采用动态电阻抗成像技术对脑损伤动物模型监测的实验研究

发布时间：2018-08-21 13:50

【摘要】：脑损伤（Brain Injury, BI）具有病情凶险、死亡率高的特点，是急性脑病中最严重的一种，预后较差，是人类致死性疾病之一[1]。目前临床尚无法实现脑损伤的早期检测与实时监测，脑损伤不能得到及时干预和治疗是导致预后差的主要原因[2]。脑损伤主要的辅助诊断技术包括X射线、CT、MRI、超声波检查、脑血管造影、颅内压监测（ICP）、脊髓穿刺等，这些方法虽能获得一些有价值的诊断信息，但都无法进行脑损伤的实时动态监测并在第一时间预警，致使患者错过最佳的治疗时间窗，临床中因脑损伤引起的致死、致残时有发生，因而迫切需要一种有效方法实现对脑损伤的实时动态监测。电阻抗断层成像(Electrical Impedance Tomography, EIT)是一种以人体内部电阻(电导)率的分布为成像目标的医学成像技术[3]。其主要思想是通过对测量目标外加驱动信号（驱动电压或电流）并测量其边界电压或电流分布，通过对偏微分方程的逆问题进行求解，近似计算出目标区域内的电导率分布。这一新技术具有无创伤、功能成像、成本低廉、体积小、操作简单、动态实时监护等优点，在脑损伤的床旁动态图像监测应用上具有广阔的应用前景和研究价值。我们课题组经过近二十年的研究，在电阻抗成像的硬件采集系统和成像算法以及动物、临床实验等方面取得了突破性的进展，在颅脑动态图像监护领域更是达到国际水平。在此基础上，为进一步推进EIT的临床应用，针对脑损伤电阻抗动态图像监护研究中的实际问题，本文主要从以下两个方面开展研究： (1)脑水肿动物模型电阻抗动态图像监护的实验研究为使研究更贴近于临床，改进了实验电极。前期的动物实验将实验电极嵌入颅骨内，此种方法虽然有效地降低了电极系统的接触阻抗，但是容易引起出血并且破坏颅内压环境而影响实验结果。因此，为使电极系统满足实验要求，在前期实验电极的基础上改进了电极系统，其构成包括绝缘板、外部牵引系统和设置在绝缘板上的电极探头。该电极探头可自由调节长度，并通过下拉部件使其方便且严密的接触于实验动物颅骨顶部。利用两电极法对改进后的实验电极与EIT临床实验中Ag/AgCl电极的性能进行对比。放射脑水肿动物模型的制备采用单次大剂量Dt30Gy，剂量率300cGy/min，利用CADPLAN/HELIOS三维治疗计划系统严格按照实验要求设计放疗计划。并利用电阻抗成像系统对动物模型进行监测，观察和分析随着时间的改变放射损伤性脑水肿在EIT图像中的变化。之后再利用解剖学方法、影像学方法、病理学方法等对模型和结果进行验证。本研究采用高能X线，构造了三维准确定位的放射损伤脑水肿动物模型，该模型具有以下优点：准确定位；闭合性；水肿范围可控；更好的模拟临床。因此我们提出利用放射损伤的方法制造脑水肿动物模型，并首次开展了采用EIT技术对此种脑水肿动物模型进行检测的实验研究。 (2)内源性脑出血动物模型电阻抗动态图像监护的实验研究利用胶原蛋白酶诱导法建立脑出血动物模型，选择纹状体部位注射胶原蛋白酶制造脑实质出血模型，简要实验过程包括，麻醉、脱毛、钻孔、注射胶原酶和模型验证等。其优势在于此种模型可以根据胶原蛋白酶浓度和量的调节控制出血量和范围，出血具有延迟性，可以用EIT方法监测整个出血过程，并且注射微量胶原蛋白酶，不形成自身药物在颅内的占位效应，更接近于实际脑出血，更为重要的是采用此模型可以封闭注射孔，保证脑出血过程中颅内压的存在，更好的模拟临床中脑出血的情况，利用电阻抗成像系统对动物模型进行监测，观察和分析随着时间的改变放射损伤性脑水肿在EIT图像中的变化。研究结果表明： (1)利用电阻抗成像技术监测放射损伤性脑水肿早期的电阻抗改变，发现EIT局部重构均值和动态图像时间序列发生明显改变，实验组MLRV每小时变化量为（0.003529±0.00089），与对照组(3.1±1.2)E-5有显著性差异(P0.05)，阻抗明显升高，位置和造模的位置基本吻合。通过影像学、病理学和解剖学检测，我们发现，组织切片在照射12小时后不能从解剖学上发现放射性脑水肿，利用CT在脑组织照射三天很难发现放射损伤性脑水肿，在光学显微镜下发现照射后24小时细胞发生水肿和损伤，电镜检测结果显示照射后10小时能够检测放射损伤性脑水肿。初步实验结果表明：利用电阻抗方法可检测到处于急性期内的脑放射损伤即放射性脑水肿，证明了EIT在检测脑水肿的敏感性和可行性。 (2)利用电阻抗成像技术监测动物脑出血早期电阻抗改变，通过EIT一维信息重构幅值最大值和二维动态图像时间序列的变化，AM每分钟变化量为0.012±0.0075，与对照组有显著性差异(P0.05)，解剖学切片、病理学、影像学、及阻抗分析仪检测结果，发现：随着时间的延长、血肿的加剧和范围的扩大，其脑部阻抗值升高。初步实验结果表明：目标区域的电阻抗变化是由脑出血引起，EIT可监测到这种变化；结合CT扫描结果，说明脑出血早期组织的阻抗改变可能早于密度变化，EIT有可能成为比影像学更敏感的检测手段。本研究旨在为脑损伤的早期诊断提供一种实时、动态、无创的监测方法，，通过动物实验验证了EIT成像技术对脑损伤监测的可行性和敏感性，证明了EIT具备脑损伤早期检测的应用前景，对EIT的临床应用具有深远影响。
[Abstract]:Brain Injury (BI) is one of the most serious acute encephalopathy with poor prognosis and is one of the fatal diseases of human beings. The main auxiliary diagnostic techniques for brain injury include X-ray, CT, MRI, ultrasonic examination, cerebral angiography, intracranial pressure monitoring (ICP), spinal cord puncture and so on. Although these methods can obtain some valuable diagnostic information, they can not real-time dynamic monitoring of brain injury and early warning at the first time, resulting in patients missing the best treatment window. In clinic, death and disability caused by brain injury occur frequently, so an effective method is urgently needed to realize real-time dynamic monitoring of brain injury.
Electrical Impedance Tomography (EIT) is a medical imaging technique that targets the distribution of electrical resistance (conductivity) in the body [3]. This new technique has many advantages, such as non-invasive, functional imaging, low cost, small size, simple operation, dynamic real-time monitoring and so on. It has broad application prospects and research value in the application of bedside dynamic image monitoring of brain injury.
After nearly 20 years of research, our research group has made breakthroughs in hardware acquisition system, imaging algorithm, animal and clinical experiments of EIT, and has reached the international level in the field of brain dynamic image monitoring. The practical problems in image monitoring research are studied in the following two aspects:
(1) experimental study of electrical impedance monitoring in animal models of cerebral edema
In order to make the study closer to the clinic and improve the experimental electrode, the experimental electrode was embedded in the skull in the previous animal experiment. Although this method effectively reduces the contact impedance of the electrode system, it is easy to cause bleeding and destroy the intracranial pressure environment and affects the experimental results. The electrode system is improved on the basis of the electrode test, which consists of an insulating plate, an external traction system and an electrode probe mounted on the insulating plate. The electrode probe can be freely adjusted in length and can be conveniently and tightly contacted on the top of the skull of experimental animals by pulling down the parts. The improved electrode and EIT are clinically applied by two-electrode method. The performance of Ag/AgCl electrode was compared in the experiment.
The animal model of radiation brain edema was prepared with a single high dose of Dt30Gy and a dose rate of 300cGy/min. The radiotherapy plan was designed strictly according to the experimental requirements by using CADPLAN/HELIOS three-dimensional treatment planning system. The animal model was monitored by electrical impedance imaging system, and the EIT images of radiation-induced brain edema were observed and analyzed with time. Then the model and results were validated by anatomy, imaging and pathology.
In this study, we used high-energy X-ray to construct an animal model of radiation-induced brain edema, which has the following advantages: accurate localization; closure; controlled edema range; better clinical simulation. The experimental study of animal models of cerebral edema.
(2) experimental study on dynamic image monitoring of electrical impedance in animal models of intracerebral hemorrhage
Intracerebral hemorrhage animal model was established by collagenase-induced method, and the striatum was injected with collagenase to make the model of cerebral parenchymal hemorrhage. The brief experimental process included anesthesia, depilation, drilling, injection of collagenase and model validation. And the hemorrhage is delayed. EIT method can be used to monitor the whole hemorrhage process, and injection of micro-collagenase, not forming their own drug occupying effect in the brain, more close to the actual cerebral hemorrhage, more importantly, the use of this model can close the injection hole, ensure the existence of intracranial pressure in the process of cerebral hemorrhage, better simulation of impending. In order to observe and analyze the changes of brain edema caused by radiation injury in EIT images with the change of time, electrical impedance tomography (EIT) was used to monitor the animal model of cerebral hemorrhage in bed.
The results show that:
(1) Electrical impedance changes in the early stage of radiation-induced brain edema were monitored by electrical impedance tomography (EIT). It was found that the mean value of local EIT reconstruction and the time series of dynamic images changed significantly. The hourly variation of MLRV in the experimental group was (0.003529 [0.00089], which was significantly different from that in the control group (3.1 [1.2] E-5) (P 0.05). Impedance increased significantly, location and modeling. By imaging, pathological and anatomical examination, we found that the tissue slices could not find radioactive brain edema from anatomy 12 hours after irradiation. It was difficult to find radiation-induced brain edema by CT in three days after irradiation, and the cells were found to have edema and injury 24 hours after irradiation under optical microscope. The results of electron microscopy showed that the brain edema could be detected 10 hours after irradiation. The preliminary results showed that the brain edema in acute stage could be detected by electrical impedance method, which proved the sensitivity and feasibility of EIT in detecting brain edema.
(2) Electrical impedance tomography (EIT) was used to monitor the changes of electrical impedance in the early stage of cerebral hemorrhage. The maximum amplitude and the time series of two-dimensional dynamic images were reconstructed by one-dimensional EIT information. The change of AM per minute was 0.012 (+ 0.0075), which was significantly different from that of the control group (P 0.05). Preliminary results showed that the electrical impedance changes in the target area were caused by cerebral hemorrhage and could be monitored by EIT. Combined with CT scan results, the impedance changes in early cerebral hemorrhage tissues may be earlier than the density changes, and EIT may be possible. It can become a more sensitive detection method than imaging.
The purpose of this study is to provide a real-time, dynamic and non-invasive monitoring method for the early diagnosis of brain injury. The feasibility and sensitivity of EIT imaging technology for monitoring brain injury are verified by animal experiments. It is proved that EIT has the application prospect of early detection of brain injury and has a profound impact on the clinical application of EIT.
【学位授予单位】：第四军医大学
【学位级别】：硕士
【学位授予年份】：2012
【分类号】：R-332

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