Striatal Stimulation for Augmentation of Recovery after Brain Injury

描述（由申请人提供）：本提案的目的是证明脑深部电刺激（DBS）在促进啮齿动物和非人灵长类动物创伤性脑损伤（TBI）后恢复方面的疗效。在过去的十年里，我们的团队广泛研究了纹状体和皮层在学习中的作用，发现刺激尾状核可以增强学习。最近，我们已经取得了一个重要的突破，初步证明，这种方法可以用来加速和提高TBI动物模型的恢复。在本提案中，我们将测试有关最佳大脑位置和刺激模式的具体假设，以获得TBI治疗的最大效果。我们有相当数量的初步数据，在啮齿动物和灵长类动物，证明有一个显着的改善恢复通过使用适当的目标和定时DBS。这项工作具有重大的公共卫生意义，可能会为TBI患者带来新的治疗方式，并可能为患有其他疾病的患者，如中风，阿尔茨海默病或自闭症。 我们小组和其他人的工作表明，尾状核（Cd），伏核（NAcc）和前额叶皮层之间的联系在学习和动机中起着关键作用，这是脑损伤恢复的关键方面。我们的小组还发表了研究表明，镉刺激增强学习超过正常动物的基线率。最近，我们已经收集了初步的数据，联合刺激的镉和NAcc导致更大的增强学习，相比，孤立的镉刺激。我们有证据表明，刺激通过增强内在学习回路的功效而不是简单的奖励来起作用。此外，我们在实验室中开发了一种新的能力，可以使用经过验证的TBI动物模型。我们有非常有希望的初步数据表明，间歇性刺激可以促进TBI后的恢复。我们现在寻求支持，以提供明确的证据表明，定时DBS的镉和NAcc可用于加速恢复TBI后。我们将使用啮齿动物和灵长类动物的TBI模型来严格和系统地评估间歇性刺激对功能恢复的影响。此外，我们将采用神经元可塑性和神经发生的组织学研究，提供有关刺激的生物学效应的证据。到资助期结束时，我们将启动第一阶段人体试验。

DESCRIPTION (provided by applicant): The goal of this proposal is demonstrate the efficacy of deep brain stimulation (DBS) in enhancing recovery following traumatic brain injury (TBI) in rodents and non- human primates. Over the past decade our group has extensively studied the role of the striatum and cortex in learning, and found that stimulation in the caudate can enhance learning. More recently, we have made an important breakthrough in demonstrating, in a preliminary fashion, that this approach can be used to accelerate and enhance recovery in an animal model of TBI. In this proposal, we will test specific hypotheses regarding the optimal brain location and mode of stimulation for maximal effect in the treatment of TBI. We have a considerable amount of preliminary data, in both rodents and primates, demonstrating that there is a significant improvement in recovery by using appropriately targeted and timed DBS. This work has great public health significance and may lead to a new treatment modality for TBI patients and potentially for patients with other disorders such as stroke, Alzheimer disease or autism. Work from our group, and others, has demonstrated that connections between the Caudate (Cd), Nucleus Accumbens (NAcc), and prefrontal cortex play a critical role in learning and motivation which are key aspects of recovery from brain injury. Our group has also published studies demonstrating that Cd stimulation enhances learning beyond baseline rates in normal animals. Recently, we have gathered preliminary data that combined stimulation of the Cd and NAcc leads to an even greater enhancement of learning, compared to isolated Cd stimulation. We have evidence suggesting that stimulation works by enhancing efficacy of the intrinsic learning circuitry and not by being simply rewarding. In addition, we have developed a new capability in our laboratory to use a validated animal model of TBI. We have very promising preliminary data that intermittent stimulation can enhance recovery after TBI. We now seek support to provide definitive evidence that timed DBS of the Cd and NAcc can be used to accelerate recovery following TBI. We will use models of TBI in rodents and primates to rigorously and systematically assess the effects of intermittent stimulation on functional recovery. In addition, we will employ histological studies of neuronal plasticity and neurogenesis to provide evidence regarding the biological effects of stimulation. By the end of the funding period, we will be positioned to initiate a Phase I human trial.