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PubMed2005

Growth-associated gene expression after stroke: evidence for a growth-promoting region in peri-infarct cortex.

Stroke induces axonal sprouting in peri-infarct cortex. A set of growth-associated genes important in axonal sprouting in peripheral nervous system regeneration and cortical development has recently been defined. The expression profiles of these growth-associated genes were defined during the post-stroke axonal sprouting response using a model of stroke in barrel field cortex. Stroke induces sequential waves of neuronal growth-promoting genes during the sprouting response: an early expression peak (SPRR1), a mid expression peak (p21, Ta1 tubulin, L1, MARCKS), a late peak (SCG10, SCLIP), and an early/sustained pattern (GAP43, CAP23, c-jun). These expression peaks correspond to specific time points in the sprouting response. The expression of the growth-inhibiting chondroitin sulfate proteoglycans aggrecan, brevican, versican, and phosphacan are induced late in the sprouting process; except neurocan, which is increased during the peak of the growth-promoting gene expression. The developmentally associated growth inhibitors ephrin-A5, ephB1, semaphorin IIIa, and neuropilin 1 are also induced in the early phases of the sprouting response. At the cellular level, chondroitin sulfate proteoglycans, in the form of peri-neuronal nets, are reduced in the region of axonal sprouting, during the peak of growth-promoting gene expression. These results identify a unique profile of growth-promoting gene expression in adult cortex after stroke, the inhibitory molecules that are present during the sprouting response, and a region in which growth-promoting genes are increased, growth-inhibitory proteins are diminished and axonal sprouting occurs. This region may be a growth-promoting zone after stroke.

Aggrecans↗
PubMed2005

Tiagabine-induced generalised non convulsive status epilepticus in patients with lesional focal epilepsy.

PURPOSE: To report 3 cases with focal lesional epilepsy that had non-convulsive status epilepticus (NCSE) induced by treatment with tiagabine (TGB) and review the previously published cases. Drugs that enhance GABAnergic transmission are recognised to promote absence seizures in patients with generalised epilepsy syndromes and may on occasions even induce NCSE. However, that TGB can also induce NCSE in focal lesional epilepsy is not widely recognised in clinical practice. METHOD: The clinical history, EEG and MRI findings were reviewed in 3 patients with lesional focal epilepsy who presented to our epilepsy programs over a 12 month period with TGB-induced NCSE. All previously reported cases in the English medical literature were reviewed. RESULTS: The three patients had longstanding complex partial and secondarily generalised seizures refractory to multiple different anti-epileptic drugs. In two cases, MRI demonstrated a focal malformation of cortical development in the left parieto-occipital region and in the third left mesial temporal sclerosis. Following commencement of TGB in one patient and dose escalation in two, prolonged episodes of confusion and poor responsiveness were noted. Prolonged EEG monitoring demonstrated continuous high amplitude, generalised, 2-4 Hz delta activity with intermingled spikes during the episodes of unresponsiveness, consistent with NCSE. The clinical and EEG activity normalised following the administration of IV clonazepam followed by dose reduction or withdrawal of the TGB. Eleven previously reported cases of patients with partial epilepsy and a focal underlying lesion on MRI were identified, all of whom had similar features to that seen in our cases. CONCLUSIONS: These cases illustrate that TGB may induce generalised NCSE in patients with focal lesional epilepsy, in addition to those with generalised syndromes. We hypothesise that patients may have developed an acquired alteration in the sensitivity of their thalamocortical circuitry that renders them more sensitive to the effects of drugs that enhance GABAnergic activity.

Adolescent↗
PubMed2006

Site-specific dephosphorylation of doublecortin (DCX) by protein phosphatase 1 (PP1).

Mutations in doublecortin (DCX) cause X-linked lissencephaly ("smooth brain") and double cortex syndrome in humans. DCX is highly phosphorylated in migrating neurons. Here, we demonstrate that dephosphorylation of specific sites phosphorylated by JNK is mediated by Neurabin II, which recruits the phosphatase PP1. During cortical development, the expression pattern of PP1 is widespread, while the expression of DCX and Neurabin II is dynamic, and they are coexpressed in migrating neurons. In vitro, DCX is site-specific dephosphorylated by PP1 without the presence of Neurabin II, this dephosphorylation requires an intact RVXF motif in DCX. Overexpression of the coiled-coil domain of Neurabin II, which is sufficient for interacting with DCX and recruiting the endogenous Neurabin II with PP1, induced dephosphorylation of DCX on one of the JNK-phosphorylated sites. We hypothesize that the transient recruitment of DCX to different scaffold proteins, JIP-1/2, which will regulate its phosphorylation by JNK, and Neurabin II, which will regulate its dephosphorylation by PP1, plays an important role in normal neuronal migration.

Adaptor Proteins, Signal Transducing↗
PubMed2006

In vivo inactivation of pRb, p107 and p130 in murine neuroprogenitor cells leads to major CNS developmental defects and high seizure rates.

Nestin-positive cells were targeted for pRb, p107 and p130 (pRb(f)) inactivation by expression of T(121), a truncated SV40 large T antigen that selectively binds to and inactivates pRb(f). Cre expression was initiated under GFAP control, resulting in T(121) expression restricted to neuroprogenitor cells beginning at embryonic day 11.5 (E11.5). Bi-transgenic embryos showed aberrant central nervous system (CNS) cell proliferation and apoptosis by E13.5. Defects in cortical development were evident with primary effects resulting in depletion of neural progenitors and aberrant cellular migration. Consequently, juvenile and adult brain morphology was reproducibly abnormal, including disorganization of neocortical, hippocampal and cerebellar regions. These aberrations resulted in behavioral phenotypes, including ataxia and seizures. The data indicate that inactivation of pRb(f) in radial glial cells, a population of neuroprogenitor cells, leads to specific disruptions in CNS patterning. The neuroprogenitor-restricted transgene expression provides a model in which to explore both developmental mechanisms and functional neurological outcomes.

Animals↗
PubMed2006

Homeostatic synaptic scaling in self-organizing maps.

Various forms of the self-organizing map (SOM) have been proposed as models of cortical development [Choe Y., Miikkulainen R., (2004). Contour integration and segmentation with self-organized lateral connections. Biological Cybernetics, 90, 75-88; Kohonen T., (2001). Self-organizing maps (3rd ed.). Springer; Sirosh J., Miikkulainen R., (1997). Topographic receptive fields and patterned lateral interaction in a self-organizing model of the primary visual cortex. Neural Computation, 9(3), 577-594]. Typically, these models use weight normalization to contain the weight growth associated with Hebbian learning. A more plausible mechanism for controlling the Hebbian process has recently emerged. Turrigiano and Nelson [Turrigiano G.G., Nelson S.B., (2004). Homeostatic plasticity in the developing nervous system. Nature Reviews Neuroscience, 5, 97-107] have shown that neurons in the cortex actively maintain an average firing rate by scaling their incoming weights. In this work, it is shown that this type of homeostatic synaptic scaling can replace the common, but unsupported, standard weight normalization. Organized maps still form and the output neurons are able to maintain an unsaturated firing rate, even in the face of large-scale cell proliferation or die-off. In addition, it is shown that in some cases synaptic scaling leads to networks that more accurately reflect the probability distribution of the input data.

Animals↗
PubMed2005

Extra-hippocampal grey matter density abnormalities in paediatric mesial temporal sclerosis.

The aim of this study was to identify grey matter density abnormalities in children with temporal lobe epilepsy and mesial temporal sclerosis. Magnetic resonance T1 weighted 3D datasets were obtained in children with temporal lobe epilepsy (20 left and 10 right sided, mean age 11.9 years, range 6.6-17.5) and compared to scans obtained from age-matched controls (n = 22, mean age 12.8 years, range 7.1-17.5) using voxel-based morphometry. This method detected reduced grey matter ipsilateral to the seizure focus not only in the hippocampus, but also in the lateral temporal lobe and in extra-temporal regions including the thalamus, posterior cingulate cortex and cerebellum. Bilateral differences were present in the frontal and parietal opercular cortices and lateral temporal regions. These grey matter density reductions broadly reflect the pattern of hippocampal connections and may be caused by the disruption of cortical development by the recurrent seizures, as well as by loss of functional input from the sclerotic hippocampus.

Adolescent↗
PubMed2006

Imaging the neocortex in epilepsy with double inversion recovery imaging.

The neocortices of 10 patients with partial seizures and acquired lesions, 14 patients with malformations of cortical development (MCD) and 33 patients with partial seizures and normal conventional MRI were quantitatively evaluated using whole brain double inversion recovery imaging (DIR) and Statistical Parametric Mapping (SPM). Compared to a group of 30 control subjects, DIR and objective voxel-by-voxel statistical comparison identified regions of significantly abnormal DIR signal intensity (DSI) in 9 out of 10 patients with acquired nonprogressive cerebral lesions and partial seizures. In all 9 patients, the areas of abnormal DSI concurred with abnormalities identified on visual inspection of conventional MRI. In all 14 patients with MCD, SPM detected regions of significantly abnormal DSI; all of which corresponded to abnormalities identified on visual inspection of conventional MRI. In addition, in both groups, there were areas that were normal on conventional imaging, which demonstrated abnormal DSI. Voxel-by-voxel statistical analysis identified significantly abnormal DSI in 15 of the 33 patients with cryptogenic focal epilepsy. In 10 of these, the areas of abnormal DSI concurred with epileptic EEG abnormality and clinical seizure semiology. Group analysis of MRI-negative patients with electroclinical seizure onset localising to the left temporal and left and right frontal regions revealed significantly abnormal DSI within the white matter of each respective lobe. DIR analysed using SPM was sensitive in patients with MCDs and acquired cerebral damage. Significant abnormalities in DSI in individual and grouped MRI-negative patients suggest that occult epileptogenic cerebral lesions are associated with subtle structural abnormalities. DIR is, therefore, a useful quantitative MRI technique for characterising epileptic foci and may contribute to presurgical evaluation.

Adult↗
PubMed2006

Human cerebral cortex: a system for the integration of volume- and surface-based representations.

We describe an MRI-based system for topological analysis followed by measurements of topographic features for the human cerebral cortex that takes as its starting point volumetric segmentation data. This permits interoperation between volume-based and surface-based topographic analysis and extends the functionality of many existing segmentation schemes. We demonstrate the utility of these operations in individual as well as to group analysis. The methodology integrates analyses of cortical segmentation data generated by manual and semi-automated volumetric morphometry routines (such as the program cardviews) with the procedures of the FreeSurfer program to generate a cortical ribbon of the cerebrum and perform cortical topographic measurements (including thickness, surface area and curvature) in individual subjects as well as in subject populations. This system allows the computation of topographical cortical measurements for segmentation data generated from manual and semi-automated volumetric sources other than FreeSurfer. These measurements can be regionally specific and integrated with systems of cortical parcellation that subdivides the neocortex into gyral-based parcellation units (PUs). This system of topographical analysis of the cerebral cortex is consistent with current views of cortical development and neural systems organization of the human and non-human primate brain.

Adult↗
PubMed2004

Calcium waves rule and divide radial glia.

Radial glial proliferation is a critical step in the construction of cerebral cortex. In this issue of Neuron, Weissman and colleagues use time-lapse calcium imaging techniques to demonstrate that spontaneous calcium waves sweeping through cohorts of radial glia in the ventricular zone can modulate their proliferation during cerebral cortical development.

Adenosine Triphosphate↗
PubMed2006

Regulation of thalamocortical patterning and synaptic maturation by NeuroD2.

During cortical development, both activity-dependent and genetically determined mechanisms are required to establish proper neuronal connectivity. While activity-dependent transcription may link the two processes, specific transcription factors that mediate such a process have not been identified. We identified the basic helix-loop-helix (bHLH) transcription factor Neurogenic Differentiation 2 (NeuroD2) in a screen for calcium-regulated transcription factors and report that it is required for the proper development of thalamocortical connections. In neuroD2 null mice, thalamocortical axon terminals fail to segregate in the somatosensory cortex, and the postsynaptic barrel organization is disrupted. Additionally, synaptic transmission is defective at thalamocortical synapses in neuroD2 null mice. Total excitatory synaptic currents are reduced in layer IV in the knockouts, and the relative contribution of AMPA and NMDA receptor-mediated currents to evoked responses is decreased. These observations indicate that NeuroD2 plays a critical role in regulating synaptic maturation and the patterning of thalamocortical connections.

2-Amino-5-phosphonovalerate↗
PubMed2005

Increased temporal lobe gyrification in preterm children.

Preterm birth often results in significant learning disability, and previous magnetic resonance imaging (MRI) studies of preterm children have demonstrated reduction in overall cortical tissue with particular vulnerability in the temporal lobe. We measured cortical gyrification in 73 preterm and 33 term control children at 8 years of age and correlated these findings with tests of language ability to determine the associations among preterm birth, neurodevelopment and functional outcome. Preterm children demonstrated significantly increased bilateral temporal lobe gyrification index compared to term controls. Left temporal gyrification index was significantly negatively correlated with left temporal lobe gray matter volume as well as reading recognition scores in the preterm group. Cortical development in the temporal lobe appears to be differentially vulnerable to preterm birth.

Cerebral Cortex↗
PubMed2006

Histometric changes and cell death in the thalamus after neonatal neocortical injury in the rat.

Freezing injury to the developing cortical plate results in a neocortical malformation resembling four-layered microgyria. Previous work has demonstrated that following freezing injury to the somatosensory cortex, males (but not females) have more small and fewer large cells in the medial geniculate nucleus. In the first experiment, we examined the effects of induced microgyria to the somatosensory cortex on neuronal numbers, neuronal size, and nuclear volume of three sensory nuclei: ventrobasal complex, dorsal lateral geniculate nucleus, and medial geniculate nucleus. We found that there was a decrease in neuronal number and nuclear volume in ventrobasal complex of microgyric rats when compared with shams, whereas there were no differences in these variables in the dorsal lateral geniculate nucleus or medial geniculate nucleus. We also found that there were more small and fewer large neurons in both ventrobasal complex and medial geniculate nucleus. In experiment 2, we attempted to determine the role of cell death in the thalamus on these histometric measures. We found that cell death peaked within 24 h of the freezing injury and was concentrated mostly in ventrobasal complex. In addition, there was evidence of greater cell death in males at this age. Taken together, these results support the notion that males are more severely affected by early injury to the cerebral cortex than females.

Age Factors↗
PubMed2006

Septo-optic dysplasia complex: a heterogeneous malformation syndrome.

Septo-optic dysplasia is defined by a variable combination of dysgenesis of midline brain structures including optic nerve hypoplasia and hypothalamic-pituitary dysfunction often associated with a wide variety of brain malformations of cortical development. Multiple congenital anomalies have been reported only sporadically. Despite recent demonstration of the possible pathogenic role of HESX1/Hesx1 gene (a homeobox gene important for development of prosencephalon), the etiology of most cases of septo-optic dysplasia still remains unclear. This report describes eight children (4 males, 4 females; age 2 to 17 years) with septo-optic dysplasia who manifested dysmorphic features (involving not only the midline facial structures) and a spectrum of additional clinical and imaging features including autism, facial hemangioma, and holoprosencephaly. Full mutational screening for the HESX1 gene in seven of eight children was negative. Based on the extreme variability of the clinical and imaging phenotypes hereby observed, on literature review, and on septo-optic dysplasia animal models, this study confirmed that the phenotypic heterogeneity in septo-optic dysplasia is high. We suggest that: (1) dysmorphic features are more frequent than previously thought--they may represent a relevant part of the phenotype; (2) septo-optic dysplasia should be recategorized as an heterogeneous malformation syndrome (septo-optic dysplasia complex) (encompassing multiple brain, endocrine, and systemic anomalies) rather than a single precisely defined entity.

Abnormalities, Multiple↗
PubMed2006

Agenesis of the corpus callosum: clinical and genetic study in 63 young patients.

This study reports the clinical features of 63 patients with agenesis of the corpus callosum who received in-depth genetic, clinical, and laboratory testing with the aim to contribute to a better description of the large spectrum of associated malformations and to assist clinicians in the diagnosis. Thirty patients manifested complete agenesis and 33 patients displayed partial agenesis. Other associated nervous system malformations were detected in 14 patients with partial agenesis of the corpus callosum (mostly correlated to posterior fossa malformations) and in 10 patients with complete agenesis (more frequently associated with malformations of cortical development). Involvement of organs and apparatus other than the nervous system was present in 41 patients (ascribed to known syndromes in 21 cases). Cytogenetically detectable chromosomal abnormalities (7 patients) and subtelomeric rearrangements (3 patients) were found. Neuromotor skills were impaired in almost all cases (58/63). Mental retardation of different severity was present in 52 cases, whereas 2 patients were borderline and 9 patients had normal intelligence quotient. This study demonstrates that there is no unique prognosis for agenesis of the corpus callosum as this condition is associated with a broad range of clinical manifestations, oscillating between the limits of the norm and severe psychomotor delay.

Abnormalities, Multiple↗
PubMed2005

Temporal lobe epilepsy surgery in children and adolescents: clinical characteristics and post-surgical outcome.

BACKGROUND AND PURPOSE: Temporal lobe epilepsy (TLE) encompasses 10-20% of the cases of intractable epilepsy in pediatric patients. Mesial temporal sclerosis (MTS) can still be encountered in adolescent patients, but is rare in children under 5 years of age. In this paper we report on the surgical outcome of a series of TLE patients ranging in age from 1 to 18 years at the time of operation. PATIENTS AND METHODS: Thirty-five patients (37 surgeries) with medically intractable TLE were operated upon between January 1996 and December 2002. The following variables were analyzed: age at surgery, age at epilepsy onset, history of an initial precipitating injury, etiology, seizure semiology, interictal and ictal EEG findings, surgical complications, and post-surgical seizure outcome. RESULTS: There were 68.6% females and 31.3% males, and complex partial seizures (CPS) occurred in 86.5%. The most common etiology was MTS (40%) followed by isolated cortical developmental abnormalities (22.9%). In the age group up to 5 years, cortical development abnormalities predominated, and 71% of these children had multifocal interictal EEG. Patients older than 10 years had more frequently MTS (78.6%) and focal temporal interictal EEG abnormalities. Post-surgical seizure outcome showed that 88.5% of patients were in Engel classes I and II. CONCLUSIONS: Adolescents with TLE had clinical features, electrographic findings, and seizure outcome similar to those observed in adult patients. However, younger children up to 5 years of age had distinct ictal semiology and different etiological, electrophysiological and outcome profiles, clearly suggesting that they behave as a special subgroup within the TLE.

Adolescent↗
PubMed2004

Temporal regulation of cerebellar EGL migration through a switch in cellular responsiveness to the meninges.

We have studied the temporal and spatial control of cell migration from the external germinal layer (EGL) in the mammalian cerebellum as a model for cortical migration. Our results have demonstrated that embryonic EGL cells do not migrate into internal layers because they respond to a diffusible attractant in the meninges, the nonneural tissues covering the nervous system, and to a repellent in the neuroepithelium. Two developmental changes are important for postnatal EGL migration: the disappearance of the repellent in the inner layers and a switch in cellular responsiveness of EGL cells so that the postnatal EGL cells respond to the repellent, but not the attractant in the meninges. Besides revealing the signaling role of meninges in cortical development, our study suggests that an active mechanism is required to prevent cell migration, and that mechanisms of cell migration should be studied even in the absence of apparent changes in cell positions. We propose a model for the developmental control of neuronal migration in the cerebellar cortex.

Animals↗
PubMed2005

Periventricular heterotopia.

Periventricular heterotopia (PH) is clinically diagnosed on the basis of the radiographic characteristics of heterotopic nodules composed of disorganized neurons along the lateral ventricles of the brain. Epilepsy is the main presenting symptom of patients with PH. Behaviorally, patients generally are of normal intelligence, although there have been associated findings of learning disabilities, namely, dyslexia. Two genes responsible for PH have been identified: FilaminA, which encodes for the protein filamin A, and ARFGEF2, which encodes for the vesical transport-regulating protein ARFGEF2. The much more common X-linked dominant form of this disorder is due to filamin A, affects females, and is typically lethal in males. A much rarer autosomal recessive form due to ARFGEF2 mutations leads to microcephaly and developmental delay in addition to PH. Cell motility, adhesion defects, and weakening along the neuroepithelial lining may result from defects in these genes during cortical development and contribute to PH, but the mechanisms are not clear yet. Treatment of PH is largely symptomatic, following basic principles for epilepsy management and genetic counseling.

Animals↗
PubMed2006

Epileptogenesis in pediatric cortical dysplasia: the dysmature cerebral developmental hypothesis.

Cortical dysplasia (CD) is the most frequent pathology found in pediatric epilepsy surgery patients with a nearly 80% incidence in children younger than 3 years of age. Younger cases are more likely to have multilobar and severe forms of CD compared with older patients with focal and mild CD. Using clinico-pathologic techniques, we have initiated studies that unravel the timing of CD pathogenesis that in turn suggest mechanisms of epileptogenesis. Morphological comparisons provided the first clue when we observed that cytomegalic neurons have similarities with human subplate cells, and balloon cells have features analogous to radial glia. This suggested that failure of prenatal cell degeneration before birth could explain the presence of postnatal dysmorphic cells in CD tissue. Neuronal density and MRI volumes indicate that there were more neurons than expected in CD tissue, and they were probably produced in later neurogenesis cell cycles. Together these findings imply that there is partial failure in later phases of cortical development that might explain the distinctive histopathology of CD. If correct, epileptogenesis should be the consequence of incomplete cellular maturation in CD tissue. In vitro electrophysiological findings are consistent with this notion. They show that balloon cells have glial features, cytomegalic neurons and recently discovered cytomegalic interneurons reveal atypical hyperexcitable intrinsic membrane properties, there are more GABA than glutamate spontaneous synaptic inputs onto neurons, and in a subset of cells NMDA and GABA(A) receptor-mediated responses and subunit expression are similar to those of immature neurons. Our studies support the hypothesis that there are retained prenatal cells and neurons with immature cellular and synaptic properties in pediatric CD tissue. We propose that local interactions of dysmature cells with normal postnatal neurons produce seizures. This hypothesis will drive future studies aimed at elucidating mechanisms of epileptogenesis in pediatric CD tissue.

Cerebral Cortex↗