A large percentage of individuals with intractable epilepsies have an accompanying cortical malformation, the underlying cellular mechanisms of which are poorly understood. It is known however that in an animal model for one such malformation, polymicrogyria, epileptogenesis occurs most easily from an adjacent area termed the paramicrogyral region (PMR). Previous studies implicate SS interneurons as a potential contributor to this pathology, which lead to our hypothesis: in PMR, SS interneurons exert a higher modulatory influence on excitatory pyramidal cells, as compared to the same by SS interneurons within homologous control cortex. Using a freeze-lesion model for polymicrogyria in transgenic mice that selectively express either Channelrhodopsin or Archaerhodopsin optogenetic channels in these cells, we assessed the contribution of SS interneurons as it potentially differs between layer V of PMR and control cortex. These studies provided the following biological examples in support of previous extrapolations that indicate SS over-activation within PMR: (1) SS interneuron mediated evocation of inhibitory events in layer V excitatory neurons is more robust in PMR than in control. Similarly, electrically-evoked inhibitory events in these excitatory neurons trend towards being larger, signifying a larger contribution by interneurons. (2) SS interneuron mediated suppression of electrically-evoked responses trends towards being stronger in PMR; and (3) the selective silencing of SS interneurons might not impart an effect on spontaneous inhibitory postsynaptic events.

Cortical malformations from altered development are common causes of human epilepsy. The cellular mechanisms responsible for the epileptic state of cortex remain unclear and a significant portion of these cases do not respond to treatment. Previous electrophysiological recordings in the Jacobs lab in a rat polymicrogyria model indicated an increased response to group I metabotropic glutamate receptor agonists in the region adjacent to the malformation (PMZ). In addition there was a novel response in low threshold spiking (LTS) interneurons via mGluR5 activation. To determine whether cell specific expression of these receptors was altered in malformed cortex immunohistochemical stains were performed for group I mGluRs along with non-overlapping interneuron subtype specific markers, a neuronal marker and general inhibitory cell marker. There was no altered mGluR5 expression seen in the PMZ. There was an altered expression seen in PMZ mGluR1α labeled cells and cells in other cortical regions.

Epilepsy has been previously attributed to either increased excitation or decreased inhibition. With this closed frame of mind, modern medicine has been unable to develop a permanent treatment against the mechanisms of epilepsy. In order to treat patients with intractable seizures, especially those caused by developmental malformations, it is essential to understand the entirety of mechanisms that could possibly play a role in the abnormal cortical function. One such developmental malformation is known as polymicrogyria. Epileptogenesis occurs in an area laterally adjacent to this malformation known as the paramicrogyral region (PMR). Past studies have narrowed down the potential cause of this increased network excitation to a certain type of inhibitory interneuron, the somatostatin (SS) interneuron. Additionally, previous studies have shown an increase in the mGlu5 receptor on this interneurons in the PMR region only and not in control tissue, meaning that targeting these receptors as treatment will not affect normal functioning tissue. These results lead to our hypothesis: blockade of the mGluRs will decrease the 2 activity of SS interneurons and thereby prevent the generation of epileptiform activity and increased SS output in malformed cortex. Utilizing the freeze-lesion model for microgyria in transgenic mice expressing Channelrhodopsin optogenetic channels in SS interneurons, we assessed the contribution of these SS interneurons in four different animal groups: control or PMR treated with either Gabapentin, a current AED (antiepileptic drug), or MTEP, an mGlu5 receptor antagonist. We tested the effects of these two drugs on SS interneuron output to determine whether they decrease the over activation in the PMR that has been previously studied. The following study revealed no correlation between Gabapentin-treated animals and a decrease in epileptiform activity. Additionally, no significant difference was seen between the MTEP-treated groups in the protocols that were measured.

La polymicrogyrie est un type de malformation corticale dans laquelle on retrouve un excès de gyrations et une surface corticale irrégulière. La polymicrogyrie peut être provoquée par des causes environnementales ou génétiques. C'est ces dernières auxquelles nous nous sommes intéressés et que nous avons étudié afin d'approfondir nos connaissances sur les bases génétiques de la polymicrogyrie. Nous traitons trois projets qui se situent à trois niveaux de recherche différents : étude d'un gène dont la pathogénicité est établie pour le premier, étude de gènes candidats pour le deuxième et recherche de nouveaux gènes candidats pour le troisième. Dans le premier projet, nous avons réussi à prouver l'implication du gène NHEJ1 dans le développement du cortex cérébral. Nous avons montré, grâce à l'ARN interférence in utero que la dérégulation de Nhej1 chez le rat perturbe la migration neuronale, déclenche un phénomène de mort neuronale massive et désorganise les couches corticales. Dans le deuxième projet, après une étude par hybridation génomique comparative sur puce d'ADN, nous avons identifié une duplication dans la région 1p36 chez un patient présentant une polymicrogyrie bilatérale. Nous avons montré que cette duplication casse le gène ENO1 et diminue son expression. L'expression spatio-temporelle d'ENO1 est en accord avec un rôle de celui-ci pendant le développement cérébral. Nous avons également montré que la diminution de l'expression du gène Eno1 perturbe la migration neuronale radiale. / Polymicrogyria is a cortical malformation characterized by excessive gyration and an irregular cortex surface. Environmental and genetic causes can be responsible for this disorder. Our principal aim was to better understand the genetic basis of polymicrogyria. Three projects were conducted. The first focused on the NHEJ1 gene. Using RNA interference and in utero electroporation, we showed that deregulation of NHEJ1 disrupts neuronal migration, triggers massive neuronal cell death and disorganizes the cortical layers. In the second project, we identified by comparative genomic hybridization microarray, a duplication in the 1p36 region in a patient with bilateral polymicrogyria. We have shown that this duplication breaks the ENO1 gene and reduces its expression. The spatio-temporal expression of ENO1 and the fact that its deregulation disrupts neuronal migration indicates that ENO1 is a good candidate gene for cortical development. Finally, in the third project, we identified by exome sequencing of familial cases of bilateral polymicrogyria, one coding variation in the GABRA3 gene. Our work allowed us to generate new knowledge for several candidate genes for polymicrogyria.

Orientador: Marilisa Mantovani Guerreiro / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas / Made available in DSpace on 2018-08-15T13:01:17Z (GMT). No. of bitstreams: 1 Boscariol_Mirela_D.pdf: 3474565 bytes, checksum: fe5a39b063ae82822e086a45293c4311 (MD5) Previous issue date: 2010 / Resumo: A síndrome perisylviana (SP) refere-se a manifestações clínicas decorrentes de lesões na região perisylviana ou opercular. Caracteriza-se pela presença da polimicrogiria, uma malformação do desenvolvimento cortical em que o padrão normal de giros é substituído por múltiplos microgiros ao redor da fissura sylviana, agrupados e com sulcos pouco pronunciados entre eles, podendo ser vista em exame de neuroimagem. Estudos sugerem que distúrbios de linguagem e aprendizagem podem fazer parte desta síndrome, cuja clínica varia desde quadros específicos de linguagem até quadros mais amplos envolvendo sinais pseudobulbares e epilepsia. As áreas do processamento auditivo, representado por complexa resposta envolvendo habilidades corticais interconexas frente a um estímulo sonoro, podem estar comprometidas devido à proximidade com a fissura sylviana. Dessa forma, este estudo teve por objetivo avaliar os aspectos da linguagem, leitura e escrita e do processamento auditivo na SP e em escolares com ressonância magnética normal e correlacioná-los aos achados neurológicos, neuropsicológicos e de neuroimagem. Foram avaliados escolares com histórico de distúrbios de linguagem ou aprendizagem em presença de polimicrogiria perisylviana e em presença de neuroimagem normal, sendo submetidos a avaliações neurológica, neuropsicológica e fonoaudiológica, a qual incluiu avaliações de linguagem, leitura, escrita e processamento auditivo. Os resultados mostraram que o distúrbio específico de linguagem e os distúrbios de aprendizagem podem coexistir com o distúrbio do processamento auditivo e que os escolares com malformação do desenvolvimento cortical podem apresentar alterações neurolingüísticas mais significativas, concluindo que o córtex polimicrogírico pode se apresentar funcionalmente anormal e que as malformações corticais quando presentes devem ser consideradas fatores de risco para os distúrbios específicos de linguagem, distúrbios de aprendizagem e do processamento auditivo / Abstract: Perisylvian syndrome (PS) comprises a variety of clinical manifestations due to lesions on the perisylvian or opercular regions. Bilateral perisylvian polymicrogyria is a malformation of cortical development characterized by excessively small gyri seen around the Sylvian fissure on magnetic resonance imaging. Studies suggest that language and learning impairment may be part of this syndrome, whose clinical may vary from specific language impairment to the severe cases involving pseudobulbar signs and epilepsy. The areas of auditory processing, a complex set of interdependent cortical abilities due to a sound stimulus, may be compromised because perisylvian areas harbor the auditory processing function. Thus, this study was to evaluate language, learning and auditory processing abilities in PS and in children with normal magnetic resonance imaging and associates them with the neuropsychological, neurological and neuroimaging findings. Children with a history of language and learning impairment in the presence of perisylvian polymicrogyria and in the presence of normal neuroimaging were assessed with neurological, neuropsychological and assessments of language, literacy and auditory processing. The results showed that the specific language impairment and learning disabilities can coexist with auditory processing disorder and children with malformation of cortical development may have more significant neurolinguistic deficits. Our study concluded that the polymicrogyric cortex can be functionally abnormal and display that cortical malformations if present should be considered risk factors for the specific language impairment, learning impairments and auditory processing disorders / Doutorado / Ciencias Biomedicas / Doutor em Ciências Médicas

Orientador: Marilisa Mantovani Guerreiro / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas / Made available in DSpace on 2018-08-08T00:49:32Z (GMT). No. of bitstreams: 1 Teixeira_KarineCoutoSarmento_M.pdf: 1612063 bytes, checksum: b67ceb8ce8a89e338f504be9b41ab015 (MD5) Previous issue date: 2006 / Resumo: Polimicrogiria é uma malformação da organização cortical que se caracteriza por múltiplos pequenos giros separados por espessos e rasos sulcos. O objetivo do presente estudo foi descrever as manifestações clínicas e eletroencefalográficas de pacientes com polimicrogiria, que têm epilepsia e/ou distúrbio específico de linguagem e dos familares dos pacientes com distúrbio específico de linguagem, correlacionando-os com a neuroimagem. Os pacientes foram submetidos a exame clínico e neurológico, com particular atenção aos sinais pseudobulbares, e realizaram eletroencefalograma de rotina com até 4 horas de duração. Quando possível, foram submetidos a vídeo-monitorização. Os dados de neuroimagem foram classificados em: polimicrogiria perisylviana (subdividida em holosylviana, parietal posterior bilateral, generalizada), polimicrogiria hemisférica e polimicrogiria frontal. Os achados eletroencefalográficos foram categorizados em: normal; anormal com atividade epileptiforme; anormal com atividade não epileptiforme; anormal com atividade epileptiforme e não epileptiforme; anormal com estado de mal elétrico (EME); anormal com atividade epileptiforme contínua e quanto à presença ou não de ativação da atividade epileptiforme pelo sono. Foram estudados 40 pacientes: 16 pacientes com polimicrogiria holosylviana, 14 com polimicrogiria parietal posterior, quatro com polimicrogiria generalizada, três com polimicrogiria hemisférica e três com polimicrogiria frontal. Observou-se nos pacientes com polimicrogiria holosylviana: sinais pseudobulbares em 11, hemiparesia em seis sendo um paciente com dupla hemiparesia. Três possuíam deficiência mental e cinco tinham epilepsia. O eletroencefalograma estava alterado em oito pacientes e atividade epileptiforme foi registrada em seis, sendo que em dois foi registrada atividade epileptiforme contínua focal. Entre os pacientes com polimicrogiria parietal posterior bilateral, cinco apresentavam sinais pseudobulbares e um possuía hemiparesia. Nenhum tinha alteração cognitiva ou epilepsia. Apenas um paciente apresentou ao eletroencefalograma atividade epileptiforme focal. Todos os pacientes com polimicrogiria generalizada tinham sinal pseudobulbar, deficiência mental e epilepsia. O quadro motor estava presente em três pacientes e apenas um deles não apresentava atividade epileptiforme no eletroencefalograma. Entre os pacientes com polimicrogiria hemisférica, todos apresentavam sinal pseudobulbar e hemiparesia, dois pacientes tinham deficiência mental e epilepsia, e um paciente atraso do desenvolvimento neuropsicomotor. Nos registros eletroencefalográficos, dois pacientes apresentaram EME focal. Os pacientes com polimicrogiria frontal não possuíam sinal pseudobulbar e em um único paciente foi detectada hemiparesia. Epilepsia estava presente em dois pacientes. No registro eletroencefalográfico, dois exames apresentaram anormalidades não-epileptiformes. Com os dados acima descritos foi possível observar que: os sinais pseudobulbares foram mais freqüentes em pacientes com idade menor ou igual a 15 anos; atividade epileptiforme e lentificação da atividade de base teve associação com epilepsia e alteração cognitiva e o distúrbio específico de linguagem apresentou uma relação inversa com estes achados eletroencefalográficos; a maioria dos nossos pacientes apresentou exame eletroencefalográfico normal; na polimicrogiria holosylviana, as atividades epileptiformes predominaram na região fronto-temporal e as atividades não epileptiformes predominaram na região fronto-centro-temporal; EME ocorreu em polimicrogiria hemisférica e atividade epileptiforme contínua focal ocorreu em polimicrogiria holosylviana bilateral assimétrica com provável displasia cortical associada; a ativação da atividade epileptiforme pelo sono foi um achado freqüente em nossa casuística; existe correlação direta entre as manifestações clínicas e anormalidades eletroencefalográficas e extensão do córtex polimicrogírico / Abstract: Polymicrogyria is a malformation of cortical organization that is characterized by multiple and small gyri. The aim of this study was do describe clinical and eletrographic features of patients with polymicrogyria, whom have epilepsia and/or developmental language disorder, and to correlate these data with neuroimaging findings. Our patients underwent clinical and neurological examination, and a routine electroencephalogram. Whenever possible, video-electroencephalographic monitoring was performed. Neuroimaging data were classified as: perisylvian polymicrogyria (subdivided as holosylvian, posterior parietal and generalized), hemispheric polymicrogyria and frontal polymicrogyria. Electrographic findings were classified as: normal; abnormal with epileptiform activity; abnormal with non-epileptiform activity; abnormal with epileptiform and non-epileptiform activities; abnormal with electrographic status (ES); abnormal with continuous epileptiform activity; sleep activation. We studied 40 patients: 16 with holosylvian polymicrogyria; 14 with posterior parietal polymicrogyria; four with generalized polymicrogyria; three with hemispheric polymicrogyria; and three with frontal polymicrogyria. Patients with holosylvian polymicrogyria showed: pseudobulbar signs in 11; hemiparesis in six one of them with double hemiparesis. Three had mental retardation and five had epilepsy. The elecgroencephalogram was abnormal in eight patients and epileptiform activity was registered in six, two of them with focal. Patients with posterior parietal polymicrogyria showed: five with pseudobulbar sign and one with hemiparesis. Cognitive delay and epilepsy was not found in this group. Only one patient had electroencephalogram with focal epileptiform discharges. Patients with generalized polymicrogyria had pseudobulbar sign, epilepsy and mental retardation. Motor deficit was found in three patients. Electroencephalogram findings showed epileptiform activity in three. Patients with hemispheric polymicrogyria had pseudobulbar sign and hemiparesis. Two of them had mental retardation and epilepsy. One had neurodevelopmental delay. Electrographic examinations showed focal ES in two patients. Patients with frontal polymicrogyria had no pseudobulbar sign and one of them had hemiparesis. Two patients had epilepsy. Electroencephalogram findings showed non-epileptiform activities in two patients. Our data demonstrated that: pseudobulbar sign are more frequent among patients under 15 years old; epilepsy and cognitive delay are both correlated with epileptiform activity and slowness of the background activity and developmental language disorder had a inverse correlation with this finds; in holosylvian polymicrogyria, epileptiform activities predominated in fronto-temporal regions and non-epileptiform activities predominated in centro-temporal regions; ES occurred in hemispheric polymicrogyria and focal continuous epileptiform activities in asymmetric bilateral holosylvian polymicrogyria with associated cortical dysplasia; sleep activation was a frequent finding; the severity of clinical and electrographic features correlated with the extent of cortical lesion / Mestrado / Neurologia / Mestre em Ciências Médicas

Sleep is vital for optimal physical and mental health, as well as cognitive and social functioning. Young adults with developmental disabilities (DD) are at greater risk for physical and mental health disorders and experience limitations in cognitive and social functioning in ways that can prevent participation in meaningful activities associated with young adulthood. Sleep literature has reflected that persons with DD experience worse sleep than persons without DD. Suboptimal sleep could compromise functionality and thus participation in young adulthood activities. Not much is known however of the nature of sleep problems experienced by young adults with DD. This study is a short-term longitudinal descriptive study on the sleep of young adults with DD using actigraphy. Results identify potential sleep problems with getting enough sleep and maintaining sleep. With a better understanding of sleep issues, efforts can be made to improve the sleep, functionality, and outcomes for young adults with DD.

Polymicrogyria (PMG) is one brain disease that mainly occurs in the pediatric brain. Heavy PMG will cause seizures, delayed development, and a series of problems. For this reason, it is critical to effectively identify PMG and start early treatment. Radiologists typically identify PMG through magnetic resonance imaging scans. In this study, we create and open a pediatric MRI dataset (named PPMR dataset) including PMG and controls from the Children's Hospital of Eastern Ontario (CHEO), Ottawa, Canada. The difference between PMG MRIs and control MRIs is subtle and the true distribution of the features of the disease is unknown. Hence, we propose a novel center-based deep contrastive metric learning loss function (named cDCM Loss) to deal with this difficult problem. Cross-entropy-based loss functions do not lead to models with good generalization on small and imbalanced dataset with partially known distributions. We conduct exhaustive experiments on a modified CIFAR-10 dataset to demonstrate the efficacy of our proposed loss function compared to cross-entropy-based loss functions and the state-of-the-art Deep SAD loss function. Additionally, based on our proposed loss function, we customize a deep learning model structure that integrates dilated convolution, squeeze-and-excitation blocks and feature fusion for our PPMR dataset, to achieve 92.01% recall. Since our suggested method is a computer-aided tool to assist radiologists in selecting potential PMG MRIs, 55.04% precision is acceptable. To our best knowledge, this research is the first to apply machine learning techniques to identify PMG only from MRI and our innovative method achieves better results than baseline methods.

Cortical malformations as a result of altered development are a common cause of human epilepsy. The cellular mechanisms that render neurons of malformed cortex epileptogenic remain unclear. Using a rat model of the malformation of microgyria, a previous study showed an alteration in the number of immunocytochemically-identified parvalbumin cells, a GABAergic inhibitory interneurons subtype (Rosen et al., 1998). A second study showed no change in the total number of GABAergic neurons (Schwarz et al., 2000). Consequently, we hypothesize that interneuron subtypes are differentially affected by maldevelopment. The present study investigated (1) whether interneuron subtype identity is retained in malformed cortex, based on chemical content, and (2) whether the proportion of three chemical subtypes is altered in malformed cortex. Here we demonstrate that three non-overlapping subtype markers remain non-overlapping in malformed cortex, but show altered distributions. These findings suggest that an increase in one subpopulation of interneurons may compensate for a corresponding decrease in a second subset.

Orientador: Marilisa Mantovani Guerreiro / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas / Made available in DSpace on 2018-08-07T04:56:07Z (GMT). No. of bitstreams: 1 Oliveira_EcilaPauladosMesquitade_M.pdf: 5362719 bytes, checksum: be0757cf15e62b4a49b979053422be33 (MD5) Previous issue date: 2006 / Resumo:Distúrbio específico do desenvolvimento da linguagem (DEDL) se refere à aquisição inadequada da linguagem em crianças que não tenham outras alterações do desenvolvimento, ou seja, o prejuízo no desenvolvimento da linguagem é a principal dificuldade do paciente, mesmo havendo queixas secundárias de menor relevância. O quadro de manifestações lingüísticas de crianças com DEDL pode ser freqüentemente correlacionado com a presença de polimicrogiria perisylviana em exames de neuroimagem (síndrome perisylviana). O objetivo do presente estudo foi investigar famílias de crianças que possuem um quadro de DEDL associado à polimicrogiria e caracterizar as manifestações lingüísticas nos membros (crianças e adultos) dessas famílias, além de correlacionar os achados com exames de neuroimagem. Foram selecionadas três famílias com história de alterações no desenvolvimento da linguagem e com exames de neuroimagem evidenciando polimicrogiria na região sylviana. Os pacientes foram submetidos à avaliação psicológica e fonoaudiológica (audiológica e específica de linguagem). Os nossos dados confirmaram que quadros de alterações específicas de linguagem fazem parte do espectro da síndrome perisylviana; o presente estudo verificou a presença de distúrbios do desenvolvimento de linguagem co-ocorrendo com alterações na leitura e/ou escrita em membros de uma mesma família; os nossos achados mostraram que na síndrome perisylviana, em crianças, observa-se predominantemente alterações na linguagem oral e, em adultos, observa-se predominantemente alterações na linguagem escrita; os nossos resultados confirmaram que sujeitos com envolvimento cortical extenso apresentam manifestações clínicas mais graves, enquanto sujeitos com imagens evidenciando comprometimento cortical posterior e/ou focal apresentam manifestações clínicas mais sutis; ressalta-se finalmente que o exame de ressonância magnética realizado com critério e dirigido para a hipótese diagnóstica, frente a uma criança com atraso na aquisição e desenvolvimento da linguagem associado a sinais clínicos de disfunção oromotora e/ou sinais pseudobulbares é bem indicado / Abstract: Specific language impairment (SLI) refers to inadequate language development in a child without other development disorder, that is, inadequate language acquisition is the main difficulty, even if the child may present with other symptoms. SLI may occur in patients who have polymicrogyria around Sylvian fissure on neuroimaging studies (perisylvian syndrome). The aim of this study was to investigate family members of children with perisylvian syndrome and characterize the linguistic profile found in those families. We selected three families with perisylvian syndrome. Patients underwent a psychological assessment and a comprehensive phonologic evaluation (audiologic evaluation and language evaluation). This study found that SLI and reading/writing impaiment may co-occur in different members of the same family; our data showed that children with perisylvian syndrome present mostly with SLI while adults with perisylvian syndrome present mostly with reading/writing impairment; our results confirmed that clinical picture is correlated with the extent of cerebral involvement; and finally, MRI imaging is indicated when a child has SLI and pseudobulbar signs / Mestrado / Ciencias Biomedicas / Mestre em Ciências Médicas