Longitudinal multimodal mapping to decipher the neurovascular impact of microinfarcts

纵向多模态映射破译微梗塞对神经血管的影响

• 批准号: 9762529
• 负责人: Lan Luan
• 金额: $ 47.48万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9762529
• 关键词: Acute; Aging; Anesthesia procedures; Animal Model; Animals; Behavior assessment; Behavioral; Brain; Brain Injuries; Brain region; Cerebrovascular Circulation; Cerebrovascular Disorders; Chronic; Clinical; Detection; Electrodes; Electrophysiology (science); Event; Evolution; Functional Imaging; Goals; Histologic; Human; Image; Imaging Techniques; Impaired cognition; Impairment; Individual; Infarction; Intervention; Investigation; Lead; Lesion; Link; Location; Maps; Measurement; Methods; Microscopic; Microvascular Dysfunction; Neurodegenerative Disorders; Neurologic; Neurologic Dysfunctions; Neurons; Optical Methods; Optics; Outcome; Pathologic; Patients; Pattern; Physiological; Recording of previous events; Resolution; Risk Factors; Severities; Site; Spatial Distribution; Stroke; Surface; System; Techniques; Therapeutic; Time; Time Factors; Tissues; Variant; Work; aged; awake; cerebral microinfarct; clinically relevant; density; effective intervention; experimental study; flexibility; hemodynamics; implantation; improved; in vivo; innovation; insight; millimeter; mouse model; multimodality; neuroimaging; neurophysiology; neurovascular; novel; relating to nervous system; response; serial imaging; spatiotemporal; two-dimensional

PROJECT SUMMARY: Cerebral microinfarcts are in association with neurologic dysfunctions in aged and injured brain where they are found to be prevalent, but often escape clinical detection owing to their small sizes. Although evidence suggests that microinfarcts likely have a distinct time course and spatial pattern compared to larger infarcts, spatially-resolved, longitudinal tracking of both hemodynamic and neural responses in the same brain has not been realized, largely due to a lack of methods capable of quantifying multiple neurophysiological and hemodynamic parameters with sufficient spatial resolution over periods of weeks to months. As a result, the neurophysiological consequences of individual or cumulative microinfarcts, including their spatiotemporal evolution and long-term outcome, remain largely unknown, limiting our ability to identify and target them for intervention strategies. The long-term goal is to understand the pathological impacts of microinfarcts with variability, abundance, spatial distribution, occurrence time and risk factors similar to human patients. The objective of this project is to determine the neural and hemodynamic impact of individual and cumulative cerebral microinfarcts in an aged mouse model. The hypothesis is that microinfarcts lead to spatiotemporally varying neuronal impairment and hemodynamic deficits that extend well beyond the lesion site and into chronic time scales, which requires spatially resolving and longitudinal tracking of multiple neurophysiological parameters over weeks to months to reveal their full impacts. We will use two types of ultra-flexible neural electrode arrays for spatially-resolved surface and intracortical recording, both of which are compatible with chronic optical methods. We will combine neural recording with a set of optical systems that are able to induce targeted micro-occlusions with controlled size, location and onset time, and to map and quantify cerebral blood flow and oxygenation over a global field of view and at depth-resolved microscopic scales. Using awake, behaving animals, we will determine 1) the correlation between hemodynamic and neural changes induced by individual microinfarcts, 2) the hemodynamic, neural and behavioral impacts of individual microinfarcts at controlled lesion sizes, and 3) the impacts of cumulative microinfarcts with delayed onset time. The application is highly innovative, in the applicant’s opinion, because it integrates technical advancements on both functional imaging and neural recording to provide a highly novel and powerful combination that permits longitudinal, spatially resolved quantification of multiple neurophysiological parameters in the same brain region and allows for investigation of microinfarcts in previously unattainable regimes. The project will improve the understanding of the physiological impact of microinfarcts and their contribution to neurologic dysfunctions in a variety of neurodegenerative and cerebrovascular diseases that they coexist with, and provide new insight into the therapeutic time window for intervention.

项目概要： 脑微梗塞与老年和受伤大脑的神经功能障碍有关 被发现很普遍，但由于体积小而经常逃避临床检测。虽然证据 表明与较大的梗塞相比，微梗塞可能具有独特的时间过程和空间模式， 对同一大脑中的血流动力学和神经反应进行空间分辨的纵向跟踪尚未实现 之所以能够实现，很大程度上是由于缺乏能够量化多种神经生理学和 数周至数月内具有足够空间分辨率的血流动力学参数。结果， 个体或累积微梗塞的神经生理学后果，包括其时空 进化和长期结果仍然很大程度上未知，限制了我们识别和瞄准它们的能力 干预策略。长期目标是了解微梗塞的病理影响 变异性、丰度、空间分布、发生时间和危险因素与人类患者相似。这 该项目的目标是确定个体和累积的神经和血液动力学影响 老年小鼠模型中的脑微梗塞。该假设是微梗塞会导致时空 不同的神经元损伤和血流动力学缺陷，远远超出病变部位并发展成慢性 时间尺度，这需要对多个神经生理学进行空间解析和纵向跟踪 数周至数月的参数以揭示其全部影响。我们将使用两种类型的超灵活神经网络 用于空间分辨表面和皮质内记录的电极阵列，两者都兼容 慢性光学方法。我们将把神经记录与一组能够诱导 具有受控大小、位置和发生时间的有针对性的微闭塞，并绘制和量化脑血 在全局视野和深度分辨微观尺度上的流动和氧合。使用清醒， 行为动物，我们将确定 1) 引起的血流动力学和神经变化之间的相关性 个体微梗塞，2) 个体微梗塞的血流动力学、神经和行为影响 受控的病变大小，以及 3) 累积微梗死的影响以及延迟的发作时间。应用 申请人认为，该技术具有高度创新性，因为它集成了功能性和功能性方面的技术进步。 成像和神经记录提供了一种高度新颖且强大的组合，允许纵向、 对同一大脑区域中的多个神经生理学参数进行空间分辨量化，并允许 用于在以前无法实现的方案中研究微梗塞。该项目将增进理解 微梗塞的生理影响及其对各种神经功能障碍的影响 它们同时存在的神经退行性疾病和脑血管疾病，并提供了新的见解 干预的治疗时间窗口。