; pre-clinical; stroke patient; vagus nerve stimulation

PROJECT ABSTRACT Spinal cord injury (SCI) is a major cause of disability, currently affecting 276,000 individuals in the U.S. alone and millions more worldwide. Cervical SCI (cSCI) accounts for 55% of all SCIs and typically results in impaired upper extremity motor function. The majority of cSCI patients have bilateral damage to the spinal cord. Identifying and developing rehabilitative therapies that promote recovery of upper extremity function after bilateral cSCI is of great clinical importance. We propose to evaluate a novel therapeutic intervention which uses precisely timed stimulation of the vagus nerve paired with rehabilitative training. Pairing vagus nerve stimulation (VNS) with movement engages pro- plasticity neuromodulatory systems and results in highly specific, long-lasting neuroplasticity in rat motor cortex. Based on this enhancement of plasticity, our recent results demonstrate that VNS paired with rehabilitation significantly enhances recovery of forelimb motor function in rat models of ischemic stroke, hemorrhagic stroke, and traumatic brain injury. Moreover, our preliminary results suggest that VNS therapy is effective in a unilateral model of SCI. To test this in a model that more accurately represents the clinical SCI population, we propose to evaluate VNS paired with rehabilitative training in a model of chronic, bilateral cSCI and examine the neuroplasticity in cortical and spinal motor networks that may underlie recovery. In addition, we will define the role of two key neuromodulatory systems, the cholinergic and noradrenergic systems, in recovery after SCI. We hypothesize the VNS paired with rehabilitative training will support functional and anatomical plasticity in descending motor networks to enhance recovery of function after bilateral cSCI. The results of the proposed experiments will clarify the relationship between bilateral cervical spinal damage, neuroplasticity, neuromodulatory function, and upper limb motor recovery. Moreover, this proposal will provide a proof-of-concept evaluation of VNS paired with rehabilitative training to improve recovery of forelimb function after a severe bilateral SCI and elucidate the mechanisms that support recovery.

项目摘要 脊髓损伤（SCI）是残疾的主要原因，目前仅在美国就有276，000人受到影响 全世界还有数百万人颈椎SCI（cSCI）占所有SCI的55%，通常会导致脊髓损伤。 上肢运动功能大多数cSCI患者的脊髓都有双侧损伤。 确定和发展康复治疗，促进上肢功能的恢复后， 双侧颈脊髓损伤具有重要的临床意义。 我们建议评估一种新的治疗干预，使用精确定时的迷走神经刺激 神经再加上康复训练将迷走神经刺激（VNS）与运动配对， 可塑性神经调节系统，并导致高度特异性，持久的神经可塑性，在大鼠运动 皮层基于这种可塑性的增强，我们最近的研究结果表明，VNS与 康复显著增强缺血性中风大鼠模型中前肢运动功能的恢复， 出血性中风和创伤性脑损伤此外，我们的初步结果表明，迷走神经刺激治疗是 在单侧SCI模型中有效。为了在更准确地代表临床SCI的模型中测试这一点， 人群中，我们建议在慢性双侧cSCI模型中评估VNS与康复训练配对 并检查可能是恢复基础的皮层和脊髓运动网络的神经可塑性。此外，本发明还提供了一种方法， 我们将定义两个关键的神经调节系统，胆碱能和去甲肾上腺素能系统， SCI后的康复我们假设VNS与康复训练相结合将支持功能和 下行运动网络的解剖可塑性，以增强双侧cSCI后的功能恢复。 实验结果将阐明双侧颈椎损伤， 神经可塑性、神经调节功能和上肢运动恢复。此外，该提案将提供 VNS结合康复训练改善前肢功能恢复的概念验证评估 在严重的双侧SCI后，并阐明支持恢复的机制。

项目成果

How to fail with paired VNS therapy.

配对 VNS 疗法如何失败。

• DOI: 10.1016/j.brs.2023.08.009
• 发表时间: 2023
• 期刊: Brain stimulation
• 影响因子: 7.7
• 作者: Hays,SethA;Rennaker2nd,RobertL;Kilgard,MichaelP
• 通讯作者: Kilgard,MichaelP

Radial nerve injury causes long-lasting forelimb sensory impairment and motor dysfunction in rats.

• DOI: 10.1097/pr9.0000000000000957
• 发表时间: 2021-09
• 期刊: Pain reports
• 影响因子: 4.8
• 作者: Adcock KS;Hulsey DR;Danaphongse T;Haider Z;Morrison RA;Kilgard MP;Hays SA
• 通讯作者: Hays SA

Vagus Nerve Stimulation as a Potential Adjuvant to Rehabilitation for Post-stroke Motor Speech Disorders.

• DOI: 10.3389/fnins.2021.715928
• 发表时间: 2021
• 期刊: Frontiers in neuroscience
• 影响因子: 4.3
• 作者: Morrison RA;Hays SA;Kilgard MP
• 通讯作者: Kilgard MP

The tactile experience paired with vagus nerve stimulation determines the degree of sensory recovery after chronic nerve damage.

• DOI: 10.1016/j.bbr.2020.112910
• 发表时间: 2021-01-01
• 期刊: Behavioural brain research
• 影响因子: 2.7
• 作者: Darrow MJ;Mian TM;Torres M;Haider Z;Danaphongse T;Seyedahmadi A;Rennaker RL 2nd;Hays SA;Kilgard MP
• 通讯作者: Kilgard MP

Restoration of Somatosensory Function by Pairing Vagus Nerve Stimulation with Tactile Rehabilitation.

• DOI: 10.1002/ana.25664
• 发表时间: 2020-02
• 期刊: ANNALS OF NEUROLOGY
• 影响因子: 11.2
• 作者: Darrow, Michael J.;Mian, Tabarak M.;Torres, Miranda;Haider, Zainab;Danaphongse, Tanya;Rennaker, Robert L., Jr.;Kilgard, Michael P.;Hays, Seth A.
• 通讯作者: Hays, Seth A.