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Alfonso Represa - One of the best experts on this subject based on the ideXlab platform.
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Normotopic cortex is the major contributor to epilepsy in experimental double cortex.
Annals of Neurology, 2014Co-Authors: Ludovic Franck Petit, Alfonso Represa, Emmanuelle Buhler, Marion Jalabert, Arnaud Malvache, Angélique Peret, Yoann Chauvin, Françoise Watrin, Jeanbernard ManentAbstract:OBJECTIVE: Subcortical band Heterotopia (SBH) is a cortical malformation formed when neocortical neurons prematurely stop their migration in the white matter, forming a heterotopic band below the normotopic cortex, and is generally associated with intractable epilepsy. Although it is clear that the band Heterotopia and the overlying cortex both contribute to creating an abnormal circuit prone to generate epileptic discharges, it is less understood which part of this circuitry is the most critical. Here, we sought to identify the origin of epileptiform activity in a targeted genetic model of SBH in rats. METHODS: Rats with SBH (Dcx-KD rats) were generated by knocking down the Dcx gene using shRNA vectors transfected into neocortical progenitors of rat embryos. Origin, spatial extent, and laminar profile of bicuculline-induced interictal-like activity on neocortical slices were analyzed by using extracellular recordings from 60-channel microelectrode arrays. Susceptibility to pentylenetetrazole-induced seizures was assessed by electrocorticography in head-restrained nonanesthetized rats. RESULTS: We show that the band Heterotopia does not constitute a primary origin for interictal-like epileptiform activity in vitro and is dispensable for generating induced seizures in vivo. Furthermore, we report that most interictal-like discharges originating in the overlying cortex secondarily propagate to the band Heterotopia. Importantly, we found that in vivo suppression of neuronal excitability in SBH does not alter the higher propensity of Dcx-KD rats to display seizures. INTERPRETATION: These results suggest a major role of the normotopic cortex over the band Heterotopia in generating interictal epileptiform activity and seizures in brains with SBH. Ann Neurol 2014.
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spontaneous epileptic manifestations in a dcx knockdown model of human double cortex
Cerebral Cortex, 2010Co-Authors: Damien Lapray, Isabel Jorquera, Irina Y Popova, Jennifer Kindler, Helene Becq, Jeanbernard Manent, Heiko J Luhmann, Alfonso RepresaAbstract:Previous reports indicate that in utero knockdown of doublecortin (DCX) results in the genesis of a subcortical Heterotopia reminiscent of the doublecortex observed in female patients with DCX mutations. It has also been shown that these rats display an increased susceptibility to convulsant agents and increased cortical neurons excitability; but it is presently unknown whether they display spontaneous seizures. Furthermore, the link between the size of Heterotopia and the clinical manifestation remained to be elucidated. Using video--electrocorticogram recordings, we now report that DCX knockdown induces frequent spontaneous seizures commonly associated with myoclonic jerks in adult rats. Surprisingly, epilepsy occurred even in rats with very small subcortical Heterotopias, as revealed by histological analysis of recorded animals. Moreover, the severity of the epileptic manifestations was positively correlated with both the size of the subcortical Heterotopia and the age of recorded animals; thus, epileptic features were not detected in immature affected rats. In conclusion, our data demonstrate for the first time that subtle alterations can yield epilepsy and reveal a strong correlation between thicknesses of subcortical Heterotopia, age of affected individuals and clinical impairment.
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Neuronal migration disorders: heterotopic neocortical neurons in CA1 provide a bridge between the hippocampus and the neocortex.
Proceedings of the National Academy of Sciences of the United States of America, 1998Co-Authors: Nicolas Chevassus-au-louis, Yezekiel Ben-ari, Alfonso Represa, Patrice Congar, Jean-luc GaïarsaAbstract:Neuronal migration disorders have been involved in various pathologies, including epilepsy, but the properties of the neural networks underlying disorders have not been determined. In the present study, patch clamp recordings were made from intrahippocampal heterotopic as well as from neocortical and hippocampal neurons from brain slices of rats with prenatally methylazoxymethanol-induced cortical malformation. We report that heterotopic neurons have morphometrical parameters and cellular properties of neocortical supragranular neurons and are integrated in both neocortical and hippocampal networks. Thus, stimulation of the white matter induces both antidromic and orthodromic response in heterotopic and neocortical neurons. Stimulation of hippocampal afferents evokes a monosynaptic response in the majority of heterotopic neurons and a polysynaptic all-or-none epileptiform burst in the presence of bicuculline to block gamma-aminobutyric acid type A inhibition. Furthermore, hippocampal paroxysmal activity generated by bath application of bicuculline can spread directly to the neocortex via the Heterotopia in methylazoxymethanol-treated but not in naive rats. We conclude that Heterotopias form a functional bridge between the limbic system and the neocortex, providing a substrate for pathological conditions.
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Neocortex in the hippocampus: an anatomical and functional study of CA1 Heterotopias after prenatal treatment with methylazoxymethanol in rats.
Journal of Comparative Neurology, 1998Co-Authors: Nicolas Chevassus-au-louis, Amina Rafiki, Isabel Jorquera, Yezekiel Ben-ari, Alfonso RepresaAbstract:Migration disorders cause neurons to differentiate in an abnormal heterotopic position. Although significant insights have been gained into the etiology of these disorders, very little is known about the anatomy of Heterotopias. We have studied heterotopic masses arising in the hippocampal CA1 region after prenatal treatment with methylazoxymethanol (MAM) in rats. Heterotopic cells were phenotypically similar to neocortical supragranular neurons and exhibited the same temporal profile of migration and neurogenesis. However, they did not express molecules characteristic of CA1 neurons such as the limbic-associated membrane protein. Horseradish peroxidase injections in Heterotopia demonstrated labeled fibers not only in the neocortex and white matter but also in the CA1 stratum radiatum and stratum lacunosum. To study the pathophysiological consequences of this connectivity, we compared the effects of neocortical and limbic seizures on the expression of Fos protein and on cell death in MAM animals. After metrazol-induced seizures, Fos-positive cells were present in CA1 Heterotopias, the only hippocampal region to be activated with the neocortex. By contrast, kainic acid-induced seizures caused a prominent delayed cell death in limbic regions and in CA1 Heterotopias. Together, these results suggest that neocortical Heterotopias in the CA1 region are integrated in both the hippocampal and neocortical circuitry.
R Leblanc - One of the best experts on this subject based on the ideXlab platform.
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periventricular nodular Heterotopia and intractable temporal lobe epilepsy poor outcome after temporal lobe resection
Annals of Neurology, 1997Co-Authors: Francois Dubeau, F Andermann, D R Fish, Craig Watson, G D Cascino, Samuel F Berkovic, N Moran, John S Duncan, Andre Olivier, R LeblancAbstract:We describe 5 women and 5 men with periventricular nodular Heterotopia and electroclinical features suggestive of temporal lobe epilepsy, who were surgically treated for control of medically refractory seizures. Magnetic resonance imaging revealed bilateral periventricular nodular Heterotopia in 7 of the 10 patients. Because of the lack of clear localization, 6 patients were studied with intracranial depth electrode recordings. Seizures were of hippocampal onset (3 patients), regional temporal lobe onset (2 patients), or occipital-temporal onset (1 patient). Anterior temporal lobectomy was performed in 6 patients; selective amygdalohippocampectomy, in 1; and anterior temporal lobectomy plus resection of the heterotopic tissue, in 3. None of the 9 patients followed for more than 12 months postoperatively were seizure free. Two patients were initially seizure free for approximately 18 months, but then seizures recurred. One patient had a major reduction in seizure frequency at a 39-month follow-up after most of the unilateral heterotopic tissue was included in the temporal resection. Temporal resection did not lead to a long-term favorable outcome in this group of patients with periventricular nodular Heterotopia and epileptogenic discharges involving the temporal lobe. This suggests a more widespread disorder with epileptogenic activity possibly originating in or near the heterotopic tissue. The clinical and electrographic features of periventricular nodular Heterotopia pointing to temporal lobe origin are misleading and temporal resection does not result in long-term cessation of seizures.
Nicolas Chevassus-au-louis - One of the best experts on this subject based on the ideXlab platform.
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Neuronal migration disorders: heterotopic neocortical neurons in CA1 provide a bridge between the hippocampus and the neocortex.
Proceedings of the National Academy of Sciences of the United States of America, 1998Co-Authors: Nicolas Chevassus-au-louis, Yezekiel Ben-ari, Alfonso Represa, Patrice Congar, Jean-luc GaïarsaAbstract:Neuronal migration disorders have been involved in various pathologies, including epilepsy, but the properties of the neural networks underlying disorders have not been determined. In the present study, patch clamp recordings were made from intrahippocampal heterotopic as well as from neocortical and hippocampal neurons from brain slices of rats with prenatally methylazoxymethanol-induced cortical malformation. We report that heterotopic neurons have morphometrical parameters and cellular properties of neocortical supragranular neurons and are integrated in both neocortical and hippocampal networks. Thus, stimulation of the white matter induces both antidromic and orthodromic response in heterotopic and neocortical neurons. Stimulation of hippocampal afferents evokes a monosynaptic response in the majority of heterotopic neurons and a polysynaptic all-or-none epileptiform burst in the presence of bicuculline to block gamma-aminobutyric acid type A inhibition. Furthermore, hippocampal paroxysmal activity generated by bath application of bicuculline can spread directly to the neocortex via the Heterotopia in methylazoxymethanol-treated but not in naive rats. We conclude that Heterotopias form a functional bridge between the limbic system and the neocortex, providing a substrate for pathological conditions.
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Neocortex in the hippocampus: an anatomical and functional study of CA1 Heterotopias after prenatal treatment with methylazoxymethanol in rats.
Journal of Comparative Neurology, 1998Co-Authors: Nicolas Chevassus-au-louis, Amina Rafiki, Isabel Jorquera, Yezekiel Ben-ari, Alfonso RepresaAbstract:Migration disorders cause neurons to differentiate in an abnormal heterotopic position. Although significant insights have been gained into the etiology of these disorders, very little is known about the anatomy of Heterotopias. We have studied heterotopic masses arising in the hippocampal CA1 region after prenatal treatment with methylazoxymethanol (MAM) in rats. Heterotopic cells were phenotypically similar to neocortical supragranular neurons and exhibited the same temporal profile of migration and neurogenesis. However, they did not express molecules characteristic of CA1 neurons such as the limbic-associated membrane protein. Horseradish peroxidase injections in Heterotopia demonstrated labeled fibers not only in the neocortex and white matter but also in the CA1 stratum radiatum and stratum lacunosum. To study the pathophysiological consequences of this connectivity, we compared the effects of neocortical and limbic seizures on the expression of Fos protein and on cell death in MAM animals. After metrazol-induced seizures, Fos-positive cells were present in CA1 Heterotopias, the only hippocampal region to be activated with the neocortex. By contrast, kainic acid-induced seizures caused a prominent delayed cell death in limbic regions and in CA1 Heterotopias. Together, these results suggest that neocortical Heterotopias in the CA1 region are integrated in both the hippocampal and neocortical circuitry.
Bernard S Chang - One of the best experts on this subject based on the ideXlab platform.
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abnormal structural and functional brain connectivity in gray matter Heterotopia
Epilepsia, 2012Co-Authors: Joanna A Christodoulou, Linsey M Walker, Stephanie N Del Tufo, Tami Katzir, John D E Gabrieli, Susan Whitfieldgabrieli, Bernard S ChangAbstract:Summary Purpose: Periventricular nodular Heterotopia (PNH) is a malformation of cortical development associated with epilepsy and dyslexia. Evidence suggests that heterotopic gray matter can be functional in brain malformations and that connectivity abnormalities may be important in these disorders. We hypothesized that nodular Heterotopia develop abnormal connections and systematically investigated the structural and functional connectivity of Heterotopia in patients with PNH. Methods: Eleven patients were studied using diffusion tensor tractography and resting-state functional connectivity MRI with bold oxygenation level–dependent (BOLD) imaging. Fiber tracks with a terminus within heterotopic nodules were visualized to determine structural connectivity, and brain regions demonstrating resting-state functional correlations to heterotopic nodules were analyzed. Relationships between these connectivity results and measures of clinical epilepsy and cognitive disability were examined. Key Findings: A majority of Heterotopia (69%) showed structural connectivity to discrete regions of overlying cortex, and almost all (96%) showed functional connectivity to these regions (mean peak correlation coefficient 0.61). Heterotopia also demonstrated connectivity to regions of contralateral cortex, other heterotopic nodules, ipsilateral but nonoverlying cortex, and deep gray matter structures or the cerebellum. Patients with the longest durations of epilepsy had a higher degree of abnormal functional connectivity (p = 0.036). Significance: Most heterotopic nodules in PNH are structurally and functionally connected to overlying cortex, and the strength of abnormal connectivity is higher among patients with the longest duration of epilepsy. Along with prior evidence that cortico-cortical tract defects underlie dyslexia in this disorder, the current findings suggest that altered connectivity is likely a critical substrate for neurologic dysfunction in brain malformations.
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gray matter volumes and cognitive ability in the epileptogenic brain malformation of periventricular nodular Heterotopia
Epilepsy & Behavior, 2009Co-Authors: Linsey M Walker, Tami Katzir, David B Hackney, Margaret Oconnor, Tianming Liu, Kathleen H Corriveau, Mirit Barzillai, Felicia Chu, Bernard S ChangAbstract:Periventricular nodular Heterotopia (PNH) is a brain malformation clinically characterized by the triad of epilepsy, normal intelligence, and dyslexia. We investigated the structure-function relationship between cerebral volumes and cognitive ability in this disorder by studying 12 subjects with PNH and 6 controls using volumetric analysis of high-resolution anatomical MRI and neuropsychological testing. Total cerebral volumes and specific brain compartment volumes (gray matter, white matter, and cerebrospinal fluid) in subjects with PNH were comparable to those in controls. There was a negative correlation between heterotopic gray matter volume and cortical gray matter volume. Cerebral and cortical volumes in PNH did not correlate with Full Scale IQ, unlike in normal individuals. Our findings support the idea that heterotopic nodules contain misplaced neurons that would normally have migrated to the cortex, and suggest that structural correlates of normal cognitive ability may be different in the setting of neuronal migration failure.
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reading impairment in the neuronal migration disorder of periventricular nodular Heterotopia
Neurology, 2005Co-Authors: Bernard S Chang, B Appignani, Adria Bodell, Kira Apse, R S Ravenscroft, Volney L Sheen, M J Doherty, David B Hackney, Margaret Oconnor, Albert M GalaburdaAbstract:Objective: To define the behavioral profile of periventricular nodular Heterotopia (PNH), a malformation of cortical development that is associated with seizures but reportedly normal intelligence, and to correlate the results with anatomic and clinical features of this disorder. Methods: Ten consecutive subjects with PNH, all with epilepsy and at least two periventricular nodules, were studied with structural MRI and neuropsychological testing. Behavioral results were statistically analyzed for correlation with other features of PNH. Results: Eight of 10 subjects had deficits in reading skills despite normal intelligence. Processing speed and executive function were also impaired in some subjects. More marked reading difficulties were seen in subjects with more widely distributed Heterotopia. There was no correlation between reading skills and epilepsy severity or antiepileptic medication use. Conclusion: The neuronal migration disorder of periventricular nodular Heterotopia is associated with an impairment in reading skills despite the presence of normal intelligence. NEUROLOGY 2005;64:799-803 Malformations of cortical development (MCDs) are a common finding in patients with epilepsy and other neurologic conditions. 1 Research into their molecular and genetic basis has advanced our understanding of the mechanisms of cerebral cortical development. 2 However, our knowledge of the clinical consequences of these malformations remains incomplete. The be- havioral characterization of patients with MCDs of- fers an opportunity to assess the impact of anatomic abnormalities on cognitive function. Periventricular nodular Heterotopia (PNH) is an MCD in which nodules of heterotopic gray matter line the lateral ventricles bilaterally 3 ; most com- monly, it is associated with mutations in the FLNA (filamin A) gene. 4 Most patients with PNH have epi- lepsy but are generally said to be of normal intelli- gence. 5,6 Functional neuroimaging studies in PNH have suggested that the overlying cerebral cortex re- tains its usual map of functional localization, 7 de- spite the potential lack of a full complement of neurons due to migration failure. There is also evi- dence that the heterotopic nodules may form white matter connections with each other and with overly- ing cortex 8-10 and even become activated themselves during the performance of certain tasks. 11,12 We sought to study the behavioral characteristics of PNH and relate our findings to measures of sever- ity of the malformation and accompanying seizure disorder.
Renzo Guerrini - One of the best experts on this subject based on the ideXlab platform.
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Nodular Heterotopia is built upon layers
Neurology, 2009Co-Authors: Russell J. Ferland, Renzo GuerriniAbstract:Gray matter Heterotopia, agglomerates of morphologically normal cortical neurons at an abnormal site, is the most common human neuronal migration disorder. Heterotopia can be unilateral or bilateral, subependymal or subcortical, or it can extend from the subependymal region to the subcortex.1 Most individuals with Heterotopia come to medical attention because of epileptic seizures, although the spectrum of clinical presentation is wide.2 A lingering question concerns precisely how impairments in neuronal migration give rise to diverse syndromes. For instance, the most notable feature of lissencephaly, subcortical band Heterotopia (SBH), and nodular Heterotopia (NH) is a failure in the migration of early postmitotic neurons from their site of birth in the ventricular zone to the cortical plate. This migration failure results in the thickened and abnormally laminated cerebral cortex found in lissencephaly, the abnormal band of neurons found beneath the cerebral cortex in SBH, and the neuronal nodules lining the ventricular zone or just beneath a normal-appearing cerebral cortex in NH.3 As yet undetermined is whether other cellular defects occur in these syndromes, in addition to the migration defects. A better understanding of the functional organization of heterotopic nodules could also have practical implications for the planning of surgical treatment for the associated epilepsy. There appears to be no difference in …
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familial periventricular Heterotopia missense and distal truncating mutations of the fln1 gene
Neurology, 2002Co-Authors: F Moro, Romeo Carrozzo, Pierangelo Veggiotti, Gaetano Tortorella, D Toniolo, Anna Volzone, Renzo GuerriniAbstract:Objective: To examine the clinical and MRI associations in bilateral periventricular nodular Heterotopia (BPNH) (MIM # 300049) in two families segregating a missense mutation and a C-terminal deletion of the filamin 1 ( FLN1 ) gene. Background: Classical familial BPNH, an X-linked dominant disorder, has been associated with protein truncations or splicing mutations, which tend to cluster at the N-terminal of the FLN1 protein, causing severe predicted loss of the protein function. The clinical syndrome includes symmetrical contiguous nodular Heterotopia lining the lateral ventricles, epilepsy, mild retardation to normal cognitive level in affected females, and prenatal lethality in hemizygous boys. Methods: Clinical examination, cognitive testing, MRI, mutation analysis (direct sequencing, single-strand conformation polymorphism) in seven patients from two families with BPNH. Results: In Family 1, harboring an A > T change in exon 2 (E82V), heterotopic nodules were few, asymmetric, and noncontiguous. Five boys born from affected females had died unexpectedly early in life. In Family 2, harboring an 8 base pair deletion in exon 47 (7627_7634del TGTGCCCC), heterotopic nodules were thick and contiguous. Affected females in both families showed normal to borderline IQ and epilepsy. Conclusion: Missense mutations and distal truncations consistent with partial loss of FLN1 function cause familial BPNH with the classical clinical phenotype including epilepsy and mild mental retardation, if any. However, missense mutations have milder anatomic consequences in affected females and are possibly compatible with live birth but short survival of boys.
