Lentiviral delivery of glial cell line-derived neurotrophic factor (lenti-GDNF) was tested for its trophic effects upon degenerating nigrostriatal neurons in nonhuman primate models of Parkinson's disease (PD). We injected lenti-GDNF into the striatum and substantia nigra of nonlesioned aged rhesus monkeys or young adult rhesus monkeys treated 1 week prior with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Extensive GDNF expression with anterograde and retrograde transport was seen in all animals. In aged monkeys, lenti-GDNF augmented dopaminergic function. In MPTP-treated monkeys, lenti-GDNF reversed functional deficits and completely prevented nigrostriatal degeneration. Additionally, lenti-GDNF injections to intact rhesus monkeys revealed long-term gene expression (8 months). In MPTP-treated monkeys, lenti-GDNF treatment reversed motor deficits in a hand-reach task. These data indicate that GDNF delivery using a lentiviral vector system can prevent nigrostriatal degeneration and induce regeneration in primate models of PD and might be a viable therapeutic strategy for PD patients.

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Background With the decrease in the number of cerebral aneurysms treated surgically and the increase of complexity of those treated surgically, there is a need for simulation-based tools to teach future neurosurgeons the operative techniques of aneurysm clipping. Objective To develop and evaluate the usefulness of a new haptic-based virtual reality (VR) simulator in the training of neurosurgical residents. Methods A real-time sensory haptic feedback virtual reality aneurysm clipping simulator was developed using the Immersive Touch platform. A prototype middle cerebral artery aneurysm simulation was created from a computed tomography angiogram. Aneurysm and vessel volume deformation and haptic feedback are provided in a 3-D immersive VR environment. Intraoperative aneurysm rupture was also simulated. Seventeen neurosurgery residents from three residency programs tested the simulator and provided feedback on its usefulness and resemblance to real aneurysm clipping surgery. Results Residents felt that the simulation would be useful in preparing for real-life surgery. About two thirds of the residents felt that the 3-D immersive anatomical details provided a very close resemblance to real operative anatomy and accurate guidance for deciding surgical approaches. They believed the simulation is useful for preoperative surgical rehearsal and neurosurgical training. One third of the residents felt that the technology in its current form provided very realistic haptic feedback for aneurysm surgery. Conclusion Neurosurgical residents felt that the novel immersive VR simulator is helpful in their training especially since they do not get a chance to perform aneurysm clippings until very late in their residency programs.

Parkinson's disease (PD) is associated with increased excitatory activity within the subthalamic nucleus (STN). We sought to inhibit STN output in hemiparkinsonian macaques by transfection with adeno-associated virus (AAV) containing the gene for glutamic acid decarboxylase (GAD). In total, 13 macaques were rendered hemiparkinsonian by right intracarotid 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine injection. Seven animals were injected with AAV-GAD into the right STN, and six received an AAV gene for green fluorescent protein (GFP). Videotaped motor ratings were performed in a masked fashion on a weekly basis over a 55-week period. At 56 weeks, the animals were scanned with (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET). Histological examination was performed at the end of the study. No adverse events were observed after STN gene therapy. We found that the clinical rating scores for the two treatment groups had different patterns of change over time (group x time interaction, P<0.001). On FDG PET, the GAD animals exhibited an increase in glucose utilization in the right motor cortex relative to GFP controls (P<0.001). Metabolism in this region correlated with clinical ratings at end point (P<0.01). Histology confirmed GAD expression in treated animals. These findings suggest that STN AAV-GAD is well tolerated and potentially effective in a primate model of PD. The changes in motor cortical glucose utilization observed after gene therapy are consistent with the modulation of metabolic brain networks associated with this disorder.

Previous nonhuman primate stroke models have employed temporary occlusion of arteries, had limited behavioral testing and imaging, and focused on the short-term outcome. Our goals were 1. to develop a stable model of chronic stroke in the nonhuman primate, 2. to study in vivo the long-term biochemical changes in the area adjacent to the infarct, using proton magnetic resonance spectroscopy (H MRS), and 3. evaluate these changes in relation to the histopathological effects of stroke. Four adult cynomologous monkeys had an occlusion of the M1 segment of the right MCA. Behavioral tests included a clinical rating scale, motor planning task, fine motor task, and activity monitoring. Eight months afterwards, MRI and 1H MRS were performed. Following the imaging studies the monkeys were perfused transcardially, their brains extracted and processed. Nissl staining and immunohistochemistry for neuronal markers (NeuN) were performed and used to measure the lesion volume and neuronal optical density (OD). All animals developed a left hemiparesis and were unable to perform a fine motor task with the left hand. There was a significant (31%) decline in the motor planning ability with the nonparetic extremity. Monkeys displayed a stooped posture, episodes of rotation to the side of the lesion, partial left hemianopsia, and transient changes in activity. The clinical signs improved over the first 6-8 weeks but the deficits remained stable for the remaining six months of follow up. MRI demonstrated a subcortical and cortical infarction in the right MCA distribution. 1H MRS data detected a significant decrease in the N-acetyl-aspartate (NAA)/creatine (Cr) ratio in the area adjacent to the infarction (VOl-St) compared to a mirror area in the contralateral hemisphere (VOl-Co). Histopathological measurements revealed a significant decline in neuronal cross-sectional area and neuronal optical density in the region of the VOl-St. We established a stable and reproducible model of chronic stroke in the MCA distribution, in the macaque monkey. Our data indicate that NAA detected by 1H MRS can be used to measure neuronal loss in vivo and help target this area for intervention. Our model may be particularly suitable for studies testing the effects of therapeutic strategies involving neural or stem cell transplantation, trophic factors or gene therapy.

An FRI score created by discriminant function analysis can predict whether or not a permanent shunt is required, even if separate factors are not in agreement with each other or show a weak correlation when considered separately. An increased FRI score was strongly and linearly correlated with the risk of EVD challenge failure. A prospective study is necessary to validate the FRI.

Background We evaluated the use of a part-task simulator with 3D and haptic feedback as a training tool for a common neurosurgical procedure – placement of thoracic pedicle screws. Objective To evaluate the learning retention of thoracic pedicle screw placement on a high-performance augmented reality and haptic technology workstation. Methods Fifty-one fellows and residents performed thoracic pedicle screw placement on the simulator. The virtual screws were drilled into a virtual patient’s thoracic spine derived from a computed tomography data set of a real patient. Results With a 12.5% failure rate, a two-proportion z-test yielded P= 0.08. For performance accuracy, an aggregate Euclidean distance deviation from entry landmark on the pedicle and a similar deviation from the target landmark in the vertebral body yielded P=0.04 from a two-sample t-test in which the rejected null hypothesis assumes no improvement in performance accuracy from the practice to the test sessions, and the alternative hypothesis assumes an improvement. Conclusion The performance accuracy on the simulator was comparable to the accuracy reported in literature on recent retrospective evaluation of such placements. The failure rates indicated a minor drop from practice to test sessions, and also indicated a trend (P=0.08) towards learning retention resulting in improvement from practice to test sessions. The performance accuracy showed a 15% mean score improvement and over 50% reduction in standard deviation from practice to test. It showed evidence (P=0.04) of performance accuracy improvement from practice to test session.

The present paper is a retrospective analysis of 27 consecutive patients, treated for abdominal cerebrospinal fluid (CSF) pseudocyst at the Children’s Memorial Hospital in the years 1991–1996. This series is compared to the previous experience from our institution. Treatment consisted of the removal of the ventriculoperitoneal (VP) shunt and placement of an external ventricular drain. Antibiotics were administered intravenously for 10 days. The cysts were aspirated intraoperatively in 9 patients and postoperatively with ultrasound guidance in 3 patients, while they resolved spontaneously in 15 others. In 21 of 27 cases (78%), the shunt could be reinserted into the abdomen in a new location. Four patients had a ventriculopleural shunt, and in 2 patients, a ventriculoatrial shunt was inserted. Forty-four percent of the patients had a positive culture on presentation. The positive culture rate was 77% for those 4 years old and younger and only 28% for those aged 5 and above (p = 0.03). We conclude that abdominal CSF pseudocysts are resolved by externalizing the shunt. A VP shunt can be safely reinserted in the majority of the patients. Infection, while an important factor, is not likely to account for all cases of pseudocyst.