Disturbance Of Neuronal Migration Research Articles

Lymphocytic choriomeningitis virus injures the developing brain: effects and mechanisms.

Lymphocytic choriomeningitis virus (LCMV) is a prevalent pathogen, whose natural host and reservoir is the wild mouse. Humans can be infected when they contact the secretions of mice. Most infections of postnatal humans result in mild illness. However, the consequences can be severe when the infection occurs during pregnancy, as the virus crosses the placenta to infect the fetus. LCMV infection of the human fetus can lead to severe neuropathologic effects, including microencephaly, hydrocephalus, focal destructive lesions, and cerebellar hypoplasia. Outcomes among children with congenital LCMV are variable, but most are permanently and severely disabled. The neonatal rat inoculated with LCMV models human prenatal infection. The rat model has demonstrated that effects of LCMV depend on host age at the time of infection. Some effects, including encephalomalacia and neuronal migration disturbances, are immune-mediated and depend on the actions of T-lymphocytes. Other effects, including cerebellar hypoplasia, are virus-mediated and do not depend on T-lymphocytes. Cerebellar neuronal migration disturbances are caused by immune-mediated corruption of Bergmann glia structure. The rat pup inoculated with LCMV is a superb animal model for human congenital infection. All neuropathologic effects observed in human congenital LCMV infection can be recapitulated in the rat model. IMPACT: Lymphocytic choriomeningitis virus (LCMV) is a prevalent human pathogen that can cause serious neurologic birth defects when the infection occurs during pregnancy. The effects of the virus on the developing brain depend strongly on the age of the host at the time of infection. Some of the pathologic effects of LCMV are immune-mediated and are driven by T-lymphocytes, while other pathologic effects are due to the virus itself.

OTHR-19. Disordered cell migration in the cerebral cortex caused by Lin28A overexpression and Wnt pathway activation in neural precursor cells

Abstract LIN28A overexpression and mutations of the Wnt pathway gene CTNNB1 have been described in rare malignant brain tumors of early childhood. In order to investigate the interplay of the oncogenic proteins Lin28A and Ctnnb1 during embryonal brain development, we overexpressed these components in neural progenitor cells in vivo. The sole overexpression of either Lin28A, stabilized Ctnnb1 (Ctnnb1Δex3) or the combination of both in hGFAP-positive forebrain precursor cells did not lead to brain tumor formation but resulted in distinct phenotypes in the cerebral cortex during embryonal development. The hGFAP-cre::IsI-Lin28A (GL) mouse model showed transiently increased proliferation in the cerebral ventricular zone and proper isocortical layering. hGFAP-cre::Ctnnb1Δex3fl/+ (GB) and hGFAP-cre::Ctnnb1Δex3fl/+::IsI-Lin28A (GBL) mice developed a hydrocephalus and showed disturbed cortical layering. GB mice displayed cerebral hypoplasia with a thinned cortex, while the GBL cortices showed variable thickness. Immunostainings with the pial marker Laminin and dendritic marker Map2c revealed a porous pia mater and aggregations of neurons above the pial border in the GBL model at embryonal day 14 (E14.5). At later embryonal stage (E18.5), the GBL model showed also large blood vessels located in deeper cortical layers. Proteome analyses of GB and GBL cortices revealed decreased abundance of the Lissencephaly associated component Reelin-receptor Lrp8 compared to hGFAP-cre control mice. Additionally, we found 92 proteins, which were altered specifically in the GBL mouse model. These results indicate that the co-expression of Lin28A and Ctnnb1Δex3 in neural precursor cells does not lead to brain tumor formation but results in neuronal migration disturbances with ectopic neurons in the subarachnoid area. Whereas the GB phenotype is reminiscent of human lissencephaly type I, GBL brain morphology showed similarities to neuronal overmigration observed in the migration disorder of human Cobblestone (Type II) Lissencephaly.

A Peptide Link Between Human Cytomegalovirus Infection, Neuronal Migration, and Psychosis.

Alongside biological, psychological, and social risk factors, psychotic syndromes may be related to disturbances of neuronal migration. This highly complex process characterizes the developing brain of the fetus, the early postnatal brain, and the adult brain, as reflected by changes within the subventricular zone and the dentate gyrus of the hippocampus, where neurogenesis persists throughout life. Psychosis also appears to be linked to human cytomegalovirus (HCMV) infection. However, little is known about the connection between psychosis, HCMV infection, and disruption of neuronal migration. The present study addresses the hypothesis that HCMV infection may lead to mental disorders through mechanisms of autoimmune cross-reactivity. Searching for common peptides that underlie immune cross-reactions, the analyses focus on HCMV and human proteins involved in neuronal migration. Results demonstrate a large overlap of viral peptides with human proteins associated with neuronal migration, such as ventral anterior homeobox 1 and cell adhesion molecule 1 implicated in GABAergic and glutamatergic neurotransmission. The present findings support the possibility of immune cross-reactivity between HCMV and human proteins that—when altered, mutated, or improperly functioning—may disrupt normal neuronal migration. In addition, these findings are consistent with a molecular and mechanistic framework for pathological sequences of events, beginning with HCMV infection, followed by immune activation, cross-reactivity, and neuronal protein variations that may ultimately contribute to the emergence of mental disorders, including psychosis.

Disorders Caused by Genetic Mosaicism.

Genetic mosaics arise through new mutations occurring after fertiliza- tion (i.e., postzygotic mutations). Mosaics have been described in recent years as the cause of many different disorders; many of these are neurocutaneous diseases and syndromal developmental disorders, each with a characteristic phenotype. In some of these disorders, there is a genetic predisposition to the development of tumors. This article is intended as an overview of selected mosaic diseases. This review is based on publications retrieved by a selective search in PubMed, with particular attention to recent articles in high-ranking journals dealing with asymmetric growth disturbances, focal brain malformations, mosaic diseases due to dysregulation of the RAS/RAF signaling pathway (mosaic RASopathies), and vascular malformations. The identification of postzygotic mutations has led to the reclassification of traditional disease entities and to a better understanding of their pathogenesis. Diagnosis is aided by modern next-generation sequencing (NGS) techniques that allow the detection even of low-grade mosaics. Many mosaic mutations are not detectable in blood, but only in the affected tissue, e.g., the skin. Genetic mosaic diseases often manifest themselves in the skin and brain, and by facial dysmorphism, asymmetrical growth disturbances, and vascular malformations. The possibility of a mosaic disease should be kept in mind in the diag- nostic evaluation of patients with asymmetrical growth disturbances, focal neuronal migration disturbances, vascular malformations, and linear skin abnormalities. The demonstration of a postzygotic mutation often affords relief to the parents of an affected child, since this means that there is no increased risk for recurrence of the same disorder in future children. Correct classification is important, as molecular available for certain mosaic diseases, e.g., PIK3CA-related overgrowth spectrum (PROS) disorder.

Congenital Zika virus infection: a neuropathological review.

A relationship between Zika virus (ZikV) infection in pregnancy and the occurrence of microcephaly was established during the Zika outbreak in Brazil (2015-2016). Neuropathological findings in congenital Zika syndrome helped to understand its pathogenetic mechanisms. The most relevant postmortem findings in the central nervous system (CNS) of fetuses and neonates infected with ZikV early in gestation are microcephaly with ex-vacuo ventriculomegaly and large head circumference associated with obstructive hydrocephalus due to severe midbrain and aqueduct distortion. Babies with severe brain lesions are born with arthrogryposis. Histologically, there is extensive destruction of the hemispheric parenchyma, calcifications, various disturbances of neuronal migration, reactive gliosis, microglial hyperplasia and occasional perivascular cuffs of lymphocytes, also in the meninges. Hypoplastic lesions secondary to the lack of descending nerve fibers include small basis pontis, pyramids and spinal corticospinal tracts. Cerebellar hypoplasia is also common. Severe nerve motor nerve cell loss is observed in the anterior horn of the spinal cord. A spectrum of neuropathological changes, from severe microcephaly to obstructive hydrocephalus was observed. The severity of the lesions is directly related to the gestational age, the most severe occurring when the mother is infected in the first trimester. Infection of progenitor cells at the germinal matrix was demonstrated. The lack of spinal motor neurons is responsible for fetal acynesia and consequent arthrogryposis.

T-Cells Underlie Some but Not All of the Cerebellar Pathology in a Neonatal Rat Model of Congenital Lymphocytic Choriomeningitis Virus Infection.

Lymphocytic choriomeningitis virus (LCMV) infection during pregnancy injures the human fetal brain. Neonatal rats inoculated with LCMV are an excellent model of congenital LCMV infection because they develop cerebellar injuries similar to those in humans. To evaluate the role of T-lymphocytes in LCMV-induced cerebellar pathology, congenitally athymic rats, deficient in T-lymphocytes were compared with euthymic rats. Peak viral titers and cellular targets of infection were similar, but viral clearance from astrocytes was impaired in the athymic rats. Cytokines and chemokines rose to higher levels and for a greater duration in the euthymic rats than in their athymic counterparts. The euthymic rats developed an intense lymphocytic infiltration, accompanied by destructive lesions of the cerebellum and a neuronal migration defect because of T-cell-mediated alteration of Bergmann glia. These pathologic changes were absent in the athymic rats but were restored by adoptive transfer of lymphocytes. Athymic rats were not free of pathologic effects, however, as the virus induced cerebellar hypoplasia. Thus, T-lymphocytes play key roles in LCMV clearance, cytokine/chemokine responses, and pathogenesis of destructive lesions and neuronal migration disturbances but not all pathology is T-lymphocyte-dependent. Cerebellar hypoplasia from LCMV occurs even in the absence of T-lymphocytes and is likely due to the viral infection itself.

A Novel c-Jun N-terminal Kinase (JNK) Signaling Complex Involved in Neuronal Migration during Brain Development

Disturbance of neuronal migration may cause various neurological disorders. Both the transforming growth factor-β (TGF-β) signaling and microcephaly-associated protein WDR62 are important for neuronal migration during brain development; however, the underlying molecular mechanisms involved remain unclear. We show here that knock-out or knockdown of Tak1 (TGFβ-activated kinase 1) and Jnk2 (c-Jun N-terminal kinase 2) perturbs neuronal migration during cortical development and that the migration defects incurred by knock-out and/or knockdown of Tβr2 (type II TGF-β receptor) or Tak1 can be partially rescued by expression of TAK1 and JNK2, respectively. Furthermore, TAK1 forms a protein complex with RAC1 and two scaffold proteins of the JNK pathway, the microcephaly-associated protein WDR62 and the RAC1-interacting protein POSH (plenty of Src homology). Components of the complex coordinate with each other in the regulation of TAK1 as well as JNK activities. We suggest that unique JNK protein complexes are involved in the diversified biological and pathological functions during brain development and pathogenesis of diseases.

Sevoflurane induces short‐term changes in proteins in the cerebral cortices of developing rats

Exposure to intravenous or inhaled anesthetic agents has potential deleterious effects on the developing brain. However, the mechanisms are not clear. Herein, we investigated protein expression changes in neonatal rat brains after exposure to sevoflurane, an inhalational anesthetic commonly used for pediatric patients. Seven-day-old rats were treated with 1.8% sevoflurane or 30% oxygen for 4 h. Cerebral cortices were obtained at 3 h and 3 days after sevoflurane exposure for cell apoptosis detection, proteomic analysis and Western blotting. There was a significant increase of cleaved caspase 3 at 3 h after sevoflurane exposure. Six proteins had 1.5-fold or higher changes in expression at 3 h after sevoflurane anesthesia as compared with sham-treated pups. No proteins had this degree of change at 3 days after sevoflurane anesthesia. Proteins whose expression was downregulated included collapsin response mediator protein-1 (CRMP-1), truncated CRMP-4, beta-tubulin IIc and neuron-specific class III beta-tubulin. These four proteins are important for neuronal migration and differentiation. Adenosine triphosphate synthase beta subunit, a protein associated with energy metabolism, was also downregulated. Guanine nucleotide-binding protein beta 1, a signaling protein, was upregulated. Sevoflurane also increased phosphorylation of glycogen synthase kinase 3β (GSK-3β) at 3 h after anesthesia and inhibited the normal increase of GSK-3β at 72 h after anesthesia. These findings suggest that sevoflurane may cause short-term neuronal apoptosis and disturbances of neuronal migration, differentiation and energy metabolism in neonatal rat brains, and that these disturbances may contribute to its neurodegenerative effects.

Polymicrogyria and Congenital Parvovirus B19 Infection

Fetal parvovirus B19 infection causes anemia, hydrops, and pregnancy loss but is generally not considered teratogenic. Nevertheless, disturbances of neuronal migration have been described with congenital parvovirus infection. We evaluated a term infant with congenital parvovirus disease and polymicrogyria. We compared this case with four other reports of central nervous system disease after birth to parvovirus-infected mothers. After an extensive diagnostic evaluation, this infant was found to have congenital parvovirus disease with severe anemia and nonimmune hydrops as well as extensive polymicrogyria. Although rare, this report and literature review suggest that parvovirus B19 has the potential to disrupt normal neurodevelopment. We suggest that infants with severe congenital parvovirus infection have close developmental surveillance and if symptomatic undergo neuroimaging to assess for disorders of neuromigration.

Does subtle disturbance of neuronal migration contribute to schizophrenia and other neurodevelopmental disorders? Potential genetic mechanisms with possible treatment implications

Pathways associated with genes that regulate neuronal migration by influencing the function of microtubules in the developing fetal brain may be interfered with as part of the "first-hit" of schizophrenia. In the fully-developed brain, these same pathways that impact microtubule function mediate at least some aspects of experience-dependent plasticity, which may also be impaired in schizophrenia. Whereas severe presentations of "lissencephaly" are associated with mutations and deletions of DISC1, LIS1 and the gene for the very low-density lipoprotein receptor, genetic variations of these loci are good candidate schizophrenia genes. Importantly, in the fully-developed brain, there is a possibility that at least some of the consequences of these disturbed genetic pathways that adversely affect microtubule function may be "bypassed" or mitigated.

Extracellular Matrix-Glial Abnormalities in the Amygdala and Entorhinal Cortex of Subjects Diagnosed With Schizophrenia

Chondroitin sulfate proteoglycans (CSPGs), a main component of the brain extracellular matrix, regulate developmental and adult neural functions that are highly relevant to the pathogenesis of schizophrenia. Such functions, together with marked expression of CSPGs in astrocytes within the normal human amygdala and evidence of a disruption of astrocytic functions in this disease, point to involvement of CSPG-glial interactions in schizophrenia. Chondroitin sulfate proteoglycan-related abnormalities involve glial cells and extracellular matrix pericellular aggregates (perineuronal nets) in the amygdala and entorhinal cortex of subjects with schizophrenia. Postmortem case-control study. The Translational Neuroscience Laboratory at McLean Hospital, Harvard Medical School. Specimens were obtained from the Harvard Brain Tissue Resource Center at McLean Hospital. Two separate cohorts of healthy control (n = 15; n = 10) and schizophrenic (n = 11; n = 10) subjects and a cohort of subjects with bipolar disorder (n = 11). Quantitative, immunocytological, and histological postmortem investigations. Numerical densities of CSPG-positive glial cells and perineuronal nets, glial fibrillary acidic protein-positive astrocytes, and total numbers of parvalbumin-positive neurons in the deep amygdala nuclei and entorhinal cortex. In schizophrenia, massive increases in CSPG-positive glial cells were detected in the deep amygdala nuclei (419%-1162%) and entorhinal cortex (layer II; 480%-1560%). Perineuronal nets were reduced in the lateral nucleus of the amygdala and lateral entorhinal cortex (layer II). Numerical densities of glial fibrillary acidic protein-positive glial cells and total numbers of parvalbumin-positive neurons were unaltered. Changes in CSPG-positive elements were negligible in subjects with bipolar disorder. Marked changes in functionally relevant molecules in schizophrenia point to a pivotal role for extracellular matrix-glial interactions in the pathogenesis of this disease. Disruption of these interactions, unsuspected thus far, may represent a unifying factor contributing to disturbances of neuronal migration, synaptic connectivity, and GABAergic, glutamatergic, and dopaminergic neurotransmission in schizophrenia. The lack of CSPG abnormalities in bipolar disorder points to a distinctive aspect of the pathophysiology of schizophrenia in key medial temporal lobe regions.

Clinical and genetic analysis of a Korean patient with Fukuyama congenital muscular dystrophy

Fukuyama congenital muscular dystrophy (FCMD) is an autosomal recessive disorder with early onset severe muscular dystrophy and neuronal migration disturbances. Although FCMD is the second most common muscular dystrophy in Japan, there has been no report of FCMD in Korea. Recently, we found a 10-year-old Korean boy with characteristic clinical features of FCMD. A PCR-based diagnostic method to detect the 3-kb retrotransposal insertion in the 3′ non-coding region of the fukutin ( FKTN) gene revealed that the patient was homozygous for the insertion mutation and his parents were heterozygous carriers of the same mutation. To the best of our knowledge, this is the first report of a clinically and genetically confirmed Korean patient with FCMD and the first non-Japanese patient carrying homozygous founder insertion mutation.

The effect of acute and chronic exposure to ethanol on the developing encephalon: a review

OBJECTIVES: to compare the acute and chronic effects of ethanol on the neural development, by analysis of the ontogenetic neural structure of mammals. METHODS: searches were performed in the following electronic databases: MEDLINE, SciElo, PubMed, LILACS, CAPES periodical, and the Open Journal System. The descriptors used were: "chronic ethanol toxicity", "chronic alcohol toxicity", "acute ethanol toxicity", "acute alcohol", "neural ontogenic development", "neuronal migration disturbances", "neural structure". The following inclusion criteria were used: articles published between 2003 and 2007, some classic articles in the field and an important neuropsychology textbook. RESULTS: the analysis of papers revealed that, although several studies of the chronic effects of ethanol exposure on the mammalian nervous system have been conducted, only a few have investigated the acute effects of ethanol on specific days of gestation, and these studies have revealed important disorders relating to the cerebral tissue. CONCLUSIONS: it should be recommended that women refrain from the consumption of ethanol during gestational phase to protect the fetus' health. Furthermore, the acute consumption of ethanol by women nearing the eighth or ninth week of gestation has been shown to be potentially harmful to the nervous tissue of the fetus.

Congenital Viral Infections of the Brain: Lessons Learned from Lymphocytic Choriomeningitis Virus in the Neonatal Rat

The fetal brain is highly vulnerable to teratogens, including many infectious agents. As a consequence of prenatal infection, many children suffer severe and permanent brain injury and dysfunction. Because most animal models of congenital brain infection do not strongly mirror human disease, the models are highly limited in their abilities to shed light on the pathogenesis of these diseases. The animal model for congenital lymphocytic choriomeningitis virus (LCMV) infection, however, does not suffer from this limitation. LCMV is a well-known human pathogen. When the infection occurs during pregnancy, the virus can infect the fetus, and the developing brain is particularly vulnerable. Children with congenital LCMV infection often have substantial neurological deficits. The neonatal rat inoculated with LCMV is a superb model system of human congenital LCMV infection. Virtually all of the neuropathologic changes observed in humans congenitally infected with LCMV, including microencephaly, encephalomalacia, chorioretinitis, porencephalic cysts, neuronal migration disturbances, periventricular infection, and cerebellar hypoplasia, are reproduced in the rat model. Within the developing rat brain, LCMV selectively targets mitotically active neuronal precursors. Thus, the targets of infection and sites of pathology depend on host age at the time of infection. The rat model has further shown that the pathogenic changes induced by LCMV infection are both virus-mediated and immune-mediated. Furthermore, different brain regions simultaneously infected with LCMV can undergo widely different pathologic changes, reflecting different brain region–virus–immune system interactions. Because the neonatal rat inoculated with LCMV so faithfully reproduces the diverse neuropathology observed in the human counterpart, the rat model system is a highly valuable tool for the study of congenital LCMV infection and of all prenatal brain infections In addition, because LCMV induces delayed-onset neuronal loss after the virus has been cleared, the neonatal rat infected with LCMV may be an excellent model system to study neurodegenerative or psychiatric diseases whose etiologies are hypothesized to be virus-induced, such as autism, schizophrenia, and temporal lobe epilepsy.

Prenatal diagnosis of Fukuyama congenital muscular dystrophy

Fukuyama congenital muscular dystrophy (FCMD) is characterized by infantile hypotonia, symmetrical generalized muscle weakness, and neuronal migration disturbances that result in changes consistent with cobblestone lissencephaly with cerebral and cerebellar cortical dysplasia. FCMD is recognized as an autosomal recessive genetic defect. Genetic counselling is recommended for parents at risk of having a child with FCMD. Given the high risk and overwhelming prospect of having another child with this incurable devastating condition leads many couples to consider prenatal diagnosis. In Japanese families, haplotype analysis using microsatellite markers is available. In non-Japanese families, DNA sequence analysis is available. Both disease-causing alleles of an affected family member must be identified before prenatal testing can be performed.

210 Congenital Cytomegalovirus (CMV) Infection and Agenesis of Corpus Callosum

Background: Congenital CMV infection is associated with a wide spectrum of neuropathology, ranging from inflammation to destruction and malformation. Disturbances of neuronal migration with polymicrogyria involving cerebellar and cerebral cortex, lissencephaly, pachygyria, and schizencephaly have been observed. We present a newborn with congenital CMV infection exhibiting agenesis of the corpus callosum. Case presentation: Prenatal ultrasound at 32 wks gestational age showed corpus callosum agenesis in the fetus. Subsequent serologic tests detected primary CMV infection in the pregnant woman. The 2530g-girl was delivered at 39 wks. Besides a dysmorphic face with hypertelorism, no other anomalies were noted. Results: Serology confirmed CMV infection, but CMV early antigen was negative and PCR for DNA positive in only one of several urine specimens indicating that infection was no longer active. Utrasound of the brain showed agenesis of the corpus callosum and hypoplasia of the vermis. MR additionally detected pachygyria. There was no CMV-retinitis and auditory brain stem responses were normal. Clinically, the girl showed feeding difficulties. Conclusion: This is only the second report of corpus callosum agenesis in a newborn infant with congenital CMV infection. As the corpus callosum develops at approximately 10 weeks of gestation, the primary infection probably occurred in the first trimester, disturbing differentiation and migration of neuronal precursor cells.

Relation between schizophrenia and Alzheimer's disease: the reelin signaling pathway

AbstractReelin is an extracellular matrix protein that is related to neuronal migration at the embryonic stage. Recently, the relation between reelin and schizophrenia and Alzheimer's disease was established. The authors summarize these two disorders from the perspective of the reelin signaling pathway. Reelin and reelin mRNA are reduced in the schizophrenic brain and Cajal–Retzius cells, which secrete reelin, are reduced in the Alzheimer's brain. From the reelin signaling pathway, a reduction or deficit of reelin leads to the disturbance of neuronal migration and abnormal phosphorylation of tau protein, and may be a pathologic factor involved in the etiology of schizophrenia and Alzheimer's disease. Reelin may be the common feature of both schizophrenia and Alzheimer's disease.

Peroxisome biogenesis disorders: The role of peroxisomes and metabolic dysfunction in developing brain

Peroxisome biogenesis disorders, of which Zellweger syndrome is the most severe, result in severe neurological dysfunction associated with abnormal CNS neuronal migrations due to the lack of functional peroxisomes. The PEX2-/- mouse model for Zellweger syndrome has enabled us to evaluate the role of peroxisomes in the development and functioning of the nervous system. These studies have shown that, in addition to disturbances in neuronal migration in developing cerebral cortex and cerebellum, defects in neuronal differentiation, proliferation and survival may also contribute to the CNS malformations. However, owing to the multiorgan dysfunction in peroxisomal disorders, it has been difficult to clearly define an intrinsic role for the peroxisome in brain cells. The use of several in vitro cell culture assays to evaluate the migration and differentiation of cerebellar neurons demonstrates a persistence of defects in peroxisome-deficient neurons. The absence of potential systemically derived, extrinsic factors in these in vitro systems indicates that CNS intrinsic defects contribute to the pathogenesis of disease in these disorders. However, bile acid treatment also increases the survival and growth of PEX2-/- mice and improves some aspects of cerebellar development, indicating that extrinsic factors also affect the developing peroxisome-deficient brain. Therefore, the final phenotype of nervous system dysfunction in peroxisomal disorders will reflect a combination of both CNS intrinsic and extrinsic factors.

Grey and white matter flumazenil binding in neocortical epilepsy with normal MRI. A PET study of 44 patients.

In 20-30% of potential surgical candidates with refractory focal epilepsy, standard MRI does not identify the cause. gamma-Aminobutyric acid (GABA) is the principal inhibitory neurotransmitter in the brain. [(11)C]Flumazenil (FMZ) PET images most subtypes of GABA(A) receptors, present on most neurons. We investigated [(11)C]FMZ binding in grey and white matter in 16 normal controls and in 44 patients with refractory neocortical focal epilepsy and normal optimal MRI. Fourteen patients had unilateral frontal lobe epilepsy, five occipital lobe epilepsy (OLE), six parietal lobe epilepsy (PLE) and 19 neocortical epilepsy that was not clearly lobar. Parametric images of FMZ volume of distribution (FMZ-V(d)) were computed. Statistical parametric mapping (SPM99) with explicit masking, including the white matter, was used to analyse individual patients and groups. Thirty-three of the 44 patients showed focal abnormal FMZ-V(d); increases in 16, decreases in eight, and both increases and decreases in nine. In seven patients, the increases in FMZ binding were periventricular, in locations normally seen in periventricular nodular heterotopia on MRI. There were frontal and parietal increases in FMZ binding in grey and white matter in the PLE group and decreases in the cingulate gyrus in the OLE group. FMZ binding increases, particularly periventricular increases, were a prominent feature of MRI-negative focal epilepsies and may represent neuronal migration disturbances.

Mechanisms and disturbances of neuronal migration.

Neuronal migration appears as a complex ontogenic step occurring early during embryonic and fetal development. Control of neuronal migration involves different cell populations including Cajal-Retzius neurons, subplate neurons, neuronal precursors or radial glia. The integrity of multiple molecular mechanisms, such as cell cycle control, cell-cell adhesion, interaction with extracellular matrix protein, neurotransmitter release, growth factor availability, platelet-activating factor degradation or transduction pathways seems to be critical for normal neuronal migration. The complexity and the multiplicity of these mechanisms probably explain the clinical, radiologic and genetic heterogeneity of human disorders of neuronal migration. The present review will be focused on mechanisms and disturbances of migration of neurons destined to the neocortex. New insights gained from the analysis of animal models as well as from the study of human diseases will be included.