Longitudinal multimodal mapping to decipher the neurovascular impact of microinfarcts

项目概要： 脑微梗死与老年人和脑损伤患者的神经功能障碍有关 发现它们普遍存在，但由于它们体积小，往往无法在临床上发现。虽然有证据 提示与较大梗塞相比，微小梗塞可能具有不同的时间进程和空间模式， 在同一大脑中对血流动力学和神经反应进行空间分辨的纵向跟踪， 这主要是由于缺乏能够量化多种神经生理学和 血流动力学参数具有足够的空间分辨率，持续数周至数月。结果导致 单个或累积性微梗死的神经生理学后果，包括其时空 进化和长期结果在很大程度上仍然未知，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死的病理影响， 变异性、丰度、空间分布、发生时间和风险因素与人类患者相似。的 本项目的目的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死。假设是微梗死导致时空 不同的神经元损伤和血流动力学缺陷，远远超出病变部位，并进入慢性 时间尺度，这需要空间分辨和纵向跟踪多个神经生理 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 用于空间分辨表面和皮层内记录的电极阵列，两者都与 慢性光学方法我们将联合收割机与一套光学系统相结合， 具有受控大小、位置和发作时间的靶向微闭塞，以及绘制和量化脑血 在全球视野和深度分辨微观尺度上的流动和氧合。使用awake， 行为动物，我们将确定1）血液动力学和神经变化之间的相关性， 个体微梗死，2）个体微梗死的血流动力学、神经和行为影响， 控制病变大小，和3）具有延迟发作时间的累积微梗死的影响。应用 在申请人看来，该系统是高度创新的，因为它集成了功能和性能上的技术进步， 成像和神经记录以提供高度新颖和强大的组合， 在同一脑区域中的多个神经生理学参数的空间分辨量化， 用于研究以前无法实现的微梗死。该项目将增进对 微梗死的生理影响及其对各种神经功能障碍的影响， 神经退行性疾病和脑血管疾病，他们共存，并提供了新的见解， 干预的治疗时间窗。

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.