Longitudinal multimodal mapping to decipher the neurovascular impact of microinfarcts

项目总结： 脑微梗塞与老年和脑损伤患者的神经功能障碍有关 被发现是流行的，但由于它们的体积小，往往没有被临床发现。尽管有证据表明 表明与较大的梗塞相比，微小梗塞可能有不同的时间进程和空间模式， 在同一个大脑中对血流动力学和神经反应的空间分辨的纵向跟踪没有 很大程度上是由于缺乏能够量化多种神经生理学和 血流动力学参数与足够的空间分辨率在几周到几个月的时间段。因此， 单个或累积微梗塞的神经生理学后果，包括它们的时空分布 进化和长期结果在很大程度上仍然未知，限制了我们识别和定位它们的能力 干预策略。长期目标是了解微梗塞的病理影响。 与人类患者相似的丰度、空间分布、发生时间和危险因素的变异性。这个 本项目的目的是确定神经和血流动力学对个体和累积的影响 小鼠模型中的脑微梗塞。假设是微梗塞导致时空变化。 神经损伤和血流动力学障碍远远超出病变部位并延伸到慢性时间 尺度，这需要空间分辨率和对多个神经生理参数的纵向跟踪 几周到几个月的时间来揭示它们的全部影响。我们将使用两种类型的超灵活神经电极阵列 用于空间分辨表面和皮质内记录，两者都与慢性光学兼容 方法：研究方法。我们将神经记录与一套光学系统相结合，这些光学系统能够诱导靶向微 控制大小、位置和起效时间的闭塞，并绘制和量化脑血流量和 全球视野和深度分辨微观尺度上的氧合作用。使用唤醒，行为 动物，我们将1)确定个体引起的血液动力学和神经变化之间的相关性 微梗塞，2)在受控病变大小下绘制和跟踪微梗塞的空间范围，以及3)确定 起病时间延迟的累积性微梗塞对血流动力学和神经的影响。该应用程序是 在申请人看来，非常具有创新性，因为它整合了功能和功能上的技术进步 成像和神经记录提供高度新颖和强大的组合，允许纵向， 空间分辨量化同一大脑区域的多个神经生理参数，并允许 用于在以前无法达到的状态下研究微梗塞。该项目将提高对 微梗塞的生理学影响及其对各种神经功能障碍的贡献 与之共存的神经退行性疾病和脑血管疾病，并提供了对 干预的治疗时间窗口。

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 in 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 a 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 1) determine the correlation between hemodynamic and neural changes induced by individual microinfarcts, 2) map and track the spatial extent of microinfarcts at controlled lesion sizes, and 3) determine the hemodynamic and neural 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.