Striatal Stimulation for Augmentation of Recovery after Brain Injury

纹状体刺激可促进脑损伤后的恢复

• 批准号: 8739333
• 负责人: Emad N Eskandar
• 金额: $ 51.51万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-30 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8739333
• 关键词: Alzheimer' s Disease; Animal Model; Animals; Autistic Disorder; Behavior; Behavioral; Behavioral Assay; Biological; Brain; Brain Injuries; Brain region; Cognitive; Corpus striatum structure; Data; Deep Brain Stimulation; Disease; Electrodes; Family; Foundations; Funding; Goals; Human; IACUC; Immunohistochemistry; Implant; Implanted Electrodes; Injury; Intrinsic drive; Ipsilateral; Laboratories; Lead; Learning; Lesion; Location; Methods; Modality; Modeling; Motivation; Motor; Mus; Neurites; Neuronal Plasticity; Neurons; Nucleus Accumbens; Patients; Performance; Phase; Play; Positioning Attribute; Prefrontal Cortex; Primates; Protocols documentation; Public Health; Publishing; Quality of life; Reaction Time; Recovery; Recovery of Function; Regimen; Rewards; Rodent; Rodent Model; Role; Severities; Simulate; Staining method; Stains; Stroke; Testing; Time; Training; Traumatic Brain Injury; Work; base; caudate nucleus; classical conditioning; cognitive function; cohort; controlled cortical impact; disability; improved; injured; miniaturize; mouse model; neurogenesis; neurophysiology; nonhuman primate; professor; public health relevance; research study; simulation; success; visual motor

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.

描述（由申请人提供）：本提案的目标是证明深部脑刺激（DBS）在促进啮齿动物和非人类灵长类动物创伤性脑损伤（TBI）后恢复方面的功效。在过去的十年里，我们的小组广泛研究了纹状体和皮层在学习中的作用，发现尾状核的刺激可以增强学习。最近，我们取得了重要突破，初步证明这种方法可用于加速和增强 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，以实现 TBI 治疗的最大效果。我们在啮齿动物和灵长类动物中拥有大量初步数据，表明通过使用适当的针对性和定时 DBS 可以显着改善恢复。这项工作具有重大的公共卫生意义，可能为 TBI 患者以及患有中风、阿尔茨海默病或自闭症等其他疾病的患者带来新的治疗方式。 我们小组和其他小组的工作表明，尾状核 (Cd)、伏隔核 (NAcc) 和前额皮质之间的联系在学习和动机中发挥着关键作用，而学习和动机是脑损伤恢复的关键方面。我们的小组还发表了研究，证明镉刺激可以提高正常动物的学习能力，使其超出基线水平。最近，我们收集到的初步数据表明，与单独的 Cd 刺激相比，Cd 和 NAcc 的联合刺激可以更大程度地增强学习效果。我们有证据表明，刺激是通过增强内在学习回路的功效而发挥作用的，而不是简单地通过奖励来发挥作用。此外，我们的实验室还开发了一项新功能，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，证明 Cd 和 NAcc 的定时 DBS 可用于加速 TBI 后的恢复。我们将使用啮齿类动物和灵长类动物的 TBI 模型来严格、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来提供有关刺激的生物学效应的证据。在资助期结束时，我们将启动第一阶段人体试验。