CONVECTION-ENHANCED DELIVERY OF THERAPEUTIC AGENTS TO THE PUTAMEN

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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.