Wearable real-time functional brain mapping for a non-human primate stroke model

摘要 非人灵长类动物（NHP）模型已被推荐为临床前研究的理想动物模型， 中风治疗学术行业圆桌会议（STAIR）委员会的翻译中风研究， 啮齿类动物中的翻译失败和显著的脑血管、神经解剖学和生物分子相似性 NHP和人类之间的关系。作为对这一建议的回应，Nudo博士（目前提案的主要研究者之一）， 在过去的几十年里，他开创并进一步发展了NHP中风模型。尽管与临床相关 NHP中风模型现在是可用的，成像方式的局限性，可以映射神经激活在深 清醒猴子的大脑阻碍了当前的研究。功能磁共振成像 已被广泛用于检测大脑的功能变化。然而，这种技术受到不良的限制。 在收集功能信息时的时间和空间分辨率。特别是，对于大脑研究， 清醒的，行为活跃的猴子，有限的fMRI时间分辨率可能是一个重大的障碍， 运动伪影或者，许多研究使用慢性侵入性微电极植入物进行记录 动作电位和局部场电位在清醒的猴子;然而，微电极电记录是相当 侵入性的，具有差的空间分辨率，并且不提供深度分辨的信息。 我们提出开发一种基于新兴光声（PA）的可穿戴式全脑成像系统 脑缺血性脑卒中研究中的脑血管造影（派）。缺血性中风的特征是 大脑的血液动力学由大脑主要动脉或其分支闭塞引发的缺血性中风 导致急性和慢性脑血管适应。派基于光学吸收对比度， 本质上对脑血流动力学的变化敏感，包括血容量（灌注）和血液 氧耗（oxygen consumption）因此，派提供了很好的能力，了解急性和慢性 脑卒中后脑血管的适应，以及脑卒中后功能激活引起的血流动力学变化， 大脑基于我们在PA脑成像方面的强大专业知识，特别是在清醒行为活跃的派方面 恒河猴，我们建议开发一种实时可穿戴PA脑成像系统，可用于深 通过颅窗进行脑成像通过利用最先进的电容式微机械超声 换能器（CMUT）技术，所提出的派技术可以提供深度分辨的功能信息 以高空间分辨率实时观察大脑深部区域。提出了两个目标：1）评价和优化 一种可穿戴的、基于多波长CMUT的派系统，用于实时可视化大脑中的功能激活， NHP脑;和2）NHP脑功能激活和脑血管适应的图像变化 中风模型在纵向研究。这项研究的成功将为重要的科学问题提供答案。 探讨了NHP模型在脑卒中治疗中的应用，为脑卒中治疗的新发展铺平了道路。

ABSTRACT Non-human primate (NHP) models have been recommended as ideal animal models for preclinical, translational stroke research by the Stroke Therapy Academic Industry Roundtable (STAIR) committee due to translational failures in rodents and significant cerebrovascular, neuroanatomical and biomolecular similarities between NHPs and humans. In response to this recommendation, Dr. Nudo (one of PIs on the current proposal), has pioneered and further developed NHP stroke models in the past few decades. Although clinically-relevant NHP stroke models are now available, limitations in imaging modalities that can map neural activates in deep brains of awake monkeys are hindering the current research. Functional magnetic resonance imaging (fMRI) has been widely used to detect functional changes in the brain. However, this technique is limited by poor temporal and spatial resolution when collecting functional information. Particularly, for brain research involving awake, behaviorally active monkeys, the limited temporal resolution of fMRI can be a significant barrier because of motion artifacts. Alternatively, many studies have used chronic, invasive microelectrode implants for recording action potential and local field potentials in awake monkeys; however, microelectrode electrical recording is quite invasive, has poor spatial resolution, and does not provide depth-resolved information. We propose to develop a wearable, whole brain imaging system based on the emerging photoacoustic (PA) imaging (PAI) for ischemic stroke research with NHP models. Ischemic stroke is characterized by changes in hemodynamics in the brain. Triggered by the occlusion of a major cerebral artery or its branches, ischemic stroke leads to cerebrovascular adaptations both acutely and chronically. PAI, based on optical absorption contrast, is intrinsically sensitive to the changes in brain hemodynamics including both blood volume (perfusion) and blood oxygenation (oxygen consumption). Therefore, PAI offers excellent ability to understand the acute and chronic cerebrovascular adaption after stroke, as well as hemodynamic changes resulting from functional activation in the brain. Built on our strong expertise in PA brain imaging, especially in PAI of an awake behaviorally active rhesus monkey, we propose to develop a real-time wearable PA brain imaging system that can be used for deep brain mapping through a cranial window. By utilizing state-of-the-art capacitive micromachined ultrasonic transducer (CMUT) technology, the proposed PAI technology can provide depth-resolved functional information in deep brain regions in real-time with high spatial resolution. Two aims are proposed: 1) Evaluate and optimize a wearable, multi-wavelength CMUT-based PAI system for real-time visualization of functional activation in the NHP brain; and 2) Image changes in brain functional activations and cerebrovascular adaptations in an NHP stroke model in a longitudinal study. The success of this study will provide answers to important scientific questions about stroke with NHP models, and pave the way for new stroke therapy development.