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PubMed2006

Correlation of neuroradiological, electroencephalographic and clinical findings in cortical dysplasias in children.

INTRODUCTION: Cortical dysplasias (CD) are defined as malformations of cortical development. They result from impairment of neuronal proliferation, migration and differentiation. CD are common pathological substrates in patients with early-onset childhood epilepsy and/or developmental delay as well as neurological signs. Recognition of the importance of cortical dysplasias has been shown in many studies when introducing structural MRI. The following study was performed in order to correlate the neuroimaging findings with the electroencephalographic and clinical picture of children with cortical dysplasias. MATERIALS AND METHODS: 46 patients with the presence of CD features in MRI were identified. There were 18 female and 28 male patients. The age ranged from 3 months to 12 years (mean age = 6.2, median age = 3.1). The objectives of the study were explained to the parents or legal representatives of children when possible and also informed consent was obtained. Multiple EEG recordings as well as detailed clinical analysis of all patients were performed. Statistical analysis was conducted in order to correlate the type of CD with clinical outcome and electrophysiological findings. RESULTS: There were 31 patients with focal dysplasias, 6 with schizencephaly, 4 with heterotopias, 3 lissencephaly and 2 with band heterotopia. 80% presented epilepsy (60% of them drug-resistant). Additionally, we tried to elucidate the clinical characteristics of epilepsy. In 75% of epilepsy patients the electroencephalographic changes correlated with anatomical localization of CD. 74% of patients were mentally retarded and 30% had focal neurological deficits. CONCLUSIONS: There were no correlations between the type of CD and the severity of the clinical picture, especially the level of mental retardation and presence of drug-resistant epilepsy. Different age at epilepsy onset and various responsiveness to antiepileptic drugs in the majority of patients may reflect different dynamics in epileptogenicity of the underlying CD.

Cerebral Cortex↗
PubMed1995

Alterations in cerebral cortical galanin concentrations following neurotransmitter-specific subcortical lesions in the rat.

Galanin is associated with multiple projection neurons, and its immunoreactivity in the cerebral cortex may be derived from diverse sources. We investigated the effects of subcortical lesions on cerebral cortical galanin concentrations. Lesions of the anterior noradrenergic bundle (ANB) comparably reduced cerebral cortical galanin and norepinephrine (NE) concentrations. The effects of the ANB lesions on galanin were immediate and became most pronounced 1 week later. Extensive unilateral lesions of the nucleus basalis of Meynert (NBM) decreased galanin concentrations, although not as markedly as after ANB lesions. The NBM lesions had no additional effect in the presence of an ANB lesion. Decreases in cerebral cortical galanin concentrations depended upon the extent and the duration of the NBM lesion and were not as pronounced as the decreases in markers of cholinergic activity. Acute treatments with physostigmine, which inhibit cerebral cortical AChE, had no effect on galanin concentrations. The depletion of galanin following an NBM lesion was most pronounced within hours of the insult, while the depletion of ChAT following the same lesions required several days to develop. Cortical concentrations of galanin and 5-HT increased 1 hr after dorsal raphe nucleus (DRN) lesions and then decreased 7 d later. Six weeks later, galanin concentrations recovered in the cerebral cortex despite the continued depletion of 5-HT. These studies suggest that a substantial portion of cerebral cortical galanin may derive from noradrenergic neurons and may be modulated by cortically-projecting ACh and 5-HT neurons.

Animals↗
PubMed2006

Overlapping expression of ARFGEF2 and Filamin A in the neuroependymal lining of the lateral ventricles: insights into the cause of periventricular heterotopia.

Periventricular heterotopia (PH) is a malformation of cortical development characterized by nodules of neurons, ectopically located along the lateral ventricles of the brain. Mutations in the vesicle transport ADP-ribosylation factor guanine exchange factor 2 gene (ARFGEF2) or the actin-binding Filamin A (FLNA) gene cause PH. Previous studies have shown that FLNA expression is developmentally regulated, with strongest expression observed along the ventricular zone (VZ) and to a lesser degree in postmitotic neurons in the cortex. Here we characterize the expression patterns for ARFGEF2 within the central nervous systems of human and mouse in order to better understand their potential roles in causing PH. ARFGEF2 mRNA was widely expressed in all cortical layers, especially in the neural precursors of the ventricular and subventricular zones (SVZ) during development, with persistent but diminished expression in adulthood. ARFGEF2 encodes for the protein brefeldin-inhibited guanine exchange factor 2 (BIG2). BIG2 protein immunoreactivity was most strongly localized to the neural progenitors along the neuroependymal lining of the VZ during development, with decreased expression in adulthood. Furthermore, overlapping BIG2 and FLNA expression was greatest in these same neuroependymal cells of human embryonic brain and was co-expressed in progenitors by Western blot. Finally, transfection of a dominant-negative construct of ARFGEF2 in SHSY5Y neuroblastoma cells partially blocked FLNA transport from the Golgi apparatus to the cell membrane. These results suggest that mutations in ARFGEF2 may impair targeted transport of FLNA to the cell surface within neural progenitors along the neuroependyma and that disruption of these cells could contribute to PH formation.

Animals↗
PubMed2002

Analytical characterization of spontaneous firing in networks of developing rat cultured cortical neurons.

We have used a multiunit electrode array in extracellular recording to investigate changes in the firing patterns in networks of developing rat cortical neurons. The spontaneous activity of continual asynchronous firing or the alternation of asynchronous spikes and synchronous bursts changed over time so that activity in the later stages consisted exclusively of synchronized bursts. The spontaneous coordinated activity in bursts produced a variability in interburst interval (IBI) sequences that is referred to as "form." The stochastic and nonlinear dynamical analysis of IBI sequences revealed that these sequences reflected a largely random process and that the form for relatively immature neurons was largely oscillatory while the form for the more mature neurons was Poisson-like. The observed IBI sequences thus showed changes in form associated with both the intrinsic properties of the developing cells and the neural response to correlated synaptic inputs due to interaction between the developing neural circuits.

Journal Article↗
PubMed2006

Hyperglycemia inhibits retinoic acid-induced activation of Rac1, prevents differentiation of cortical neurons, and causes oxidative stress in a rat model of diabetic pregnancy.

Diabetes is a risk factor for neuronal dysfunction. Impairment in signaling mechanisms that regulate differentiation of neurons is hypothesized to be one of the main causes of neuronal dysfunction. Retinoic acid, a physiologically active retinoid synthesized from vitamin A, regulates neuronal differentiation during embryonic development and is required for maintenance of plasticity in differentiated neurons. To date, little is known about the molecular events underlying hyperglycemia-induced complications in the central nervous system (CNS). Here, we provide evidence, in a diabetes rat model, of hyperglycemia-induced oxidative stress along with apoptotic stress in developing cortical neurons isolated from 16-day-old rat embryos. We also demonstrate impaired retinoic acid signaling that is involved in neuronal differentiation. Retinoic acid-induced neurite outgrowth and expression of neuronal markers were reduced in this model. The activation of small-molecular weight G-protein, Rac1, that mediates these effects was also reduced. Retinoic acid applied at a physiological concentration significantly decreased hyperglycemia-induced oxidative stress and thus supported the antioxidant defense system. These results suggest that diabetes-induced neuronal complications during pregnancy might be due to impaired retinoic acid signaling, and exogenously administered retinoic acid may be useful against CNS complications associated with diabetes.

Animals↗
PubMed2003

[Contrast enhanced fast fluid-attenuated inversion-recovery MR imaging for diagnosing cerebral venous angioma: report of two cases].

It has been reported that contrast-enhanced fluid-attenuated inversion-recovery (FLAIR) sequences were useful for detecting superficial abnormalities, such as meningeal disease, because they do not demonstrate contrast enhancement of cortical vessels with slow flow as do T1-weighted images. We reported the usefulness of contrast-enhanced FLAIR images to differentiate cerebral venous angioma from tumor in two patients. Case 1 was a 71-year-old man developed cortical hemorrhage. Post contrast-enhanced T1-weighted images showed an enhanced lesion around the hematoma, whereas contrast-enhanced FLAIR images showed no enhancement of the lesion, thus he was diagnosed as cortical hemorrhage from cerebral venous angioma. Case 2 was a 72-year-old woman, who was examined MR images because of the jugular foramen neurinoma. There was a T2-high-intensity lesion in the right frontal lobe, and post contrast-enhanced T1-weighted images showed an enhanced lesion in and around the T2-high-intensity lesion. Post-contrast FLAIR images showed no enhancement, and she was diagnosed as cerebral venous angioma. Contrast-enhanced fast FLAIR sequences was useful in differentiation between venous angiomas and tumors. Identification of these lesions was due to the flow-void phenomenon in vessels with slow-flowing blood such as venous angioma, which could not be differentiated from tumors on T1-weighted images.

Aged↗
PubMed2003

Neuroimaging of focal cortical dysplasia: neuropathological correlations.

Focal cortical dysplasia is a well-known cause of intractable epilepsy with early onset of seizures, and is potentially amenable to surgical therapy. It was first described by Taylor in 1971 as a peculiar malformative disorganisation of the neocortex characterised at histology by loss of cortical lamination and accompanied by giant, dysmorphic neurones and, most frequently, by "balloon cells" littered throughout the cortex and sub-cortical white matter. While in the past decades the term "cortical dysplasia" has referred to various malformations of cortical development, such as agyria, pachygyria, polymicrogyria, heterotopia and hemimegalencephaly, it is now widely accepted that the entity identified by Taylor should be considered separately, from both histological and neuroimaging standpoints. More recently, the recognition of various histological subtypes of focal cortical dysplasia characterised by different degrees of cortical disruption with or without cytological abnormalities has generated several classifications that are still unsatisfactory. With better magnetic resonance capability, subtle and very small focal cortical dysplasias may now be visualised and the differential magnetic resonance aspects of the histological subgroups can be established. We will discuss the problem of histopathological classification and magnetic resonance imaging differentiation of the various subtypes of focal cortical dysplasia in the light of personal data collected from a large series of epileptic patients who underwent surgery and had a histological diagnosis of focal cortical dysplasia.

Atrophy↗
PubMedDate not supplied

[Neurophysiological characteristics of the rat sensorimotor cortex in early motor deprivation and training].

Young rats, beginning with the age of 1 month, were kept in small size cages for 3 months, i.e., were exposed to 3-month motor deprivation. This exposure caused a modulating effect of a diminished activity of neuronal populations in the sensorimotor cortex which manifested as a prolongation of the latent periods of primary responses and recovery cycles of excitation of the neuronal populations generating the responses. The differences in the opposite changes in the sensorimotor cortex of the young animals that developed following prolonged deprivation and training of similar duration were seen in the parameters of excitation recovery cycles rather than in the latent periods. The reserve capabilities of the developing cortical structure associated with the modulation of excitation recovery cycles during training were 2.0-2.5 times greater than the dysfunctional changes in the same neuronal populations during motor deprivation. Both early motor deprivation and training did not influence the heterochronic development, emergence and subsequent attainment of the maximum amplitude of components of the testing primary response in the process of a gradual increase of the stimulus-to-stimulus interval.

Animals↗
PubMedDate not supplied

Brain-derived neurotrophic factor and epilepsy--a missing link?

It has been known for some time that brain-derived neurotrophic factor (BDNF) is critical to normal development of the CNS, and more recently, studies also have documented the ability of BDNF to modify adult CNS structure and function. Therefore, it is no surprise that BDNF has been linked to diseases, such as epilepsy, which may involve abnormal cortical development or altered brain structure and function after maturity. This review evaluates the evidence, particularly from recent studies, that BDNF contributes to the development of temporal lobe epilepsy (TLE).

Journal Article↗
PubMed2003

Epilepsy in neurofibromatosis 1.

Neurofibromatosis 1 is the most common neurocutaneous disease. Neurologic manifestations are mainly represented by tumors such as optic gliomas, focal areas of high T2-weighted signal known as unidentified bright objects, and mental retardation or learning disabilities. The prevalence of seizures has been reported to range from 3.8 to 6%. In the present study, we evaluated prevalence, type, and etiology of epilepsy in a neurofibromatosis 1 population. A retrospective analysis of 198 patients affected by neurofibromatosis 1 was performed. Fourteen patients (7%) were found to be epileptic. Every patient underwent electroencephalographic examination and neuroimaging investigations. Thirteen were submitted to magnetic resonance imaging (MRI) study and one to computed tomographic (CT) scanning. Single-photon emission computed tomographic and positron emission tomographic studies were performed in a few selected cases. Seizures were partial in 12 of these (85%) and generalized in 2 (15%). In nine (64%), epilepsy was secondary to brain lesions: five of these had cerebral tumors (three with epilepsy as the fist symptom), three had cortical malformation, and one had mesial temporal sclerosis. Seizures were controlled rapidly in eight (57%) and drug resistant in four (29%). Two patients were lost at follow-up. All patients with uncontrolled seizures had severe mental retardation, and three of these had malformations of cortical development. Our observations and our re-evaluation of the literature indicate that patients with neurofibromatosis 1 have an increased risk of epilepsy related to intracranial masses and cytoarchitectural abnormalities, and seizures can represent the first symptom of a tumor or cortical malformation. Brain MRI and, in selected cases, functional studies appear to be useful in patients with neurofibromatosis 1 who present with seizures, especially if associated with mental retardation.

Adolescent↗
PubMed2006

A role for proneural genes in the maturation of cortical progenitor cells.

We showed previously that the proneural genes Neurogenin1 (Ngn1) and Ngn2 are required to specify the phenotypes of early- and not late-born neurons in the neocortex, acting in part through repression of Mash1, a third cortically expressed proneural gene. The precise timing of Ngn1/2 specification activity was unexpected given these genes are expressed throughout cortical development, prompting us to search for a later function. Here we reveal that Ngn2 and Mash1 are expressed in a dynamic fashion, acquiring a cell cycle-biased, nonoverlapping distribution, with preferential expression in prospective basal progenitors, during mid corticogenesis. We also identified a new function for Ngn2 during this latter period, demonstrating that it is required to regulate the transit of cortical progenitors from the ventricular zone (VZ) to the subventricular zone. Notably, Ngn2 regulates progenitor maturation at least in part through repression of Mash1 as misexpression of Mash1 strongly enhanced progenitor cell exit from the VZ. Significantly, the ability of Mash1 to promote progenitor cell maturation occurred independently of its ability to respecify cortical cells and is thus a novel function for Mash1. Taken together, these data support a model whereby Ngn2 and Mash1 function together to regulate the zonal distribution of progenitors in the developing neocortex.

Aging↗
PubMed1995

Cell dispersion patterns in different cortical regions studied with an X-inactivated transgenic marker.

Inactivation of the X-linked lacZ transgene provides a novel and powerful way of distinguishing between clonally related cellular populations in X inactivation mosaics. This ability to distinguish between clonal populations of cells in the mature cortex permits inferences to be made about cellular dispersion patterns during cortical development. The present study addresses the extent to which radial and tangential dispersion patterns contribute to different regions of the cerebral cortex by quantifying the extent of cellular mixing between clonally distinct cells in separate domains of the medial, dorsolateral and lateral cortices. We show that stripes running perpendicular to the cortical layers are more likely to be seen in the medial and dorsolateral regions, and that the appearance of a stripe is attributed to about two-thirds of the cells being of the same colour. Both neurons and glia appeared to exhibit the same ratio of cell mixing. In the lateral regions of the cortex, stripes were not apparent, and cell mixing was roughly equal. In the barrel-field region of the somatosensory cortex we looked for a correspondence between cytoarchitectural features and clonal borders but found no correlation. These results demonstrate, first, that although there is widespread radial dispersion, no cortical region is composed of radially arrayed stripes of cells in which all members of a stripe are derived from a single progenitor. Second, they demonstrate that, within regions containing a sizeable fraction of cells that do migrate radially, the boundaries of individual stripes do not always coincide with single anatomical units of cortical specialization, such as individual barrels.

Animals↗
PubMed2003

Evaluation of nerve cell distribution in cerebral cortex--a proposal for a new method applied to patients with epilepsy.

Microdysgenesis is a microscopic malformation of cortical development (MCD) associated with epilepsy, but its significance in epileptogenesis is debated. This is partly since the histopathological aberrations associated with microdysgenesis can also be found in normal brains. We here report a method for objective analysis of one criterion for microdysgenesis, irregular cortical nerve cell distribution. Tissue from the lateral temporal lobe from two epilepsy patients was compared with tissue from two post-mortem controls. An expansion/shrinkage factor was calculated to determine the change in tissue size during cutting and mounting. Neurons were identified and the positions of their nucleoli were marked and stored. The spatial distribution of neurons was analysed using distance to nearest neighbouring neuron and Voronoi tessellation. Specimens from the epilepsy patients expanded markedly during mounting compared with controls. Epilepsy specimens had shorter mean distances to nearest neighbour than controls and smaller Voronoi tessellation areas than controls. Both measurements suggest more densely packed neurons in epilepsy specimens. This pilot study describes a new objective method for identification of cortical neurons and their spatial distribution. Voronoi tessellation and distance to nearest neighbouring neuron might provide robust methods for objective analysis of cortical nerve cell distribution. The yield of such comparisons might be improved if each cortical layer is analysed separately.

Adult↗
PubMed2005

Integrin-linked kinase deletion from mouse cortex results in cortical lamination defects resembling cobblestone lissencephaly.

Integrin-linked kinase (Ilk) is a scaffold and kinase that links integrin receptors to the actin cytoskeleton and to signaling pathways involved in cell adhesion, migration, and extracellular matrix deposition. Targeted deletion of Ilk from embryonic mouse dorsal forebrain neuroepithelium results in severe cortical lamination defects resembling cobblestone (type II) lissencephaly. Defects in adult mutants include neuronal invasion of the marginal zone, downward displacement of marginal zone components, fusion of the cerebral hemispheres, and scalloping of the dentate gyrus. These lesions are associated with abundant astrogliosis and widespread fragmentation of the basal lamina at the cortical surface. During cortical development, neuronal ectopias are associated with severe disorganization of radial glial processes and displacement of Cajal-Retzius cells. Lesions are not seen when Ilk is specifically deleted from embryonic neurons. Interestingly, targeted Ilk deletion has no effect on proliferation or survival of cortical cells or on phosphorylation of two Ilk substrates, Pkb/Akt and Gsk-3beta, suggesting that Ilk does not regulate cortical lamination via these enzymes. Instead, Ilk acts in vivo as a major intracellular mediator of integrin-dependent basal lamina formation. This study demonstrates a critical role for Ilk in cortical lamination and suggests that Ilk-associated pathways are involved in the pathogenesis of cobblestone lissencephalies.

Animals↗
PubMed2001

Estrogen-induced gonadal sex reversal in the tammar wallaby.

Estrogens have a feminizing effect on gonadal differentiation in fish, amphibians, reptiles, and birds. However, the role of estrogen during gonadal differentiation in mammals is less clear. We investigated the effect of estrogen on gonadal differentiation of male tammar wallabies. Male pouch young were treated orally with estradiol benzoate or oil from the day of birth, before seminiferous cords develop, to Day 25 postpartum and were killed at Day 50 postpartum. In all estrogen-treated neonates, a decrease in gonadal volume, volume of the seminiferous cords, thickness of the tunica albuginea, and number of germ cells was found. The stage of treatment affected the magnitude of the response. Two of three male young born prematurely after 25 days of gestation and treated subsequently with estradiol had ovary-like gonads, with well-developed cortical and medullary regions and primordial follicle formation. Furthermore, at Day 50 postpartum, many (21%) of the germ cells in these sex-reversed ovaries were in the leptotene and zygotene stages of meiosis, similar to female germ cells at the same stage of development. In the other males born on Day 26 of gestation or later, estradiol treatment from the day of birth caused development of dysgenetic testes, with abnormal Sertoli cells, atrophy of the seminiferous tubules and tunica albuginea, and absence of meiotic germ cells. In this marsupial, therefore, estradiol can induce either partial or complete transformation of the male gonads into an ovary with meiotic germ cells. These results confirm that estrogen can inhibit early testicular development, and that testis determination occurs during a narrow window of time.

Animals↗
PubMed2004

Altered neurotrophin receptor function in the developing prefrontal cortex leads to adult-onset dopaminergic hyperresponsivity and impaired prepulse inhibition of acoustic startle.

BACKGROUND: Survival and differentiation of neurons and the formation and maintenance of synapses in the cerebral cortex may be affected in schizophrenia. Since neurotrophins play an important role in these events, behavioral effects relevant to schizophrenia were investigated in rats that had compromised neurotrophin function during prefrontal cortical development. METHODS: Neonatal rat pups were injected into the developing prefrontal cortex with a depot preparation of p75 receptor antibody conjugated to saporin. Animals were tested for dopaminergic hyperresponsivity and prepulse inhibition of acoustic startle at 5 or 10 weeks. Neonatal and adult brain sections were examined for morphologic abnormality. RESULTS: Animals that received neonatal injections of p75 antibody conjugated to saporin showed significantly increased amphetamine-induced locomotion and rearing and impairment of prepulse inhibition of acoustic startle at 10 weeks of age but not at 5 weeks. Examination of adult brain sections revealed apparently normal structure, whereas neonatal brain sections showed apoptotic cells in the developing prefrontal cortex in pups that received p75 antibody conjugated to saporin. CONCLUSIONS: Compromised p75 neurotrophin receptor function in the developing prefrontal cortex may be associated with the manifestation of adult-onset dopaminergic hyperresponsivity and impaired prepulse inhibition and therefore may be involved in the pathogenesis of schizophrenia.

Acoustic Stimulation↗
PubMed2006

[Cortical malformations and epilepsy: Role of MR imaging].

Malformations of cortical development are increasingly recognized as important causes of epilepsy, developmental delay and other neurological disorders. Our purpose is to present the relevance of the MRI in these pathologies with the clinical, genetic and therapeutic aspects. This classification is based on the three fundamental events of cortical formation: proliferation of neurons and glie in the periventricular zone, migration of postmitotic neurons to the periphery, subsequent cortical organization. MR analysis evaluates particularly the cortical thickness, sulcal and cortical morphology, gray-white matter junction, and looks for gray matter in abnormal location. These data coupled with the familial history, the seizure characteristics and genetic findings should allow an appropriate classification of the lesions. MR imaging allows the detection and classification of cortical malformations. MR imaging findings are primordial to consider surgery when the epilepsy becomes refractory to the anti-epileptic drugs. An adequate classification of these malformations should help to provide to the family an appropriate counseling both in terms of genetics and outcome.

Adolescent↗
PubMed2006

EphA7-ephrin-A5 signaling in mouse somatosensory cortex: developmental restriction of molecular domains and postnatal maintenance of functional compartments.

Members of the Eph family of receptor tyrosine kinases and their ligands, the ephrins, are expressed in distinct patterns in the forming cortex. EphA7 is expressed early in cortical development, becoming concentrated in anterior and posterior domains, whereas ephrin-A5 is expressed later in corticogenesis, highest in the middle region that has low levels of EphA7. The EphA7 gene produces full-length and truncated isoforms, which are repulsive and adhesive, respectively. Analysis of cortical RNA expression demonstrates that proportions of these isoforms change with time, from a more repulsive mix during embryogenesis to a more permissive mix postnatally. To examine how EphA7 and ephrin-A5 influence the formation of cortical regions, EphA7-/- mice were analyzed. Within the cortex of EphA7-/- mice, the distribution of ephrin-A5 was more extensive, encompassing its usual medial domain but also extending more posteriorly toward the occipital pole. Moreover, relative levels of ephrin-A5 along the cortex's anatomical axes changed in EphA7-/- animals, creating less striking shifts in ligand abundance. Furthermore, in vivo functional studies revealed that EphA7 exerts a repulsive influence on ephrin-A5-expressing cells during corticogenesis. In contrast, EphA7 appears to mediate permissive interactions in the postnatal cortex: the area of somatosensory cortex was significantly reduced in EphA7-/- mice. A similar reduction was present in ephrin-A5-/- animals and a more pronounced decrease was observed in EphA7/ephrin-A5-/- cortex. Taken together, this study supports a role for EphA7 and ephrin-A5 in the establishment and maintenance of certain cortical domains and suggests that the nature of their interactions changes with cortical maturity.

Animals↗