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1.
Hum Mol Genet ; 31(6): 901-913, 2022 03 21.
Artigo em Inglês | MEDLINE | ID: mdl-34617111

RESUMO

Synaptic inhibition is essential for shaping the dynamics of neuronal networks, and aberrant inhibition is linked to epilepsy. Gephyrin (Geph) is the principal scaffolding protein at inhibitory synapses and is essential for postsynaptic clustering of glycine (GlyRs) and GABA type A receptors. Consequently, gephyrin is crucial for maintaining the relationship between excitation and inhibition in normal brain function and mutations in the gephyrin gene (GPHN) are associated with neurodevelopmental disorders and epilepsy. We identified bi-allelic variants in the GPHN gene, namely the missense mutation c.1264G > A and splice acceptor variant c.1315-2A > G, in a patient with developmental and epileptic encephalopathy. We demonstrate that the splice acceptor variant leads to nonsense-mediated mRNA decay. Furthermore, the missense variant (D422N) alters gephyrin structure, as examined by analytical size exclusion chromatography and circular dichroism-spectroscopy, thus leading to reduced receptor clustering and sensitivity towards calpain-mediated cleavage. In addition, both alterations contribute to an observed reduction of inhibitory signal transmission in neurons, which likely contributes to the pathological encephalopathy.


Assuntos
Encefalopatias , Epilepsia , Encefalopatias/metabolismo , Proteínas de Transporte/metabolismo , Epilepsia/metabolismo , Humanos , Proteínas de Membrana/metabolismo , Receptores de GABA-A/metabolismo , Sinapses/metabolismo
2.
Genet Med ; 26(5): 101087, 2024 05.
Artigo em Inglês | MEDLINE | ID: mdl-38288683

RESUMO

PURPOSE: Interneuronopathies are a group of neurodevelopmental disorders characterized by deficient migration and differentiation of gamma-aminobutyric acidergic interneurons resulting in a broad clinical spectrum, including autism spectrum disorders, early-onset epileptic encephalopathy, intellectual disability, and schizophrenic disorders. SP9 is a transcription factor belonging to the Krüppel-like factor and specificity protein family, the members of which harbor highly conserved DNA-binding domains. SP9 plays a central role in interneuron development and tangential migration, but it has not yet been implicated in a human neurodevelopmental disorder. METHODS: Cases with SP9 variants were collected through international data-sharing networks. To address the specific impact of SP9 variants, in silico and in vitro assays were carried out. RESULTS: De novo heterozygous variants in SP9 cause a novel form of interneuronopathy. SP9 missense variants affecting the glutamate 378 amino acid result in severe epileptic encephalopathy because of hypomorphic and neomorphic DNA-binding effects, whereas SP9 loss-of-function variants result in a milder phenotype with epilepsy, developmental delay, and autism spectrum disorder. CONCLUSION: De novo heterozygous SP9 variants are responsible for a neurodevelopmental disease. Interestingly, variants located in conserved DNA-binding domains of KLF/SP family transcription factors may lead to neomorphic DNA-binding functions resulting in a combination of loss- and gain-of-function effects.


Assuntos
Transtorno do Espectro Autista , Epilepsia , Deficiência Intelectual , Interneurônios , Fatores de Transcrição Sp , Fatores de Transcrição , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/patologia , Epilepsia/genética , Epilepsia/patologia , Heterozigoto , Deficiência Intelectual/genética , Deficiência Intelectual/patologia , Interneurônios/metabolismo , Interneurônios/patologia , Mutação de Sentido Incorreto/genética , Transtornos do Neurodesenvolvimento/genética , Transtornos do Neurodesenvolvimento/patologia , Fenótipo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Fatores de Transcrição Sp/genética
3.
Am J Med Genet A ; 188(5): 1556-1561, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35019233

RESUMO

Autosomal dominant and recessive mutations in COL12A1 cause the Ehlers-Danlos/myopathy overlap syndrome. Here, we describe a boy with fetal hypokinesia, severe neonatal weakness, striking hyperlaxity, high arched palate, retrognathia, club feet, and pectus excavatum. His motor development was initially delayed but muscle strength improved with time while hyperlaxity remained very severe causing recurrent joint dislocations. Using trio exome sequencing and a copy number variation (CNV) analysis tool, we identified an in-frame de novo heterozygous deletion of the exons 45 to 54 in the COL12A1 gene. Collagen XII immunostaining on cultured skin fibroblasts demonstrated intracellular retention of collagen XII, supporting the pathogenicity of the deletion. The phenotype of our patient is slightly more severe than other cases with dominantly acting mutations, notably with the presence of fetal hypokinesia. This case highlights the importance of CNVs analysis in the COL12A1 gene in patients with a phenotype suggesting Ehlers-Danlos/myopathy overlap syndrome.


Assuntos
Síndrome de Ehlers-Danlos , Doenças Musculares , Colágeno Tipo XII/genética , Variações do Número de Cópias de DNA , Síndrome de Ehlers-Danlos/diagnóstico , Síndrome de Ehlers-Danlos/genética , Éxons , Humanos , Hipocinesia/genética , Masculino , Doenças Musculares/genética , Mutação
4.
Neuroimage ; 239: 118281, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34147627

RESUMO

Plasticity of synaptic strength and density is a vital mechanism enabling memory consolidation, learning, and neurodevelopment. It is strongly dependent on the intact function of N-Methyl-d-Aspartate Receptors (NMDAR). The importance of NMDAR is further evident as their dysfunction is involved in many diseases such as schizophrenia, Alzheimer's disease, neurodevelopmental disorders, and epilepsies. Synaptic plasticity is thought to be reflected by changes of sleep slow wave slopes across the night, namely higher slopes after wakefulness at the beginning of sleep than after a night of sleep. Hence, a functional NMDAR deficiency should theoretically lead to altered overnight changes of slow wave slopes. Here we investigated whether pediatric patients with anti-NMDAR encephalitis, being a very rare but unique human model of NMDAR deficiency due to autoantibodies against receptor subunits, indeed show alterations in this sleep EEG marker for synaptic plasticity. We retrospectively analyzed 12 whole-night EEGs of 9 patients (age 4.3-20.8 years, 7 females) and compared them to a control group of 45 healthy individuals with the same age distribution. Slow wave slopes were calculated for the first and last hour of Non-Rapid Eye Movement (NREM) sleep (factor 'hour') for patients and controls (factor 'group'). There was a significant interaction between 'hour' and 'group' (p = 0.013), with patients showing a smaller overnight decrease of slow wave slopes than controls. Moreover, we found smaller slopes during the first hour in patients (p = 0.022), whereas there was no group difference during the last hour of NREM sleep (p = 0.980). Importantly, the distribution of sleep stages was not different between the groups, and in our main analyses of patients without severe disturbance of sleep architecture, neither was the incidence of slow waves. These possible confounders could therefore not account for the differences in the slow wave slope values, which we also saw in the analysis of the whole sample of EEGs. These results suggest that quantitative EEG analysis of slow wave characteristics may reveal impaired synaptic plasticity in patients with anti-NMDAR encephalitis, a human model of functional NMDAR deficiency. Thus, in the future, the changes of sleep slow wave slopes may contribute to the development of electrophysiological biomarkers of functional NMDAR deficiency and synaptic plasticity in general.


Assuntos
Encefalite Antirreceptor de N-Metil-D-Aspartato/fisiopatologia , Ondas Encefálicas/fisiologia , Eletroencefalografia/métodos , Plasticidade Neuronal , Receptores de N-Metil-D-Aspartato/deficiência , Fases do Sono/fisiologia , Adolescente , Encefalite Antirreceptor de N-Metil-D-Aspartato/diagnóstico por imagem , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Receptores de N-Metil-D-Aspartato/imunologia , Estudos Retrospectivos , Adulto Jovem
5.
Genet Med ; 23(10): 1922-1932, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34163037

RESUMO

PURPOSE: CACNA1C encodes the alpha-1-subunit of a voltage-dependent L-type calcium channel expressed in human heart and brain. Heterozygous variants in CACNA1C have previously been reported in association with Timothy syndrome and long QT syndrome. Several case reports have suggested that CACNA1C variation may also be associated with a primarily neurological phenotype. METHODS: We describe 25 individuals from 22 families with heterozygous variants in CACNA1C, who present with predominantly neurological manifestations. RESULTS: Fourteen individuals have de novo, nontruncating variants and present variably with developmental delays, intellectual disability, autism, hypotonia, ataxia, and epilepsy. Functional studies of a subgroup of missense variants via patch clamp experiments demonstrated differential effects on channel function in vitro, including loss of function (p.Leu1408Val), neutral effect (p.Leu614Arg), and gain of function (p.Leu657Phe, p.Leu614Pro). The remaining 11 individuals from eight families have truncating variants in CACNA1C. The majority of these individuals have expressive language deficits, and half have autism. CONCLUSION: We expand the phenotype associated with CACNA1C variants to include neurodevelopmental abnormalities and epilepsy, in the absence of classic features of Timothy syndrome or long QT syndrome.


Assuntos
Transtorno Autístico , Canais de Cálcio Tipo L , Síndrome do QT Longo , Sindactilia , Transtorno Autístico/genética , Canais de Cálcio Tipo L/genética , Humanos , Fenótipo
6.
Brain ; 142(10): 2996-3008, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31532509

RESUMO

Epilepsy of infancy with migrating focal seizures was first described in 1995. Fifteen years later, KCNT1 gene mutations were identified as the major disease-causing gene of this disease. Currently, the data on epilepsy of infancy with migrating focal seizures associated with KCNT1 mutations are heterogeneous and many questions remain unanswered including the prognosis and the long-term outcome especially regarding epilepsy, neurological and developmental status and the presence of microcephaly. The aim of this study was to assess data from patients with epilepsy in infancy with migrating focal seizures with KCNT1 mutations to refine the phenotype spectrum and the outcome. We used mind maps based on medical reports of children followed in the network of the French reference centre for rare epilepsies and we developed family surveys to assess the long-term outcome. Seventeen patients were included [age: median (25th-75th percentile): 4 (2-15) years, sex ratio: 1.4, length of follow-up: 4 (2-15) years]. Seventy-one per cent started at 6 (1-52) days with sporadic motor seizures (n = 12), increasing up to a stormy phase with long lasting migrating seizures at 57 (30-89) days. The others entered this stormy phase directly at 1 (1-23) day. Ten patients entered a consecutive phase at 1.3 (1-2.8) years where seizures persisted at least daily (n = 8), but presented different semiology: brief and hypertonic with a nocturnal (n = 6) and clustered (n = 6) aspects. Suppression interictal patterns were identified on the EEG in 71% of patients (n = 12) sometimes from the first EEG (n = 6). Three patients received quinidine without reported efficacy. Long-term outcome was poor with neurological sequelae and active epilepsy except for one patient who had an early and long-lasting seizure-free period. Extracerebral symptoms probably linked with KCNT1 mutation were present, including arteriovenous fistula, dilated cardiomyopathy and precocious puberty. Eight patients (47%) had died at 3 (1.5-15.4) years including three from suspected sudden unexpected death in epilepsy. Refining the electro-clinical characteristics and the temporal sequence of epilepsy in infancy with migrating focal seizures should help diagnosis of this epilepsy. A better knowledge of the outcome allows one to advise families and to define the appropriate follow-up and therapies. Extracerebral involvement should be investigated, in particular the cardiac system, as it may be involved in the high prevalence of sudden unexpected death in epilepsy in these cases.


Assuntos
Epilepsias Parciais/genética , Mutação , Proteínas do Tecido Nervoso/genética , Canais de Potássio Ativados por Sódio/genética , Morte Súbita Inesperada na Epilepsia , Adolescente , Mapeamento Encefálico/métodos , Criança , Pré-Escolar , Eletroencefalografia/métodos , Epilepsias Parciais/metabolismo , Feminino , Humanos , Estudos Longitudinais , Masculino , Proteínas do Tecido Nervoso/metabolismo , Fenótipo , Canais de Potássio/genética , Canais de Potássio/metabolismo , Canais de Potássio Ativados por Sódio/metabolismo
7.
Hum Reprod ; 34(2): 356-364, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30496424

RESUMO

STUDY QUESTION: Is assisted conception associated with neonatal morbidity and mortality and with neurodevelopmental impairment at 2 years of corrected age in preterm infants born before 34 weeks of gestational age? SUMMARY ANSWER: Assisted conception is not associated with an increase in neonatal morbidity and mortality and is even significantly associated with a better 2-year neurodevelopmental outcome in preterm infants. WHAT IS KNOWN ALREADY: Assisted conception appears to increase the rate of preterm births, though few studies have analysed outcomes for these preterm infants. STUDY DESIGN, SIZE, DURATION: This prospective observational study included 703 preterm infants born between January 2009 and December 2013 and 573 of them were assessed at 2 years of corrected age. PARTICIPANTS/MATERIALS, SETTING, METHODS: All infants born alive between 24+0 and 33+6 weeks of gestational age and hospitalised at the Angers University Hospital were eligible as long as the mode of conception was known for neonatal outcome assessment. They were enroled in the Loire Infant Follow-up Team (LIFT) prospective longitudinal cohort and included for neurodevelopmental outcome assessment. Neonatal morbidity and mortality were evaluated during hospitalisation based on a composite score including death, intraventricular haemorrhage Grade ≥3, periventricular leukomalacia, treated patent ductus arteriosus and bronchopulmonary dysplasia at 36 weeks of gestational age. The neurodevelopmental outcome at 2 years of corrected age was determined by a physical examination, a neuropsychological test and a parental questionnaire. In order to ensure comparability, infants were matched 1:1 according to maternal age, twin status and propensity score,calculated from variables usually associated (positively or negatively) with assisted conception, including gestational age, z-score of birth weight, antenatal corticosteroids and magnesium sulphate treatments, gender, parity, maternal body mass index, tobacco consumption, outborn delivery (i.e. not at a tertiary-care medical centre) and maternal socio-economic status. MAIN RESULTS AND THE ROLE OF CHANCE: There were 703 preterm infants included in the analysis of neonatal morbidity and mortality, including 137 born after assisted conception. After matching, 184 preterm infants were included for neonatal morbidity and mortality analysis. There was no significant association between assisted conception and neonatal morbidity and mortality (aOR 0.67, 95% CI [0.25, 1.77], P = 0.422). 573 infants were assessed at 2 years, including 121 born after assisted conception. After matching, 154 preterm infants were included for neurodevelopmental outcome analysis. Assisted conception was significantly associated with a reduction in the probability of non-optimal neurological development at 2 years (aOR 0.26, 95% CI [0.09, 0.80], P = 0.019). LIMITATION, REASONS FOR CAUTION: Further studies remain necessary to fully confirm these results. This was a monocentric study and 14% of enroled infants were lost to follow up at 2 years of corrected age. WIDER IMPLICATIONS OF THE FINDINGS: These findings are relevant for providing appropriate information to parents considering assisted conception, and more importantly for those with a preterm infant following a pregnancy achieved by assisted conception. STUDY FUNDING/COMPETING INTEREST(S): The authors report external funding and no conflicts of interest for this work. TRIAL REGISTRATION NUMBER: N/A.


Assuntos
Desenvolvimento Infantil/fisiologia , Mortalidade Infantil , Recém-Nascido Prematuro/fisiologia , Transtornos do Neurodesenvolvimento/epidemiologia , Técnicas de Reprodução Assistida/efeitos adversos , Adolescente , Adulto , Peso ao Nascer/fisiologia , Índice de Massa Corporal , Pré-Escolar , Feminino , Seguimentos , Idade Gestacional , Humanos , Lactente , Recém-Nascido , Masculino , Idade Materna , Pessoa de Meia-Idade , Gravidez , Estudos Prospectivos , Adulto Jovem
8.
Epilepsia ; 59(10): 1867-1880, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30178479

RESUMO

Attention-deficit/hyperactivity disorder (ADHD) is a common and challenging comorbidity affecting many children with epilepsy. A working group under the International League Against Epilepsy (ILAE) Pediatric Commission identified key questions on the identification and management of ADHD in children with epilepsy. Systematic reviews of the evidence to support approaches to these questions were collated and graded using criteria from the American Academy of Neurology Practice Parameter. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) requirements were followed, with PROSPERO registration (CRD42018094617). No increased risk of ADHD in boys with epilepsy compared to girls with epilepsy was found (Level A). Valproate use in pregnancy is associated with inattentiveness and hyperactivity in offspring (1 class I study), and children with intellectual and developmental disabilities are at increased risk of ADHD (Level A). Impact of early seizure onset on development of ADHD was unclear (Level U), but more evident with poor seizure control (Level B). ADHD screening should be performed from 6 years of age, or at diagnosis, and repeated annually (Level U) and reevaluated after change of antiepileptic drug (AED) (Level U). Diagnosis should involve health practitioners with expert training in ADHD (Level U). Use of the Strength and Difficulties Questionnaire screening tool is supported (Level B). Formal cognitive testing is strongly recommended in children with epilepsy who are struggling at school (Level U). Behavioral problems are more likely with polytherapy than monotherapy (Level C). Valproate can exacerbate attentional issues in children with childhood absence epilepsy (Level A). Methylphenidate is tolerated and effective in children with epilepsy (Level B). Limited evidence supports that atomoxetine is tolerated (Level C). Multidisciplinary involvement in transition and adult ADHD clinics is essential (Level U). In conclusion, although recommendations could be proposed for some of the study questions, this systematic review highlighted the need for more comprehensive and targeted large-population prospective studies.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Gerenciamento Clínico , Epilepsia , Anticonvulsivantes/uso terapêutico , Transtorno do Deficit de Atenção com Hiperatividade/complicações , Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico , Transtorno do Deficit de Atenção com Hiperatividade/epidemiologia , Transtorno do Deficit de Atenção com Hiperatividade/terapia , Estimulantes do Sistema Nervoso Central/uso terapêutico , Epilepsia/complicações , Epilepsia/diagnóstico , Epilepsia/epidemiologia , Epilepsia/terapia , Humanos
9.
J Neurosci ; 36(5): 1596-606, 2016 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-26843641

RESUMO

Using a continuous listening task, we evaluated the coupling between the listener's cortical activity and the temporal envelopes of different sounds in a multitalker auditory scene using magnetoencephalography and corticovocal coherence analysis. Neuromagnetic signals were recorded from 20 right-handed healthy adult humans who listened to five different recorded stories (attended speech streams), one without any multitalker background (No noise) and four mixed with a "cocktail party" multitalker background noise at four signal-to-noise ratios (5, 0, -5, and -10 dB) to produce speech-in-noise mixtures, here referred to as Global scene. Coherence analysis revealed that the modulations of the attended speech stream, presented without multitalker background, were coupled at ∼0.5 Hz to the activity of both superior temporal gyri, whereas the modulations at 4-8 Hz were coupled to the activity of the right supratemporal auditory cortex. In cocktail party conditions, with the multitalker background noise, the coupling was at both frequencies stronger for the attended speech stream than for the unattended Multitalker background. The coupling strengths decreased as the Multitalker background increased. During the cocktail party conditions, the ∼0.5 Hz coupling became left-hemisphere dominant, compared with bilateral coupling without the multitalker background, whereas the 4-8 Hz coupling remained right-hemisphere lateralized in both conditions. The brain activity was not coupled to the multitalker background or to its individual talkers. The results highlight the key role of listener's left superior temporal gyri in extracting the slow ∼0.5 Hz modulations, likely reflecting the attended speech stream within a multitalker auditory scene. SIGNIFICANCE STATEMENT: When people listen to one person in a "cocktail party," their auditory cortex mainly follows the attended speech stream rather than the entire auditory scene. However, how the brain extracts the attended speech stream from the whole auditory scene and how increasing background noise corrupts this process is still debated. In this magnetoencephalography study, subjects had to attend a speech stream with or without multitalker background noise. Results argue for frequency-dependent cortical tracking mechanisms for the attended speech stream. The left superior temporal gyrus tracked the ∼0.5 Hz modulations of the attended speech stream only when the speech was embedded in multitalker background, whereas the right supratemporal auditory cortex tracked 4-8 Hz modulations during both noiseless and cocktail-party conditions.


Assuntos
Estimulação Acústica/métodos , Atenção/fisiologia , Córtex Auditivo/fisiologia , Percepção da Fala/fisiologia , Lobo Temporal/fisiologia , Adulto , Feminino , Humanos , Imageamento por Ressonância Magnética/métodos , Magnetoencefalografia/métodos , Masculino , Adulto Jovem
10.
Neuroimage ; 134: 213-222, 2016 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-27039143

RESUMO

Behavioral evidence shows that sleep is crucial for the consolidation of declarative memories in children as in adults. However, the underlying cerebral mechanisms remain virtually unexplored. Using magnetoencephalography, we investigated in children (8.0-12.5years) the impact of sleep (90-minute nap) on the neurophysiological processes underlying the creation and consolidation of novel associations between unknown objects and their functions. Learning-dependent changes in brain activity were observed within hippocampal and parahippocampal regions, followed by sleep-dependent changes in the prefrontal cortex, whereas no equivalent change was observed after a similar period of wakeful rest. Hence, our results show that in school-age children a 90-minute daytime nap after learning is sufficient to trigger the reorganization of memory-related brain activity toward prefrontal areas, where it incorporates into pre-existing semantic knowledge. This functional reorganization process in children is similar to that observed in adults but occurs at a much faster rate, which may contribute to the development of the impressive learning skills that characterize childhood.


Assuntos
Hipocampo/fisiologia , Rememoração Mental/fisiologia , Plasticidade Neuronal/fisiologia , Córtex Pré-Frontal/fisiologia , Sono/fisiologia , Aprendizagem Verbal/fisiologia , Vigília/fisiologia , Mapeamento Encefálico , Criança , Feminino , Humanos , Masculino , Rede Nervosa/fisiologia , Tempo de Reação/fisiologia
11.
Hum Brain Mapp ; 37(8): 3017-30, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27133021

RESUMO

The aim of this study was to investigate the age-related changes in resting-state neurometabolic connectivity from childhood to adulthood (6-50 years old). Fifty-four healthy adult subjects and twenty-three pseudo-healthy children underwent [(18) F]-fluorodeoxyglucose positron emission tomography at rest. Using statistical parametric mapping (SPM8), age and age squared were first used as covariate of interest to identify linear and non-linear age effects on the regional distribution of glucose metabolism throughout the brain. Then, by selecting voxels of interest (VOI) within the regions showing significant age-related metabolic changes, a psychophysiological interaction (PPI) analysis was used to search for age-induced changes in the contribution of VOIs to the metabolic activity in other brain areas. Significant linear or non-linear age-related changes in regional glucose metabolism were found in prefrontal cortices (DMPFC/ACC), cerebellar lobules, and thalamo-hippocampal areas bilaterally. Decreases were found in the contribution of thalamic, hippocampal, and cerebellar regions to DMPFC/ACC metabolic activity as well as in the contribution of hippocampi to preSMA and right IFG metabolic activities. Increases were found in the contribution of the right hippocampus to insular cortex and of the cerebellar lobule IX to superior parietal cortex metabolic activities. This study evidences significant linear or non-linear age-related changes in regional glucose metabolism of mesial prefrontal, thalamic, mesiotemporal, and cerebellar areas, associated with significant modifications in neurometabolic connectivity involving fronto-thalamic, fronto-hippocampal, and fronto-cerebellar networks. These changes in functional brain integration likely represent a metabolic correlate of age-dependent effects on sensory, motor, and high-level cognitive functional networks. Hum Brain Mapp 37:3017-3030, 2016. © 2016 Wiley Periodicals, Inc.


Assuntos
Envelhecimento/metabolismo , Encéfalo/crescimento & desenvolvimento , Encéfalo/metabolismo , Glucose/metabolismo , Vias Neurais/crescimento & desenvolvimento , Vias Neurais/metabolismo , Adolescente , Adulto , Mapeamento Encefálico , Criança , Feminino , Fluordesoxiglucose F18 , Humanos , Masculino , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos , Adulto Jovem
13.
Neuroimage ; 119: 221-8, 2015 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-26123380

RESUMO

Motor information conveyed by viewing the kinematics of an agent's action helps to predict how the action will unfold. Still, how observed movement kinematics is processed in the brain remains to be clarified. Here, we used magnetoencephalography (MEG) to determine at which frequency and where in the brain, the neural activity is coupled with the kinematics of executed and observed motor actions. Whole-scalp MEG signals were recorded from 11 right-handed healthy adults while they were executing (Self) or observing (Other) similar goal-directed hand actions performed by an actor placed in front of them. Actions consisted of pinching with the right hand green foam-made pieces mixed in a heap with pieces of other colors placed on a table, and put them in a plastic pot on the right side of the heap. Subjects' and actor's forefinger movements were monitored with an accelerometer. The coherence between movement acceleration and MEG signals was computed at the sensor level. Then, cortical sources coherent with movement acceleration were identified with Dynamic Imaging of Coherent Sources. Statistically significant sensor-level coherence peaked at the movement frequency (F0) and its first harmonic (F1) in both movement conditions. Apart from visual cortices, statistically significant local maxima of coherence were observed in the right posterior superior temporal gyrus (F0), bilateral superior parietal lobule (F0 or F1) and primary sensorimotor cortex (F0 or F1) in both movement conditions. These results suggest that observing others' actions engages the viewer's brain in a similar kinematic-related manner as during own action execution. These findings bring new insights into how human brain activity covaries with essential features of observed movements of others.


Assuntos
Objetivos , Movimento , Desempenho Psicomotor/fisiologia , Córtex Sensório-Motor/fisiologia , Percepção Visual/fisiologia , Adulto , Fenômenos Biomecânicos , Eletromiografia , Feminino , Mãos/fisiologia , Humanos , Magnetoencefalografia , Masculino , Adulto Jovem
14.
Hum Brain Mapp ; 36(11): 4604-21, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26331630

RESUMO

Spatial leakage effects are particularly confounding for seed-based investigations of brain networks using source-level electroencephalography (EEG) or magnetoencephalography (MEG). Various methods designed to avoid this issue have been introduced but are limited to particular assumptions about its temporal characteristics. Here, we investigate the usefulness of a model-based geometric correction scheme (GCS) to suppress spatial leakage emanating from the seed location. We analyze its properties theoretically and then assess potential advantages and limitations with simulated and experimental MEG data (resting state and auditory-motor task). To do so, we apply Minimum Norm Estimation (MNE) for source reconstruction and use variation of error parameters, statistical gauging of spatial leakage correction and comparison with signal orthogonalization. Results show that the GCS has a local (i.e., near the seed) effect only, in line with the geometry of MNE spatial leakage, and is able to map spatially all types of brain interactions, including linear correlations eliminated after signal orthogonalization. Furthermore, it is robust against the introduction of forward model errors. On the other hand, the GCS can be affected by local overcorrection effects and seed mislocation. These issues arise with signal orthogonalization too, although significantly less extensively, so the two approaches complement each other. The GCS thus appears to be a valuable addition to the spatial leakage correction toolkits for seed-based FC analyses in source-projected MEG/EEG data.


Assuntos
Mapeamento Encefálico/métodos , Interpretação Estatística de Dados , Eletroencefalografia/métodos , Magnetoencefalografia/métodos , Humanos
15.
Epilepsia ; 56(3): e26-32, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25690317

RESUMO

Fever-associated syndromic epilepsies ranging from febrile seizures plus (FS+) to Dravet syndrome have a significant genetic component. However, apart from SCN1A mutations in >80% of patients with Dravet syndrome, the genetic underpinnings of these epilepsies remain largely unknown. Therefore, we performed a genome-wide screening for copy number variations (CNVs) in 36 patients with SCN1A-negative fever-associated syndromic epilepsies. Phenotypes included Dravet syndrome (n = 23; 64%), genetic epilepsy with febrile seizures plus (GEFS+) and febrile seizures plus (FS+) (n = 11; 31%) and unclassified fever-associated epilepsies (n = 2; 6%). Array comparative genomic hybridization (CGH) was performed using Agilent 4 × 180K arrays. We identified 13 rare CNVs in 8 (22%) of 36 individuals. These included known pathogenic CNVs in 4 (11%) of 36 patients: a 1q21.1 duplication in a proband with Dravet syndrome, a 14q23.3 deletion in a proband with FS+, and two deletions at 16p11.2 and 1q44 in two individuals with fever-associated epilepsy with concomitant autism and/or intellectual disability. In addition, a 3q13.11 duplication in a patient with FS+ and two de novo duplications at 7p14.2 and 18q12.2 in a patient with atypical Dravet syndrome were classified as likely pathogenic. Six CNVs were of unknown significance. The identified genomic aberrations overlap with known neurodevelopmental disorders, suggesting that fever-associated epilepsy syndromes may be a recurrent clinical presentation of known microdeletion syndromes.


Assuntos
Variações do Número de Cópias de DNA/genética , Epilepsia/etiologia , Epilepsia/genética , Febre/complicações , Canal de Sódio Disparado por Voltagem NAV1.1/genética , Adolescente , Adulto , Criança , Pré-Escolar , Aberrações Cromossômicas , Deleção Cromossômica , Hibridização Genômica Comparativa , Feminino , Estudos de Associação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Adulto Jovem
16.
Epilepsia ; 56(8): 1185-97, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26122601

RESUMO

Evidence-based guidelines, or recommendations, for the management of infants with seizures are lacking. A Task Force of the Commission of Pediatrics developed a consensus document addressing diagnostic markers, management interventions, and outcome measures for infants with seizures. Levels of evidence to support recommendations and statements were assessed using the American Academy of Neurology Guidelines and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. The report contains recommendations for different levels of care, noting which would be regarded as standard care, compared to optimal care, or "state of the art" interventions. The incidence of epilepsy in the infantile period is the highest of all age groups (strong evidence), with epileptic spasms the largest single subgroup and, in the first 2 years of life, febrile seizures are the most commonly occurring seizures. Acute intervention at the time of a febrile seizure does not alter the risk for subsequent epilepsy (class 1 evidence). The use of antipyretic agents does not alter the recurrence rate (class 1 evidence), and there is no evidence to support initiation of regular antiepileptic drugs for simple febrile seizures (class 1 evidence). Infants with abnormal movements whose routine electroencephalography (EEG) study is not diagnostic, would benefit from video-EEG analysis, or home video to capture events (expert opinion, level U recommendation). Neuroimaging is recommended at all levels of care for infants presenting with epilepsy, with magnetic resonance imaging (MRI) recommended as the standard investigation at tertiary level (level A recommendation). Genetic screening should not be undertaken at primary or secondary level care (expert opinion). Standard care should permit genetic counseling by trained personal at all levels of care (expert opinion). Genetic evaluation for Dravet syndrome, and other infantile-onset epileptic encephalopathies, should be available in tertiary care (weak evidence, level C recommendation). Patients should be referred from primary or secondary to tertiary level care after failure of one antiepileptic drug (standard care) and optimal care equates to referral of all infants after presentation with a seizure (expert opinion, level U evidence). Infants with recurrent seizures warrant urgent assessment for initiation of antiepileptic drugs (expert opinion, level U recommendation). Infantile encephalopathies should have rapid introduction and increment of antiepileptic drug dosage (expert opinion, level U recommendation). There is no high level evidence to support any particular current agents for use in infants with seizures. For focal seizures, levetiracetam is effective (strong evidence); for generalized seizures, weak evidence supports levetiracetam, valproate, lamotrigine, topiramate, and clobazam; for Dravet syndrome, strong evidence supports that stiripentol is effective (in combination with valproate and clobazam), whereas weak evidence supports that topiramate, zonisamide, valproate, bromide, and the ketogenic diet are possibly effective; and for Ohtahara syndrome, there is weak evidence that most antiepileptic drugs are poorly effective. For epileptic spasms, clinical suspicion remains central to the diagnosis and is supported by EEG, which ideally is prolonged (level C recommendation). Adrenocorticotropic hormone (ACTH) is preferred for short-term control of epileptic spasms (level B recommendation), oral steroids are probably effective in short-term control of spasms (level C recommendation), and a shorter interval from the onset of spasms to treatment initiation may improve long-term neurodevelopmental outcome (level C recommendation). The ketogenic diet is the treatment of choice for epilepsy related to glucose transporter 1 deficiency syndrome and pyruvate dehydrogenase deficiency (expert opinion, level U recommendation). The identification of patients as potential candidates for epilepsy surgery should be part of standard practice at primary and secondary level care. Tertiary care facilities with experience in epilepsy surgery should undertake the screening for epilepsy surgical candidates (level U recommendation). There is insufficient evidence to conclude if there is benefit from vagus nerve stimulation (level U recommendation). The key recommendations are summarized into an executive summary. The full report is available as Supporting Information. This report provides a comprehensive foundation of an approach to infants with seizures, while identifying where there are inadequate data to support recommended practice, and where further data collection is needed to address these deficits.


Assuntos
Guias de Prática Clínica como Assunto , Convulsões Febris/terapia , Espasmos Infantis/terapia , Comitês Consultivos , Anticonvulsivantes , Gerenciamento Clínico , Eletroencefalografia , Epilepsia/diagnóstico , Epilepsia/terapia , Humanos , Lactente , Recém-Nascido , Neuroimagem , Convulsões Febris/diagnóstico , Espasmos Infantis/diagnóstico
17.
Brain Topogr ; 28(1): 95-103, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24752907

RESUMO

Reporting the ink color of a written word when it is itself a color name incongruent with the ink color (e.g. "red" printed in blue) induces a robust interference known as the Stroop effect. Although this effect has been the subject of numerous functional neuroimaging studies, its neuronal substrate is still a matter of debate. Here, we investigated the spatiotemporal dynamics of interference-related neural events using magnetoencephalography (MEG) and voxel-based analyses (SPM8). Evoked magnetic fields (EMFs) were acquired in 12 right-handed healthy subjects performing a color-word Stroop task. Behavioral results disclosed a classic interference effect with longer mean reaction times for incongruent than congruent stimuli. At the group level, EMFs' differences between incongruent and congruent trials spanned from 380 to 700 ms post-stimulus onset. Underlying neural sources were identified in the left pre-supplementary motor area (pre-SMA) and in the left posterior parietal cortex (PPC) confirming the role of these regions in conflict processing.


Assuntos
Encéfalo/fisiologia , Conflito Psicológico , Função Executiva/fisiologia , Desempenho Psicomotor/fisiologia , Teste de Stroop , Percepção Visual/fisiologia , Adulto , Feminino , Humanos , Magnetoencefalografia , Masculino , Estimulação Luminosa , Tempo de Reação , Processamento de Sinais Assistido por Computador
18.
Epilepsy Behav ; 43: 16-23, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25546732

RESUMO

OBJECTIVE: Declarative memory is consolidated during sleep in healthy children. We tested the hypothesis that consolidation processes are impaired in idiopathic focal epilepsies (IFE) of childhood in association with frequent interictal epileptiform discharges (IEDs) during sleep. METHODS: A verbal (word-pair association) and a nonverbal (2D object location) declarative memory task were administrated to 15 children with IFEs and 8 control children 6-12 years of age. Patients had either centrotemporal (11 patients) or occipital (4 patients) IEDs. All but 3 patients had a history of unprovoked seizures, and 6 of them were treated with valproate (VPA). The learning procedure (location of object pairs presented on a grid; association of word pairs) was executed in the evening. Retrieval was tested immediately after learning and on the next morning after a night of sleep. Participants were tested twice, once in natural home conditions and one month later in the unfamiliar conditions of the sleep unit under EEG monitoring. RESULTS: Overnight recall performance was lower in children with IFE than in control children on both tasks (ps<0.05). Performance in home conditions was similar to that in hospital conditions. Higher spike-wave index (SWI) during nonrapid eye movement (NREM) sleep was associated with poorer performance in the nonverbal task (p<0.05). Valproate treatment was not associated with overnight recall performance for both tasks (ps>0.05). CONCLUSION: Memory consolidation is impaired in IFE of childhood. The association between higher SWI during NREM sleep and poorer nonverbal declarative memory consolidation supports the hypothesis that interictal epileptic activity could disrupt sleep memory consolidation.


Assuntos
Epilepsias Parciais/complicações , Epilepsias Parciais/psicologia , Transtornos da Memória/etiologia , Transtornos da Memória/psicologia , Transtornos do Sono-Vigília/etiologia , Transtornos do Sono-Vigília/psicologia , Anticonvulsivantes/efeitos adversos , Anticonvulsivantes/uso terapêutico , Criança , Eletroencefalografia , Epilepsia Rolândica/complicações , Epilepsia Rolândica/psicologia , Feminino , Humanos , Deficiências da Aprendizagem/etiologia , Deficiências da Aprendizagem/psicologia , Masculino , Rememoração Mental , Polissonografia , Desempenho Psicomotor , Convulsões/psicologia , Sono , Ácido Valproico/efeitos adversos , Ácido Valproico/uso terapêutico , Testes de Associação de Palavras
19.
Ann Neurol ; 74(3): 496-501, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23686771

RESUMO

We identified a small family with autosomal recessive, infantile onset epilepsy and intellectual disability. Exome sequencing identified a homozygous missense variant in the gene TNK2, encoding a brain-expressed tyrosine kinase. Sequencing of the coding region of TNK2 in 110 patients with a similar phenotype failed to detect further homozygote or compound heterozygote mutations. Pathogenicity of the variant is supported by the results of our functional studies, which demonstrated that the variant abolishes NEDD4 binding to TNK2, preventing its degradation after epidermal growth factor stimulation. Definitive proof of pathogenicity will require confirmation in unrelated patients.


Assuntos
Epilepsia/genética , Proteínas Tirosina Quinases/genética , Pré-Escolar , Feminino , Genótipo , Humanos , Lactente , Masculino , Mutação , Mutação de Sentido Incorreto , Linhagem , Análise de Sequência de DNA
20.
Brain Topogr ; 27(5): 620-34, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24777562

RESUMO

Functional connectivity studies conducted at the group level using magnetoencephalography (MEG) suggest that resting state networks (RSNs) emerge from the large-scale envelope correlation structure within spontaneous oscillatory brain activity. However, little is known about the consistency of MEG RSNs at the individual level. This paper investigates the inter- and intra-subject variability of three MEG RSNs (sensorimotor, auditory and visual) using seed-based source space envelope correlation analysis applied to 5 min of resting state MEG data acquired from a 306-channel whole-scalp neuromagnetometer (Elekta Oy, Helsinki, Finland) and source projected with minimum norm estimation. The main finding is that these three MEG RSNs exhibit substantial variability at the single-subject level across and within individuals, which depends on the RSN type, but can be reduced after averaging over subjects or sessions. Over- and under-estimations of true RSNs variability are respectively obtained using template seeds, which are potentially mislocated due to inter-subject variations, and a seed optimization method minimizing variability. In particular, bounds on the minimal number of subjects or sessions required to obtain highly consistent between- or within-subject averages of MEG RSNs are derived. Furthermore, MEG RSN topography positively correlates with their mean connectivity at the inter-subject level. These results indicate that MEG RSNs associated with primary cortices can be robustly extracted from seed-based envelope correlation and adequate averaging. MEG thus appears to be a valid technique to compare RSNs across subjects or conditions, at least when using the current methods.


Assuntos
Encéfalo/fisiologia , Magnetoencefalografia/métodos , Rede Nervosa/fisiologia , Adolescente , Adulto , Feminino , Humanos , Masculino , Reprodutibilidade dos Testes , Adulto Jovem
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