Preclinical Evaluation of Sodium Selenite in Mice: Toxicological and Tumor Regression Studies after Striatum Implantation of Human Glioblastoma Stem Cells.

Glioblastoma (GBM) is the most aggressive malignant glioma, with a very poor prognosis; as such, efforts to explore new treatments and GBM's etiology are a priority. We previously described human GBM cells (R2J-GS) as exhibiting the properties of cancer stem cells (growing in serum-free medium and proliferating into nude mice when orthotopically grafted). Sodium selenite (SS)-an in vitro attractive agent for cancer therapy against GBM-was evaluated in R2J-GS cells. To go further, we launched a preclinical study: SS was given orally, in an escalation-dose study (2.25 to 10.125 mg/kg/day, 5 days on, 2 days off, and 5 days on), to evaluate (1) the absorption of selenium in plasma and organs (brain, kidney, liver, and lung) and (2) the SS toxicity. A 6.75 mg/kg SS dose was chosen to perform a tumor regression assay, followed by MRI, in R2J-GS cells orthotopically implanted in nude mice, as this dose was nontoxic and increased brain selenium concentration. A group receiving TMZ (5 mg/kg) was led in parallel. Although not reaching statistical significance, the group of mice treated with SS showed a slower tumor growth vs. the control group (p = 0.08). No difference was observed between the TMZ and control groups. We provide new insights of the mechanisms of SS and its possible use in chemotherapy.

Role of fronto-striatal tract and frontal aslant tract in movement and speech: an axonal mapping study.

Despite a better understanding of their anatomy, the functional role of frontal pathways, i.e., the fronto-striatal tract (FST) and frontal aslant tract (FAT), remains obscure. We studied 19 patients who underwent awake surgery for a frontal glioma (14 left, 5 right) by performing intraoperative electrical mapping of both fascicles during motor and language tasks. Furthermore, we evaluated the relationship between these tracts and the eventual onset of transient postoperative disorders. We also performed post-surgical tract-specific measurements on probabilistic tractography. All patients but one experienced intraoperative inhibition of movement and/or speech during subcortical electrostimulation. On postoperative tractography, the subcortical distribution of stimulated sites corresponded to the spatial course of the FST and/or FAT. Furthermore, we found a significant correlation between postoperative worsening and distances between these tracts and resection cavity. A resection close to the (right or left) FST was correlated with transitory motor initiation disorders (p = 0.026), while a resection close to the left FAT was associated with transient speech initiation disorders (p = 0.003). Moreover, the measurements of average distances between resection cavity and left FAT showed a positive correlation with verbal fluency in both semantic (p = 0.019) and phonemic scores (p = 0.017), while average distances between surgical cavity and left FST showed a positive correlation with verbal fluency scores in both semantic (p = 0.0003) and phonemic modalities (p = 0.037). We suggest that FST and FAT would cooperatively play a role in self-initiated movement and speech, as a part of "negative motor network" involving the pre-supplementary motor area, left inferior frontal gyrus and caudate nucleus.

Combined diffuse light reflectance and electrical impedance measurements as a navigation aid in deep brain surgery.

AIM: The aim of this study is to assess reflected light intensity combined with impedance as a navigation aid during stereotactic neurosurgery. METHODS: During creation of 21 trajectories for stereotactic implantation of deep brain stimulation electrodes in the globus pallidus internus or subthalamus (zona incerta or subthalamic nucleus), impedance at 512 kHz and reflected light intensity at 780 nm were measured continuously and simultaneously with a radio frequency electrode containing optical fibres. The signals were compared with the anatomy, determined from pre- and post-operative MRI and CT. The measurements were performed within minutes, and signal analysis was done post-operatively. RESULTS: Reflected light intensity was low from the cortex, lateral ventricle, caudate nucleus and putamen; intermediate from the globus pallidus and thalamus; while it was high from the subcortical white matter, internal capsule and subthalamus. The electrical impedance was less consistent, but generally low in the cortex, intermediate in the subcortical white matter, putamen, globus pallidus and thalamus, and high in the internal capsule and subthalamus. CONCLUSION: Reflected light intensity and electrical impedance give complementary information about passed tissue, and the combination seems promising as a navigation aid during stereotactic neurosurgery.

[Surgical treatment of Parkinson's disease as a supplement to pharmacological therapy]. / Leczenie chirurgiczne choroby Parkinsona jako uzupelnienie leczenia zachowawczego.

The aim of the study was review of literature and description of surgical treatment of Parkinson's disease, based on neuroanatomical and neurophysiological aspects ofnigrostriatal system. Parkinson's disease is the neurodegenerative disorder characterized by dopaminergic cell loss in the compact part of substantia nigra. It is treated pharmacologically or surgically. The surgical treatment is the supplement to the pharmacological one in severe and drug resistant cases. In this study the common methods of surgical treatment of Parkinson's disease: ablative lesions and deep brain stimulation procedures in globus pallidus internus, thalamus and subthalamic nucleus and also the intrastriatal transplantation ofdopaminergic cells (into the striatum) were described.

Identification of dopaminergic neurons of nigral and ventral tegmental area subtypes in grafts of fetal ventral mesencephalon based on cell morphology, protein expression, and efferent projections.

Transplants of fetal ventral mesencephalic tissue are known to contain a mixture of two major dopamine (DA) neuron types: the A9 neurons of the substantia nigra pars compacta (SNpc) and the A10 neurons of the ventral tegmental area (VTA). Previous studies have suggested that these two DA neuron types may differ in their growth characteristics, but, because of technical limitations, it has so far been difficult to identify the two subtypes in fetal ventral mesencephalon (VM) grafts and trace their axonal projections. Here, we have made use of a transgenic mouse expressing green fluorescent protein (GFP) under the tyrosine hydroxylase promoter. The expression of the GFP reporter allowed for visualization of the grafted DA neurons and their axonal projections within the host brain. We show that the SNpc and VTA neuron subtypes in VM grafts can be identified on the basis of their morphology and location within the graft, and their expression of a G-protein-gated inwardly rectifying K+ channel subunit (Girk2) and calbindin, respectively, and also that the axonal projections of the two DA neuron types are markedly different. By retrograde axonal tracing, we show that dopaminergic innervation of the striatum is derived almost exclusively from the Girk2-positive SNpc cells, whereas the calbindin-positive VTA neurons project to the frontal cortex and probably also other forebrain areas. The results suggest the presence of axon guidance and target recognition mechanisms in the DA-denervated forebrain that can guide the growing axons to their appropriate targets and indicate that cell preparations used for cell replacement in Parkinson's disease will be therapeutically useful only if they contain cells capable of generating the correct nigral DA neuron phenotype.

Future and current surgical therapies in Parkinson's disease.

PURPOSE OF REVIEW: The mainstay of treatment for Parkinson's disease remains medical therapy. With improved surgical precision and decreased morbidity, stereotactic lesioning and deep brain stimulation have become more popular. New therapies currently in clinical trials include gene therapy and direct drug delivery to the brain. The present review discusses surgical therapies for the treatment of Parkinson's disease and the status of experimental strategies currently in preclinical and clinical testing. RECENT FINDINGS: Both stereotactic ablation and deep brain stimulation of the thalamus, globus pallidus interna, and subthalamic nucleus are discussed and compared in the current literature. New therapies such as drug infusions into the brain, gene therapy, and neural transplantation are in clinical trials and have been tested extensively in animals. Safety and efficacy of such therapies are discussed in recent literature. SUMMARY: Although medication remains the first and main line of treatment and the mainstay for Parkinson's disease, advances in techniques and safety of operations have made surgical interventions more popular. Thalamic surgery remains helpful only in a limited subset of patients with predominent tremor that is unresponsive to medication. Bilateral subthalamic nucleus DBS holds the most promising results for patients with tremor, severe motor fluctuations and dyskinesias from L-dopa, with the best improvements seen in daily activities and quality of life. Newer therapies currently in clinical trial include gene therapy to replace lost gamma-aminobutyric acid inputs to the subthalamic nucleus and globus pallidus interna/substantia nigra pars reticulata, and infusion of recombinant glial derived neurotrophic factor to support at-risk nigrostriatal neurons. Further developments in these areas, along with evolution in stem cell science that hopefully will permit replacement of lost neurons, may alter the nature of surgical practice in Parkinson's disease patients in the not too distant future.

Tauroursodeoxycholic acid improves the survival and function of nigral transplants in a rat model of Parkinson's disease.

There is accumulating evidence showing that the majority of cell death in neural grafts results from apoptosis when cells are implanted into the brain. Tauroursodeoxycholic acid (TUDCA), a taurine-conjugated hydrophilic bile acid, has been found to possess antiapoptotic properties. In the present study we have examined whether the supplementation of TUDCA to cell suspensions prior to transplantation can lead to enhanced survival of nigral grafts. We first conducted an in vitro study to examine the effects of TUDCA on the survival of dopamine neurons in serum-free conditions. The number of tyrosine hydroxylase (TH)-positive neurons in the TUDCA-treated cultures was significantly greater than that of control cultures 7 days in vitro. In addition, a terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-biotin nick end labeling (TUNEL) assay showed that the number of apoptotic cells in the TUDCA-treated cultures was dramatically smaller than that in the control cultures. In the transplantation study, a 50 microM concentration of TUDCA was added to the media when nigral tissue from Sprague-Dawley (SD) rats was trypsinized and dissociated. Two microliters of cell suspension containing TUDCA was then stereotaxically injected into the striatum of adult SD rats subjected to an extensive unilateral 6-hydroxydopamine lesion of the nigrastriatal dopamine pathway. At 2 weeks after transplantation, the rats that received a cell suspension with TUDCA exhibited a significant reduction in amphetamine-induced rotation scores when compared with pretransplantation value. There was a significant increase (approximately threefold) in the number of TH-positive cells in the neural grafts for the TUDCA-treated group when compared with the controls 6 weeks postgrafting. The number of apoptotic cells was much smaller in the graft areas in the TUDCA-treated groups than in the control group 4 days after transplantation. These data demonstrate that pretreatment of the cell suspension with TUDCA can reduce apoptosis and increase the survival of grafted cells, resulting in an improvement of behavioral recovery.

[Stereotactic thalamotomy for Parkinsonian and others types of tremor. Experiences of thalamic multiunit burst activity by means of semimicroelectrode]. / Talamotomía estereotáxica de la enfermedad de Parkinson y otros tipos de temblor. Experiencias de la actividad multiunitaria burst en el tálamo basada en semimicroelectrodos.

INTRODUCTION: Better understanding of the basic mechanism of disorders of movement, together with improvements in surgery and electrophysiological techniques have led to a resurge of interest in the surgical treatment of patients with tremor. Ventrolateral thalamotomy has been considered to be an alternative neurosurgical treatment for disabled persons including those with drug-resistant Parkinson s disease and other types of tremor. PATIENTS AND METHODS: Thirty four of 47 patients had Parkinson s disease (n= 23), essential tremor (n= 4), multiple sclerosis (n= 5), olivopontocerebellar lesion (n= 1) and posttraumatic tremor (n= 1) and did not show satisfactory improvement after drug treatment. The lesions were made in the thalamic nucleus. In 26 patients simultaneous recordings were made of nerve activity in the thalamus and of burst activity. RESULTS: In 23% of the cases the appropriate site for the final lesion could not be determined in accordance with electrostimulation of the empirical objective. In these patients the objective was determined after observation of the electrophysiological activity localized to the burst activity seen during the operation. The patients were followed-up for 6-24 months (average 12 months); 88% of them had no tremor or moderate contralateral tremor. The patients were assessed on a modified Fahn scale. Average scoring fell from a preoperative evaluation of 73.8 points to 34.0 after three months; 30.7 after six months, 32.0 after 9 months, 37.1 after 12 months and 35.2 points after 18 months. CONCLUSION: Of 47 thalamotomies done, 13 (29%) were successful and 5 (10%) maintained their original state, but no cases became worse or had serious complications.

[Pathophysiological bases, clinical results and indications for surgical treatment in Parkinson disease]. / Bases fisiopatológicas, resultados clínicos e indicaciones del tratamiento quirúrgico de la enfermedad de Parkinson.

We review the present status of surgery for Parkinson's disease. Surgical options for Parkinson's disease are rapidly spanding. The main objectives of surgical techniques are to restore the dopaminergic deficit in the striatum (transplantation) and to normalize the neuronal activity of the subthalamic-pallidal circuit (pallidotomy and deep brain stimulation). Whereas cell transplantation is still considered an experimental procedure, ablative procedures and deep brain stimulation are widely used. Both types of surgical procedures are supported by strong scientific data. However, much work remains to be done in order to understand several aspects not clearly elucidated at present. The results and current indications for pallidotomy and deep brain stimulation are analyzed.

Surgery for deeply seated arteriovenous malformation: with special reference to thalamic and striatal arteriovenous malformation.

Surgery for deeply seated arteriovenous malformation (AVM) is controversial because stereotactic irradiation is applicable to the lesion. We have, however, experienced 30 deeply seated AVMs treated by direct surgery and/or endovascular treatment. The present study shows profiles of those patients and results of surgery. They include AVM in the thalamus in 12 cases, striatum in four cases, paraventricular area in five cases, medial temporal lobe in three cases, intraventricular area in three cases, and other regions in three cases. They were treated by surgery alone in 23 cases, embolization followed by surgery in four cases, and embolization alone in three cases. AVM in the mediodorsal thalamus and fornix (5 cases) was best treated by transcallosal approach. Venous aneurysm was commonly found in the AVM of this region and was a good navigator to the AVM. Pulvinar AVM was accessible through posterior interhemispheric approach (2 cases). None of these cases had additional neurological deficits. Cadaver dissection was useful for acquisition of surgical approach. Striatal AVM was approached through hematoma cavity with minimal manipulation to the surrounding structures, yet two of four cases showed progression of their weakness. The present study indicates that thalamic AVM can be approached surgically with careful selection of the approach. On the other hand, striatal AVM is not a good candidate for direct surgery and better treated by stereotactic irradiation.

Localization of TNF alpha and IL-1 alpha immunoreactivities in striatal neurons after surgical injury to the hippocampus.

Since the inflammatory process develops after transplantation to the brain, we sought to determine the presence of cytokines following a surgical trauma to the brain of an adult mouse. We report the early and marked presence of tumor necrosis factor-alpha and interleukin-1 alpha in neuronal somata of the striatum following a surgical injury to the hippocampus. The expression of cytokines later extends to neuronal cells of the hippocampus, thalamus, cerebral cortex, brain stem, and cerebellum and to glial cells of the corpus callosum. By contrast, these cytokines are not expressed by neuronal cells following injury to other regions, such as the striatum, cerebellum, and cortex. This study suggests a possible role for certain neurons in the brain's early reaction to a penetrating injury.

Surgical treatment of arteriovenous malformations of the striatothalamocapsular region.

Sixteen patients with arteriovenous malformations (AVM's) located in the striatothalamocapsular region were treated microsurgically at the Hau Shan Hospital, Shanghai. These AVM's had a tendency to bleed intracerebrally and typically presented with hemiplegia, hemianesthesia, and hemianopsia. Angiographically the lesions were primarily located in the triangle of Reil. Postoperative outcome was not as good as that of AVM's in other locations, but the operation may have prevented the risk of further hemorrhage. This report details the operative technique used and the clinical course in this group of patients.

The future role of neurosurgery in medicine.

Illustrated by several examples from the past it is demonstrated how difficult it is to predict future developments in neurosurgery. Several determinants can be recognized as exerting a positive or a negative influence in this respect. Careful observation of unexpected events and consequent consideration in combination with a spiritual independency, are aspects which will contribute in a positive way. The reverse will unavoidably lead to abolition of new ideas and concepts. Authority in a personal as well as in an impersonal way, may act as a negative determinant. This aspect is illustrated by some examples regarding the phenomenon of the "medical mandarin" as a personal authority, and the irrational adherence to paradigms as an impersonal one. Based upon recent experiments new ways for neurosurgical activities are indicated, concerning 1st transplantation of fetal central nervous tissue and of adrenal medullary tissue, and 2nd deep long-term stimulation of the beta endorphin-serotonin system for the control of chronic pain.

Active avoidance behavior following archistriatal lesions in pigeons.

Experiment 1 examined the performance of 10 pigeons, 5 with bilateral medial archistriatal lesions and 5 sham-operated controls, in the acquisition and maintnenance of a discrete-press avoidance response. The archistriatal subjects had longer response latencies and never attained the level of performance achieved by the controls. In Experiment 2 eight pigeons learned a treadle-press response to avoid or escape shock on a signaled free-operant schedule. After 17 daily sessions four subjects received bilateral lesions in the medial archistriatum, and four received control lesions in the neostriatum. After recovery from surgery, all subjects were returned to the experimental procedure. Avoidance of those subjects with archistriatal lesions was impaired relative to the postoperative level while that of the control group was unchanged. These results are interpreted in the light of earlier experiments showing reduced escape and avoidance behavior both in order avian species and in mammals with lesions in the amygdala, to which the archistriatum is considered homologous.