Brain Stimulation- aided Stroke Rehabilitation: Neural Mechanisms of Recovery

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，一个是中风康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，专门针对患者特定的疾病和康复机制定制干预措施。她在这份申请中提出的短期目标，将进一步帮助她进行培训，帮助她朝着长期目标前进。作为一名对中风偏瘫上肢残存缺陷的机制和治疗感兴趣的物理治疗师，候选人决定攻读康复科学博士学位，重点是神经科学。她发现，使用功能磁共振成像(FMRI)，基于技能学习的康复通过促进运动皮质的神经可塑性，促进了偏瘫上肢的恢复。在她的博士后研究期间，她开始对使用非侵入性脑刺激(经颅磁刺激和经颅直流电刺激)直接调节幸存大脑皮层的可塑性以提高康复疗效感兴趣。在一项小型的先导性研究中，候选人证实了在卒中后视力恢复中，将存活的高视力区域的tDCs与同时进行视觉康复相结合的协同优势。这些发现激发了她将这一范例转化为减轻瘫痪上肢缺陷的兴趣。 候选人建议应用这一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)，该方法通过促进皮质网络的适应性可塑性来缓解残留的缺陷，但由于其劳动密集型方案和不足的收获，其临床实用性较差。通过在CIMT过程中结合皮质刺激，候选患者的前提是其效率和疗效可以提高。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质刺激与偏瘫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质(M1)作为刺激的目标，这可能在人类中的生存能力有限，以及对恢复机制的缺乏了解。目前的建议将通过靶向刺激较高运动区-前额叶皮质(PMC)来解决临床研究中的这些空白，PMC距离较远，但与M1连接良好，具有独立的皮质-脊髓束，并通过康复表现出适应性可塑性。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)以及皮质驱动和瘫痪肌肉之间的耦合(EEG-EMG)来探索全面的结构和功能恢复的神经机制。这些多模式技术的独特而互补的性质将增加对康复功能潜力的预测，并揭示中风患者神经运动恢复的完整图景。因此，该提案的研究目标是：1)比较TDC加CIMT和单独CIMT在改善慢性卒中偏瘫上肢功能方面的有效性。2)应用多模式结构和功能成像技术，从基线到康复后，探索和比较TDC加CIMT和单纯CIMT的神经恢复机制。30名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，为期5周。 尽管候选人在之前的培训中获得了重要的技能，如进行基于实验室的康复研究，使用功能磁共振成像、TMS和tdcs，但她需要额外的培训来实现研究目标。因此，她的短期目标是：1)培训临床康复研究，通过教学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)培训多模式结构和功能神经成像，以学习DTI、fcMRI和EEG-EMG分析，它们与功能磁共振成像和TMS的相互作用，以及进行研究目标2.候选人的短期目标将提供她在进行随机临床试验方面的经验，为神经康复创造证据基础。此外，通过揭示康复机制，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必要的支持和资源。她作为项目科学家的职位为研究提供了100%受保护的时间。跨研究所的合作，即勒纳研究-生物医学工程、物理医学与康复、神经学和成像研究所创造了一支由知名导师和合作者组成的理想的多学科团队，以促进她的学习。指导团队包括1)一位将培训候选人脑电-肌电的著名神经生理学家，2)一位在应用脑刺激方面具有临床研究专长的领先的功能和立体定位神经外科医生，他将培训她识别中风脑中的PMC靶点，3)一位在开发DTI和fcMRI最新分析方面经验的著名成像物理学家，以及4)一位神经放射科医生，他已经开发出复杂的成像分析来解决损伤影响。

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.