Stroke research in non-human primates (NHPs) with gyrencephalic brains is a critical step in overcoming the translational barrier that limits the development of new pharmaceutical and rehabilitative strategies for stroke. White-matter stroke (WMS) has a unique pathophysiology from graymatter stroke and is not well understood because of a lack of pertinent animal models. To create a precise capsular infarct model in the cynomolgus macaque, we first used electrical stimulation to map hand movements, followed by viral tracing of the hand motor fibers (hMFs). This enabled us to identify stereotactic targets in the posterior limb of the internal capsule (PLIC). Neural tracing showed that hMFs occupy the full width of the PLIC, owing to overlap with the motor fibers for the leg. Furthermore, the hMFs were distributed in an oblique shape, requiring coronal tilting of the target probe. We used the photothrombotic infarct lesioning technique to precisely destroy the hMFs within the internal capsule. Double-point infarct lesioning that fully compromised the hMFs resulted in persistent hand motor and walking deficits whereas single-point lesioning did not. Minor deviations in targeting failed to produce persistent motor deficits. Accurate stereotactic targeting with thorough involvement of motor fibers is critical for the production of a capsular infarct model with persistent motor deficits. In conclusion, the precision capsular infarct model can be translated to the NHP system to show persistent motor deficits and may be useful to investigate the mechanism of post-stroke recovery as well as to develop new therapeutic strategies for the WMS.

The brain grows with age in non-human primates (NHPs). Therefore, atlas-based stereotactic coordinates cannot be used directly to target subcortical structures if the size of the animal's brain differs from that used in the stereotactic atlas. Furthermore, growth is non-uniform across different cortical regions, making it difficult to simply apply a single brain-expansion ratio. We determined the skull reference lines that best reflect changes in brain size along the X, Y, and Z axes and plotted the changes in reference-line length against the changes in body weight. The skull reference lines had a linear relationship with body weight. However, comparison of skull reference lines with body weight confirmed the non-uniform skull growth during postnatal development, with skull growth more prominent in the X and Y axes than the Z axis. Comparing the differences between the atlas-based lengths and those calculated empirically from plot-based linear fits, we created craniometric indices that can be used to modify stereotactic coordinates along all axes. We verified the accuracy of the corrected stereotactic targeting by infusing dye into internal capsule in euthanized and preserved NHP brains. Our axis-specific, craniometric-index-adjusted stereotactic targeting enabled us to correct for targeting errors arising from differences in brain size. Histological verification showed that the method was accurate to within 1 mm. Craniometric index-adjusted targeting is a simple and relatively accurate method that can be used for NHP stereotactic surgery in the general laboratory, without the need for high-resolution imaging.
Body Weight ; Brain ; Internal Capsule ; Methods ; Primates ; Skull

BACKGROUND: Stroke involving the cerebral white matter (WM) has increased in prevalence, but most experimental studies have focused on ischemic injury of the gray matter. This study was performed to investigate the WM in a unique rat model of photothrombotic infarct targeting the posterior limb of internal capsule (PLIC), focusing on the identification of the most vulnerable structure in WM by ischemic injury, subsequent glial reaction to the injury, and the fundamental histopathologic feature causing different neurologic outcomes. METHODS: Light microscopy with immunohistochemical stains and electron microscopic examinations of the lesion were performed between 3 hours and 21 days post-ischemic injury. RESULTS: Initial pathological change develops in myelinated axon, concomitantly with reactive change of astrocytes. The first pathology to present is nodular loosening to separate the myelin sheath with axonal wrinkling. Subsequent pathologies include rupture of the myelin sheath with extrusion of axonal organelles, progressive necrosis, oligodendrocyte degeneration and death, and reactive gliosis. Increase of glial fibrillary acidic protein (GFAP) immunoreactivity is an early event in the ischemic lesion. WM pathologies result in motor dysfunction. Motor function recovery after the infarct was correlated to the extent of PLIC injury proper rather than the infarct volume. CONCLUSIONS: Pathologic changes indicate that the cerebral WM, independent of cortical neurons, is highly vulnerable to the effects of focal ischemia, among which myelin sheath is first damaged. Early increase of GFAP immunoreactivity indicates that astrocyte response initially begins with myelinated axonal injury, and supports the biologic role related to WM injury or plasticity. The reaction of astrocytes in the experimental model might be important for the study of pathogenesis and treatment of the WM stroke.
Astrocytes ; Axons ; Coloring Agents ; Extremities ; Glial Fibrillary Acidic Protein ; Gliosis ; Gray Matter ; Internal Capsule* ; Ischemia ; Microscopy ; Models, Animal ; Models, Theoretical ; Myelin Sheath ; Necrosis ; Neurons ; Oligodendroglia ; Organelles ; Pathology ; Plastics ; Prevalence ; Recovery of Function ; Rupture ; Stroke ; White Matter

OBJECTIVE: The purpose of this study is to find the optimal stiffness and volume of bone cement and their biomechanical effects on the adjacent vertebrae to determine a better strategy for conducting vertebroplasty. METHODS: A three-dimensional finite-element model of a functional spinal unit was developed using computed tomography scans of a normal motion segment, comprising the T11, T12 and L1 vertebrae. Volumes of bone cement, with appropriate mechanical properties, were inserted into the trabecular core of the T12 vertebra. Parametric studies were done by varying the volume and stiffness of the bone cement. RESULTS: When the bone cement filling volume reached 30% of the volume of a vertebral body, the level of stiffness was restored to that of normal bone, and when higher bone cement exceeded 30% of the volume, the result was stiffness in excess of that of normal bone. When the bone cement volume was varied, local stress in the bony structures (cortical shell, trabecular bone and endplate) of each vertebra monotonically increased. Low-modulus bone cement has the effect of reducing strain in the augmented body, but only in cases of relatively high volumes of bone cement (>50%). Furthermore, varying the stiffness of bone cement has a negligible effect on the stress distribution of vertebral bodies. CONCLUSION: The volume of cement was considered to be the most important determinant in endplate fracture. Changing the stiffness of bone cement has a negligible effect on the stress distribution of vertebral bodies.
Bone Cements ; Finite Element Analysis ; Spine ; Sprains and Strains ; Vertebroplasty

We investigated the migration of endogenous neural stem cells (NSCs) toward an infarct lesion in a photo-thrombotic stroke model. The lesions produced by using rose bengal dye (20 mg/kg) with cold light in the motor cortex of Sprague-Dawley rats were also evaluated with sequential magnetic resonance imaging (MRI) from 30 minutes through 8 weeks. Migration of NSCs was identified by immunohistochemistry for nestin monoclonal antibody in the lesion cortex, subventricular zone (SVZ), and corpus callosum (CC). The contrast to noncontrast ratio (CNR) on MRI was greatest at 12 hours in DWI and decreased over time. By contrast, T1-weighted and T2-weighted images showed a constant CNR from the beginning through 8 weeks. MRI of the lesional cortex correlated with histopathologic findings, which could be divided into three stages: acute (edema and necrosis) within 24 hours, subacute (acute and chronic inflammatory cell infiltration) at 2 to 7 days, and chronic (gliofibrosis) at 2 to 4 weeks. The volume of the infarct was significantly reduced by reparative gliofibrosis. The number of nestin+ NSCs in the contralateral SVZ was similar to that of the ipsilateral SVZ in each group. However, the number of nestin+ NSCs in the ipsilateral cortex and CC increased at 12 hours to 3 days compared with the contralateral side (p<0.01) and was reduced significantly by 7 days (p<0.01). Active emigration of internal NSCs from the SVZ toward the infarct lesion may also contribute to decreased volume of the infarct lesion, but the self-repair mechanism by endogenous NSCs is insufficient to treat stroke causing extensive neuronal death. Further studies should be focused on amplification technologies of NSCs to enhance the collection of endogenous or transplanted NSCs for the treatment of stroke.
Cold Temperature ; Corpus Callosum ; Emigration and Immigration ; Immunohistochemistry ; Intermediate Filament Proteins ; Light ; Magnetic Resonance Imaging ; Models, Theoretical ; Motor Cortex ; Nerve Tissue Proteins ; Neural Stem Cells ; Neurons ; Rats, Sprague-Dawley ; Rose Bengal ; Stem Cells ; Stroke ; Transplants

Trigeminal neuralgia is sudden, usually unilateral, severe brief stabbing recurrent pain in the distribution of one or more branches of the 5th cranial nerve. Treatments of trigeminal neuralgia include systemic trials of medications and surgical procedures such as microvascular decompression, stereotactic radiosurgery, percutaneous glycerol or alcohol rhizolysis, percutaneous radiofrequency rhizotomy, and percutaneous balloon compression (PBC). PBC of the trigeminal ganglion using a balloon catheter was introduced by Mullan and Lichtor in 1983. Since then, many papers have been published describing results of this technique. Typically, this procedure is performed under general anesthesia. However, little is known about the use of PBC for the treatment of trigeminal neuralgia in Korea. We report here our anesthetic management of percutaneous balloon compression of trigeminal ganglion for the treatment of the trigeminal neuralgia by total intravenous anesthesia.
Anesthesia, General ; Anesthesia, Intravenous ; Catheters ; Cranial Nerves ; Glycerol ; Korea ; Microvascular Decompression Surgery ; Radiosurgery ; Rhizotomy ; Trigeminal Ganglion ; Trigeminal Neuralgia

OBJECTIVE: Few studies on the clinical spectrum of automated pressure-controlled discography (APCD)-defined positive discs have been reported to date. Thus, the present study was undertaken to analyze clinical parameters critical for diagnosis of discogenic pain and to correlate imaging findings with intradiscal pressures and pain responses in patients with APCD-positive discs. METHODS: Twenty-three patients who showed APCD-positive discs were selected for analysis. CT discogram findings and the degrees of nuclear degeneration seen on MRI were analyzed in comparison to changes of intradiscal pressure that provoked pain responses; and clinical pain patterns and dynamic factors were evaluated in relation to pain provocation. RESULTS: Low back pain (LBP), usually centralized, with diffuse leg pain was the most frequently reported pattern of pain in these patients. Overall, LBP was most commonly induced by sitting posture, however, standing was highly correlated with L5/S1 disc lesions (p < 0.01). MRI abnormalities were statistically correlated with grading of CT discogram results (p < 0.05); with most pain response observed in CT discogram Grades 3 and 4. Pain-provoking pressure was not statistically correlated with MRI grading. However, it was higher in Grade 3 than Grade 4. CONCLUSION: APCD-positive discs were demonstrated in patients reporting centralized low back pain with diffuse leg pain, aggravated by sitting and standing. MRI was helpful to assess the degree of nuclear degeneration, yet it could not guarantee exact localization of the painful discs. APCD was considered to be more useful than conventional discography for diagnosis of discogenic pain.
Humans ; Intervertebral Disc ; Leg ; Low Back Pain ; Posture

OBJECTIVES: Balloon cells and dysplastic neurons are histopathological hallmarks of the cortical tubers of tuberous sclerosis complex (TSC) and focal cortical dysplasia (FCD) of the Taylor type. They are believed to be the epileptogenic substrate and cause therapeutic drug resistant epilepsy in man. P-glycoprotein (P-gp) is the product of multidrug resistance gene (MDR1), and it maintains intracellular drug concentration at a relatively low level. The authors investigated expression of P-gp in balloon cells and dysplastic neurons of cortical tubers in patients with TSC. METHODS: An immunohistochemical study using the primary antibody for P-gp, as an indicative of drug resistance, was performed in the cortical tuber tissues in two patients of surgical resection for epilepsy and six autopsy cases. RESULTS: Balloon cells of each lesion showed different intensity and number in P-gp immunopositivity. P-gp immunopositivity in balloon cells were 28.2%, and dysplastic neurons were 22.7%. These immunoreactivities were more prominent in balloon cells distributed in the subpial region than deeper region of the cortical tubers. Capillary endothelial cells within the cortical tubers also showed P-gp immunopositivity. CONCLUSION: In this study, the drug resistance protein P-glycoprotein in balloon cells and dysplastic neurons might explain medically refractory epilepsy in TSC.
Autopsy ; Drug Resistance* ; Drug Resistance, Multiple ; Endothelial Cells ; Epilepsy ; Genes, MDR ; Humans ; Malformations of Cortical Development ; Neurons ; P-Glycoprotein ; Tuberous Sclerosis* ; Up-Regulation*

OBJECTIVE: Congenital bilateral perisylvian syndrome (CBPS) has been defined as a characteristic malformative perisylvian polymicrogyria (PMG) in patients with clinical symptoms of pseudobulbar palsy and epileptic seizures. For the present study, we investigate clinicopathologic features of CBPS associated with timing of lesion formation. METHODS: Clinicopathologic features of CBPS from 6 patients with surgical resection of the cerebral lesions due to medically intractable seizures were studied. RESULTS: Seizure onset ranged from 1 to 10years (average 6.7years) of age, and average duration of seizure was 23years. All had complex partial seizures, and two patients had additional tonic clonic seizures. Magnetic resonance (MR) images showed polymicrogyria, atropic gyri with gliosis. In the histopathologic examination, the cortical lesions revealed features of ulegyria ; atrophic and sclerotic gyri, laminar loss of neurons, extensive lobular gliosis throughout the gray and white matter, neuronoglial nodule formation, and many amyloid bodies. Unlayered or four-layered PMG was not identified. CONCLUSION: Above data suggest that CBPS might be caused by ulegyria resulting from developmental cortical defect during early fetal stage or acquired hypoxic/ischemic injury in prenatal or postnatal life.
Amyloid ; Epilepsy ; Gliosis ; Humans ; Malformations of Cortical Development ; Neuronal Migration Disorders ; Neurons ; Pseudobulbar Palsy ; Seizures

Following kainate (KA)-induced epilepsy, rat hippocampal neurons strongly ex-press immediate early gene (IEG) products, i.e., c-FOS and c-JUN, and neural stress protein, HSP72. Prolonged expression of c-JUN and c-FOS 48 hr after cerebral ischemia has been underwent delayed neuronal death. However, it is not yet clear whether IEGs actually assume the essential roles in the cell death process or simply as a by-product due to external stimuli because of the prolonged expression of c-FOS, more than one week, on intact CA2 neurons of the hippocampus in a KA-induced epilepsy model. This study investigated the relationships between prolonged expression of c-JUN and hippocampal neuronal apoptosis in a KA-induced epilepsy model. Epileptic seizure was induced in rats by a single microinjection of KA (1g/l) into the left amygdala. Characteristic seizures and hippocampal neuronal injury were developed. The expression of c-JUN was evaluated by immunohistochemistry, and neuronal apoptosis by in situ end labeling. The seizures were associated with c-JUN expression in the hippocampal neurons, of which the level showed a positive correlation with that of apoptosis. Losses of hippocampal neurons, especially in the CA3 region, were partly caused by apoptotic cell death via a c-JUN-mediated signaling pathway. This is thought to be an important component in the pathogenesis of hippocampal neuronal injury via KA-induced epilepsy.
Animal ; *Apoptosis ; Epilepsy, Temporal Lobe/chemically induced/*metabolism/pathology ; Hippocampus/*chemistry/pathology ; Immunohistochemistry ; Kainic Acid/*toxicity ; Male ; Proto-Oncogene Proteins c-jun/*analysis ; Rats ; Rats, Wistar