光学成像研究大鼠皮层激活与缺血后的血流动态变化
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摘要
脑是高度依赖持续血流供应的器官,脑组织中存在着精巧的神经血管调节机制来稳定地维持大脑正常生理功能活动所需的能量和氧。生理状态下,这种神经血管耦合调节机制(也称为功能性充血)是脑功能成像信号的基础,而在缺血等病理状态下,这种血管调节机制就会被影响和破坏,进而造成脑功能的失活和组织的损伤。对这种生理和缺血状态下血流调节分布规律以及内在机制的深入探讨,对理解功能成像探测信号的神经生理基础,确立缺血半暗带的诊断标准以及寻找新的缺血治疗作用靶点有着重要的科学和临床意义。内源信号光学成像与激光散斑成像等光学成像手段可以同时提供非常好的时间和空间分辨率,已被广泛应用于神经组织血流动力学过程的监测中,为常规的脑功能成像研究提供了新的信息以及有益的补充。
在本文中,我们联合应用内源信号光学成像与激光散斑成像技术监测了皮层在外周伤害性刺激诱发的功能激活状态下血容量的动态变化过程,皮层微小缺血和再灌注后的血流调节分布特征,以及微小缺血后皮层自发扩散性抑制波(Spreading depression, SD)的区域异质性与其局部血流灌注水平之间的联系。主要研究内容和结论如下:
1)利用内源信号光学成像方法监测了不同强度外周神经刺激在大鼠对侧初级躯体感受皮层激活的血容量相关时空响应模式,发现了伤害性刺激和非伤害性刺激所激活的功能性充血早期响应空间模式的差异性。伤害性刺激诱发的空间响应范围可明显地扩展到邻近动脉分支供应区域,同时在激活皮层区域周围诱发出更明显的光强上升信号。镇痛剂芬太尼可以显著减少伤害性刺激响应的空间范围和峰值幅度。以上结果表明初级躯体感受皮层参与了伤害性刺激的传导与调制过程,激活区域周围的反信号可能可能影响了功能成像研究结果的一致性。
2)提出了一种新的皮层微小缺血再灌注模型,可以方便地实现结扎微动脉的再通,在先前的缺血中心区域形成充分的再灌注。利用激光散斑成像方法,在成像皮层区域可以明确地观察到整个重度缺血中心区域,半暗带区域以及部分的正常脑实质组织。在再灌注24小时后可出现明显的再通后高灌注现象。此外这种新模型还可以部分地限制目标缺血区域周围的侧枝循环,使得缺血的区域更加局限地定位于特定的功能区域中,因而适用于光学成像方法来研究神经血管耦合、再灌注损伤以及中风康复机制。
3)结合激光散斑成像与内源信号光学成像技术,发现了微小缺血后皮层自发SD波相关光信号与局部血流水平之间的相关性,提出SD波相关光信号的综合特征参数可以反映脑组织缺血后血流分布的四种状态:光强波动不明显的区域已处于梗死状态;以显著光强上升相为主的区域为趋于梗死的半暗带组织;光强上升相与下降相幅值相近的区域对应为预后较好的轻度缺血区域;正常的四相光强变化则表现在正常灌注水平的皮层区域。
The brain is critically dependent on a continuous supply of blood to function. The cerebral vasculature is endowed with neurovascular control mechanisms that assure that the blood supply of the brain is commensurate to the needs of energy and oxygen. In the normal state of brain, this neurovascular coupling regulation mechanism (functional hyperemia) is the basis for several modern imaging techniques that have revolutionized the study of human brain activity. However, in several brain pathologies, such as the cerebral ischemia, the control of cerebral blood flow (CBF) is influenced and disrupted, and the resulting homeostatic unbalance may contribute to brain dysfunction and even irreversible massive damage. To study this evolution and essential mechanism of the regulation of CBF in brain normal and ischemic state is benefit to promote understanding of neurophysiological basis of the detected signals in neuroimaging techniques, to determine the standard of the diagnosis of the ischemic penumbra tissue and seek a therapeutic target for ischemia. Optical intrinsic signal imaging (OISI) and laser speckle imaging (LSI), which can simultaneously provide high temporal and spatial resolution, have been extensively applied into the studies focusing on cortical hemodynamic response , and bring on fresh insight, validation and relavant supplement to the conventional brain functional imaging studies.
In this dissertation, OIIS combined with LSI was applied into our study to monitor the dynamic changes of cerebral blood volume (CBV) in primary somatosensory cortex evoked by peripheral noxious stimuli, the distribution of CBF associated with cortical mini-ischemia/reperfusion, and to elucidate the relationship between the regional heterogeneity of ischemia induced spontaneous spreading depression (SD) and the local CBF level. The main results and conclusion are listed as following:
1) Although the dimensions of peak response defined in the spatial domain (CBV increase) in the S1 cortex presented no significant difference under non-/noxious stimuli, its early response component revealed by OISI technique was suggested to differentiate the loci of activated cortical region due to different stimulation in this study. The magnitude and duration of the optical intrinsic signal (OIS) response was found increasing with the varying stimulus intensity. Regions activated by the delivery of a noxious stimulus were surrounded by a ring of inverted optical intrinsic signal, the amplitude of that was inversely proportional to the strength of the optical signal attributable to activation. The selective hypoalgesic effect of fentanyl could suppress the magnitude of OIS and evoke different response pattern while suffering from the same nociceptive stimuli. These results indicated that the contralateral S1 cortex acts a role in the perception of nociception.
2) A new mini-ischemia/reperfusion stroke model was developed by sharing feathers from previous mini-stroke model and cortical compression model. Our results showed that a distinct CBF gradient from ischemic core, penumbra zone to normal tissue immediately after cortical ischemia was clearly presented in the imaged cortex. This model could facilicate vascular recannulation, while confining the collateral flow and draining veins to localize the infarct into a special cortical area.
3) In the early phase of ischemia, the maximum increase in OIS related the saoteneous SD was inversive propational to the rCBF, whereas the maximum decrease in OIS has an opposite tendency. The spontenous SD originated from the penumbra zone and bypassed the severe ischemic core, and presented four types of OIS through the propagation of the imaged cortex: SD could not invade the ischemic core, and dominated with significant increase of optical reflectance in the mild ischemic region distal to infarct core. In the normal tissue with fully perfusion, the OIS was represented as the typical four-phase fluctuation. In the oligemic tissue abuts on the fully perfused region, the increase and decrease phases in the OIS were equivalent in amplitude and prominence. This comparison suggests that the OIS characteristics could reflect the severity of ischemia and collateral flow, beside for the regional CBF level.
在本文中,我们联合应用内源信号光学成像与激光散斑成像技术监测了皮层在外周伤害性刺激诱发的功能激活状态下血容量的动态变化过程,皮层微小缺血和再灌注后的血流调节分布特征,以及微小缺血后皮层自发扩散性抑制波(Spreading depression, SD)的区域异质性与其局部血流灌注水平之间的联系。主要研究内容和结论如下:
1)利用内源信号光学成像方法监测了不同强度外周神经刺激在大鼠对侧初级躯体感受皮层激活的血容量相关时空响应模式,发现了伤害性刺激和非伤害性刺激所激活的功能性充血早期响应空间模式的差异性。伤害性刺激诱发的空间响应范围可明显地扩展到邻近动脉分支供应区域,同时在激活皮层区域周围诱发出更明显的光强上升信号。镇痛剂芬太尼可以显著减少伤害性刺激响应的空间范围和峰值幅度。以上结果表明初级躯体感受皮层参与了伤害性刺激的传导与调制过程,激活区域周围的反信号可能可能影响了功能成像研究结果的一致性。
2)提出了一种新的皮层微小缺血再灌注模型,可以方便地实现结扎微动脉的再通,在先前的缺血中心区域形成充分的再灌注。利用激光散斑成像方法,在成像皮层区域可以明确地观察到整个重度缺血中心区域,半暗带区域以及部分的正常脑实质组织。在再灌注24小时后可出现明显的再通后高灌注现象。此外这种新模型还可以部分地限制目标缺血区域周围的侧枝循环,使得缺血的区域更加局限地定位于特定的功能区域中,因而适用于光学成像方法来研究神经血管耦合、再灌注损伤以及中风康复机制。
3)结合激光散斑成像与内源信号光学成像技术,发现了微小缺血后皮层自发SD波相关光信号与局部血流水平之间的相关性,提出SD波相关光信号的综合特征参数可以反映脑组织缺血后血流分布的四种状态:光强波动不明显的区域已处于梗死状态;以显著光强上升相为主的区域为趋于梗死的半暗带组织;光强上升相与下降相幅值相近的区域对应为预后较好的轻度缺血区域;正常的四相光强变化则表现在正常灌注水平的皮层区域。
The brain is critically dependent on a continuous supply of blood to function. The cerebral vasculature is endowed with neurovascular control mechanisms that assure that the blood supply of the brain is commensurate to the needs of energy and oxygen. In the normal state of brain, this neurovascular coupling regulation mechanism (functional hyperemia) is the basis for several modern imaging techniques that have revolutionized the study of human brain activity. However, in several brain pathologies, such as the cerebral ischemia, the control of cerebral blood flow (CBF) is influenced and disrupted, and the resulting homeostatic unbalance may contribute to brain dysfunction and even irreversible massive damage. To study this evolution and essential mechanism of the regulation of CBF in brain normal and ischemic state is benefit to promote understanding of neurophysiological basis of the detected signals in neuroimaging techniques, to determine the standard of the diagnosis of the ischemic penumbra tissue and seek a therapeutic target for ischemia. Optical intrinsic signal imaging (OISI) and laser speckle imaging (LSI), which can simultaneously provide high temporal and spatial resolution, have been extensively applied into the studies focusing on cortical hemodynamic response , and bring on fresh insight, validation and relavant supplement to the conventional brain functional imaging studies.
In this dissertation, OIIS combined with LSI was applied into our study to monitor the dynamic changes of cerebral blood volume (CBV) in primary somatosensory cortex evoked by peripheral noxious stimuli, the distribution of CBF associated with cortical mini-ischemia/reperfusion, and to elucidate the relationship between the regional heterogeneity of ischemia induced spontaneous spreading depression (SD) and the local CBF level. The main results and conclusion are listed as following:
1) Although the dimensions of peak response defined in the spatial domain (CBV increase) in the S1 cortex presented no significant difference under non-/noxious stimuli, its early response component revealed by OISI technique was suggested to differentiate the loci of activated cortical region due to different stimulation in this study. The magnitude and duration of the optical intrinsic signal (OIS) response was found increasing with the varying stimulus intensity. Regions activated by the delivery of a noxious stimulus were surrounded by a ring of inverted optical intrinsic signal, the amplitude of that was inversely proportional to the strength of the optical signal attributable to activation. The selective hypoalgesic effect of fentanyl could suppress the magnitude of OIS and evoke different response pattern while suffering from the same nociceptive stimuli. These results indicated that the contralateral S1 cortex acts a role in the perception of nociception.
2) A new mini-ischemia/reperfusion stroke model was developed by sharing feathers from previous mini-stroke model and cortical compression model. Our results showed that a distinct CBF gradient from ischemic core, penumbra zone to normal tissue immediately after cortical ischemia was clearly presented in the imaged cortex. This model could facilicate vascular recannulation, while confining the collateral flow and draining veins to localize the infarct into a special cortical area.
3) In the early phase of ischemia, the maximum increase in OIS related the saoteneous SD was inversive propational to the rCBF, whereas the maximum decrease in OIS has an opposite tendency. The spontenous SD originated from the penumbra zone and bypassed the severe ischemic core, and presented four types of OIS through the propagation of the imaged cortex: SD could not invade the ischemic core, and dominated with significant increase of optical reflectance in the mild ischemic region distal to infarct core. In the normal tissue with fully perfusion, the OIS was represented as the typical four-phase fluctuation. In the oligemic tissue abuts on the fully perfused region, the increase and decrease phases in the OIS were equivalent in amplitude and prominence. This comparison suggests that the OIS characteristics could reflect the severity of ischemia and collateral flow, beside for the regional CBF level.
引文
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