Ultrahigh-resolution optical tomography of cocaine-induced neurovascular toxicity

描述（由申请人提供）：累积的临床证据表明，许多滥用药物（包括可卡因）具有血管活性作用，可能导致脑血管病变和脑血流（CBF）功能障碍，如脑血管痉挛样出血、出血性和缺血性卒中。可卡因的神经血管毒性的机制仍然不明确，因此，有效的治疗可能会受到阻碍，难以评估可卡因的血管活性作用的性质和严重程度。这种关键的知识差距部分是由于当前神经成像技术的局限性（即，缺乏高时空分辨率或足够的视野来成像毛细血管CBF网络），用于研究动物模型中可卡因诱导的血管效应。在这项R21 CEBRA资助中，我们建议通过开发一种基于超高分辨率光学相干多普勒断层扫描的新型神经成像技术来弥合差距，该技术能够对毛细血管CBF网络进行定量3D成像，并允许评估体内的实时功能变化。我们初步动物研究的结果表明，该成像技术能够准确检测激光诱导的微血管破裂和随后的CBF中断，以及量化响应高碳酸血症的3D CBF网络变化（包括毛细血管CBF），所有这些都为拟议的技术开发和动物验证研究奠定了坚实的基础。我们在该应用中的新策略是将联合收割机超高分辨率3D光学血管造影和多普勒断层扫描结合起来，以研究可卡因诱导的神经血管病理（微出血）和血流动力学功能障碍（包括毛细血管CBF变化）。提出了以下具体目标：（1）开发和优化超高分辨率激光多普勒断层扫描，以实现毛细血管CBF网络的体内定量3D成像，（2）使用已建立的可卡因强迫使用大鼠模型验证这种用于可卡因诱导的神经血管毒性的实时成像评估的新技术。这项新技术的成功开发和验证将允许毛细血管CBF网络的无标记定量3D成像及其对可卡因的高空间和时间分辨率（<35 m，~ 30 s）的实时响应，这将允许在体内评估可卡因对微血管的潜在毒性作用以及其他技术无法检测到的微循环损伤。这种技术，除了提供新的见解可卡因的脑血管毒性的机制，也将是有价值的评估药物，以帮助恢复可卡因的脑血管毒性和其他脑血管病变。 公共卫生相关性：无标记，定量成像的脑血流（CBF）在高的时间和空间分辨率将提高我们的能力，调查潜在的机制药物引起的神经血管毒性（包括可卡因）以及其他脑血管疾病。基于超高分辨率光学相干多普勒断层扫描，这R21 CEBRA建议寻求开发一种新的神经成像技术，这是第一次允许定量成像的三维毛细血管CBF网络及其变化在高时空分辨率在一个大的视野。此外，我们将测试其在体内评估可卡因诱导的神经血管病理（微血管破裂）和血流动力学功能障碍（包括毛细血管CBF变化）的有效性。该提案的结果将提供更好的工具来对慢性药物暴露发生的动态血管变化进行成像，因此是一种测试潜在药物以逆转神经血管病理的工具。从它的应用到评估慢性可卡因的影响，我们也希望获得新的见解，慢性可卡因暴露导致的神经血管病理学。

DESCRIPTION (provided by applicant): Accumulating clinical evidence shows that many of the drugs of abuse (including cocaine) have vasoactive effects that may result in cerebrovascular pathology and cerebral blood flow (CBF) dysfunction such as aneurysm-like bleeds, hemorrhagic and ischemic strokes. The mechanisms underlying cocaine's neurovascular toxicity remain ambiguous, and as a result effective treatment may be hindered by difficulties in assessing the nature and severity of vasoactive effects of cocaine. This key knowledge gap is due in part to the limitations of current neuroimaging techniques (i.e., lack of either high spatiotemporal resolution or sufficient field of view for imaging capillary CBF networks) used to investigate cocaine-induced vascular effects in animal models. In this R21 CEBRA grant, we propose to bridge the gap by developing a novel neuroimaging technique based on ultrahigh-resolution optical coherence Doppler tomography, which enables quantitative 3D imaging of capillary CBF networks and allows one to assess real-time functional changes in vivo. Results from our preliminary animal studies have shown the capabilities of this imaging technique to accurately detect laser-induced micro-vessel rupture and the consequent CBF disruption, as well as to quantify 3D CBF network changes (including capillary CBF) in response to hypercapnia, all of which have laid a solid foundation for the proposed technological development and animal validation study. Our new strategy in this application is to combine ultrahigh-resolution 3D optical angiography and Doppler tomography to investigate cocaine- induced neurovascular pathology (micro hemorrhage) and hemodynamic dysfunction (including capillary CBF changes). The following Specific Aims are proposed: (1) develop and optimize ultrahigh-resolution laser Doppler tomography to enable in vivo quantitative 3D imaging of capillary CBF networks, (2) validate this new technique for real-time imaging assessment of cocaine-induced neurovascular toxicity using a well-established rat model of compulsive cocaine use. Successful development and validation of this new technique will permit label-free, quantitative 3D imaging of capillary CBF networks and their real-time responses to cocaine at high spatial and temporal resolution (<35m, ~30s), which will permit an in vivo assessment of potential toxic effects of cocaine to micro vessels and concomitant impairment to the microcirculation that would be undetected by other technologies. Such a technology, in addition to providing new insights into the mechanisms underlying cocaine's cerebrovascular toxicity, will also be valuable to evaluate medications to help recover from cerebrovascular toxicity of cocaine and other cerebrovascular pathologies. PUBLIC HEALTH RELEVANCE: Label-free, quantitative imaging of cerebral blood flow (CBF) at high temporal and spatial resolution would improve our ability to investigate the mechanisms underlying drug induced neurovascular toxicity (including cocaine) as well as that of other cerebrovascular diseases. Based on ultrahigh-resolution optical coherence Doppler tomography, this R21 CEBRA proposal seeks to develop a novel neuroimaging technique, which for the first time permits quantitative imaging of 3D capillary CBF networks and their changes at high spatiotemporal resolutions across a large field of view. In addition, we will test its efficacy for assessing cocaine-induced neurovascular pathology (micro-vessel rapture) and hemodynamic dysfunction (including capillary CBF changes) in vivo. The outcomes from this proposal will provide with better tools to image dynamic vascular changes that occur with chronic drug exposures and hence a tool with which to test potential medications to reverse neurovascular pathology. From its application into assessing the effects of chronic cocaine we also expect to gain with new insights into the neurovascular pathology resulting from chronic cocaine exposure.