Evolution of Learned Nonuse in Stroke Hemiparesis

描述（由申请人提供）：最近开发的用于亚急性-慢性卒中后轻偏瘫的康复计划，约束诱导运动疗法（CI疗法），由于其成功地从基础神经科学研究转化而来，并且在许多随机对照临床试验中证明了其有效性，因此已被越来越多地采用，迄今为止已在全球300多项研究中进行了研究。 该疗法的主要价值在于，当肢体具有足够的运动能力来完成日常生活任务时，改善麻痹上肢在现实生活环境中的自发使用。中风后瘫痪肢体的使用减少，被称为习得性不使用（LNU），被假设是由于瘫痪肢体参与现实世界活动的行为抑制，由于其反复无效的运动尝试，同时有效的补偿较少受影响的上肢。 然而，尽管基础神经科学研究已经通过详细的观察支持轻偏瘫动物模型中的LNU制剂，并且慢性期的许多CI治疗试验的结果表明中风患者在治疗前已经发展了LNU，但LNU假设迄今尚未在人类中进行测试。 拟议的2年研究将通过纵向评估急性轻偏瘫卒中患者（N = 66）在生活环境中的自发性麻痹肢体使用和实验室中的最大运动能力的有效措施来解决这一知识差距。患者将在卒中后7-10天进行评估，并在3个月时再次进行评估。假设不使用（定义为最大运动能力和同时自发肢体使用之间的差异）在此期间增加，与学习机制一致。拟议的研究将前瞻性地确定在这段时间内，不使用是否会显著增加，正如LNU假设所预测的那样。协调性、灵巧性、触觉敏感性、握力、肢体张力、疼痛、抑郁、空间注意力和一般卒中损伤的同步临床评价将确定这些因素是否调节LNU。还将评价脑MRI弥散加权成像上急性缺血性损伤的程度，特别是皮质脊髓束大脑过程的损伤程度，以确定其对LNU的贡献。 研究结果将确定LNU的证据是否发生在急性-亚急性卒中后阶段，以及是否与临床或结构神经影像学相关。这一发现将有助于进一步了解急性亚急性轻偏瘫卒中期间神经功能的连续纵向变化，这些变化与轻瘫肢体的运动有关，以及这些变化如何调节肢体的不使用。研究结果将用于支持中风后LNU的流行病学和神经科学机制的后续扩展研究提案，这对于改善中风幸存者的神经康复治疗非常重要。 公共卫生相关性：这项提议将测试有关习得性不使用的起源的假设，这是减少日常使用的手臂，已受损的中风，当手臂仍然有足够的运动能力来执行日常生活活动。不使用似乎通常发生在中风后，并且已经发现在特定形式的运动疗法，特别是约束诱导运动疗法（CI疗法）后显著且有益地改善。该研究预计将提供试点数据，以帮助确定中风中学习性不使用的频率以及预测其发作的临床因素，这反过来将有助于改善中风康复模型，这些模型将在以后更全面的资助提案中进一步测试。

DESCRIPTION (provided by applicant): A recently developed rehabilitation program for subacute-chronic post-stroke hemiparesis, Constraint-Induced Movement therapy (CI therapy), has become increasingly adopted, and has been investigated worldwide in over 300 studies to date, due to its successful translation from basic neuroscience research studies and its demonstrated efficacy in numerous randomized controlled clinical trials. The therapy's principal value is for improving the spontaneous use of the paretic upper extremity in the real-life setting when the limb has sufficient movement ability to complete daily living tasks. The reduced use of the paretic limb post-stroke, termed learned nonuse (LNU), is hypothesized to result from the behavioral suppression of the paretic limb's participation in real-world activities due to its repeated ineffectual movement attempts and simultaneously effective compensation by the less-affected upper extremity. However, although basic neuroscience research has supported the LNU formulation in animal models of hemiparesis through detailed observations, and outcomes from numerous CI therapy trials in the chronic phase have suggested that stroke patients had developed LNU before treatment, the LNU hypothesis thus far has not been tested in humans. The proposed 2 year research will address this knowledge gap by longitudinally evaluating acutely hemiparetic stroke patients (N = 66) on validated measures of spontaneous paretic limb use in the life setting and maximal movement ability in the laboratory. Patients will be evaluated at 7-10 days post-stroke and again at 3 months. Nonuse (defined as the difference between maximal movement ability and simultaneous spontaneous limb use) is hypothesized to increase during this period, consistent with a learning mechanism. The proposed research will prospectively determine whether nonuse significantly increases over this time interval, as predicted by the LNU hypothesis. Concurrent clinical evaluations of coordination, dexterity, tactile sensitivity, grip strength, limb tone, pain, depression, spatial attention, and general stroke impairment will determine whether these factors modulate LNU. The extent of acute ischemic injury on Diffusion-Weighted Imaging on brain MRI, and in particular the extent of injury to the cerebral course of the corticospinal tract, will also be evaluated for their contribution to LNU. The findings will determine whether evidence for LNU occurs in the acute-subacute poststroke phase and whether it has clinical or structural neuroimaging correlates. The findings will help to improve understanding the sequential longitudinal changes of neurologic functions during acute-subacute hemiparetic stroke that relate to movement of the paretic limb and how these may modulate limb nonuse. The findings will be used to support subsequent extended research proposals on the epidemiology and neuroscientific mechanisms of LNU after stroke, which will be important for improving the delivery of neurologic rehabilitation to stroke survivors. PUBLIC HEALTH RELEVANCE: This proposal will test hypotheses concerning the origin of learned nonuse, which is the reduction in the amount of daily use by the arm that has been impaired by stroke, when the arm nonetheless has sufficient movement ability to perform daily living activities. Nonuse appears to commonly occur after stroke and has been found to significantly and enduringly improve after specific forms of movement therapy, particularly Constraint-Induced Movement therapy (CI therapy). The research is expected to provide pilot data to help determine how frequently learned nonuse occurs in stroke and what clinical factors predict its onset, which in turn would help to improve models for stroke rehabilitation that will be tested further in later, more comprehensive funding proposals.