Kenneth P. Vives

Comparative transduction efficiency of AAV vector serotypes 1-6 in the substantia nigra and striatum of the primate brain.

Vectors derived from adeno-associated virus (AAV) are promising candidates for neural cell transduction in vivo because they are nonpathogenic and achieve long-term transduction in the central nervous system. AAV serotype 2 (AAV2) is the most widely used AAV vector in clinical trials based largely on its ability to transduce neural cells in the rodent and primate brain. Prior work in rodents suggests that other serotypes might be more efficient; however, a systematic evaluation of vector transduction efficiency has not yet been performed in the primate brain. In this study, AAV viral vectors of serotypes 1-6 with an enhanced green-fluorescent protein (GFP) reporter gene were generated at comparable titers, and injected in equal amounts into the brains of Chlorocebus sabaeus. Vector injections were placed in the substantia nigra (SN) and the caudate nucleus (CD). One month after injection, immunohistochemistry for GFP was performed and the total number of GFP+ cells was calculated using unbiased stereology. AAV5 was the most efficient vector, not only transducing significantly more cells than any other serotype, but also transducing both NeuN+ and glial-fibrillary-acidic protein positive (GFAP+) cells. These results suggest that AAV5 is a more effective vector than AAV2 at delivering potentially therapeutic transgenes to the nigrostriatal system of the primate brain.

Complications and Expected Outcome of Glioma Surgery

The management of patients with intracerebral glioma is focused upon the selection of treatment modalities that prolong survival while minimizing the risk of complications and maintaining an adequate quality of life. In the authors experience, patients with low-grade gliomas are best treated with gross total resection in order to decrease the risk of recurrence with higher grade lesions. In patients with high-grade glioma, age, Karnofsky Performance Status, histology and the use of radiotherapy are major predictors of survival. The extent of surgical resection is less important than these factors, but recent series support a survival advantage in patients that undergo more extensive surgery. The major complication from surgical resection is neurologic impairment. Careful preoperative planning with the assistance of functional MRI and intraoperative mapping is useful for accomplishing the maximum safe resection.

Decreased hippocampal volume on MRI is associated with increased extracellular glutamate in epilepsy patients

Purpose: Temporal lobe epilepsy (TLE) is associated with smaller hippocampal volume and with elevated extracellular (EC) glutamate levels. We investigated the relationship between the hippocampal volume and glutamate in refractory TLE patients.

Low-grade gliomas of chronic epilepsy: A distinct clinical and pathological entity

The authors present a summary of their recent experience regarding the management of patients with a variety of low-grade gliomas found during the evaluation for chronic epilepsy. These tumors are notable because the long-term patient outcome in this population is significantly better than the anticipated results of patients with the same tumors who do not have chronic epilepsy. Based on the long history of preoperative seizures (median 14 years), the frequent cortical location, and the absence of tumor recurrence or anaplastic transformation and the lack of mortality in this population, low-grade gliomas of chronic epilepsy appear to define a specific pathological entity that separates them from other histologically similar low-grade gliomas. Low-grade gliomas of chronic epilepsy also are notable for the absence of morphological features that characterize with dysembryoplastic neuroepithelial tumors (DNTs). Our evidence suggests that low-grade gliomas of chronic epilepsy should be recognized as a distinct pathological entity.

Novel interaction techniques for neurosurgical planning and stereotactic navigation

Neurosurgical planning and image guided neurosurgery require the visualization of multimodal data obtained from various functional and structural image modalities, such as magnetic resonance imaging (MRI), computed tomography (CT), functional MRI, Single photon emission computed tomography (SPECT) and so on. In the case of epilepsy neurosurgery for example, these images are used to identify brain regions to guide intracranial electrode implantation and resection. Generally, such data is visualized using 2D slices and in some cases using a 3D volume rendering along with the functional imaging results. Visualizing the activation region effectively by still preserving sufficient surrounding brain regions for context is exceedingly important to neurologists and surgeons. We present novel interaction techniques for visualization of multimodal data to facilitate improved exploration and planning for neurosurgery. We extended the line widget from VTK to allow surgeons to control the shape of the region of the brain that they can visually crop away during exploration and surgery. We allow simple spherical, cubical, ellipsoidal and cylindrical (probe aligned cuts) for exploration purposes. In addition we integrate the cropping tool with the image-guided navigation system used for epilepsy neurosurgery. We are currently investigating the use of these new tools in surgical planning and based on further feedback from our neurosurgeons we will integrate them into the setup used for image-guided neurosurgery.

Development of a research interface for image guided intervention: initial application to epilepsy neurosurgery

This paper describes the development and application of methods to integrate research image analysis methods and software with a commercial image guided surgery navigation system (the BrainLAB VectorVision Cranial System.) The integration was achieved using a custom designed client/server architecture termed VectorVision Link (VV Link) which extends functionality from the Visualization Toolkit. VV Link enables bi-directional data transfer such as image data sets, visualizations and tool positions in real time. The system was tested in both laboratory experiments and in real epilepsy neurosurgeries with highly promising results

Image-Guided Intraoperative Cortical Deformation Recovery Using Game Theory: Application to Neocortical Epilepsy Surgery

During neurosurgery, nonrigid brain deformation prevents preoperatively-acquired images from accurately depicting the intraoperative brain. Stereo vision systems can be used to track intraoperative cortical surface deformation and update preoperative brain images in conjunction with a biomechanical model. However, these stereo systems are often plagued with calibration error, which can corrupt the deformation estimation. In order to decouple the effects of camera calibration from the surface deformation estimation, a framework that can solve for disparate and often competing variables is needed. Game theory, which was developed to handle decision making in this type of competitive environment, has been applied to various fields from economics to biology. In this paper, game theory is applied to cortical surface tracking during neocortical epilepsy surgery and used to infer information about the physical processes of brain surface deformation and image acquisition. The method is successfully applied to eight in vivo cases, resulting in an 81% decrease in mean surface displacement error. This includes a case in which some of the initial camera calibration parameters had errors of 70%. Additionally, the advantages of using a game theoretic approach in neocortical epilepsy surgery are clearly demonstrated in its robustness to initial conditions.

AAV2-mediated gene transfer of GDNF to the striatum of MPTP monkeys enhances the survival and outgrowth of co-implanted fetal dopamine neurons

Neural transplantation offers the potential of treating Parkinsons disease by grafting fetal dopamine neurons to depleted regions of the brain. However, clinical studies of neural grafting in Parkinsons disease have produced only modest improvements. One of the main reasons for this is the low survival rate of transplanted neurons. The inadequate supply of critical neurotrophic factors in the adult brain is likely to be a major cause of early cell death and restricted outgrowth of fetal grafts placed into the mature striatum. Glial derived neurotrophic factor (GDNF) is a potent neurotrophic factor that is crucial to the survival, outgrowth and maintenance of dopamine neurons, and so is a candidate for protecting grafted fetal dopamine neurons in the adult brain. We found that implantation of adeno-associated virus type 2 encoding GDNF (AAV2-GDNF) in the normal monkey caudate nucleus induced overexpression of GDNF that persisted for at least 6 months after injection. In a 6-month within-animal controlled study, AAV2-GDNF enhanced the survival of fetal dopamine neurons by 4-fold, and increased the outgrowth of grafted fetal dopamine neurons by almost 3-fold in the caudate nucleus of MPTP-treated monkeys, compared with control grafts in the other caudate nucleus. Thus, the addition of GDNF gene therapy to neural transplantation may be a useful strategy to improve treatment for Parkinsons disease.

Nonrigid 3d brain registration using intensity/feature information

The brain deforms non-rigidly during neurosurgery, preventing preoperatively acquired images from accurately depicting the intraoperative brain. If the deformed brain surface can be detected, biomechanical models can be applied to calculate the resulting volumetric deformation. The reliability of this volumetric calculation is dependent on the accuracy of the surface detection. This work presents a surface tracking algorithm which relies on Bayesian analysis to track cortical surface movement. The inputs to the model are 3D preoperative brain images and intraoperative stereo camera images. The addition of a camera calibration optimization term creates a more robust model, capable of tracking the cortical surface in the presence of camera calibration error.

Volumetric Intraoperative Brain Deformation Compensation: Model Development and Phantom Validation

During neurosurgery, nonrigid brain deformation may affect the reliability of tissue localization based on preoperative images. To provide accurate surgical guidance in these cases, preoperative images must be updated to reflect the intraoperative brain. This can be accomplished by warping these preoperative images using a biomechanical model. Due to the possible complexity of this deformation, intraoperative information is often required to guide the model solution. In this paper, a linear elastic model of the brain is developed to infer volumetric brain deformation associated with measured intraoperative cortical surface displacement. The developed model relies on known material properties of brain tissue, and does not require further knowledge about intraoperative conditions. To provide an initial estimation of volumetric model accuracy, as well as determine the models sensitivity to the specified material parameters and surface displacements, a realistic brain phantom was developed. Phantom results indicate that the linear elastic model significantly reduced localization error due to brain shift, from >; 16 mm to under 5 mm, on average. In addition, though in vivo quantitative validation is necessary, preliminary application of this approach to images acquired during neocortical epilepsy cases confirms the feasibility of applying the developed model to in vivo data.