Brain Stimulation- aided Stroke Rehabilitation: Neural Mechanisms of Recovery

脑刺激辅助中风康复：恢复的神经机制

• 批准号: 8878831
• 负责人: Ela B Plow
• 金额: $ 11.04万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-10 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8878831
• 关键词: Address; Affect; Algorithms; Animals; Area; Bilateral; Biomedical Engineering; Brachial Paresis; Brain; Clinic; Clinical; Clinical Research; Clinical Trials; Clinical Trials Design; Collaborations; Complement; Corticospinal Tracts; Coupling; Decision Making; Diffusion Magnetic Resonance Imaging; Disease; Doctor of Philosophy; Effectiveness; Electroencephalography; Electromyography; Equilibrium; Fellowship; Functional Imaging; Functional Magnetic Resonance Imaging; Goals; Health Care Costs; Human; Image; Image Analysis; Impairment; Institutes; Instruction; Intervention; K-Series Research Career Programs; Laboratories; Learning; Lesion; Limb structure; Magnetism; Maps; Mentors; Methods; Motor; Motor Activity; Motor Cortex; Muscle; Nature; Neurologic; Neuronal Plasticity; Neurorehabilitation; Neurosciences; Neurosurgeon; Paresis; Patients; Performance; Physical Medicine; Physical Rehabilitation; Pilot Projects; Positioning Attribute; Postdoctoral Fellow; Protocols documentation; Randomized; Randomized Clinical Trials; Recovery; Recovery of Function; Rehabilitation therapy; Research; Residual state; Resources; Scientist; Spinal; Stroke; Techniques; Testing; Therapeutic; Time; Training; Transcranial magnetic stimulation; Translating; Upper Extremity; Visual; Wolves; base; chronic stroke; clinical practice; clinically relevant; compare effectiveness; constraint induced movement therapy; cortex mapping; design; evidence base; experience; extrastriate visual cortex; follow-up; functional outcomes; improved; improved functioning; interest; motor recovery; neuroimaging; neuromechanism; novel; post stroke; preclinical study; rehabilitation science; restraint; skills; spinal tract; stem; stroke recovery; stroke rehabilitation

DESCRIPTION (provided by applicant): The candidate's training, thus far, has involved two major themes, one as a rehabilitation scientist in the field of stroke recovery and the other as a neuroscientist with interest in revealing and modulating the underlying mechanisms. The candidate's long-term goal is to become a successful, independent clinical neuro-rehabilitation scientist specializing in customizing interventions to patient-specific mechanisms of disease and recovery. Her short term goals, proposed in this application, will further her training to help advance her towards her long term goal. As a physical therapist intrigued by the mechanisms and treatment of residual deficits of paretic upper limb in stroke, the candidate decided to pursue PhD in Rehabilitation Science with a focus in Neuroscience. She found, using functional Magnetic Resonance Imaging (fMRI), that skill learning-based rehabilitation enhanced recovery of the paretic upper limb by promoting neuroplasticity in motor cortices. In her post-doctoral fellowship, she became interested in directly modulating plasticity in the surviving cortices using non-invasive brain stimulation (Transcranial Magnetic Stimulation, TMS, and Transcranial Direct Current Stimulation, tDCS) to enhance efficacy of rehabilitation. In a small pilot study, the candidate confirmed the synergistic advantage of combining tDCS of the surviving higher visual areas with concurrent visual rehabilitation in post-stroke visual recovery. These findings engendered her interest in translating this paradigm to alleviate deficits of the paretic upper limb. The candidate proposes to apply this paradigm to improve the effectiveness of a novel, clinical rehabilitative method, called Constraint-Induced Movement Therapy (CIMT), which alleviates residual deficits by promoting adaptive plasticity in the cortical networks, but has poor clinical utility due to its labor-intensive protocols and inadequate gains. By combining cortical stimulation during CIMT, the candidate premises that its efficiency and efficacy could be improved. Unlike animal and preclinical studies, however, two clinical trials failed to support the efficacy of combining motor cortical stimulation with rehabilitation of the paretic upper limb. In a critical appraisal, the candidate concluded that discrepancies stem from over-reliance on the surviving motor cortex (M1) as a target for stimulation, which may have limited viability in humans, and lack of understanding of mechanisms of recovery. The current proposal will address these gaps in clinical research by targeting stimulation of a higher motor area, Premotor Cortex (PMC), which is remote, yet well connected to M1, has independent cortico-spinal tracts, and demonstrates adaptive plasticity with rehabilitation. Further, the candidate proposes to explore comprehensive structural and functional neural mechanisms of recovery using Diffusion Tensor Imaging (integrity of corticospinal tracts), TMS (functioning of corticospinal tracts), fMRI (balance between bilateral motor cortices), fcMRI (functional connectivity between multiple cortices) and coupling between cortical drive and paretic muscle (EEG-EMG). The unique yet complementary nature of these multi-modal techniques will increase the prediction of functional potential of recovery and reveal a complete picture of neuro-motor recovery in stroke. Thus, the research goals for the proposal are: 1) to compare the effectiveness of tDCS, delivered to surviving PMC, plus CIMT versus CIMT delivered alone in improving function of the paretic upper limb in chronic stroke. 2) To explore and contrast neural mechanisms of recovery underlying tDCS plus CIMT versus CIMT alone using multimodal structural and functional imaging from baseline to post-rehabilitation. Thirty patients will be randomly assigned to one of two groups and training will last 30 min, 3 days/week for 5 weeks. Although the candidate has gained important skills in her previous training, such as conducting laboratory-based rehabilitation studies, use of fMRI, TMS and tDCS, she requires additional training to achieve the research aims. Thus, her short-term goals are: 1) to train in Clinical Rehabilitative Research to understand clinical trial design and analyses through instruction, and research with mentors and collaborators to accomplish research aim 1 and 2) to train in Multimodal Structural and Functional Neuroimaging to learn DTI, fcMRI and EEG-EMG analyses, their interaction with fMRI and TMS, and lesions to conduct research aim 2. The candidate's short-term goals will provide her experience in conducting randomized clinical trials to create an evidence-base for neuro-rehabilitation. Further, by revealing mechanisms of recovery, an algorithm for patient-specific interventions could be devised, which will advance her towards her long-term goal. Her current position at the Cleveland Clinic provides the required support and resources for her aims. Her position as a Project Scientist offers 100% protected time for research. Collaborations across institutes, i.e., Lerner Research - Biomedical Engineering, Physical Medicine & Rehabilitation, Neurological and Imaging Institutes have created an ideal, multi-disciplinary team of established mentors and collaborators to further her learning. The mentoring team includes 1) an eminent neurophysiologist who will train the candidate in EEG-EMG, 2) a leading functional and stereotaxic neurosurgeon with clinical research expertise in applying brain stimulation who will train her to identify PMC targets in stroke brains, 3) a renowned imaging physicist with experience in developing the latest analyses for DTI and fcMRI and 4) a neuroradiologist who has developed sophisticated imaging analyses to address lesion effects.

描述（由申请人提供）：到目前为止，候选人的培训涉及两个主要主题，一个是中风恢复领域的康复科学家，另一个是对揭示和调节潜在机制感兴趣的神经科学家。候选人的长期目标是成为一名成功的，独立的临床神经康复科学家，专门从事定制干预患者特定的疾病和恢复机制。她的短期目标，在这个应用程序中提出，将进一步她的培训，以帮助推进她对她的长期目标。 作为一名物理治疗师，他对中风中瘫痪上肢的残余缺陷的机制和治疗很感兴趣，因此决定攻读康复科学博士学位，重点是神经科学。她发现，使用功能性磁共振成像（fMRI），技能学习为基础的康复促进运动皮层的神经可塑性，提高偏瘫上肢的恢复。在她的博士后研究中，她开始对使用非侵入性脑刺激（经颅磁刺激，TMS和经颅直流电刺激，tDCS）直接调节幸存皮层的可塑性感兴趣，以提高康复的效果。在一项小型试点研究中，该候选人证实了在卒中后视力恢复中将幸存的较高视觉区域的tDCS与同时进行的视力康复相结合的协同优势。这些发现引起了她的兴趣，翻译这一范例，以减轻缺陷的麻痹上肢。 候选人建议应用这种范式来提高一种新的临床康复方法的有效性，称为约束诱导运动疗法（CIMT），该方法通过促进皮层网络的自适应可塑性来消除残余缺陷，但由于其劳动密集型协议和收益不足，临床实用性较差。通过在CIMT期间结合皮层刺激，候选前提是其效率和功效可以提高。然而，与动物和临床前研究不同，两项临床试验未能支持运动皮层刺激与瘫痪上肢康复相结合的疗效。在一次关键的评估中，候选人得出结论，差异源于过度依赖幸存的运动皮层（M1）作为刺激目标，这可能限制了人类的生存能力，以及缺乏对恢复机制的理解。 目前的提案将通过靶向刺激更高的运动区域来解决临床研究中的这些差距，前运动皮质（PMC）是远程的，但与M1连接良好，具有独立的皮质脊髓束，并表现出康复的适应性可塑性。此外，候选人建议使用扩散张量成像（皮质脊髓束的完整性），TMS（皮质脊髓束的功能），fMRI（双侧运动皮质之间的平衡），fcMRI（多个皮质之间的功能连接）以及皮质驱动和轻瘫肌肉之间的耦合（EEG-EMG）来探索全面的结构和功能神经恢复机制。这些多模式技术的独特而互补的性质将增加对恢复功能潜力的预测，并揭示中风神经运动恢复的全貌。 因此，该提案的研究目标是：1）比较tDCS（输送至存活PMC）+CIMT与单独输送CIMT在改善慢性卒中中麻痹上肢功能方面的有效性。2)使用多模态结构和功能成像，从基线到康复后，探索和对比tDCS + CIMT与单独CIMT的恢复神经机制。30例患者将被随机分配到两组中的一组，训练将持续30分钟，每周3天，持续5周。 虽然候选人在之前的培训中获得了重要的技能，例如进行基于实验室的康复研究，使用fMRI，TMS和tDCS，但她需要额外的培训才能实现研究目标。因此，她的短期目标是：1）在临床参考研究中进行培训，通过指导了解临床试验设计和分析，并与导师和合作者进行研究，以实现研究目标1和2）在多模态结构和功能神经成像中进行培训，学习DTI，fcMRI和EEG-EMG分析，它们与fMRI和TMS的相互作用，以及进行研究目标2的病变。候选人的短期目标将提供她进行随机临床试验的经验，为神经康复创造证据基础。此外，通过揭示恢复机制，可以设计出针对患者的干预算法，这将推动她实现长期目标。 她目前在克利夫兰诊所的职位为她的目标提供了所需的支持和资源。她作为项目科学家的职位提供了100%的研究时间。各机构之间的合作，即， 勒纳研究-生物医学工程，物理医学与康复，神经和成像研究所已经建立了导师和合作者的理想，多学科团队，以进一步她的学习。指导团队包括1）一位杰出的神经生理学家，他将对候选人进行EEG-EMG培训，2）一位领先的功能和立体定位神经外科医生，具有应用脑刺激的临床研究专业知识，他将培训她识别中风脑中的PMC目标，3）著名的成像物理学家，具有开发DTI和fcMRI最新分析的经验，以及4）一位神经放射学家，他开发了复杂的成像分析来解决病变的影响。

项目成果

The effect of motor overflow on bimanual asymmetric force coordination.

• DOI: 10.1007/s00221-016-4867-2
• 发表时间: 2017-04
• 期刊: Experimental brain research
• 影响因子: 2
• 作者: Cunningham DA;Roelle SM;Allexandre D;Potter-Baker KA;Sankarasubramanian V;Knutson JS;Yue GH;Machado AG;Plow EB
• 通讯作者: Plow EB

Combined Brain and Peripheral Nerve Stimulation in Chronic Stroke Patients With Moderate to Severe Motor Impairment.

• DOI: 10.1111/ner.12717
• 发表时间: 2018-03
• 期刊: Neuromodulation : journal of the International Neuromodulation Society
• 作者: Menezes IS;Cohen LG;Mello EA;Machado AG;Peckham PH;Anjos SM;Siqueira IL;Conti J;Plow EB;Conforto AB
• 通讯作者: Conforto AB

A game of hide and seek: Is it possible to recruit more patients for NIBS studies in stroke?

捉迷藏游戏：是否有可能招募更多患者进行中风 NIBS 研究？

• DOI: 10.1016/j.jns.2015.08.030
• 发表时间: 2015
• 期刊: Journal of the neurological sciences
• 影响因子: 4.4
• 作者: Potter-Baker,KelseyA;Bonnett,CorinE;Chabra,Patrick;Roelle,Sarah;Varnerin,Nicole;Cunningham,DavidA;Sankarasubramanian,Vishwanath;Pundik,Svetlana;Conforto,AdrianaB;Machado,Andre;Plow,ElaB
• 通讯作者: Plow,ElaB

Assessment of behavioral tasks performed by hemiplegic patients with impaired dexterity post stroke.

评估中风后灵活性受损的偏瘫患者执行的行为任务。

• 发表时间: 2017
• 期刊: European review for medical and pharmacological sciences
• 影响因子: 3.3
• 作者: Bashir,S;Caipa,A;Plow,EB
• 通讯作者: Plow,EB

Stimulation targeting higher motor areas in stroke rehabilitation: A proof-of-concept, randomized, double-blinded placebo-controlled study of effectiveness and underlying mechanisms.

• DOI: 10.3233/rnn-150574
• 发表时间: 2015
• 期刊: Restorative neurology and neuroscience
• 影响因子: 2.8
• 作者: Cunningham DA;Varnerin N;Machado A;Bonnett C;Janini D;Roelle S;Potter-Baker K;Sankarasubramanian V;Wang X;Yue G;Plow EB
• 通讯作者: Plow EB