Transfontanelle photoacoustic imaging to study pathophysiology of neonatal braininjury

项目摘要/摘要： 早产儿和/或低出生体重儿是颅内出血(ICH)的高危人群，发病率为 30%-35%。并发症导致分流依赖和长期变化：出血后脑积水， 脑室周围白质软化症、神经胶质增生症和神经功能障碍。ICH有很多原因：创伤性分娩， 初产或多胎，出生时胎龄低。早期发现、分类和诊断 ICH对于减少经常导致运动(例如脑瘫)、视觉或认知的脑损伤是必不可少的 功能障碍。经穹窿超声成像(TFUSI)是一种常规的婴儿脑成像诊断方法 6个月以下，颅骨未完全融合，之间有开口； 所谓的“Fontanelle”。TFUSI因其低成本、安全性、可及性和非侵入性而得到广泛应用。 然而，TFUSI的准确性是有限的；TFUSI不能检测到小于5 mm的出血，而是 不能准确检测脑脊液中的血液。TFUSI对出血大小、位置和持续时间的低敏感性可能导致 尸检结果显示，传统的TFUSI漏诊了8-34%的脑出血。第二阶段诊断 磁共振成像(MRI)、计算机断层扫描(CT)和正电子发射断层扫描等工具 (PET)对新生儿颅内出血的研究具有足够的敏感性和特异性，但都需要 将临床不稳定的新生儿送出NICU，镇静及其相关风险(低血压、血流动力学 改变，或过敏反应)，并有较高的成本。此外，CT使用电离辐射，而PET需要 发射正电子的放射性核素。近红外光谱(NIRS)具有较差的空间分辨率，特别是对于 新生儿头部小，穿透深度差。为了解决当前临床神经成像的几个局限性， 我们开发了一种新的跨Fontanelle多光谱光声成像(TFMPI)方法来研究 病理生理学，并改进对新生儿脑出血的检测，而不需要 镇静、辐射或放射性核素。我们的体外初步结果表明，TFMPI在 比超声更早发现和量化脑出血，具有更高的敏感性和特异性；并绘制了脑血流灌注图 类似于核磁共振。这项技术可以及早诊断和治疗，从而避免神经并发症， 并改善脑瘫和认知障碍的功能结果。这样做的长期目标是 研究项目是为患有以下疾病的新生儿提供一种单一的、具有成本效益的、便携的、医疗保健点诊断筛查 潜在的脑出血。本提案四个目标中概述的研究评估了TFMPI检测脑出血的可行性 在一个大小类似于人类新生儿大脑的大型动物模型中，手术诱导的颅窗 作为新生儿的颧骨的模型。目的1：确定TFMPI检测的敏感度下限 脑脊液中的血液及其年龄。目的2：检测脑实质内出血及其年龄。目标3：测量 脑组织氧饱和度。目的4：检测脑血屏障破坏所致的血管源性水肿。

PROJECT SUMMARY/ABSTRACT: Preterm and/or low birth weight neonates are at high risk for intracranial hemorrhage (ICH) with an incidence of 30%-35%. Complications result in shunt dependence and long-term changes: post-hemorrhagic hydrocephalus, periventricular leukomalacia, gliosis, and neurological dysfunction. ICH has many causes: traumatic delivery, primiparity or extreme multiparity, and low gestational age at birth. Early detection, classification and diagnosis of ICH is essential to reduce brain injury which often leads to motor (e.g., cerebral palsy), visual or cognitive dysfunction. TransFontanelle Ultrasound Imaging (TFUSI) is a routine diagnostic brain imaging method for infants younger than 6 months, whose skull bones have not completely fused together and have openings between them; so-called ‘fontanelles’. TFUSI is widely used due to its low cost, safety, accessibility, and noninvasive nature. Nevertheless, the accuracy of TFUSI is limited; TFUSI does not detect hemorrhages smaller than 5 mm and does not accurately detect blood in CSF. The low sensitivity of TFUSI to bleed size, location and duration may lead to autopsy findings that reveal conventional TFUSI underdiagnoses ICH in 8–34% of cases. Second stage diagnostic tools like magnetic resonance imaging (MRI), computed tomography (CT), and positron emission tomography (PET) have sufficient sensitivity and specificity to study neonatal intracranial hemorrhage, however, all require moving clinically unstable newborns out of the NICU, sedation with its associated risks (hypotension, hemodynamic changes, or allergic reaction), and have high cost. Moreover, CT uses ionizing radiation and PET requires a positron-emitting radionuclide. Near InfraRed Spectroscopy (NIRS) has poor spatial resolution, especially for the small neonate head, and poor penetration depth. To address several limitations of current clinical neuroimaging, we have developed a novel TransFontanelle Multispectral Photoacoustic Imaging (TFMPI) method to study pathophysiology, and to improve the detection of brain hemorrhage in neonates without the need for sedation, radiation or radionuclides. Our ex vivo preliminary results show the surpassing capability of TFMPI in detection and quantification ICH earlier, with higher sensitivity and specificity than US; and, maps brain perfusion similar to MRI. This technique allows earlier diagnosis and treatment which may circumvent neural complications, and improve functional outcomes from cerebral palsy and cognitive impairments. The long-term goal of this research project is to provide a single, cost-effective, portable, point-of-care diagnostic screening for neonates with potential ICH. Studies outlined in the four aims of this proposal assess the feasibility of TFMPI for detection of ICH in a large animal model, similar in size to a human neonatal brain, with a surgically-induced cranial window that serves as a model for neonate’s fontanelle. Aim 1: To determine the lower limits of sensitivity of TFMPI to detect blood in CSF and its age. Aim 2: To detect intraparenchymal hemorrhages and their age. Aim 3: To measure the brain tissue oxygen saturation. Aim 4: To detect vasogenic edema due to brain blood barrier disruption.