Development of real-time, non-invasive photoacoustic imaging to rapidly detect and track perinatal focal stroke at birth

开发实时、非侵入性光声成像，以快速检测和跟踪出生时的围产期局灶性中风

• 批准号: 10063016
• 负责人: Emad M Boctor
• 金额: $ 42.11万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-12-18 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10063016
• 关键词: Acids; Adult; Aftercare; Algorithms; Anti-Inflammatory Agents; Antiepileptic Agents; Attention; Attenuated; Autoradiography; Birth; Blood; Blood - brain barrier anatomy; Blood Vessels; Blood specimen; Brain; Brain Hypoxia-Ischemia; Brain region; Catheters; Cerebral cortex; Cerebrovascular Circulation; Cerebrum; Clinical; Clinical Trials; Cognitive; Communication; Data; Development; Devices; Diagnosis; Distal; Drainage procedure; Dyes; Edema; Energy Metabolism; Epoxide hydrolase; Fetal Monitoring; Fetus; Functional disorder; Future; Generations; Geometry; Goals; Hemoglobin; Histology; Human; Hypoxia; Image; Imaging Device; Infarction; Injury; Intervention; Ischemia; Ischemic Stroke; Light; Live Birth; Location; Malignant - descriptor; Measurement; Measures; Metabolic; Middle Cerebral Artery Occlusion; Monitor; Motor; Na(+)-K(+)-Exchanging ATPase; Nature; Neocortex; Neonatal; Neonatal Screening; Nerve Degeneration; Neurons; Newborn Animals; Newborn Infant; Oxyhemoglobin; Penetration; Perinatal; Pharmaceutical Preparations; Pimonidazole; Rapid screening; Resistance; Rodent; Rodent Model; Sagittal Sinus; Scalp structure; Seizures; Sensitivity and Specificity; Series; Severities; Somatosensory Cortex; Stroke; Techniques; Technology; Testing; Therapeutic; Thrombotic Stroke; Time; Tissues; Transient Cerebral Ischemia; Treatment Efficacy; Ultrasonic wave; Ultrasonography; Vascular Endothelial Growth Factors; Venous; Work; aquaporin 4; base; blood-brain barrier disruption; blood-brain barrier permeabilization; cerebral blood volume; chromophore; cranium; cytochrome c oxidase; deoxyhemoglobin; design; detector; efficacy testing; executive function; imaging probe; improved; inhibitor/antagonist; innovation; insight; light transmission; middle cerebral artery; miniaturize; molecular size; neocortical; neuroinflammation; neurovascular; non-invasive imaging; non-invasive monitor; perinatal injury; perinatal ischemic stroke; perinatal stroke; photoacoustic imaging; postnatal; prospective; prototype; rapid diagnosis; regional difference; stroke model; therapeutic target; thrombotic; uptake; venous sinus

Perinatal arterial ischemic stroke is estimated to occur in 1/2300–1/5000 live births and can result in long-term deficits in motor, cognitive, attention, and executive functions and persistent seizures. Rapid diagnosis of focal ischemic stroke in newborns, the timing of the stroke, and differentiation of perinatal stroke from global hypoxia-ischemia allow more efficient and directed interventions/prognosticacions. In the proposed work, we will develop miniaturized noninvasive photoacoustic imaging for use on the scalp of human fetuses and newborns to dynamically track changes in oxygenation in sagittal sinus venous blood and regional cortical tissue both during and after labor. Using a newborn animal with a large gyrencephalic brain, we will validate the oxygenation measurements against directly measured sagittal sinus O2 saturation during hypoxia-ischemia and against pimonidazole-based measurements of regional tissue hypoxia during focal stroke. Based on these data, we will then develop algorithms for detecting graded progressive ischemia based on tissue hemoglobin content and O2 saturation. We will test the sensitivity and specificity of these algorithms with different size and locations of photothrombotic-induced stroke. Furthermore, secondary injury cascades that transpire in the immature brain after arterial thrombotic stroke may differ from those that transpire in mature brain and likely depend on maturation of connectivity and energy metabolism in specific brain regions. After photothrombosis of the middle cerebral artery, we will contrast dynamic changes in tissue hemoglobin content and O2 saturation in 1) the metabolically active primary sensorimotor cortex, known to be selectively vulnerable to hypoxia- ischemia, 2) the metabolically quiescent secondary sensorimotor cortex known to be resistant to hypoxia- ischemia, and 3) the watershed penumbra. In addition, we will use noninvasive imaging to track tissue uptake of photoacoustically sensitive dyes conjugated to different size molecules and relate regional differences in size-dependent blood brain-barrier permeability to markers of energy metabolism. Finally, we will investigate whether stabilizing anti-inflammatory, anti-epileptic, anti-platelet, pro-vasodilatory, and pro-angiogenic epoxyeicosatrienoic acids with an inhibitor of soluble epoxide hydrolase (sEH) is protective. Though pretreatment with such inhibitors is protective in adult rodent models of transient cerebral ischemia, post- treatment efficacy has not been determined with prolonged ischemia or in immature brain. We will test the concept that a multi-potent sEH inhibitor will attenuate neuroinflammation, blood-brain barrier permeability, perivascular loss of aquaporin-4 channels, ischemia-induced increase in Sur1-TrpM4 channels known to contribute to malignant edema, and the loss of peri-ischemic neurons, while promoting VEGF expression; we will also determine whether an inhibitor of EET synthesis will exert the opposite effects. Therefore, this application will reveal new insights into the mechanisms of injury from perinatal thrombotic ischemia, provide a potential therapeutic target, and enable an innovative technological advance for screening newborns for stroke.

据估计，围产期动脉缺血性中风发生在1/2300–1/5000活产中，可能会导致长期 运动，认知，注意力和执行功能和持续性癫痫发作的缺陷。快速诊断焦点 新生儿的缺血性中风，中风的时机以及围产期中风的分化与全球 缺氧 - 缺血剂可提供更有效和定向的干预措施/预后。在拟议的工作中，我们 将开发微型的无创光声学成像，用于人类胎儿的头皮和 新生儿动态跟踪矢状窦静脉血和区域皮质的氧合变化 在分娩过程中和之后的组织。我们将使用具有较大g脑大脑的新生动物，我们将验证 低氧 - 异化期间直接测量的矢状窦O2饱和度直接测量的氧合测量值 并反对基于吡莫替唑的局灶性中风期间区域组织缺氧的测量。基于这些 数据，我们将开发用于基于组织血红蛋白的分级进行性缺血的算法 内容和O2满意度。我们将测试这些算法的敏感性和特异性，其大小不同， 光桥性引起的中风的位置。此外，在 伪影血栓形成型伪影的未成熟大脑可能与成熟大脑中的那些人有所不同，可能 取决于特定大脑区域中连通性和能量代谢的成熟。光栓塞后 在大脑中动脉中，我们将对比组织血红蛋白含量和O2满意度的动态变化 在1）代谢活性的原发性感觉运动皮层，已知有选择性地容易受到缺氧的影响 缺血，2）代谢静止的次级感觉运动皮层已知对低氧具有抗性 缺血，3）流域半月。此外，我们将使用无创成像跟踪组织吸收 与不同大小的分子偶联的光学敏感染料和相关的区域差异 大小依赖性的血脑屏障对能量代谢标志物的渗透性。最后，我们将调查 是否稳定抗炎，抗癫痫，抗血小板，促肌和促血管生成和促血管生成 保护环氧化物水解酶（SEH）的环氧酸性酸酸是保护的。尽管 在瞬态脑缺血的成年啮齿动物模型中，对这种抑制剂进行了预处理，在 - 治疗效率尚未用长时间的缺血或未成熟大脑确定。我们将测试 多功能SEH抑制剂会减弱神经炎症，血脑屏障渗透性， 血管周围的水通道蛋白4通道的血管丧失，缺血诱导的SUR1-TRPM4通道的增加已知已知 在促进VEGF表达的同时，有助于恶性水肿和缺血性神经元的丧失； 还将确定EET合成的抑制剂是否会执行相反的效果。因此，这个 应用将揭示有关围产期血栓性缺血机制的新见解，提供 潜在的治疗目标，并为筛选新生儿的创新技术进步。

项目成果

Embolic occlusion of internal carotid artery in conscious rats: Immediate effects of cerebral ischemia.

• DOI: 10.14814/phy2.15613
• 发表时间: 2023-02
• 期刊: Physiological reports
• 影响因子: 2.5

Photoacoustic assessment of the fetal brain and placenta as a method of non-invasive antepartum and intrapartum monitoring.

• DOI: 10.1016/j.expneurol.2021.113898
• 发表时间: 2022-01
• 期刊: Experimental neurology
• 影响因子: 5.3
• 作者: Kang J;Koehler RC;Graham EM;Boctor EM
• 通讯作者: Boctor EM

Polynitroxylated PEGylated hemoglobin protects pig brain neocortical gray and white matter after traumatic brain injury and hemorrhagic shock.

• DOI: 10.3389/fmedt.2023.1074643
• 发表时间: 2023
• 期刊: FRONTIERS IN MEDICAL TECHNOLOGY
• 作者: Wang, Jun;Shi, Yanrong;Cao, Suyi;Liu, Xiuyun;Martin, Lee J.;Simoni, Jan;Soltys, Bohdan J.;Hsia, Carleton J. C.;Koehler, Raymond C.
• 通讯作者: Koehler, Raymond C.

Transcranial photoacoustic characterization of neurovascular physiology during early-stage photothrombotic stroke in neonatal pigletsin vivo.

• DOI: 10.1088/1741-2552/ac4596
• 发表时间: 2022-01-05
• 期刊: Journal of neural engineering
• 影响因子: 4

Transcranial photoacoustic imaging of NMDA-evoked focal circuit dynamics in the rat hippocampus

• DOI: 10.1088/1741-2552/ab78ca
• 发表时间: 2020-04-01
• 期刊: JOURNAL OF NEURAL ENGINEERING
• 影响因子: 4
• 作者: Kang, Jeeun;Kadam, Shilpa D.;Wong, Dean F.
• 通讯作者: Wong, Dean F.