Time-resolved laser speckle contrast imaging of resting-state functional connectivity in neonatal brain

摘要 持续监测新生儿脑发育对于有效治疗脑损伤至关重要， 因此，减少了相关的并发症，从而减轻了医疗负担和成本。一种快速发展的方法， 异常大脑发育的表征是绘制静息状态功能连接（rs-FC）， 大脑的不同区域。然而，目前可用的神经成像技术要么昂贵， 难以连续使用（fMRI和PET）或缺乏时空分辨率和大视场的组合， 视场（FOV）来成像分布式rs-FC（EEG和近红外光谱和断层扫描）。合作 与肯塔基州大学的发明者，生物光学技术正在开发，验证和商业化， 革命性的时间分辨激光散斑衬度成像（TR-LSCI）技术，可实现非接触、快速 大FOV范围内脑血流（CBF）的高分辨率成像。TR-LSCI照射皮秒脉冲， 宽场、相干、近红外光照射到大脑和大脑， 高分辨率，单光子雪崩二极管（SPAD）相机用于脑血流（CBF）的2D标测 头部不同深度通过应用时间选通策略，TR-LSCI区分短光子和长光子 在不同的深度通过分层的头部组织的路径，从而消除了耗时的复杂 近红外漫射光学层析成像技术中的三维重建。在初步研究中，持续 在不同深度的CBF映射已经通过实验室制造的台式TR-LSCI原型在流动中被证明， 模拟幻影和活体啮齿动物。在这个快速通道STTR建议通过两个阶段，我们将开发， 优化、验证和商业化用户友好的便携式TR-LSCI设备，以实现快速、高解决方案， 新生啮齿动物（第1阶段）和新生仔猪（第2阶段）中CBF和rs-FC的多尺度成像。具体地说， 第1阶段将优化和评估用于成像CBF和提取rs-FC（衍生）的台式TR-LSCI原型 从时程CBF图像）在新生儿啮齿动物与围产期缺氧缺血性脑病（HIE）。 新生大鼠用于该第1阶段可行性试验，以在TR-LSCI全面发展之前降低其风险。 2期新生仔猪。选择HIE进行研究，因为它影响每1000名足月分娩中2-9名婴儿， 与严重的神经发育问题和死亡率相关。第二阶段将开发、优化和评估 一种用户友好的便携式TR-LSCI设备，用于HIE新生仔猪的CBF和rs-FC连续成像。 选择新生仔猪进行研究，因为它们的头部大小和HIE后病理学与人类相似 新生儿TR-LSCI结果将与MRI结果和临床结局相关联，以确定 评估新生儿HIE后的脑损伤。本研究在新生大鼠和仔猪缺氧缺血性脑病模型上进行了实验研究 作为临床前商业化的第一步，TR-LSCI设备广泛适用于研究许多 在人类新生儿中发生的HIE以外的神经血管疾病，从而提供了一个重要的机会， 用于未来的临床开发和商业化。

ABSTRACT Continuous monitoring of neonatal brain development is crucial for effective management of brain injury and associated complications, thus reducing healthcare burden and costs. One rapidly developing method for early characterization of abnormal brain development is to map resting-state functional connectivity (rs-FC) across distinct regions of the brain. However, currently available neuroimaging technologies are either expensive and difficult to use continuously (fMRI and PET) or lack the combination of temporal-spatial resolution and large field- of-view (FOV) to image distributed rs-FC (EEG and near-infrared spectroscopy and tomography). In collaboration with University of Kentucky inventors, Bioptics Technology is developing, validating, and commercializing a revolutionary time-resolved laser speckle contrast imaging (TR-LSCI) technology that enables noncontact, fast, high-resolution imaging of cerebral blood flow (CBF) over a large FOV. TR-LSCI illuminates picosecond-pulsed, widefield, coherent, near-infrared light onto the brain and synchronizes a newly developed, picosecond-gated, high-resolution, single-photon avalanche diode (SPAD) camera for 2D mapping of cerebral blood flow (CBF) at different depths into the head. By applying the time-gated strategy, TR-LSCI differentiates short and long photon paths through the layered head tissues at different depths, thus eliminating the need for time-consuming complex 3D reconstruction in near-infrared diffuse optical tomography technologies. In preliminary studies, continuous mapping of CBF at different depths has been demonstrated by a lab-made benchtop TR-LSCI prototype in flow- simulating phantoms and in vivo rodents. In this Fast Track STTR proposal through two phases, we will develop, optimize, validate, and commercialize a user-friendly portable TR-LSCI device for fast, high-solution, and multiscale imaging of CBF and rs-FC in neonatal rodents (Phase 1) and neonatal piglets (Phase 2). Specifically, Phase 1 will optimize and assess the benchtop TR-LSCI prototype for imaging CBF and extracting rs-FC (derived from time-course CBF images) in neonatal rodents with perinatal hypoxic-ischemic encephalopathy (HIE). Neonatal rats are used in this Phase 1 feasibility test to de-risk the TR-LSCI before its full-scale development in neonatal piglets during Phase 2. HIE is selected to study as it affects 2-9 babies per 1000 term births and is associated with severe neurodevelopmental problems and mortality. Phase 2 will develop, optimize, and assess a user-friendly portable TR-LSCI device for continuous imaging of CBF and rs-FC in neonatal piglets with HIE. Neonatal piglets are selected to study as their head size and post-HIE pathology are analogous to human neonates. TR-LSCI results will be correlated with MRI results and clinical outcomes to identify biomarkers for assessing neonatal brain injury after HIE. While this proposal tests it on HIE models of neonatal rats and piglets as the first step for preclinical commercialization, the TR-LSCI device is broadly applicable to investigate many neurovascular diseases beyond HIE occurring in human neonates, thereby providing a significant opportunity for future clinical development and commercialization.