Striatal Stimulation for Augmentation of Recovery after Brain Injury

描述(由申请人提供)：本提案的目标是证明脑深部刺激(DBS)在促进啮齿动物和非人类灵长类动物创伤性脑损伤(TBI)后恢复方面的有效性。在过去的十年里，我们小组广泛地研究了纹状体和皮质在学习中的作用，并发现刺激尾状核可以增强学习。最近，我们取得了一项重要突破，初步证明这种方法可以用来加速和增强脑外伤动物模型的恢复。在这项提案中，我们将测试关于最佳脑位置和刺激模式的特定假设，以获得最大的脑损伤治疗效果。我们有大量啮齿动物和灵长类动物的初步数据，表明通过使用适当的有针对性和适时的DBS，在恢复方面有显著的改善。这项工作具有重大的公共卫生意义，并可能为脑外伤患者带来一种新的治疗方式，并可能为中风、阿尔茨海默病或自闭症等其他疾病患者带来一种新的治疗方式。我们团队和其他人的研究表明，尾状核(Cd)、伏隔核(NAcc)和前额叶皮质之间的联系在学习和动机方面发挥着关键作用，而学习和动机是脑损伤恢复的关键方面。我们小组还发表了一项研究，表明镉刺激可以提高正常动物的学习能力，超过基线水平。最近，我们收集了初步的数据，与单独的CD刺激相比，CD和NAcc的联合刺激导致了更大的学习增强。我们有证据表明，刺激通过提高内在学习回路的效率而起作用，而不是简单地获得回报。此外，我们在实验室开发了一种新的能力，可以使用经过验证的脑外伤动物模型。我们有非常有希望的初步数据表明，间歇刺激可以促进脑外伤后的恢复。我们现在寻求支持，以提供确凿的证据，证明CD和NAcc的定时DBS可用于加速脑损伤后的恢复。我们将使用啮齿动物和灵长类动物的脑损伤模型，严格和系统地评估间歇刺激对功能恢复的影响。此外，我们将使用神经可塑性和神经发生的组织学研究，以提供关于刺激的生物学效应的证据。到资助期结束时，我们将准备启动第一阶段的人体试验。

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.