Neuromodulation approaches for restoring dexterous control following cortical stroke.

项目摘要 在未来15年内，全球范围内导致中风的疾病、残疾和过早死亡的人数将增加一倍。 尽管进行了物理治疗，但约50%的中风幸存者手部功能受损，这严重影响了 日常生活活动和独立性;迫切需要新的治疗方法。其中之一 慢性手功能受损的预测因素包括躯体感觉的缺陷。在这里，我们建议使用 一个系统神经科学和“神经工程”框架，捕捉动态的相互作用， 开发新的基于神经生理学的神经调节， 增强运动功能。Ramanathan等人最近的研究表明，Nature Medicine 2018，在大鼠中恢复， 中风表明，与低频振荡活动（0.5- 4 Hz“LFO”）相关的群体动态跟踪 自发性恢复和皮层刺激可提高LFO功率，也可增强运动功能。 基本的翻译步骤包括测试这种方法是否也适用于旋转的大脑， 执行灵巧的任务。 这项建议的主要实验方法包括监测运动和躯体感觉活动 在非人灵长类动物（NHP）未受影响和受影响半球的灵巧控制期间， 从单侧皮质损伤中恢复线性状态空间模型将被用来描述神经活动 进展，并用于模拟体感输入对运动状态的影响。 这些模型将用于识别低频网络动态何时需要加强的标记， 恢复期和慢性赤字期。根据模型，开环和闭环低- 将测试高频皮层刺激以确定灵活性是否改善。实现这些目标将 为设计专门针对病灶周围振荡活动的治疗方法提供关键模型 低频电刺激，一个新的方向，可以改变我们的能力， 中风后肢体功能。 在这个研究期间，需要在灵长类动物解剖学和电生理学方面进行额外的培训， 在灵长类动物中建立损伤模型，以及与设计相关的材料科学和电气工程 神经调节系统这些领域的知识和技能是完成拟议的 目的，以及在奖学金期后发展独立的研究计划。最后所有 这项工作将在加州大学旧金山分校进行，加州大学旧金山分校以其实验室到临床的翻译工作和独立的 investigators.

PROJECT SUMMARY Stroke-causing illness, disability, and early death is set to double worldwide within the next 15 years. Despite physical therapy, about 50% of stroke survivors have impaired hand function, which strongly impacts activities of daily living and independence; novel treatment methods are urgently required. One of many predictors of chronically impaired hand function includes deficits in somatosensation. Here, we propose to use a systems neuroscience and `neural engineering' framework that captures dynamic interactions across somatosensory and distributed motor networks to develop novel neurophysiological based neuromodulation to enhance motor function. The recent study, Ramanathan et al., Nature Medicine 2018, in rats recovering from a stroke demonstrated that population dynamics linked to low-frequency oscillatory activity (0.5-4Hz “LFO”) tracked spontaneous recovery and cortical stimulation boosted LFO power and could also augment motor function. Essential translational steps involve testing whether this approach also works for gyrated brains during the performance of dexterous tasks. The main experimental approach of this proposal involves monitoring motor and somatosensory activity during dexterous control in unaffected and affected hemispheres of non-human primates (NHPs) following recovery from a unilateral cortical lesion. Linear state space models will be used to describe neural activity progression in perilesional motor cortices, and used to model the effects of somatosensory inputs on motor state. These models will be used to identify markers of when low-frequency network dynamics need strengthening in the recovery phase and chronic deficit phase. Informed by the models, both open-loop and closed-loop low- frequency cortical stimulation will be tested to determine if dexterity improves. Completion of these aims will provide critical models for designing therapeutic approaches that specifically target perilesional oscillatory activity with low frequency electrical stimulation, a new direction that could transform our ability to augment upper extremity function following stroke. In this fellowship period, additional training will be needed in primate anatomy and electrophysiology, creation of injury models in primates, and in material science and electrical engineering related to the design of a neuromodulation system. These areas of knowledge and skills are necessary for completion of the proposed aims, as well as development of an independent research program following the fellowship period. Finally, all work will take place at UCSF, renowned for its lab-to-clinic translational work and training of independent investigators.