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At least 19 recordsLinked to original sources

PubMed2005

Neuronal migration in cortical development.

Cortical formation in the developing brain is a highly complicated process involving neuronal production (through symmetric or asymmetric cell division) interaction of radial glia with neuronal migration, and multiple modes of neuronal migration. It has been convincingly demonstrated by numerous studies that radial glial cells are neural stem cells. However, the processes by which neurons arise from radial glia and migrate to their final destinations in vivo are not yet fully understood. Recent studies using time-lapse imaging of neuronal migration are giving investigators an increasingly more detailed understanding of the mitotic behavior of radial glia and the migrating behavior of their daughter cells. In this review, we describe recent progress in elucidating neuronal migration in brain formation and how neuronal migration is disturbed by mutations in genes that control this process.

Brain Diseases↗

PubMed1992

GABAA receptor subunit messenger RNAs show differential expression during cortical development in the rat brain.

Developmental changes of the expression of various GABAA receptor subunits (alpha 1, alpha 3, alpha 4, beta 1-3, and gamma 2) were examined in the fetal rat cerebral cortex using in situ hybridization histochemistry. The subunits showed three main patterns of development. The alpha 1 subunit showed the first pattern, in which no expression was observed during embryonic development. The alpha 4 and beta 1 subunits showed the second pattern, in which expression was observed in both the undifferentiated neuroepithelium and the developing cortical layers. The alpha 3, beta 2, beta 3, and gamma 2 subunits showed the third pattern, in which expression was only seen in the developing cortical layers. These findings strongly suggest the following: (i) the alpha 1 subunit is involved in GABAergic transmission in the mature cerebral cortex; (ii) the alpha 4 and beta 1 subunits are involved in both the differentiation of the neuroepithelium and the development of the cortical plate, and (iii) the alpha 3, beta 2, beta 3, and gamma 2 subunits are involved in the development of the cortical plate. Subunits already expressed on embryonic day 13 (beta 1, beta 3, and gamma 2) appear especially likely to have a special role in neuronal development.

Animals↗

PubMed2003

Cortical development and focal cortical dysplasia.

A brief survey of cortical development is presented, focusing on neuronal migration and its alterations. Corticogenesis is achieved through ordered temporospatial steps, via the formation of transient structures, and successive waves of cell proliferation and migration (followed by cell differentiation and maturation), and apoptotic cell death. The appearance of the proliferative ventricular zone and marginal zone, and of the superficial primordial plexiform layer, is followed by the formation of the prospective layer I, of the subplate, whose neurons are destined to die, and of the cortical plate that will give rise to layers II-VI. Cells arising in the ventricular zone migrate radially using radial glia as a scaffold, and are destined to form pyramidal cells. Cortical interneurons are mainly generated in the ganglionic eminence and migrate along axonal substrates following tangential routes. Disorders of this complex process lead to a wide range of alterations, and focal derangements of cortical organization have been grouped under the term focal cortical dysplasia (FCD). As the result of a neuropathological revision of FCD cases with intractable epilepsy, a novel classification comprising three subgroups of FCD has been introduced, and is supported by electroclinical and neuroimaging data, as well as by the postsurgical outcome of patients: i). architectural dysplasia, characterized by altered cortical lamination; ii). cytoarchitectural dysplasia, with the occurrence of giant neurons besides cortical dyslamination; iii). Taylor-type cortical dysplasia, in which altered cortical lamination is consistently associated with the occurrence of giant, dysmorphic and ectopic neurons, and frequently with the so-called balloon cells.

Cell Movement↗

PubMed2003

Focal cortical resection in malformations of cortical development.

Malformations of cortical development may be associated with drug-resistant partial epilepsy suitable for surgical therapy. From the anatomopathological point of view, this categorisation has been used in reference to a wide range of alterations of the cortical mantle. Focal cortical dysplasias represent the main group of malformations of cortical development, but there are also other types of alterations, such as heterotopias, double cortex or polymicrogyria. Defining candidacy for surgical therapy and tailored resection requires thorough pre-surgical evaluation so that the approach will be individualised for each patient. We present our series of 126 patients with malformation of cortical development selected from 321 consecutively operated patients. Within this group encompassing different types of malformation of cortical development, including periventricular heterotopia (nine patients), polymicrogyria (three patients), hemimegalencephaly (one patient) and subcortical band heterotopia (one patient), the largest group was 81 individuals with focal cortical dysplasia. For this last group, we propose a simplified classification defining 42 architectural dysplasias, 12 cytoarchitectural dysplasias and 27 Taylor's focal cortical dysplasias. In addition, at routine neuropathological investigation, the only morphological alteration shown by 31 patients was diffuse neuronal heterotopia. All patients underwent scalp EEG and video-EEG, and 75 patients (59.5%) also underwent stereo-EEG. Magnetic resonance imaging and stereotactic stereoscopic angiography represented the indispensable premises for further studies, in particular stereo-EEG, and for planning surgery and tailoring resection. Magnetic resonance imaging was unhelpful in 17 out of 81 patients with focal cortical dysplasia and in seven out of 31 with neuronal heterotopia, while signal alterations were present in all other cases. Common characteristics corresponding to clinical-histopathological homogeneous subgroups were found within the focal cortical dysplasia group. In patients with architectural dysplasia, the epileptogenic zone was mainly in the temporal lobe and there was a lower seizure frequency than in patients with Taylor's focal cortical dysplasia. Patients with Taylor's type had an epileptogenic zone that was mainly extra-temporal, and a distinctive interictal stereo-EEG. The best outcome was observed in patients with Taylor's type dysplasia: 69% seizure-free (Engel class Ia) after at least 1 year of follow-up, compared with 45% of cytoarchitectural dysplasia and 49% of architectural dysplasia patients.

Adult↗

PubMed2003

Characteristics of prolonged afterdischarges in children with malformations of cortical development.

We investigated aberrant cortical excitability in malformations of cortical development From subdural electrodes, we recorded afterdischarges lasting > or = 6 seconds in 12 of 13 patients with malformations of cortical development and 6 of 10 pediatric patients with nonmalformations of cortical development and reviewed amperage thresholds, distribution of afterdischarges, and motor responses. In patients with malformation of cortical development, motor response thresholds were high; afterdischarge and motor response thresholds, which essentially overlapped, inversely correlated with age (P < .01); afterdischarge thresholds declined with age; and 8 patients showed afterdischarges in remote sites. In nonmalformation of cortical development, afterdischarge thresholds did not significantly correlate with age; motor response thresholds tended to decline with age; and 2 patients had remote afterdischarges. Adolescent patients with malformations of cortical development had lower afterdischarge thresholds than adolescents with nonmalformation of cortical development (P < .05). From their high afterdischarge (and motor response) thresholds, we concluded that preadolescent patients with malformation of cortical development have less excitable, immature cortices, whereas adolescent patients with malformation of cortical development with low afterdischarge thresholds have hyperexcitable cortices. Remote afterdischarges over focal dysplastic cortex suggest aberrant cortical excitability and neural circuits.

Adolescent↗

PubMed2003

Morphological neuroimaging of malformations of cortical development.

Malformations of cortical development are classified on the basis of imaging features and stages of cortical development. They are grouped by causes of the malformation: abnormal glial and neuronal proliferation, abnormal neuronal migration and abnormal cortical organisation. Focal or multifocal and generalised forms are recognised in each of these groups. In the first group, generalised forms include microlissencephalies. Among focal-multifocal abnormalities, neoplastic forms include ganglioglioma and dysembryoplastic neuroepithelial tumours. Non-neoplastic forms include focal cortical dysplasia and tuberous sclerosis. Malformations due to abnormal migration include lissencephalies; cortical heterotopias are recognised in both focal and generalised forms. Abnormal cortical organisation includes polymicrogyria, in generalised or focal forms, and schizencephalies among the focal forms.

Brain Diseases↗

PubMed2002

Neuronal migration, cerebral cortical development, and cerebral cortical anomalies.

Cerebral cortical malformations are relatively common anomalies identified by neuroimaging and pathologically in patients with epilepsy and mental retardation. A disruption in neuronal migration during central nervous system development has been postulated as the pathogenesis for many of these disorders. Recently, the cell migration hypothesis has been proven accurate for lissencephaly, subcortical band heterotopia, and periventricular nodular heterotopia. Furthermore, advances in cellular and molecular biology have begun elucidating the fundamental mechanisms underlying these migration disorders. These data have resulted in redefining and recategorizing specific malformations based on their molecular genetic abnormality. In this review we shall discuss the current understanding of neuronal migration in the developing cerebral cortex, the evaluation of these patients, and attempt to describe the pathogenesis for several well-characterized human disorders of cell migration.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗

PubMed2007

Differential expression patterns of chloride transporters, Na+-K+-2Cl--cotransporter and K+-Cl--cotransporter, in epilepsy-associated malformations of cortical development.

Malformations of cortical development are recognized causes of chronic medically intractable epilepsy. An increasing number of observations suggests an important role for cation-chloride co-transporters (CCTs) in controlling neuronal function. Deregulation of their expression may contribute to the mechanisms of hyperexcitability that lead to seizures. In the present study the expression and cell-specific distribution of Na+-K+-2Cl--cotransporter (NKCC1) and K+-Cl--cotransporter (KCC2) were studied immunocytochemically in different developmental lesions, including focal cortical dysplasia (FCD) type IIB (n=9), hemimegalencephaly (HMEG, n=6) and ganglioglioma (GG, n=9) from patients with medically intractable epilepsy and in age-matched controls. In normal control adult cortex, NKCC1 displayed low neuronal and glial expression levels. In contrast KCC2 showed strong and diffuse neuropil staining. Notable glial immunoreactivity (IR) was not found for KCC2. NKCC1 was highly expressed in the majority of FCD, HMEG and GG specimens. NKCC1 IR was observed in neurons of different size, including large dysplastic neurons, in balloon cells (in FCD and HMEG cases) and in glial cells with astrocytic morphology. The immunoreactivity pattern of KCC2 in FCD, HMEG and GG specimens was characterized by less neuropil staining and more intrasomatic IR compared with control. KCC2 IR was observed in neurons of different size, including large dysplastic neurons, but not in balloon cells or in glial cells with astrocytic morphology. Double-labeling experiments confirmed the differential cellular distribution of the two CCTs and their expression in GABA(A) receptor (alpha1 subunit)-positive dysplastic neurons. The cellular distribution of CCTs, with high expression of NKCC1 in dysplastic neurons and altered subcellular distribution of KCC2 resembles that of immature cortex and suggests a possible contribution of CCTs to the high epileptogenicity of malformations of cortical development.

Adolescent↗

PubMed2002

Complex central cortex in pediatric patients with malformations of cortical development.

We investigated whether malformations of cortical development yield a complex central cortex by studying nine children with malformations of cortical development and seven without malformations who underwent epilepsy surgery following extraoperative subdural somatosensory evoked potential and electrical stimulation to identify the sensorimotor cortex. We analyzed superficial structures of the central cortex, latency, amplitude, and location of N20 and P25. Sensorimotor responses in malformations of cortical development extended across the central sulcus in 1 to 4 of 3 to 12 electrodes (mean 32%) compared with 1 to 6 of 4 to 15 electrodes (mean 12%) in cases without malformations with a statistical significance (P < .05). N20 amplitudes were lower in epileptic than nonepileptic cortices (three with and three without malformations of cortical development) (P < .05). The central vein coursed partially along the central sulcus in eight cases of malformations of cortical development and five cases without malformations. We conclude that the sensorimotor cortex in malformations of cortical development is more complex than in cases without malformations, reduced N20 amplitude is indicative of epileptic sensorimotor cortex, and superficial veins do not indicate the sensory and motor cortical boundary.

Adolescent↗

PubMed2003

Quantitative MRI detects abnormalities in relatives of patients with epilepsy and malformations of cortical development.

Malformations of cortical development (MCD) are a common etiology for epilepsy. Laminar heterotopia, bilateral subependymal heterotopia, and lissencephaly have a genetic basis. No gene mutations have yet been identified in patients with focal cortical dysplasias. The aim of this study was to use quantitative morphometric tools to determine if there were gray matter abnormalities in relatives of patients with MCD. We studied 19 relatives of 13 probands with MCD and 58 healthy controls with high-resolution MRI. The relatives and controls had no neocortical abnormalities on visual inspection. MRI data were analyzed with voxel-based morphometry and autoblock analysis. Voxel-based morphometry showed significant increases of gray matter in 9 of 10 probands, 5 of 19 relatives, and 5 of 58 controls. The autoblock analysis showed significant abnormalities in 7 of 8 probands, 8 of 19 relatives, and 2 of 57 controls. This finding suggests structural abnormality in the brains of a greater number of relatives of MCD patients than would be expected, and in the context, a reasonable inference is that this reflects subtle genetically determined cerebral abnormalities, although acquired pathologies are possible and are not excluded.

Adolescent↗

PubMed2002

Structure-function correlations in patients with malformations of cortical development.

Malformations of cortical development (MCD) are a diverse group of diseases that exhibit both genetic and phenotypic heterogeneity. While previous studies have described the clinical, MRI, and/or EEG features of specific malformations, structure and function have not been correlated across a wide spectrum of these disorders. We reviewed the medical records of 22 patients with MCD due to abnormal neuronal migration and cortical organization, and correlated levels of clinical disability with specific MRI and EEG findings. The extent of abnormality on MRI was significantly correlated with clinical disability. Compared with patients with other lesions, those with lissencephaly were more disabled. Although background slowing, suppression, fast activity, and interictal epileptiform activity were not individually predictive, the overall degree of EEG abnormality was significantly correlated with clinical disability, as were alterations in the posterior head rhythm and physiologic sleep features.

Journal Article↗

PubMed1998

Cerebral activation in malformations of cortical development.

Malformations of cortical development (MCD) are an important aetiology of localization-related epilepsy. Previous MRI and [11C]flumazenil PET studies have demonstrated widespread structural and neuroreceptor abnormalities beyond the region of MCD that is visually apparent on MRI. We investigated the ability of brain regions affected by MCD to participate in normal cognitive and motor tasks and compared the responses seen in such patients with those in normal subjects. We studied five patients known to have MCD affecting the occipital region and seven normal subjects using H2 (15)O PET whilst they were performing a visual attention task. We also studied five right-handed patients known to have MCD affecting the left frontal lobe and seven right-handed normal subjects, using H2 (15)O PET whilst they were performing a motor learning task with the right hand. The patient and normal control data were examined using statistical parametric mapping to determine the ability of the brain region affected by MCD to participate in the task and also to detect evidence for atypical organization of cortical function in association with the MCD. Eight of the ten patients with MCD showed significant alteration of relative regional cerebral blood flow during the task compared with 'rest' in the affected brain region. These regions included focally dysgenetic cortex, the cortex lining schizencephalic clefts, heterotopic bands, subependymal grey matter heterotopia, and the cortex overlying band and subependymal heterotopia. In addition there was a significant alteration in the overall activation pattern in five patients compared with the normal control groups; in all five patients this atypical organization involved regions of cortex that appeared entirely normal on MRI. We conclude that regions of MCD may participate in normal cognitive functions but widespread cortical atypical organization may be seen. These findings have implications for surgical planning in any such patients.

Adolescent↗

PubMed2004

Neuroimaging in disorders of cortical development.

Malformations of cortical development are important causes of developmental delay and epilepsy. They are classified by the presumed stage during which normal development is interrupted: neuronal proliferation and differentiation, neuronal migration, and late migration/cortical organization. This article discusses the important malformations in each of these groups, how and why the malformations develop, and their imaging findings. A better understanding of these disorders helps in genetic counseling of the parents and may help in the treatment of associated epilepsy.

Cerebral Cortex↗

PubMed2004

Malformations of cortical development.

Malformations of cortical development are an important cause of developmental delay and epilepsy. Proper identification of these malformations can greatly help in accurately counseling affected families and, in some cases, in the treatment of the epilepsy. Modem neuroimaging is an important tool in the diagnosis of these malformations.

Brain↗

PubMed2001

Diffusion tensor imaging in patients with epilepsy and malformations of cortical development.

Malformations of cortical development (MCD) are a common cause of epilepsy. Studies of structural MRIs and PET data in patients with MCD have found widespread changes outside the visually identified lesions. The aim of this study was to investigate diffusion changes interictally in patients with MCD and to test the hypothesis that MCD would be associated with widespread abnormalities of diffusion. We used diffusion tensor imaging (DTI) and statistical parametric mapping (SPM) to compare objectively tissue organization in 22 patients with partial seizures and MCD, with 30 control subjects. Whole-brain DTI was acquired using echo planar imaging. Rotationally invariant anisotropy and diffusivity maps were calculated and, after normalization to Talairach space, each patient was compared with the group of control subjects using SPM. Areas of reduced anisotropy were found in 17 patients and areas of increased diffusivity in 10. Two patients had areas of increased anisotropy. There were no patients with reduced diffusivity. Areas of increased diffusivity were in general more extensive than areas of reduced anisotropy. Changes in tissue beyond the MCD, that appeared normal on conventional MRI, were found in six patients for anisotropy and nine patients for diffusivity. Both measurements showed widespread changes in tissue beyond the MCD, i.e. adding information to conventional MRI. Increased or abnormally located grey matter or pathological white matter with abnormal myelination or ectopic neurones could cause reduced anisotropy. Increased diffusivity could be caused by a defect of neurogenesis or cell loss resulting in increased extracellular space. The widespread nature of abnormalities should be considered if surgical treatment is contemplated.

Adult↗

PubMed2006

The IL-1beta system in epilepsy-associated malformations of cortical development.

Focal cortical dysplasia (FCD) and glioneuronal tumors (GNT) are recognized causes of chronic intractable epilepsy. The cellular mechanism(s) underlying their epileptogenicity remain largely unknown. Compelling evidence in experimental models of seizures indicates an important role of interleukin (IL)-1beta in the mechanisms of hyperexcitability leading to the occurrence of seizures. We immunocytochemically investigated the brain expression and cellular distribution pattern of IL-1beta, IL-1 receptor (IL-1R) types I and II and IL-1R antagonist (IL-1Ra) in FCD and GNT specimens, and we correlate these parameters with the clinical history of epilepsy in patients with medically intractable seizures. In normal control cortex, and in perilesional regions with histologically normal cortex, IL-1beta, IL-1Rs and IL-1Ra expression was undetectable. In all FCD and GNT specimens, IL-1beta and its signalling receptor IL-1RI were highly expressed by more than 30% of neurons and glia whereas the decoy receptor IL-RII and IL-Ra were expressed to a lesser extent by approximately 10% and 20% of cells, respectively. These findings show a high expression of IL-1beta and its functional receptor (IL-1RI) in FCD and GNT specimens together with a relative paucity of mechanisms (IL-1RII and IL-1Ra) apt to inactivate IL-1beta actions. Moreover, the number of IL-1beta- and IL-1RI-positive neurons was positively correlated with the frequency of seizures, whereas the number of IL-1Ra-positive neurons and astroglial cells was negatively correlated with the duration of epilepsy prior to surgery. The expression of IL-1beta family members in these developmental lesions may contribute to their intrinsic and high epileptogenicity, thus possibly representing a novel target for antiepileptic strategies.

Adolescent↗

PubMed1997

Behavioral consequences of abnormal cortical development: insights into developmental disabilities.

Cerebral cortical development occurs in precisely-timed stages that can be divided into neurogenesis, neuronal migration and neuronal differentiation. These events occur during discrete time windows that span the late prenatal and early postnatal periods in both rodents and primates, including humans. Insults at particular developmental stages can lead to distinctive cortical abnormalities including cortical hypoplasia (reduced cell number), cortical ectopias (abnormalities in migration) and cortical dysplasias (abnormalities in the shapes or numbers of dendrites). In this review, we examine some of the most extensively-studied animal models of disrupted stages of cortical development and we compare long-term anatomical, neurochemical, and behavior abnormalities in these models. The behavioral abnormalities in these models range from alterations in simple motor behaviors to food hoarding and maternal behaviors as well as cognitive behaviors. Although we examine concisely animal models of cortical hypoplasia and cortical ectopias, we focus here on developmental manipulations that affect cortical differentiation, particularly, those that interrupt the normal ontogeny of the neurotransmitter-defined cortical afferent systems: norepinephrine, serotonin, dopamine and acetylcholine. All of these afferents presumably play a critical role in the maturation of their cortical targets; the timing of the afferents' entry into the cortex and their effects on their cortical targets, however, are different. We, therefore, compare the specific anatomical, neurochemical and behavioral effects of manipulations of the different cortical afferents. Because of the considerable evidence that cortical development proceeds differently in the two sexes, when data are available, we address whether perinatal insults differentially affect the sexes. Finally, we discuss how these developmental studies provide insights into cellular and neurochemical correlates of behavioral functional abnormalities and the relevance of these data to understanding developmental disabilities in humans.

Animals↗

PubMed2005

A developmental and genetic classification for malformations of cortical development.

Increasing recognition of malformations of cortical development and continuing improvements in imaging techniques, molecular biologic techniques, and knowledge of mechanisms of brain development have resulted in continual improvement of the understanding of these disorders. The authors propose a revised classification based on the stage of development (cell proliferation, neuronal migration, cortical organization) at which cortical development was first affected. The categories are based on known developmental steps, known pathologic features, known genetics (when possible), and, when necessary, neuroimaging features. In those cases in which the precise developmental and genetic features are uncertain, classification is based on known relationships among the genetics, pathologic features, and neuroimaging features. The major change since the prior classification has been a shift to using genotype, rather than phenotype, as the basis for classifying disorders wherever the genotype-phenotype relationship is adequately understood. Other substantial changes include more detailed classification of congenital microcephalies, particularly those in which the genes have been mapped or identified, and revised classification of congenital muscular dystrophies and polymicrogyrias. Information on genetic testing is also included. This classification allows a better conceptual understanding of the disorders, and the use of neuroimaging characteristics allows it to be applied to all patients without necessitating brain biopsy, as in pathology-based classifications.

Cerebral Cortex↗