CIF: Small: Super-Resolution Imaging in a Heavily Scattering Environment Enabled by Spatiotemporal Data

在该项目中，将开发一个数学和计算框架，以便使用在不同位置测量的传感器数据作为时间的函数，在重散射域中精确定位信号发射。虽然应用空间可以跨越所有波类型，但该项目的主要重点是首次使用荧光直接成像整个哺乳动物大脑的神经元活动。目前不可能用光在组织中超过十分之一毫米的深度成像，其他测量大脑活动的方法，包括血氧和锰的磁共振成像（MRI），无法提供与单个神经元激活相同时间尺度的活动细节。因此，尽管迄今为止进行了多方面的研究，但对大脑仍有许多未知之处。该项目提出了一种使用时空光学报告器进行全脑成像的方法，该报告器旨在监测与神经元激活相关的钙离子浓度变化。这种方法有很大的潜力影响神经科学和大脑疾病的治疗。例如，这项工作可以提供一种手段，以获得与发展对阿尔茨海默病和帕金森病以及癫痫的理解和治疗有关的新信息。更一般地说，该项目可能导致一种方法来成像组织内的蛋白质构象，从而为许多涉及蛋白质错误折叠和聚集的中枢神经系统疾病提供一个窗口。 要研究的基本原理是使用在一组空间位置获得的时间数据，以获得在复杂的多重散射环境中的大量发射体的精确位置。测量的荧光从钙报告作为时间和位置的函数在大脑周围提供了必要的时空数据，这将允许在整个哺乳动物大脑的神经元活动的体内成像的第一次。一个点荧光发射约束，使本地化框架内的钙离子报告的描述。先前的工作表明，通过厘米的组织可以实现数十微米的空间分辨率，从而允许大脑中的神经元级分辨率。有两个主要目标。首先，将开发用于全脑成像的高分辨率神经元激活报告子定位方法。模拟和测量的时空数据，从现实的打印幻影将被纳入一个非线性优化框架与扩散方程前向模型，并解决了使用多分辨率分析，无论是在光子计数制度，并有充足的信号在探测器。第二，数据将从显微镜测量的神经元钙通道标记。这将产生局部信号和先验模型信息，其可以并入体内方法中。该奖项反映了NSF的法定使命，并被认为是值得通过使用基金会的智力价值和更广泛的影响审查标准进行评估的支持。

In this project, a mathematical and computational framework will be developed to allow the precise location of signal emissions in a heavy scattering domain using sensor data measured at various locations as a function of time. While the application space can span all wave types, the primary focus of this project is to directly image neuron activity throughout the mammalian brain for the first time using fluorescence. It is currently impossible to image at a depth of much more than about one tenth of a millimeter in tissue using light, and other ways of measuring brain activity, including magnetic resonance imaging (MRI) of blood oxygen and of manganese, are unable to provide details of activity at the same time-scale as that of individual neuron activation. Therefore, despite multifaceted research efforts to date, much remains unknown about the brain. The project presents a path towards whole-brain imaging using spatio-temporal optical reporters designed to monitor changes in calcium ion concentrations associated with neuron activation. This approach has a substantial potential to impact neuroscience and the treatment of brain disorders. For instance, the effort could provide a means to obtain new information that is relevant for developing an understanding and hence a treatment of Alzheimer's disease and Parkinson's disease, as well as epilepsy. More generally, the project could lead to a means to image protein conformation inside tissue, thereby providing a window to many central nervous system diseases involving protein mis-folding and aggregation. The underlying principle to be investigated is the use of temporal data obtained at a set of spatial positions to obtain the precise locations of a large set of emitters in a complex, multiple scattering environment. Measured fluorescence from calcium reporters as a function of time and position around the brain provides the necessary spatio-temporal data that would allow the in-vivo imaging of neuron activity throughout a mammalian brain for the first time. A point fluorescent emitter constraint enables the description of the calcium ion reporters within a localization framework. Prior work suggests that a spatial resolution of tens of microns through centimeters of tissue may be achievable, allowing neuron-scale resolution in the brain. There are two primary aims. First, a high-resolution neuron activation reporter localization method for whole-brain imaging will be developed. Simulated and measured spatio-temporal data from realistic printed phantoms will be incorporated into a nonlinear optimization framework with a diffusion equation forward model and solved using a multi-resolution analysis, both in the photon-counting regime and where there is ample signal at the detectors. Second, data will be obtained from microscope measurements of neurons with calcium channel labeling. This will yield local signaling and prior model information that could be incorporated into an in-vivo approach. Neuron signaling data will also be obtained under controlled amounts of scatter to investigate localization efficacy.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.