Vivek Sudhakar, Amin Mahmoodi, John R. Bringas, Jerusha Naidoo, Adrian Kells, Lluis Samaranch, Massimo S. Fiandaca and Krystof S. Bankiewicz
Successful convection-enhanced delivery of therapeutic agents to subcortical brain structures requires accurate cannula placement. Stereotactic guiding devices have been developed to accurately target brain nuclei. However, technologies remain limited by a lack of MRI compatibility, or by devices’ size, making them suboptimal for direct gene delivery to brain parenchyma. The goal of this study was to validate the accuracy of a novel frameless skull-mounted ball-joint guide array (BJGA) in targeting the nonhuman primate (NHP) brain.
Fifteen MRI-guided cannula insertions were performed on 9 NHPs, each targeting the putamen. Optimal trajectories were planned on a standard MRI console using 3D multiplanar baseline images. After cannula insertion, the intended trajectory was compared to the final trajectory to assess deviation (euclidean error) of the cannula tip.
The average cannula tip deviation was 1.18 ± 0.60 mm (mean ± SD) as measured by 2 independent reviewers. Topological analysis showed a superior, posterior, and rightward directional bias, and the intra- and interclass correlation coefficients were > 0.85, indicating valid and reliable intra- and interobserver evaluation.
The data demonstrate that the BJGA can be used to reliably target subcortical brain structures by using MRI guidance, with accuracy comparable to current frameless stereotactic systems. The size and versatility of the BJGA, combined with a streamlined workflow, allows for its potential applicability to a variety of intracranial neurosurgical procedures, and for greater flexibility in executing MRI-guided experiments within the NHP brain.
Jeffrey H. Kordower, Massimo S. Fiandaca, Mary F. D. Notter, John T. Hansen and Don M. Gash
✓ Autopsy results on patients and corresponding studies in nonhuman primates have revealed that autografts of adrenal medulla into the striatum, used as a treatment for Parkinson's disease, do not survive well. Because adrenal chromaffin cell viability may be limited by the low levels of available nerve growth factor (NGF) in the striatum, the present study was conducted to determine if transected peripheral nerve segments could provide sufficient levels of NGF to enhance chromaffin cell survival in vitro and in vivo.
Aged female rhesus monkeys, rendered hemiparkinsonian by the drug MPTP (n-methyl-4-phenyl-1,2,3,6 tetrahydropyridine), received autografts into the striatum using a stereotactic approach, of either sural nerve or adrenal medulla, or cografts of adrenal medulla and sural nerve (three animals in each group). Cell cultures were established from tissue not used in the grafts. Adrenal chromaffin cells either cocultured with sural nerve segments or exposed to exogenous NGF differentiated into a neuronal phenotype. Chromaffin cell survival, when cografted with sural nerve into the striatum, was enhanced four- to eightfold from between 8000 and 18,000 surviving cells in grafts of adrenal tissue only up to 67,000 surviving chromaffin cells in cografts. In grafts of adrenal tissue only, the implant site consisted of an inflammatory focus. Surviving chromaffin cells, which could be identified by both chromogranin A and tyrosine hydroxylase staining, retained their endocrine phenotype.
Cografted chromaffin cells exhibited multipolar neuritic processes and numerous chromaffin granules, and were also immunoreactive for tyrosine hydroxylase and chromogranin A. Blood vessels within the graft were fenestrated, indicating that the blood-brain barrier was not intact. Additionally, cografted chromaffin cells were observed in a postsynaptic relationship with axon terminals from an undetermined but presumably a host origin.
Dali Yin, R. Mark Richardson, Massimo S. Fiandaca, John Bringas, John Forsayeth, Mitchel S. Berger and Krystof S. Bankiewicz
The purpose of this study was to optimize stereotactic coordinates for delivery of therapeutic agents into the thalamus and brainstem, using convection-enhanced delivery (CED) to avoid leakage into surrounding anatomical structures while maximizing CED of therapeutics within the target volume.
The authors recently published targeting data for the nonhuman primate putamen in which they defined infusion parameters, referred to as “red,” “blue,” and “green” zones, that describe cannula placements resulting in poor, suboptimal, and optimal volumes of distribution, respectively. In the present study, the authors retrospectively analyzed 22 MR images with gadoteridol as a contrast reagent, which were obtained during CED infusions into the thalamus (14 cases) and brainstem (8 cases) of nonhuman primates.
Excellent distribution of gadoteridol within the thalamus was obtained in 8 cases and these were used to define an optimal target locus (or green zone). Good distribution in the thalamus, with variable leakage into adjacent anatomical structures, was noted in 6 cases, defining a blue zone. Quantitative containment (99.7 ± 0.2%) of gadoteridol within the thalamus was obtained when the cannula was placed in the green zone, and less containment (85.4 ± 3.8%) was achieved with cannula placement in the blue zone. Similarly, a green zone was also defined in the brainstem, and quantitative containment of infused gadoteridol within the brainstem was 99.4 ± 0.6% when the cannula was placed in the green zone. These results were used to determine a set of 3D stereotactic coordinates that define an optimal site for infusions intended to cover the thalamus and brainstem of nonhuman primates.
The present study provides quantitative analysis of cannula placement and infusate distribution using real-time MR imaging and defines an optimal zone for infusion in the nonhuman primate thalamus and brainstem. Cannula placement recommendations developed from such translational nonhuman primate studies have significant implications for the design of anticipated clinical trials featuring CED therapy into the thalamus and brainstem for CNS diseases.
Vivek Sudhakar, Jerusha Naidoo, Lluis Samaranch, John R. Bringas, Russell R. Lonser, Massimo S. Fiandaca and Krystof S. Bankiewicz
To develop and assess a convective delivery technique that enhances the effectiveness of drug delivery to nonspherical brain nuclei, the authors developed an occipital “infuse-as-you-go” approach to the putamen and compared it to the currently used transfrontal approach.
Eleven nonhuman primates received a bilateral putamen injection of adeno-associated virus with 2 mM gadolinium-DTPA by real-time MR-guided convective perfusion via either a transfrontal (n = 5) or occipital infuse-as-you-go (n = 6) approach.
MRI provided contemporaneous assessment and monitoring of putaminal infusions for transfrontal (2 to 3 infusion deposits) and occipital infuse-as-you-go (stepwise infusions) putaminal approaches. The infuse-as-you-go technique was more efficient than the transfrontal approach (mean 35 ± 1.1 vs 88 ± 8.3 minutes [SEM; p < 0.001]). More effective perfusion of the postcommissural and total putamen was achieved with the infuse-as-you-go versus transfronatal approaches (100-µl infusion volumes; mean posterior commissural coverage 76.2% ± 5.0% vs 32.8% ± 2.9% [p < 0.001]; and mean total coverage 53.5% ± 3.0% vs 38.9% ± 2.3% [p < 0.01]).
The infuse-as-you-go approach, paralleling the longitudinal axis of the target structure, provides a more effective and efficient method for convective infusate coverage of elongated, irregularly shaped subcortical brain nuclei.
Vanja Varenika, Peter Dickinson, John Bringas, Richard LeCouteur, Robert Higgins, John Park, Massimo Fiandaca, Mitchel Berger, John Sampson and Krystof Bankiewicz
The authors have shown that convection-enhanced delivery (CED) of gadoteridol-loaded liposomes (GDLs) into different regions of normal monkey brain results in predictable, widespread distribution of this tracking agent as detected by real-time MR imaging. They also have found that this tracking technique allows monitoring of the distribution of similar nanosized agents such as therapeutic liposomes and viral vectors. A limitation of this procedure is the unexpected leakage of liposomes out of targeted parenchyma or malignancies into sulci and ventricles. The aim of the present study was to evaluate the efficacy of CED after the onset of these types of leakage.
The authors documented this phenomenon in a study of 5 nonhuman primates and 7 canines, comprising 54 CED infusion sessions. Approximately 20% of these infusions resulted in leakage into cerebral ventricles or sulci. All of the infusions and leakage events were monitored with real-time MR imaging. The authors created volume-distributed versus volume-infused graphs for each infusion session. These graphs revealed the rate of distribution of GDL over the course of each infusion and allowed the authors to evaluate the progress of CED before and after leakage.
The distribution of therapeutics within the target structure ceased to increase or resulted in significant attenuation after the onset of leakage.
An analysis of the cases in this study revealed that leakage undermines the efficacy of CED. These findings reiterate the importance of real-time MR imaging visualization during CED to ensure an accurate, robust distribution of therapeutic agents.