CONVECTION-ENHANCED DELIVERY OF THERAPEUTIC AGENTS TO THE PUTAMEN

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 目的：设计一种成功的用于人壳核内输注载药溶液的对流增强输注方案。 在这种情况下，成功意味着覆盖壳核和/或尾状核，对周围结构的覆盖最小。这项特殊研究的目标是在恒河猴中开发这样一种方案，并为人类类似方案的结果提供预测。我们将估计使用此协议实现给定覆盖的可能性。我们还专门比较了目前提出的大脑交付方法。 我们已经建立了所有的输注方法，并正在使用术中成像在非人灵长类动物中进行常规输注和凝胶。 进展： 由于其行为和解剖结构的复杂性，非人灵长类动物是临床前评估需要脑内靶向的侵入性技术的理想对象。虽然立体定位图谱提供了基本信息，但恒河猴受试者之间的个体差异需要使用MRI引导的手术技术。当研究脑实质中输注物的体内动力学时，这种需要进一步增强。在体内输注期间，对靶向结构的3D特定点进行精确靶向的能力允许控制解剖变量和识别其他因素的变化的影响。实时MRI导航系统（例如美敦力导航系统）目前已在临床上用于脑内活检和脑深部刺激电极的放置，但其在非人类灵长类动物和脑内输液MRI监测中的应用尚未报道。在本研究中，将恒河猴（5-7岁，5-8 kg）置于MRI兼容的立体定位框架中。在3.0T GE扫描机上进行轴位、冠状位和矢状位T1 MRI，以确定壳核中心的靶点。在无菌手术条件下，在基线MRI定义的进入点处在猴颅骨上钻孔。将经过改良以适应猴颅骨曲率的Navigus（MRI兼容轨迹导向器，Medtronic导航系统的一部分）的底座固定在顶部。导入前，导管和输注管路中填充钆DTPA（钆特醇;在盐水中稀释至2 mMol/l）和溴酚蓝（0.16 mg/ml）溶液。进行扫描以确定Navigus股骨柄的位置。当导管在三个平面中的投影与目标的预期轨迹匹配时，基座被锁定在适当位置。进行连续MRI扫描，以确认导管轨迹并确保单次直接通过靶点。在输注期间进行额外扫描。溴酚蓝的死后可视化与体内成像相匹配。我们在非人灵长类动物中的研究结果证实了实时MRI脑内导航结合灵活的靶向系统（如Navigus）的准确性，并表明它可以成为临床前脑内手术的有价值工具。 本研究使用WNPRC Assay Services和CPI。 出版物： Emborg M.E.，乔尔斯五世，费希尔河，Brunner K.，卡特五世，罗斯·C拉关河，Raschke J.，布雷迪M久保田，亚历山大A.. （2010）术中脑内MRI引导导航，用于非人类灵长类动物的准确定位。细胞转运6月29日。[Epub打印前）。 PMID 20587170。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Objective: To design a successful convection-enhanced infusion protocol for human intra-putamenal infusions of solutions carrying drugs. Success means, in this context, covering the putamen and/or caudate nucleus, with minimal coverage of surrounding structures. The goal of this particular study is to develop such a protocol in rhesus monkeys, and to offer a prediction for the results of a similar protocol in humans. We will estimate the likelihood of achieving a given coverage using this protocol. We are also specifically comparing current proposed methods of brain delivery. We have established all the infusion methods and are performing routing infusions and gels in nonhuman primates using intraoperative imaging. PROGRESS: Due to their behavioral and anatomical complexity nonhuman primates are ideal subjects for preclinical evaluation of invasive technologies requiring intracerebral targeting. While stereotaxic atlases provide basic information, the individual variability between rhesus monkey subjects necessitates the use of MRI-guided surgical techniques. This need is further enhanced when studying in vivo dynamics of infusates in the brain parenchyma. During in vivo infusions, the ability to perform accurate targeting towards a 3-D specific point of the targeted structure allows control of the anatomical variable and identification of the effects of variations in other factors. Real-time MRI navigation systems, such as the Medtronic Navigation System, are currently being used in the clinic for intracerebral biopsies and placement of electrodes for deep brain stimulation, yet their use in nonhuman primates and MRI monitoring of intracerebral infusions has not been reported. In this study rhesus monkeys (5-7 yrs. old, 5-8 kg) were placed in a MRI-compatible stereotaxic frame. T1 MRIs were obtained in a 3.0T GE scanner in the axial, coronal and sagittal planes to identify the target in the center of the putamen nucleus. Under sterile surgical conditions, a hole in the monkey skull was drilled at the entry point defined by the baseline MRI. The base of a Navigus (a MRI-compatible trajectory guide, part of the Medtronic Navigation system) that was modified to adapt to the curvature of the monkey skull was secured on top. Prior to introduction, the catheter and infusion lines were filled with a solution of Gadolinium DTPA (gadoteridol; diluted in saline to 2mMol/l) and bromophenol blue (0.16 mg/ml). Scans were taken to define the position of the Navigus stem. When the projection of the catheter in the three planes matched the desired trajectory to the target, the base was locked in position. Successive MRI scans were performed to confirm trajectory of the catheter and to ensure single direct passage to target. Additional scans were performed during infusion. Postmortem visualization of bromophenol blue matched in vivo imaging. Our results in nonhuman primates confirm the accuracy of real-time MRI intracerebral navigation combined with a flexible targeting system like the Navigus and suggests that it can be a valuable tool for preclinical intracerebral procedures. This research used WNPRC Assay Services and CPI. PUBLICATION: Emborg M.E., Joers V., Fisher R., Brunner K., Carter V., Ross C., Rhagavan R., Raschke J., Brady M., Kubota K., Alexander A.. (2010) Intraoperative intracerebral MRI-guided navigation for accurate targeting in nonhuman primates. Cell Transpl. Jun 29. [Epub ahead of print]. PMID 20587170.