NEURAL MECHANISMS OF COMPENSATING FOR BRAIN DAMAGE

项目总结 代偿性行为策略的发展绕过损伤以使生命活动成为可能 对出现功能性残疾的可预见的反应。增加对受影响较小的人的依赖， “非偏瘫”，手和手臂表现为中风后的日常活动是一个突出的例子 中风和上肢偏瘫作为一种慢性卒中后损害形式的患病率。这 代偿策略包括主要的行为改变，这些改变在中风后早期就开始了，并有很强的 通过经验依赖机制影响卒中后神经重组模式的可能性 可塑性。这个项目跨期的重点一直是了解神经变化驱动的 通过非轻瘫前肢的代偿经验及其对功能结局的影响，如在 初级运动皮质(M1)梗塞所致慢性上肢损伤的啮齿动物模型。我们 已经证实，学习依赖非偏瘫的前肢与缺血后的 大脑两侧大脑半球的再生反应会影响双侧的行为功能。它对中国的影响 偏瘫的一面是加重了偏瘫肢体运动康复训练的废用性，降低了其疗效。在……里面 在最近的项目期间，我们坚定地将学习的这些有害影响与非妄想症联系在一起 前肢对脑梗塞周边M1功能相关重组的干扰及对突触的促进作用 同一地区的变化。我们还发现，学习使用两个肢体的补偿方式 共同有利于偏瘫侧的单手功能。这些和相关的发现引导我们 假设非偏瘫前肢的单一体验促进了相互竞争的突触变化， 然而，双指甲体验促进了那些合作的，突触变化的模式起中介作用 改善偏瘫患者的前肢功能。我们对突触变化的时间进程缺乏详细的了解 由前肢的经历和明显的证据表明它们相互竞争，以及它们如何与 两手操作的经历是未经检验的。这个项目的一个主要目标是有效地解决这些知识差距 通过利用活体成像方法监测对前肢经验的突触结构反应 当它们随着时间的推移展开时，在梗塞周围的皮质中。另一种是探索双指甲技能培训作为一种 与非偏瘫一方竞争和对抗补偿的有害影响的战略。 具体目的是检验以下假设：(目标1)非偏瘫前肢形状的技能学习 脑梗塞周围M1区的突触连接通过对侧皮质的活动和经胼胝体的投射 降低其对瘫痪患者前肢康复训练的反应性，(目标2)相同的途径 双指甲技能训练对改善偏瘫患者梗死灶周围皮质突触结构的调节作用 前肢功能和(目标3)双指甲技能具有对抗和克服适应不良的能力 非轻瘫前肢的单一体验导致的行为和突触连接模式。

PROJECT SUMMARY The development of compensatory behavioral strategies that circumvent impairments to enable life activities is a predictable response to the onset of functional disability. Increased reliance on the less-affected, "nonparetic", hand and arm for the performance of daily activities after stroke is a prominent example due to the prevalence of stroke and of upper limb hemiparesis as a chronic post-stroke impairment modality. This compensatory strategy involves major behavioral changes which start early after stroke and have strong potential to impact post-stroke neural reorganization patterns via mechanisms of experience-dependent plasticity. The focus of this project across periods has been on understanding neural changes that are driven by compensatory experiences of the nonparetic forelimb and their impact for functional outcome, as studied in rodent models of chronic upper extremity impairments resulting from primary motor cortical (M1) infarcts. We have previously established that learning to rely on the nonparetic forelimb interacts with post-ischemic regenerative responses in both hemispheres to influence behavioral function bilaterally. Its impact for the paretic side is to exacerbate disuse and lessen the efficacy of motor rehabilitative training of the paretic limb. In the most recent project period, we have firmly linked these deleterious effects of learning with the nonparetic forelimb to its disruption of functionally relevant reorganization of peri-infarct M1 and its promotion of synaptic changes in the same region. We have also uncovered that learning compensatory ways of using the two limbs together is beneficial for unimanual function of the paretic side. These and related findings lead us to hypothesize that unimanual experiences of the nonparetic forelimb promote synaptic changes that compete, whereas bimanual experiences promote those that cooperate, with patterns of synaptic change mediating improved paretic forelimb function. We lack detailed knowledge of the time course of the synaptic changes that are promoted by experiences of either forelimb and clear evidence that they compete, and how they vary with bimanual experiences is untested. One major goal for this project is to efficiently tackle these knowledge gaps by capitalizing on in vivo imaging approaches to monitor synaptic structural responses to forelimb experiences in peri-infarct cortex as they unfold over time. Another is to probe the efficacy of bimanual skill training as a strategy for competing with and countering deleterious influences of compensating with the nonparetic side. The specific aims are to test the hypotheses that: (Aim 1) skill learning with the nonparetic forelimb shapes synaptic connectivity in peri-infarct M1 via the activity of contralesional cortex and transcallosal projections to diminish its responsiveness to rehabilitative training of the paretic forelimb, (Aim 2) the same pathway mediates synaptic structural responses in peri-infarct cortex to bimanual skill training that improves paretic forelimb function and (Aim 3) bimanual skills have the capacity to compete with and overcome maladaptive behavioral and synaptic connectivity patterns resulting from unimanual experiences of the nonparetic forelimb.