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At least 1,099 records · Page 61Linked to original sources
PubMed2004

Basic mechanisms of partial epilepsies.

PURPOSE OF REVIEW: Partial epilepsies are characterized by cell loss with consequences for neuronal organization, excitability, mnestic and cognitive functions and present with pharmaco-resistance and difficulties in clinical management. While mesial temporal lobe epilepsies present frequently with cell loss and neuronal reorganization, neocortical epilepsies frequently involve developmental alterations. RECENT FINDINGS: There is increasing evidence that nerve cells in epileptic tissue become more vulnerable to excitotoxic cell death due to impairment of mitochondrial functions and that free radical formation is critically involved in these processes. Whether and to what extent such alterations contribute to pharmaco-resistance is unclear. However, at least three mechanisms may contribute to pharmaco-resistance: changes in target molecules for antiepileptic drugs, upregulation of drug transporters, and potentially reorganization processes in inhibitory networks. Upregulation of drug transporters also seems to be involved in pharmaco-resistance of developmental alterations underlying focal epilepsies. Recent data from the literature suggest that transgenic models for disturbances of cortical development may be useful models for the study of these variable forms of partial epilepsies. SUMMARY: The data suggest that improvement of therapy could result from free radical scavenging and from manipulation of drug transport into the affected tissue. New models of developmental epilepsies may help us to understand mechanisms underlying increased vulnerability to seizures as well as improving strategies for treatment.

Anticonvulsants↗
PubMed2006

Deletion of chromosome 21 disturbs human brain morphogenesis.

PURPOSE: Humans with small deletions of chromosome 21 provide important models for understanding the role of dosage-sensitive genes in brain morphogenesis. To identify chromosome 21 genes responsible for defects of the central nervous system, we determined the deleted regions and brain malformations in three unrelated individuals with overlapping partial deletions of chromosome 21. METHODS: Fluorescent in situ hybridization and magnetic resonance imaging were used to define the chromosomal structure and structural brain abnormalities present in these three individuals. RESULTS: The regions of chromosome 21 found to be deleted in these individuals were as follows: case 1: KCNJ6 to the telomere; case 2: ITSN1 to the telomere; and case 3: ITSN1 to PCNT2. The abnormalities of brain structure shared by all included microcephaly, pachygyria, polymicrogyria, colpocephaly, hypoplastic corpus callosum and white matter, hypoplastic cerebellum, and enlarged ventricular system. The clinical features in common included mental retardation, microcephaly, facial dysmorphism, and epilepsy (severe in one patient). CONCLUSION: From analyses of the molecular, cytogenetic, and neuroimaging data from these three individuals, combined with those from previously reported cases, we infer that deletion of an 8.4-Mb region in chromosome band 21q22.2-22.3 (KCNJ6-COL6A2) is associated with cortical dysplasia. We propose that one or more dosage-sensitive genes in this region contributes to cortical development and that deletion of 21q22.2-22.3 should be considered in the diagnosis of mentally retarded patients with facial dysmorphism and cerebral dysplasia.

Adolescent↗
PubMed2004

Epilepsy.

PURPOSE OF REVIEW: The purpose of this review is to consider the current and potential role of neuroimaging from an epilepsy perspective, and to illustrate that by combining appropriate imaging techniques, neuroimaging can contribute greatly to elucidating the basic mechanisms of the various forms of epileptic disorders. RECENT FINDINGS: New magnetic resonance imaging sequences (magnetization transfer imaging) and positron emission tomography ligands (serotonergic system) were biologically validated in large groups of patients with localization-related epilepsies. Investigations in genetically determined homogenous patient populations (PAX6, juvenile myoclonic epilepsy) have strengthened the link between genetic defects and neuropathological targets (anterior commissure, thalamus). Magnetic resonance spectroscopy and electroencephalogram-triggered functional magnetic resonance imaging provided converging evidence for a key role of the thalamus in the generation of generalized seizures. The role of functional magnetic resonance imaging in identifying eloquent areas of cortex and its relationship to structural lesions, in particular malformations of cortical development, has been further elucidated. Longitudinal magnetic resonance imaging studies reported progressive volume loss after febrile convulsions and in active epilepsy. SUMMARY: Neuroimaging is essential for improving the efficacy and safety of therapeutic, in particular, surgical procedures. Investigations of larger, more homogenous genetic disorders and longitudinal rather than cross-sectional neuroimaging studies have advanced our knowledge about the cause and effect of epileptic disorders, and will ultimately link defects in molecular genetics with specific neuropathological targets.

Brain↗
PubMed2003

Cadherins and synaptic plasticity: activity-dependent cyclin-dependent kinase 5 regulation of synaptic beta-catenin-cadherin interactions.

Cyclin-dependent kinase 5 (Cdk5)/p35 kinase activity is known to decrease the affinity of beta-catenin for cadherin in developing cortical neurons. Our recent work demonstrated that depolarization causes an increased affinity between beta-catenin and cadherin. Here, we examine whether Cdk5/p35 regulates beta-catenin-cadherin affinity in response to neural activity. In hippocampal neurons depolarization caused a significant decrease in Cdk5 kinase activity, without changing the protein levels of either Cdk5 or p35, suggesting that the proteasome pathway is not involved. Decreasing Cdk5 kinase activity with the inhibitor roscovitine increased the amount of beta-catenin that was co-immunoprecipitated with cadherin. Inhibiting Cdk5 activity also resulted in a redistribution of EGFP-beta-catenin from the dendritic shaft to the spines, where cadherins are highly concentrated. The redistribution of beta-catenin induced by roscovitine is similar to that induced by depolarization. Interestingly, the redistribution induced by the Cdk5 inhibitor was completely blocked by either a tyrosine phosphatase inhibitor, orthovanadate or by point mutations of beta-catenin Tyr-654 to Glu or Phe. Immunoprecipitation studies further revealed that roscovitine increases the affinity of the wild-type, but not mutated, EGFP-beta-catenin for cadherin. These results suggest that Cdk5 activity regulates the affinity of beta-catenin for cadherin by changing the phosphorylation level of beta-catenin Tyr-654.

Animals↗
PubMed2006

Role of heat-shock factor 2 in cerebral cortex formation and as a regulator of p35 expression.

Heat-shock factors (HSFs) are associated with multiple developmental processes, but their mechanisms of action in these processes remain largely enigmatic. Hsf2-null mice display gametogenesis defects and brain abnormalities characterized by enlarged ventricles. Here, we show that Hsf2-/- cerebral cortex displays mispositioning of neurons of superficial layers. HSF2 deficiency resulted in a reduced number of radial glia fibers, the architectural guides for migrating neurons, and of Cajal-Retzius cells, which secrete the positioning signal Reelin. Therefore, we focused on the radial migration signaling pathways. The levels of Reelin and Dab1 tyrosine phosphorylation were reduced, suggesting that the Reelin cascade is affected in Hsf2-/- cortices. The expression of p35, an activator of cyclin-dependent kinase 5 (Cdk5), essential for radial migration, was dependent on the amount of HSF2 in gain- and loss-of-function systems. p39, another Cdk5 activator, displayed reduced mRNA levels in Hsf2-/- cortices, which, together with the lowered p35 levels, decreased Cdk5 activity. We demonstrate in vivo binding of HSF2 to the p35 promoter and thereby identify p35 as the first target gene for HSF2 in cortical development. In conclusion, HSF2 affects cellular populations that assist in radial migration and directly regulates the expression of p35, a crucial actor of radial neuronal migration.

Animals↗
PubMed2006

p27kip1 independently promotes neuronal differentiation and migration in the cerebral cortex.

The generation of neurons by progenitor cells involves the tight coordination of multiple cellular activities, including cell cycle exit, initiation of neuronal differentiation, and cell migration. The mechanisms that integrate these different events into a coherent developmental program are not well understood. Here we show that the cyclin-dependent kinase inhibitor p27(Kip1) plays an important role in neurogenesis in the mouse cerebral cortex by promoting the differentiation and radial migration of cortical projection neurons. Importantly, these two functions of p27(Kip1) involve distinct activities, which are independent of its role in cell cycle regulation. p27(Kip1) promotes neuronal differentiation by stabilizing Neurogenin2 protein, an activity carried by the N-terminal half of the protein. p27(Kip1) promotes neuronal migration by blocking RhoA signaling, an activity that resides in its C-terminal half. Thus, p27(Kip1) plays a key role in cortical development, acting as a modular protein that independently regulates and couples multiple cellular pathways contributing to neurogenesis.

Animals↗
PubMed2001

Neural representation of alpha-oriented moving light bars in the cortex: a neural network study.

A neural computational model is suggested in this paper for investigating the stimulus dependence of spiking patterns and the neural representation of alpha-oriented moving light bars in the cortex. In this model, a stimulus-directed cortical developing algorithm is introduced for training the neural network. Three classes of computer simulations concerned with the orientation of the stimulus are carried out. The simulation results show that the fine temporal structure of spiking patterns of single units depends on the alpha orientation of the two moving light bars, and the fine temporal structure of their combinatorial spiking patterns are also context dependent. They also show that the neural representation of an alpha-oriented moving light bar is determined not only by the stimulus itself but also the architecture of the matured network. In the end, we propose a possible neural coding mechanism underlying the temporal cell subassemblies in the cortex, which could be spontaneously and dynamically organized into a dynamical cell assembly by synchronized activity of these subassemblies.

Algorithms↗
PubMed2002

Endoplasmic microtubules configure the subapical cytoplasm and are required for fast growth of Medicago truncatula root hairs.

To investigate the configuration and function of microtubules (MTs) in tip-growing Medicago truncatula root hairs, we used immunocytochemistry or in vivo decoration by a GFP linked to a MT-binding domain. The two approaches gave similar results and allowed the study of MTs during hair development. Cortical MTs (CMTs) are present in all developmental stages. During the transition from bulge to a tip-growing root hair, endoplasmic MTs (EMTs) appear at the tip of the young hair and remain there until growth arrest. EMTs are a specific feature of tip-growing hairs, forming a three-dimensional array throughout the subapical cytoplasmic dense region. During growth arrest, EMTs, together with the subapical cytoplasmic dense region, progressively disappear, whereas CMTs extend further toward the tip. In full-grown root hairs, CMTs, the only remaining population of MTs, converge at the tip and their density decreases over time. Upon treatment of growing hairs with 1 microM oryzalin, EMTs disappear, but CMTs remain present. The subapical cytoplasmic dense region becomes very short, the distance nucleus tip increases, growth slows down, and the nucleus still follows the advancing tip, though at a much larger distance. Taxol has no effect on the cytoarchitecture of growing hairs; the subapical cytoplasmic dense region remains intact, the nucleus keeps its distance from the tip, but growth rate drops to the same extent as in hairs treated with 1 microM oryzalin. The role of EMTs in growing root hairs is discussed.

Carrier Proteins↗
PubMed2004

Irreversible loss of a subpopulation of cortical interneurons in the absence of glutamatergic network activity.

In the cerebral cortex of mammals, gamma-aminobutyric acid (GABA)ergic neurons represent 15-25% of all neurons, depending on the species and area being examined. Because converging evidence suggests that activity may play an important role in the neuritic maturation and synaptic function of GABAergic neurons, it is feasible that activity plays a role in the regulation of the proportion of GABAergic neurons. Here we provide direct evidence that early in cortical development activity blockade may deplete the network of a subpopulation of GABA immunoreactive neurons characterized by their small size and late generation in vitro. In a period of time coinciding with the emergence of synchronous network activity, the survival and morphological differentiation of GABAergic neurons was influenced by long-term blockade of synaptic activity. While GABA(A) receptor antagonists had a minor promoting effect on interneuronal survival during the second week in vitro, antagonists of ionotropic glutamate receptors strongly impaired survival and differentiation of immature GABAergic interneurons. Interneuronal loss was more severe when N-methyl-D-aspartate receptors were blocked than after blockade of alpha-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid (AMPA)/kainate receptors. The decrease in the density of GABAergic neurons was irreversible, but could be prevented by the simultaneous addition of brain-derived neurotrophic factor (BDNF). These results suggest that there is a narrow time window during neocortical development when glutamatergic activity, and specially NMDA receptor stimulation, is crucial to assure survival and maturation of a subpopulation of late developing GABAergic interneurons.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed1993

Organization of auditory callosal connections in hypothyroid adult rats.

Callosal connections were studied with tracers (horseradish peroxidase (HRP) and wheat germ agglutinin-horseradish peroxidase (WGA-HRP)) in normal rats and rats deprived of thyroid hormones with methimazole (Sigma) since embryonic day 14 and thyroidectomized at postnatal day 6. In hypothyroid rats, the auditory areas, in particular the primary auditory area, showed cytoarchitectonic changes including blurred lamination and decrease in the size of layer V pyramidal neurons. In control rats, callosally-projecting neurons were found between layers II and VI with a peak in layer III and upper layer IV. In hypothyroid rats, labelled neurons were found between layers IV and VI with two peaks corresponding to layer IV and upper layer V, and in upper layer VI. Quantitative analysis of radial distribution of callosally-projecting neurons confirmed their shift to infragranular layers in hypothyroid rats. Three-dimensional reconstructions showed a more continuous tangential distribution of callosally-projecting neurons in hypothyroid rats which may be due to the maintenance of a juvenile 'exuberant' pattern of projections. These changes in cortical connectivity may be relevant for understanding epilepsy and mental retardation associated with early hypothyroidism in humans and to clarify basic mechanisms of cortical development.

Animals↗
PubMed2006

Fibroblast growth factor receptor 3 kinase domain mutation increases cortical progenitor proliferation via mitogen-activated protein kinase activation.

We have previously shown that mice carrying the K644E kinase domain mutation in fibroblast growth factor receptor 3 (Fgfr3) (EIIa;Fgfr3(+/K644E)) have enlarged brains with increased proliferation and decreased apoptosis of the cortical progenitors. Despite its unique rostral-low caudal-high gradient expression in the cortex, how Fgfr3 temporally and spatially influences progenitor proliferation is unknown. In vivo BrdU labelling now showed that progenitor proliferation was 10-46% higher in the EIIa;Fgfr3(+/K644E) cortex compared with wild type during embryonic day 11.5 (E11.5)-E13.5. The difference in proliferation between the EIIa;Fgfr3(+/K644E) and wild-type cortices was the greatest in the caudal cortex at E12.5 and E13.5. Inhibition of mitogen-activated or extracellular signal-regulated protein kinase (MEK) in vitro at E11.5 reduced the proliferation rate of the EIIa;Fgfr3(+/K644E) cortical progenitors to similar levels observed in the wild type, indicating that the majority of the increase in cell proliferation caused by the Fgfr3 mutation is mitogen-activated protein kinase (MAPK) pathway-dependent at this stage. In addition, elevated levels of Sprouty were observed in the EIIa;Fgfr3(+/K644E) telencephalon at E14.5, indicating the presence of negative feedback that may have suppressed further MAPK activation. We suggest that temporal activation of MAPK is largely responsible for cell proliferation caused by the Fgfr3 mutation during early stages of cortical development.

Age Factors↗
PubMed1999

Multimodal MR imaging: functional, diffusion tensor, and chemical shift imaging in a patient with localization-related epilepsy.

PURPOSE: To demonstrate the integration of complementary functional and structural data acquired with magnetic resonance imaging (MRI) in a patient with localization-related epilepsy. METHODS: We studied a patient with partial and secondarily generalized seizures and a hemiparesis due to a malformation of cortical development (MCD) in the right hemisphere by using EEG-triggered functional MRI (fMRI), diffusion tensor imaging (DTI), and chemical shift imaging (CSI). RESULTS: fMRI revealed significant changes in regional blood oxygenation associated with interictal epileptiform discharges within the MCD. DTI showed a heterogeneous microstructure of the MCD with reduced fractional anisotropy, a high mean diffusivity, and displacement of myelinated tracts. CSI demonstrated low N-acetyl aspartate (NAA) concentrations in parts of the MCD. CONCLUSIONS: The applied MR methods described functional, microstructural, and biochemical characteristics of the epileptogenic tissue that cannot be obtained with other noninvasive means and thus improve the understanding of the pathophysiology of epilepsy.

Adult↗
PubMed2005

Clinical features of patients with posterior cortex epilepsies and predictors of surgical outcome.

PURPOSE: Posterior cortex epilepsies (PCEs) encompass a group of epilepsies originating from the occipital, parietal, or occipital border of the temporal lobe, or from any combination of these regions. When their seizures are refractory to pharmacologic treatment, these patients are usually referred for surgery. The aim of our study was to analyze clinical characteristics of all PCE patients referred for surgery from 1994 to 2003, and to search for predictors of surgical outcome. METHODS: We performed a retrospective analysis of clinical and laboratory data from 81 consecutive refractory PCE patients referred for surgery. Surgical and nonsurgical groups of patients were compared, and detailed analyses of all variables of the surgical cases were performed in the search for predictors of seizure outcome. RESULTS: Risk factors for PCEs included gliosis (34.56%), malformations of cortical development (33.33%), tumors (8.64%), brain trauma (3.70%), Sturge-Weber disease (4.93%), vascular malformations (3.70%), family history of epilepsy (3.70%), history of CNS infections (2.46%), and low IQ (2.46%). Of the 81 patients, 44 were submitted to surgery at the time of the completion of this study. Surgical treatment was highly effective in improving seizures (p<0.001) when compared with previous pharmacologic treatment alone. Twenty-eight (65.11%) patients became seizure free after surgery versus none in the nonsurgical group. Regarding outcome predictors, patients with shorter duration of epilepsy and those without neurologic abnormalities on clinical examination had higher chances of favorable evolution. CONCLUSIONS: Surgical treatment is effective for the treatment of PCEs and superior to pharmacologic therapy alone. In our series, shorter duration of epilepsy and normal neurologic examination were the only independent variables that predicted better surgical outcome.

Adult↗
PubMed2006

A controlled clinical trial of cathodal DC polarization in patients with refractory epilepsy.

PURPOSE: To study the effects of cathodal DC polarization in patients with refractory epilepsy and malformations of cortical development (MCDs) as indexed by seizure frequency and epileptiform EEG discharges. METHODS: Nineteen patients with MCDs and refractory epilepsy underwent one session of DC polarization (20 min, 1 mA) targeting the epileptogenic focus. The number of epileptiform discharges (EDs) in the EEG and seizures were measured before (baseline), immediately after, and 15 and 30 days after either sham or active DC polarization. Seizure frequency after the treatment was compared with baseline. RESULTS: Active compared with sham DC polarization was associated with a significant reduction in the number of epileptiform discharges [mean ED reduction of -64.3% (95% CI, -122.5% to -6.0%) for the active treatment group and -5.8% (95% CI, -26.8% to 15.2%) for the sham treatment group]. A trend (p = 0.06) was noted for decrease in seizure frequency after active compared with sham treatment [mean seizure frequency decrease of -44.0% (95% CI, -95.0% to 7.1%) for the active treatment group and -11.1% (95% CI, -22.2% to 44.4%) for the sham treatment group]. CONCLUSIONS: This randomized, controlled study shows that cathodal DC polarization does not induce seizures and is well tolerated in patients with refractory epilepsy and MCDs. Furthermore, the results suggest that this technique might have an antiepileptic effect based on clinical and electrophysiological criteria.

Adult↗
PubMed2006

Voxel-based morphometry reveals excess gray matter concentration in patients with focal cortical dysplasia.

PURPOSE: Many patients with focal cortical dysplasia (FCD) continue to have seizures after surgical treatment. The usual explanation for the poor surgical outcome is the presence of residual dysplastic tissue missed by the preoperative neuroimaging investigation and therefore not resected during surgery. We apply a voxel-based morphometry (VBM) analysis to the magnetic resonance imaging (MRI) scans from patients with epilepsy and visually detected FCD to investigate whether (a) VBM is able to detect gray-matter concentration (GMC) abnormalities in patients with FCD, and (b) whether the extent of GMC abnormalities in the brain of these patients differs from the regions observed by using visual inspection. METHODS: We studied 11 patients with visually detected FCD (eight of them with histologic confirmation of FCD). The GMC from each one of these patients was compared with the mean GMC from a control group of 96 normal healthy subjects by using an optimized VBM protocol. RESULTS: Ten of 11 patients showed statistically significant GMC excess, and among patients with GMC excess, only one showed GMC excess that was not exactly correspondent to the visually detected FCD. Seven patients exhibited excess in GMC extending beyond the area of visually detected FCD. CONCLUSIONS: This preliminary neuroimaging study suggests that (a) VBM can detect GMC excess in patients with FCD, and (b) GMC excess in these patients can extend to brain areas not visually defined as abnormal. Abnormal areas detected by VBM can possibly correspond to mild malformations of cortical development, supporting the notion that the surgical refractoriness observed in patients with FCD can be due to the incomplete resection of the dysplastic tissue.

Adolescent↗
PubMed2006

Event-related fMRI of myoclonic jerks arising from dysplastic cortex.

BACKGROUND: Malformations of cortical development can cause epileptiform activity and myoclonic jerks, yet EEG correlates of jerks can be difficult to obtain. METHODS: We studied a woman who had frequent episodes of persistent right-foot jerking since childhood. Ictal and interictal EEG had shown no localizing epileptiform activity. Functional imaging experiments were performed with concurrent video monitoring to document the timing of foot jerks. These studies mapped brain regions controlling voluntary right- and left-foot movements, and spontaneous right-foot jerks. RESULTS: High-resolution structural MR imaging revealed a dysplastic gyrus extending anteriorly off the left central sulcus. Event-related analysis of spontaneous jerks revealed prominent activation of the left precentral gyrus (right-foot motor area), bilateral medial frontal regions (supplementary motor area), and the dysplastic gyrus. Hemodynamic response modeling to foot jerks revealed the hemodynamic response peaked earlier in the dysplastic cortex and SMA regions than in the foot area. DISCUSSION: Event-related fMRI in a patient with spontaneous and induced epileptic foot jerks revealed brain regions active during jerks. The results of this analysis allowed us to tailor subsequent intracerebral recordings. Analysis of the timing of the hemodynamic response showed certain brain regions with an earlier rise in BOLD signal, suggesting a possible initiating role, or different hemodynamic response functions. Hemodynamic response timing should be considered carefully when interpreting event-related studies of epileptiform activity.

Adult↗
PubMedDate not supplied

The epiplasm gene EPC1 influences cell shape and cortical pattern in Tetrahymena thermophila.

The cortical protein Epc1p is the most abundant protein in the membrane skeleton, or epiplasm, of Tetrahymena thermophila. A partial sequence of the EPC1 gene was obtained and used to obtain a knockout construct that was successful in transforming Tetrahymena thermophila cells. The results support the conclusion that Epc1p influences cell shape and the fidelity of cortical development. It was further observed that this protein is transferred from plus to minus cells during conjugation, and that the imported protein is assembled into the epiplasm of the recipient cell in a discreet series of steps.

5' Untranslated Regions↗