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

在这个项目中，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函数，精确定位重散射域中的信号发射。虽然应用空间可以跨越所有类型的波，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中的神经元活动。目前，利用光在组织深度远大于十分之一毫米的地方成像是不可能的，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的时间尺度的活动细节。因此，尽管迄今为止做出了多方面的研究努力，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记者进行全脑成像的途径，旨在监测与神经元激活相关的钙离子浓度的变化。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，这项努力可以提供一种手段，获得与加深理解相关的新信息，从而治疗阿尔茨海默氏症、帕金森氏症以及癫痫。更广泛地说，该项目可能导致一种对组织内蛋白质构象进行成像的方法，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利用在一组空间位置获得的时间数据，在复杂的多散射环境中获得一大组发射源的准确位置。钙离子记录器测量的荧光随时间和大脑周围位置的变化提供了必要的时空数据，这将使首次在整个哺乳动物大脑中对神经元活动进行体内成像成为可能。点荧光发射体约束使得能够在定位框架内描述钙离子报告器。先前的工作表明，通过厘米的组织实现数十微米的空间分辨率是可以实现的，从而允许大脑中神经元规模的分辨率。有两个主要目标。首先，将开发一种用于全脑成像的高分辨率神经元激活报告定位方法。来自真实印刷模体的模拟和测量的时空数据将被合并到具有扩散方程正向模型的非线性优化框架中，并使用多分辨率分析来求解，在光子计数区域和在探测器有充足信号的情况下都是如此。其次，数据将从钙通道标记的神经元的显微镜测量中获得。这将产生局部信号和先前的模型信息，可以合并到体内方法中。神经元信号数据也将在受控数量的散布下获得，以调查本地化效率。这一奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

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.