Globus pallidus internus neuronal activity: a comparative study of linear and non-linear features in patients with dystonia or Parkinson's disease.

Movement disorders such as Parkinson's disease (PD) and dystonia are associated with alterations of basal ganglia motor circuits and abnormal neuronal activity in the output nucleus, the globus pallidus internus (GPi). This study aims to compare the electrophysiological hallmarks for PD and dystonia in the linear and non-linear time stamp domains in patients who underwent microelectrode recordings during functional stereotactic surgery for deep brain stimulation (DBS) or pallidotomy. We analyzed single-unit neuronal activity in the posteroventral lateral region of the GPi in awake patients prior to pallidotomy or the implantation of DBS electrodes in 29 patients with PD (N = 83 neurons) and 13 patients with dystonia (N = 41 neurons) under comparable conditions. The discharge rate and the instantaneous frequency of the GPi in dystonia patients were significantly lower than in PD patients (P < 0.001), while the total number of bursts, the percentage of spikes in bursts and the mean duration of bursts were higher (P < 0.001). Further, non-linear analysis revealed higher irregularity or entropy in the data streams of GPi neurons of PD patients compared to the dystonia patients group (P < 0.001). This study indicates that both linear and non-linear features of neuronal activity in the human GPi differ between PD and dystonia. Our results may serve as the basis for future studies on linear and non-linear analysis of neuronal firing patterns in various movement disorders.

Rationale, design and critical end points for the Riluzole in Acute Spinal Cord Injury Study (RISCIS): a randomized, double-blinded, placebo-controlled parallel multi-center trial.

BACKGROUND: Riluzole is a sodium channel-blocking agent used in treating amyotrophic lateral sclerosis. It has been approved by the U.S. Food and Drug Administration, Canadian and Australian authorities, and in many other countries. A phase I trial of riluzole for acute spinal cord injury (SCI) provided safety and pharmacokinetic data and suggested neuroprotective benefits. A phase IIB/III double-blinded randomized controlled trial (RCT) started in January 2014 (https://clinicaltrials.gov, NCT01597518). This article describes the pathophysiological rationale, preclinical experience and design of the phase IIB/III RCT of Riluzole in Acute Spinal Cord Injury Study (RISCIS). OBJECTIVES: The primary objective of the trial is to evaluate the superiority of riluzole, at a dose of 100 mg BID in the first 24 h followed by 50 mg BID for the following 13 days post injury, compared with placebo in improving neurological motor outcomes in patients with C4-C8 level, International Standards for Neurological Classification of Spinal Cord Injury Examination (ISNCSCI) grade A, B or C acute (within 12 h post injury) SCI. SETTING: Acute trauma centers worldwideMethods:A double-blind, multi-center, placebo-controlled RCT will enroll 351 participants randomized 1:1 to riluzole and placebo. The primary end point is the change between 180 days and baseline in ISNCSCI Motor Score. This study has 90% power to detect a change of nine points in ISNCSCI Motor Score at one-sided α=0.025. RESULTS: Currently enrolling in 11 centers. CONCLUSION: This study will provide class I evidence regarding the safety and neuroprotective efficacy of riluzole in patients with acute cervical SCI.

Glial-neural interaction demonstrated by the injection of Na+ and Li+ into cortical glia.

Injection of Na+ or Li+ into cortical glia evokes glial depolarization, discharge of adjacent neurons, and vascular pulsation. The effects can be explained by the extrusion of K+ from glia after cation injection, glial swelling, and the slow removal of the cation from glia. The data suggest that the reduced rate of reuptake of K+ into Na+-loaded glia results in epileptiform firing of neurons, and support the hypothesis that glia function to buffer the environment of neurons.

Ischemic injury and faulty gene transcripts in the brain.

The brain has the highest metabolic rate of all organs and depends predominantly on oxidative metabolism as a source of energy. Oxidative metabolism generates reactive oxygen species, which can damage all cellular components, including protein, lipids and nucleic acids. The processes of DNA repair normally remove spontaneous gene damage with few errors. However, cerebral ischemia followed by reperfusion leads to elevated oxidative stress and damage to genes in brain tissue despite a functional mechanism of DNA repair. These critical events occur at the same time as the expression of immediate early genes, the products of which trans-activate late effector genes that are important for sustaining neuronal viability. These findings open the possibility of applying genetic tools to identify molecular mechanisms of gene repair and to derive new therapies for stroke and brain injury.

Relationships and redundancies of selected hemodynamic and structural parameters for characterizing virtual treatment of cerebral aneurysms with flow diverter devices.

BACKGROUND AND PURPOSE: To quantify the relationship and to demonstrate redundancies between hemodynamic and structural parameters before and after virtual treatment with a flow diverter device (FDD) in cerebral aneurysms. METHODS: Steady computational fluid dynamics (CFD) simulations were performed for 10 cerebral aneurysms where FDD treatment with the SILK device was simulated by virtually reducing the porosity at the aneurysm ostium. Velocity and pressure values proximal and distal to and at the aneurysm ostium as well as inside the aneurysm were quantified. In addition, dome-to-neck ratios and size ratios were determined. Multiple correlation analysis (MCA) and hierarchical cluster analysis (HCA) were conducted to demonstrate dependencies between both structural and hemodynamic parameters. RESULTS: Velocities in the aneurysm were reduced by 0.14m/s on average and correlated significantly (p<0.05) with velocity values in the parent artery (average correlation coefficient: 0.70). Pressure changes in the aneurysm correlated significantly with pressure values in the parent artery and aneurysm (average correlation coefficient: 0.87). MCA found statistically significant correlations between velocity values and between pressure values, respectively. HCA sorted velocity parameters, pressure parameters and structural parameters into different hierarchical clusters. HCA of aneurysms based on the parameter values yielded similar results by either including all (n=22) or only non-redundant parameters (n=2, 3 and 4). CONCLUSION: Hemodynamic and structural parameters before and after virtual FDD treatment show strong inter-correlations. Redundancy of parameters was demonstrated with hierarchical cluster analysis.

Quantitative comparison of hemodynamic parameters from steady and transient CFD simulations in cerebral aneurysms with focus on the aneurysm ostium.

OBJECTIVE: To quantitatively compare hemodynamics simulated with steady-state and transient computational fluid dynamics (CFD) simulations in cerebral aneurysms with single inflow, with focus at the aneurysm ostium. METHODS: Transient and steady-state CFD simulations were performed in 10 cerebral aneurysms. Distributions and average values for pressure, helicity, vorticity, and velocity were qualitatively compared at proximal and distal parent artery locations, at the ostium plane, and in the aneurysm, and scaling factors between the two kinds of simulations were determined. Relative inflow and outflow areas at the ostium were compared, as were average inflow and outflow velocities. In addition, values for the pressure-loss coefficient (PLC), a recently introduced parameter to assess aneurysm rupture risk, were compared for both kinds of simulation. RESULTS: Distributions of hemodynamic parameters had a similar shape but were lower for transient than for steady-state simulations. Averaged scaling factors over cases and anatomical locations showed differences for hemodynamic parameters (0.485 ± 0.01 for pressure, 0.33 ± 0.02 for helicity, 0.58 ± 0.06 for vorticity and 0.56 ± 0.04 for velocity). Good agreement between ratios of inflow and outflow areas at the aneurysm ostium was obtained (Pearson correlation coefficient >0.97, p<0.001) and for the PLC (linear regression slope 0.73 ± 0.14, R(2)=0.75). CONCLUSIONS: Steady-state simulations are a quick alternative to transient simulation for visualizing and quantifying inflow and outflow areas at the aneurysm ostium, potentially of value when planning flow diverter treatment and for quantifying the PLC, a potential indicator of aneurysm rupture.

Adenovirus-mediated gene therapy in an experimental model of breast cancer metastatic to the brain.

We investigated the therapeutic efficacy of adenovirus-mediated gene therapy to treat malignant mammary tumors in vitro and in vivo in the brain. A mammary adenocarcinoma cell line derived from Fischer rats (13762 MAT B III; MAT-B) was used. In vitro studies demonstrated that the MAT-B cells could be efficiently transduced with a replication-defective adenovirus (ADV) vector that carried the herpes simplex virus gene for thymidine kinase (ADV-tk), and that ADV-tk transduction rendered the MAT-B cells sensitive to killing, in a dose-dependent manner, with ganciclovir (GCV). An animal model of a mammary tumor metastatic to the brain was produced by injecting MAT-B cells into the caudate nucleus of Fischer rats. Seven days after MAT-B cell injection, when the tumors were approximately 5 mm2 in cross-sectional size, the tumors were injected with ADV-tk or a control adenovirus vector containing the beta-galactosidase (beta-Gal) gene (ADV-beta gal). After vector injection the animals were treated with GCV or with saline for 6 days. Sixteen days after tumor cell injection, the brains were examined histologically. The rats that were injected with ADV-beta gal and treated with GCV or saline, and those that were injected with ADV-tk and treated with saline had large tumors, whereas the rats that were injected with ADV-tk and treated with GCV had no visible tumor tissue at the site of tumor cell injection. In survival studies animals treated with ADV-tk+GCV survived a significantly longer time than animals treated with ADV-beta gal+GCV. Our results demonstrate that the recombinant adenoviral vector containing the tk gene confers GCV cytotoxic sensitivity to mammary tumor cells in vitro and in the brain, and suggest that this treatment strategy may be useful in treating somatic tumors that metastasize to the brain.

Adenoviral-mediated thymidine kinase gene transfer into the primate brain followed by systemic ganciclovir: pathologic, radiologic, and molecular studies.

Transduction of experimental gliomas with the herpes simplex virus thymidine kinase gene (HSV-tk) using a replication-defective adenoviral vector (ADV/RSV-tk) confers sensitivity to ganciclovir (GCV) leading to tumor destruction and prolonged host survival in rodents. To determine treatment tolerance prior to clinical trials, we conducted toxicity studies in 6 adult baboons (Papio sp.). The animals received intracerebral injections of either a high dose of ADV/RSV-tk [1.5 x 10(9) plaque-forming units (pfu)] with or without GCV, or a low dose of ADV/RSV-tk (7.5 x 10(7) pfu) with GCV. The low dose corresponded to the anticipated therapeutic dose; the high dose was expected to be toxic. Magnetic resonance imaging (MRI) of the brain was obtained before treatment and at 3 and 6 weeks after treatment. Animals receiving the high-dose vector and GCV either died or became moribund and required euthanasia during the first 8 days of treatment. Necropsies revealed cavities of coagulative necrosis at the injection sites. Animals receiving only the high-dose vector were clinically normal; however, lesions were detected with MRI at the injection sites corresponding to cystic cavities at necropsy. Animals receiving the low-dose vector and GCV were clinically normal, exhibited small MRI abnormalities, and, although no gross lesions were present at necropsy, microscopic foci of necrosis were present. The vector sequence was detected by polymerase chain reaction (PCR) at the injection sites and in non-adjacent central nervous system tissue in all animals. Recombinant DNA sequence was detected outside of the nervous system in some animals, and persisted up to 6 weeks. The viral vector injections stimulated the production of neutralizing antibodies in the animals. No shedding of the vector was found in urine, feces, or serum 7 days after intracerebral injection. This study suggests that further investigations including clinical toxicity trials of this form of brain tumor therapy are warranted.

Disproportionate loss of CA4 parvalbumin-immunoreactive interneurons in patients with Ammon's horn sclerosis.

We studied differences in the number and morphology of parvalbumin-immunoreactive (PV-IR) interneurons in 43 hippocampal specimens from patients with classical Ammon's horn sclerosis (AHS) who underwent anterior temporal lobectomy, as compared with 14 autopsy and non-AHS surgical control specimens. PV-IR neuronal loss in the AHS specimens varied significantly from that expected based on overall AHS-associated pyramidal and granule neuron loss. Most striking was the loss of PV-IR interneurons in CA4 of the AHS specimens, which was 12 times greater than AHS-associated pyramidal neuron loss, and significantly exceeded the PV-IR interneuron loss observed in the other sectors of the hippocampus. In addition, the PV-IR interneurons in the AHS specimens had markedly smaller and less defined cell bodies and shortened and simplified dendritic arbors compared with the PV-IR interneurons in the control specimens. Other differences noted in the AHS specimens included prominent dendritic varicosities; the loss or interruption of a band formed by PV-IR terminals in the dentate gyrus; and the virtual absence of a small, intensely staining PV-IR interneuron with a short, exuberant dendritic arbor that was readily identified in the autopsy specimens. We discuss these findings in relationship to the development of classical AHS and complex partial seizures (CPS).

Corpora amylacea and heat shock protein 27 in Ammon's horn sclerosis.

Increased numbers of corpora amylacea have been observed in the resected mesial temporal lobe of many patients with complex partial seizures (CPS) and Ammon's horn sclerosis (AHS). Several heat shock proteins (HSPs) are induced by seizures and have been suggested as an etiologic factor in the formation corpora amylacea. We quantified corpora amylacea and HSP27-immunoreactive astrocytes in temporal lobe specimens from patients with CPS (28 AHS; 10 non-AHS) and in 5 autopsy controls. Corpora amylacea were increased in each sector of Ammon's horn in the AHS group, significantly so in CA1 and CA3 (p < 0.0001 and p = 0.0097, respectively), compared with the non-AHS group, although there was considerable variability among the specimens. We found HSP27 to be significantly but nonspecifically increased in the resected temporal lobe specimens from all patients with CPS, regardless of the underlying pathology. HSP27 was not, however, expressed within the corpora amylacea, and did not correlate with the number of corpora amylacea in any of the 9 mesial and lateral temporal lobe areas examined.

The clinical significance of extracellular matrix in gangliogliomas.

Based on in vitro studies which demonstrate that collagen IV and laminin inhibit the proliferation and invasiveness of glioma cells, we investigated the clinical significance of these extracellular matrix proteins (ECM) in patients with gangliogliomas, tumors in which ECM is often a prominent feature. Our study compared the relative presence and deposition pattern of collagen IV and laminin in 19 gangliogliomas and in 18 gliomas without ganglion cell differentiation (8 low-grade astrocytomas, 7 anaplastic astrocytomas, and 3 anaplastic mixed gliomas). We also examined whether the presence of collagen IV and laminin correlated with other features often observed in gangliogliomas, including perivascular lymphocytic inflammation, granular bodies, microcalcification, and subarachnoid extension, and whether any of these features were associated with the patient's clinical course. Significant deposition of collagen IV and laminin was found in 9 gangliogliomas (47%), but in none of the other gliomas. The presence of these extracellular proteins in gangliogliomas correlated with both perivascular inflammation (P = 0.003), and involvement of the leptomeninges by tumor (P = 0.008). The duration of symptoms prior to surgical resection was significantly longer for patients whose tumors showed extracellular deposition of collagen IV and laminin than for patients whose tumors lacked deposition of these proteins (mean 13.7 vs 5.1 years; P = 0.02). In addition, the duration of symptoms was significantly longer for patients whose tumors exhibited perivascular inflammation than for patients whose tumors displayed little or no perivascular inflammation (mean 14.8 vs 4.8 years; P = 0.01). These findings suggests that collagen IV and laminin and perivascular inflammation are related to the indolent behavior of gangliogliomas.

Glial cell nuclear hypertrophy in complex partial seizures.

The white matter of resected temporal lobes from patients with intractable complex partial seizures shows increased cellularity which appears to be related to glia and neurons. This study, using quantitative methods, defines an increase in glial cell numbers and a significant increase in glial nuclear size within a defined area of white matter in the lateral temporal lobe. Evaluation was made on specimens from ten patients with complex partial seizures compared with two patients with non-epileptic brain lesions and five autopsy patients with no neurologic disease. The importance of recognizing these alterations in glia and the possible relevance to the pathoetiology of epilepsy are discussed.

Behavioral sequelae of closed head injury. A quantitative study.

We determined the profile of behavioral disturbance in relation to closed head injury of graded severity. Patients with severe injuries, as defined by duration of coma and the presence of neurological deficit, were differentiated from a group of mildly injured patients by behavioral ratings that reflected cognitive disorganization, emotional withdrawal, and motor retardation. Neurologic measurements of injury related to the severity of behavioral disturbance included hemiparesis, aphasia, and abnormalities on computerized axial tomography. Agitation during the acute phase of injury was also predictive of residual behavioral disturbance. Hemispheric lateralization of the site of greatest injury had no discernible effect on behavioral sequelae.

Ventricular enlargement after closed head injury.

To study the relationship between enlargement of the cerebral ventricles and neuropsychological deficit after closed head injury (CHI), we measured the area of the lateral ventricles on computed tomographic scans obtained at least 30 days after severe CHI in 32 young adults and a control group of similar age. Enlargement of the lateral ventricles was demonstrated in 72% of the head-injured subjects, as defined by the ventricle-brain percent ratio (VBR). Ventricular dilation was related to the duration of coma after high-speed motor vehicle accidents and to intellectual and memory defects. The VBR may be a useful index of the severity of brain damage in certain categories of head-injured patients.

Posteroventral medial pallidotomy in levodopa-unresponsive parkinsonism.

BACKGROUND: Parkinsonism in a 42-year-old patient, which was presumably related to peripheral trauma, did not respond to levodopa therapy. OBSERVATION: We treated the patient with microelectrode-guided unilateral posteroventral medial pallidotomy and followed up with magnetic resonance imaging and prospective clinical evaluation. Pallidotomy resulted in marked improvement of right-sided parkinsonian symptoms and functional disability at 4.5 months after surgery. Microelectrode recording during pallidotomy revealed discharge patterns that were similar to those seen in patients with Parkinson disease. Postoperative magnetic resonance imaging confirmed the location of the lesion in the posteroventral medial pallidum. CONCLUSIONS: Posteroventral pallidotomy usually has limited benefit in patients with degenerative atypical parkinsonism who do not respond to levodopa therapy. Nevertheless, pallidotomy can be an effective treatment for other levodopa-unresponsive parkinsonian disorders.

Long-term efficacy of posteroventral pallidotomy in the treatment of Parkinson's disease.

The authors describe results of unilateral posteroventral pallidotomy (PVP) in 89 patients with PD. At 3 months after surgery, 81.9% of the patients reported marked or moderate improvement in their parkinsonian symptoms. Postoperative Unified PD Rating Scale "off" state mean total motor score improved by 35.5% and the mean activities of daily living score by 33.7% (p <0.001). Improvements in parkinsonian symptoms were maintained in both"off" and "on" states in 62 patients at 12 months after PVP and in 41 patients who were followed for 18 months or longer (mean 26.6 months).

United Parkinson Foundation Neurotransplantation Registry on adrenal medullary transplants: presurgical, and 1- and 2-year follow-up.

Thirteen centers participated in a multicenter database with systematic evaluation of US and Canadian patients who had adrenal medullary transplantation for Parkinson's disease. This voluntary registry collected demographic, safety, and efficacy data using the same scoring measures over a 2-year follow-up period. Baseline data on 61 patients and 2-year follow-up data on 56 patients were compared. Eighteen percent died during the study period, and one-half of these deaths were related or questionably related to the surgery. Of the remaining 45 patients with data, global improvement, defined as an improved summed score of the "on" and "off" motor and activities of daily living functions from the Unified Parkinson's Disease Rating Scale, occurred in 32% of the patients at 2 years after surgery. At follow-up, significant group improvement persisted in the amount of daily "on" time and the quality of "off" function, but other measures were no better than baseline. When the global improvement calculation was based on the total sample and included deaths and patients lost to follow-up as "not improved," only 19% were improved 2 years after surgery. Twenty-two percent of survivors had persistent psychiatric morbidity not present prior to surgery. These data document a modest group improvement in "off" function after neurotransplantation, but a serious level of mortality and morbidity.

Assessment of motor function after stereotactic pallidotomy.

Despite a paucity of controlled data, stereotactic pallidotomy is increasingly used for the treatment of advanced Parkinson's disease (PD). To study the efficacy of the procedure on the cardinal PD features of rigidity, tremor, bradykinesia, and postural instability, we blindly rated randomized videos of 34 patients recorded in the "off' state immediately before and 3 months after unilateral stereotactic lesioning of the globus pallidus internus. Total "off' time Unified Parkinson's Disease Rating Scale motor scores improved 13.6% from 28.9 +/- 7.5 to 25.0 +/- 7.0 (p < 0.001). Particularly robust improvement was seen in contralateral tremor, gait, and arising from a chair (p < 0.001). Significant improvement was also seen in ipsilateral tremor, contralateral and some ipsilateral dexterity measures, and body bradykinesia. Most other features tended toward improvement but did not reach statistical significance. We conclude that pallidotomy is a safe and effective treatment of parkinsonian symptoms, many of which improve bilaterally.

Selective osmoreceptor dysfunction presenting as intermittent hypernatremia following surgery for a pituitary chromophobe adenoma.

Intermittent hypernatremia following hypothalamic surgery or trauma is usually attributed to the triphasic dysfunction of vasopressin release (diabetes insipidus, inappropriate vasopressin release, and diabetes insipidus). A 39-year-old patient had hypodipsia and intermittent hypernatremia following hypothalamic surgery for a chromophobe adenoma. Mean arterial pressure fell by 25 percent during orthostasis testing and was associated with an increase in vasopressin levels from 1.3 microU/ml to 12 microU/ml. Plasma renin activity and aldosterone increased from 1.1 to 16 ng/ml per hour and from 6.7 to 39 ng/dl, respectively, and remained elevated for three and a half hours after tilt testing. Hypertonic saline infusion, on the other hand, increased serum osmolality from 290 to 304 mOsm/kg but did not result in a significant rise in vasopressin levels (all were less than 1 microU/ml). These results are consistent with a selective dysfunction of the osmoreceptor pathways of vasopressin release and intact volume receptor-mediated pathways. Patients with intermittent hypernatremia following hypothalamic surgery or trauma should be questioned specifically regarding thirst. If it is impaired or absent, these patients should be watched carefully, not only for the development of triphasic dysfunction of vasopressin release, but also for a selective osmoreceptor dysfunction associated with thirst deficits as found in patients with "essential hypernatremia."

Elevation of tumor necrosis factor in head injury.

Tumor necrosis factor (TNF) is a cytokine which mediates protein wasting in pathological states by promoting the catabolism of visceral tissues and skeletal muscle. The role that TNF plays in nitrogen wasting following head injury was studied by measuring TNF in the serum of 21 patients with severe head injury. Parallel measurements of TNF and urinary nitrogen excretion were performed on days 1, 3, and 5 after head injury. TNF values after head injury ranged from 65 pg/ml to 7500 pg/ml, with a mean of 1147 pg/ml, compared to control values of serum TNF of less than 38 pg/ml. The mean daily urinary nitrogen loss was 13 g/day with a range of 2.8 to 27.6 g/day, and the mean nitrogen balance was -5.8 g with a range of +4.6 to -19.1 g. While both serum TNF levels and nitrogen loss were increased after head injury, the elevation of TNF did not correlate strongly with nitrogen wasting.