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1.
J Neurosci ; 43(18): 3259-3283, 2023 05 03.
Artículo en Inglés | MEDLINE | ID: mdl-37019622

RESUMEN

Neuronal activity propagates through the network during seizures, engaging brain dynamics at multiple scales. Such propagating events can be described through the avalanches framework, which can relate spatiotemporal activity at the microscale with global network properties. Interestingly, propagating avalanches in healthy networks are indicative of critical dynamics, where the network is organized to a phase transition, which optimizes certain computational properties. Some have hypothesized that the pathologic brain dynamics of epileptic seizures are an emergent property of microscale neuronal networks collectively driving the brain away from criticality. Demonstrating this would provide a unifying mechanism linking microscale spatiotemporal activity with emergent brain dysfunction during seizures. Here, we investigated the effect of drug-induced seizures on critical avalanche dynamics, using in vivo whole-brain two-photon imaging of GCaMP6s larval zebrafish (males and females) at single neuron resolution. We demonstrate that single neuron activity across the whole brain exhibits a loss of critical statistics during seizures, suggesting that microscale activity collectively drives macroscale dynamics away from criticality. We also construct spiking network models at the scale of the larval zebrafish brain, to demonstrate that only densely connected networks can drive brain-wide seizure dynamics away from criticality. Importantly, such dense networks also disrupt the optimal computational capacities of critical networks, leading to chaotic dynamics, impaired network response properties and sticky states, thus helping to explain functional impairments during seizures. This study bridges the gap between microscale neuronal activity and emergent macroscale dynamics and cognitive dysfunction during seizures.SIGNIFICANCE STATEMENT Epileptic seizures are debilitating and impair normal brain function. It is unclear how the coordinated behavior of neurons collectively impairs brain function during seizures. To investigate this we perform fluorescence microscopy in larval zebrafish, which allows for the recording of whole-brain activity at single-neuron resolution. Using techniques from physics, we show that neuronal activity during seizures drives the brain away from criticality, a regime that enables both high and low activity states, into an inflexible regime that drives high activity states. Importantly, this change is caused by more connections in the network, which we show disrupts the ability of the brain to respond appropriately to its environment. Therefore, we identify key neuronal network mechanisms driving seizures and concurrent cognitive dysfunction.


Asunto(s)
Epilepsia , Pez Cebra , Animales , Masculino , Femenino , Convulsiones/inducido químicamente , Encéfalo , Neuronas/fisiología , Modelos Neurológicos
2.
Proc Natl Acad Sci U S A ; 115(42): E9916-E9925, 2018 10 16.
Artículo en Inglés | MEDLINE | ID: mdl-30262654

RESUMEN

NMDA-receptor antibodies (NMDAR-Abs) cause an autoimmune encephalitis with a diverse range of EEG abnormalities. NMDAR-Abs are believed to disrupt receptor function, but how blocking this excitatory synaptic receptor can lead to paroxysmal EEG abnormalities-or even seizures-is poorly understood. Here we show that NMDAR-Abs change intrinsic cortical connections and neuronal population dynamics to alter the spectral composition of spontaneous EEG activity and predispose brain dynamics to paroxysmal abnormalities. Based on local field potential recordings in a mouse model, we first validate a dynamic causal model of NMDAR-Ab effects on cortical microcircuitry. Using this model, we then identify the key synaptic parameters that best explain EEG paroxysms in pediatric patients with NMDAR-Ab encephalitis. Finally, we use the mouse model to show that NMDAR-Ab-related changes render microcircuitry critically susceptible to overt EEG paroxysms when these key parameters are changed, even though the same parameter fluctuations are tolerated in the in silico model of the control condition. These findings offer mechanistic insights into circuit-level dysfunction induced by NMDAR-Ab.


Asunto(s)
Anticuerpos/efectos adversos , Encéfalo/efectos de los fármacos , Corteza Cerebral/efectos de los fármacos , Sincronización Cortical/efectos de los fármacos , Encefalitis/etiología , Receptores de N-Metil-D-Aspartato/inmunología , Animales , Encéfalo/inmunología , Encéfalo/metabolismo , Corteza Cerebral/inmunología , Corteza Cerebral/metabolismo , Encefalitis/metabolismo , Encefalitis/patología , Potenciales Postsinápticos Excitadores , Humanos , Ratones
3.
PLoS Comput Biol ; 14(8): e1006375, 2018 08.
Artículo en Inglés | MEDLINE | ID: mdl-30138336

RESUMEN

Pathophysiological explanations of epilepsy typically focus on either the micro/mesoscale (e.g. excitation-inhibition imbalance), or on the macroscale (e.g. network architecture). Linking abnormalities across spatial scales remains difficult, partly because of technical limitations in measuring neuronal signatures concurrently at the scales involved. Here we use light sheet imaging of the larval zebrafish brain during acute epileptic seizure induced with pentylenetetrazole. Spectral changes of spontaneous neuronal activity during the seizure are then modelled using neural mass models, allowing Bayesian inference on changes in effective network connectivity and their underlying synaptic dynamics. This dynamic causal modelling of seizures in the zebrafish brain reveals concurrent changes in synaptic coupling at macro- and mesoscale. Fluctuations of both synaptic connection strength and their temporal dynamics are required to explain observed seizure patterns. These findings highlight distinct changes in local (intrinsic) and long-range (extrinsic) synaptic transmission dynamics as a possible seizure pathomechanism and illustrate how our Bayesian model inversion approach can be used to link existing neural mass models of seizure activity and novel experimental methods.


Asunto(s)
Calcio/metabolismo , Conectoma/métodos , Convulsiones/fisiopatología , Animales , Teorema de Bayes , Encéfalo/fisiopatología , Electroencefalografía , Epilepsia/fisiopatología , Larva/metabolismo , Modelos Neurológicos , Red Nerviosa/fisiología , Neuronas/fisiología , Convulsiones/inducido químicamente , Transmisión Sináptica/fisiología , Pez Cebra/embriología
4.
J Peripher Nerv Syst ; 19(3): 246-9, 2014 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-25413786

RESUMEN

The pathogenesis of Guillain-Barré syndrome (GBS) is considered to be, at least in part, mediated by autoantibodies directed against neuronal antigens. Antibodies to contactin-associated protein-like 2 (CASPR2), part of the voltage-gated potassium channel complex (VGKC-complex), are associated with neurological disease predominantly affecting the peripheral nervous system but are not known to be associated with GBS. We report two cases of ganglioside antibody-negative paediatric GBS associated with CASPR2 antibodies. Both patients made a complete clinical recovery. The tissue distribution and function of CASPR2 make it a biologically plausible autoimmune target in GBS and its clinical relevance in GBS should be determined in further studies.


Asunto(s)
Síndrome de Guillain-Barré/inmunología , Proteínas de la Membrana/inmunología , Proteínas del Tejido Nervioso/inmunología , Autoanticuerpos , Niño , Preescolar , Humanos , Masculino
5.
Nat Rev Neurol ; 18(7): 428-441, 2022 07.
Artículo en Inglés | MEDLINE | ID: mdl-35538233

RESUMEN

Status epilepticus is a life-threatening neurological emergency that affects both adults and children. Approximately 36% of episodes of status epilepticus do not respond to the current preferred first-line treatment, benzodiazepines. The proportion of episodes that are refractory to benzodiazepines is higher in low-income and middle-income countries (LMICs) than in high-income countries (HICs). Evidence suggests that longer episodes of status epilepticus alter brain physiology, thereby contributing to the emergence of benzodiazepine resistance. Such changes include alterations in GABAA receptor function and in the transmembrane gradient for chloride, both of which erode the ability of benzodiazepines to enhance inhibitory synaptic signalling. Often, current management guidelines for status epilepticus do not account for these duration-related changes in pathophysiology, which might differentially impact individuals in LMICs, where the average time taken to reach medical attention is longer than in HICs. In this Perspective article, we aim to combine clinical insights and the latest evidence from basic science to inspire a new, context-specific approach to efficiently managing status epilepticus.


Asunto(s)
Benzodiazepinas , Estado Epiléptico , Adulto , Anticonvulsivantes/uso terapéutico , Benzodiazepinas/farmacología , Benzodiazepinas/uso terapéutico , Niño , Humanos , Receptores de GABA-A/fisiología , Receptores de GABA-A/uso terapéutico , Estado Epiléptico/tratamiento farmacológico
6.
Commun Biol ; 5(1): 394, 2022 04 28.
Artículo en Inglés | MEDLINE | ID: mdl-35484213

RESUMEN

Network control theory provides a framework by which neurophysiological dynamics of the brain can be modelled as a function of the structural connectome constructed from diffusion MRI. Average controllability describes the ability of a region to drive the brain to easy-to-reach neurophysiological states whilst modal controllability describes the ability of a region to drive the brain to difficult-to-reach states. In this study, we identify increases in mean average and modal controllability in children with drug-resistant epilepsy compared to healthy controls. Using simulations, we purport that these changes may be a result of increased thalamocortical connectivity. At the node level, we demonstrate decreased modal controllability in the thalamus and posterior cingulate regions. In those undergoing resective surgery, we also demonstrate increased modal controllability of the resected parcels, a finding specific to patients who were rendered seizure free following surgery. Changes in controllability are a manifestation of brain network dysfunction in epilepsy and may be a useful construct to understand the pathophysiology of this archetypical network disease. Understanding the mechanisms underlying these controllability changes may also facilitate the design of network-focussed interventions that seek to normalise network structure and function.


Asunto(s)
Conectoma , Epilepsia Refractaria , Epilepsias Parciales , Epilepsia , Encéfalo/fisiología , Niño , Epilepsia Refractaria/diagnóstico por imagen , Epilepsia Refractaria/cirugía , Epilepsias Parciales/cirugía , Humanos
7.
Front Pharmacol ; 12: 788192, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34925043

RESUMEN

Variants of the SCN1A gene encoding the neuronal voltage-gated sodium channel NaV1.1 cause over 85% of all cases of Dravet syndrome, a severe and often pharmacoresistent epileptic encephalopathy with mostly infantile onset. But with the increased availability of genetic testing for patients with epilepsy, variants in SCN1A have now also been described in a range of other epilepsy phenotypes. The vast majority of these epilepsy-associated variants are de novo, and most are either nonsense variants that truncate the channel or missense variants that are presumed to cause loss of channel function. However, biophysical analysis has revealed a significant subset of missense mutations that result in increased excitability, further complicating approaches to precision pharmacotherapy for patients with SCN1A variants and epilepsy. We describe clinical and biophysical data of a familial SCN1A variant encoding the NaV1.1 L1624Q mutant. This substitution is located on the extracellular linker between S3 and S4 of Domain IV of NaV1.1 and is a rare case of a familial SCN1A variant causing an autosomal dominant frontal lobe epilepsy. We expressed wild-type (WT) and L1642Q channels in CHO cells. Using patch-clamp to characterize channel properties at several temperatures, we show that the L1624Q variant increases persistent current, accelerates fast inactivation onset and decreases current density. While SCN1A-associated epilepsy is typically considered a loss-of-function disease, our results put L1624Q into a growing set of mixed gain and loss-of-function variants in SCN1A responsible for epilepsy.

8.
Brain Commun ; 3(4): fcab235, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34755109

RESUMEN

Pathogenic variants in the voltage-gated sodium channel gene (SCN1A) are amongst the most common genetic causes of childhood epilepsies. There is considerable heterogeneity in both the types of causative variants and associated phenotypes; a recent expansion of the phenotypic spectrum of SCN1A associated epilepsies now includes an early onset severe developmental and epileptic encephalopathy with regression and a hyperkinetic movement disorder. Herein, we report a female with a developmental and degenerative epileptic-dyskinetic encephalopathy, distinct and more severe than classic Dravet syndrome. Clinical diagnostics indicated a paternally inherited c.5053G>T; p. A1685S variant of uncertain significance in SCN1A. Whole-exome sequencing detected a second de novo mosaic (18%) c.2345G>A; p. T782I likely pathogenic variant in SCN1A (maternal allele). Biophysical characterization of both mutant channels in a heterologous expression system identified gain-of-function effects in both, with a milder shift in fast inactivation of the p. A1685S channels; and a more severe persistent sodium current in the p. T782I. Using computational models, we show that large persistent sodium currents induce hyper-excitability in individual cortical neurons, thus relating the severe phenotype to the empirically quantified sodium channel dysfunction. These findings further broaden the phenotypic spectrum of SCN1A associated epilepsies and highlight the importance of testing for mosaicism in epileptic encephalopathies. Detailed biophysical evaluation and computational modelling further highlight the role of gain-of-function variants in the pathophysiology of the most severe phenotypes associated with SCN1A.

9.
Commun Biol ; 4(1): 136, 2021 01 29.
Artículo en Inglés | MEDLINE | ID: mdl-33514839

RESUMEN

Neurological disorders such as epilepsy arise from disrupted brain networks. Our capacity to treat these disorders is limited by our inability to map these networks at sufficient temporal and spatial scales to target interventions. Current best techniques either sample broad areas at low temporal resolution (e.g. calcium imaging) or record from discrete regions at high temporal resolution (e.g. electrophysiology). This limitation hampers our ability to understand and intervene in aberrations of network dynamics. Here we present a technique to map the onset and spatiotemporal spread of acute epileptic seizures in vivo by simultaneously recording high bandwidth microelectrocorticography and calcium fluorescence using transparent graphene microelectrode arrays. We integrate dynamic data features from both modalities using non-negative matrix factorization to identify sequential spatiotemporal patterns of seizure onset and evolution, revealing how the temporal progression of ictal electrophysiology is linked to the spatial evolution of the recruited seizure core. This integrated analysis of multimodal data reveals otherwise hidden state transitions in the spatial and temporal progression of acute seizures. The techniques demonstrated here may enable future targeted therapeutic interventions and novel spatially embedded models of local circuit dynamics during seizure onset and evolution.


Asunto(s)
Ondas Encefálicas , Señalización del Calcio , Corteza Cerebral/fisiopatología , Electrocorticografía/instrumentación , Grafito , Microelectrodos , Imagen Óptica/instrumentación , Convulsiones/diagnóstico , Animales , Corteza Cerebral/metabolismo , Modelos Animales de Enfermedad , Diseño de Equipo , Ratones Transgénicos , Miniaturización , Valor Predictivo de las Pruebas , Convulsiones/genética , Convulsiones/metabolismo , Convulsiones/fisiopatología , Procesamiento de Señales Asistido por Computador , Factores de Tiempo
10.
Commun Biol ; 4(1): 1106, 2021 09 20.
Artículo en Inglés | MEDLINE | ID: mdl-34545200

RESUMEN

Seizures are a prominent feature in N-Methyl-D-Aspartate receptor antibody (NMDAR antibody) encephalitis, a distinct neuro-immunological disorder in which specific human autoantibodies bind and crosslink the surface of NMDAR proteins thereby causing internalization and a state of NMDAR hypofunction. To further understand ictogenesis in this disorder, and to test a potential treatment compound, we developed an NMDAR antibody mediated rat seizure model that displays spontaneous epileptiform activity in vivo and in vitro. Using a combination of electrophysiological and dynamic causal modelling techniques we show that, contrary to expectation, reduction of synaptic excitatory, but not inhibitory, neurotransmission underlies the ictal events through alterations in the dynamical behaviour of microcircuits in brain tissue. Moreover, in vitro application of a neurosteroid, pregnenolone sulphate, that upregulates NMDARs, reduced established ictal activity. This proof-of-concept study highlights the complexity of circuit disturbances that may lead to seizures and the potential use of receptor-specific treatments in antibody-mediated seizures and epilepsy.


Asunto(s)
Autoanticuerpos/efectos adversos , Transmisión Sináptica , Animales , Encefalitis Antirreceptor N-Metil-D-Aspartato/inducido químicamente , Modelos Animales de Enfermedad , Masculino , Ratas , Ratas Wistar
11.
Epilepsy Curr ; 20(2): 108-110, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-32100552

RESUMEN

[Box: see text].

12.
Curr Biol ; 29(23): R1248-R1251, 2019 12 02.
Artículo en Inglés | MEDLINE | ID: mdl-31794761

RESUMEN

Investigations of the mechanisms generating epileptic seizures have primarily focused on neurons. However, more systemic research of brain circuits has highlighted an important role of non-neuronal cells such as glia in the genesis and spreading of generalized seizures in the brain.


Asunto(s)
Epilepsia , Neuroglía , Encéfalo , Humanos , Neuronas , Convulsiones
13.
Artículo en Inglés | MEDLINE | ID: mdl-30115499

RESUMEN

BACKGROUND: Disturbances in N-methyl-D-aspartate receptors (NMDARs)-as implicated in patients with schizophrenia-can cause regionally specific electrophysiological effects. Both animal models of NMDAR blockade and clinical studies in patients with schizophrenia have suggested that behavioral phenotypes are associated with reduction in inhibition within the frontal cortex. METHODS: Here we investigate event-related potentials to a roving auditory oddball paradigm under ketamine in healthy human volunteers (N= 18; double-blind, placebo-controlled, crossover design). Using recent advances in Bayesian modeling of group effects in dynamic causal modeling, we fit biophysically plausible network models of the auditory processing hierarchy to whole-scalp event-related potential recordings. This allowed us to identify regionally specific effects of ketamine in a distributed network of interacting cortical sources. RESULTS: We show that the effect of ketamine is best explained as a selective change in intrinsic inhibition, with a pronounced ketamine-induced reduction of inhibitory interneuron connectivity in frontal sources, compared with temporal sources. Simulations of these changes in an integrated microcircuit model shows that they are associated with a reduction in superficial pyramidal cell activity that can explain drug effects observed in the event-related potential. CONCLUSIONS: These results are consistent with findings from invasive recordings in animal models exposed to NMDAR blockers, and provide evidence that inhibitory interneuron-specific NMDAR dysfunction may be sufficient to explain electrophysiological abnormalities induced by NMDAR blockade in human subjects.


Asunto(s)
Percepción Auditiva/fisiología , Potenciales Evocados Auditivos , Antagonistas de Aminoácidos Excitadores/administración & dosificación , Ketamina/administración & dosificación , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/fisiología , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Receptores de N-Metil-D-Aspartato/fisiología , Estimulación Acústica , Adulto , Percepción Auditiva/efectos de los fármacos , Teorema de Bayes , Estudios Cruzados , Método Doble Ciego , Humanos , Masculino , Modelos Neurológicos , Adulto Joven
14.
Dis Model Mech ; 12(11)2019 11 11.
Artículo en Inglés | MEDLINE | ID: mdl-31582559

RESUMEN

Epilepsy is a common primary neurological disorder characterized by the chronic tendency of a patient to experience epileptic seizures, which are abnormal body movements or cognitive states that result from excessive, hypersynchronous brain activity. Epilepsy has been found to have numerous etiologies and, although about two-thirds of epilepsies were classically considered idiopathic, the majority of those are now believed to be of genetic origin. Mutations in genes involved in gamma-aminobutyric acid (GABA)-mediated inhibitory neurotransmission have been associated with a broad range of epilepsy syndromes. Mutations in the GABA-A receptor gamma 2 subunit gene (GABRG2), for example, have been associated with absence epilepsy and febrile seizures in humans. Several rodent models of GABRG2 loss of function depict clinical features of the disease; however, alternative genetic models more amenable for the study of ictogenesis and for high-throughput screening purposes are still needed. In this context, we generated a gabrg2 knockout (KO) zebrafish model (which we called R23X) that displayed light/dark-induced reflex seizures. Through high-resolution in vivo calcium imaging of the brain, we showed that this phenotype is associated with widespread increases in neuronal activity that can be effectively alleviated by the anti-epileptic drug valproic acid. Moreover, these seizures only occur at the larval stages but disappear after 1 week of age. Interestingly, our whole-transcriptome analysis showed that gabrg2 KO does not alter the expression of genes in the larval brain. As a result, the gabrg2-/- zebrafish is a novel in vivo genetic model of early epilepsies that opens new doors to investigate ictogenesis and for further drug-screening assays.


Asunto(s)
Modelos Animales de Enfermedad , Receptores de GABA-A/fisiología , Convulsiones/etiología , Animales , Técnicas de Inactivación de Genes , Larva , Luz , Subunidades de Proteína/fisiología , Receptores de GABA-A/deficiencia , Reflejo/fisiología , Transcriptoma , Ácido Valproico/uso terapéutico , Pez Cebra
15.
Lancet Infect Dis ; 18(1): e1-e13, 2018 01.
Artículo en Inglés | MEDLINE | ID: mdl-28844634

RESUMEN

Microcephaly is an important sign of neurological malformation and a predictor of future disability. The 2015-16 outbreak of Zika virus and congenital Zika infection brought the world's attention to links between Zika infection and microcephaly. However, Zika virus is only one of the infectious causes of microcephaly and, although the contexts in which they occur vary greatly, all are of concern. In this Review, we summarise important aspects of major congenital infections that can cause microcephaly, and describe the epidemiology, transmission, clinical features, pathogenesis, management, and long-term consequences of these infections. We include infections that cause substantial impairment: cytomegalovirus, herpes simplex virus, rubella virus, Toxoplasma gondii, and Zika virus. We highlight potential issues with classification of microcephaly and show how some infants affected by congenital infection might be missed or incorrectly diagnosed. Although Zika virus has brought the attention of the world to the problem of microcephaly, prevention of all infectious causes of microcephaly and appropriately managing its consequences remain important global public health priorities.


Asunto(s)
Infecciones del Sistema Nervioso Central/congénito , Infecciones del Sistema Nervioso Central/complicaciones , Manejo de la Enfermedad , Microcefalia/epidemiología , Microcefalia/etiología , Infecciones del Sistema Nervioso Central/epidemiología , Infecciones del Sistema Nervioso Central/patología , Humanos , Microcefalia/diagnóstico , Microcefalia/patología
16.
Neuroimage Clin ; 15: 682-688, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28702345

RESUMEN

In this opinion paper, we describe a combined view of functional and effective brain connectivity along with the free-energy principle for investigating persistent disruptions in brain networks of patients with focal epilepsy. These changes are likely reflected in effective connectivity along the cortical hierarchy and construct the basis of increased local functional connectivity in focal epilepsy. We propose a testable framework based on dynamic causal modelling and functional connectivity analysis with the capacity of explaining commonly observed connectivity changes during interictal periods. We then hypothesise their possible relation with disrupted free-energy minimisation in the Bayesian brain. This may offer a new approach for neuroimaging to specifically develop and address hypotheses regarding the network pathomechanisms underlying epileptic phenotypes.


Asunto(s)
Encéfalo/fisiopatología , Epilepsias Parciales/fisiopatología , Modelos Neurológicos , Vías Nerviosas/fisiopatología , Teorema de Bayes , Humanos
18.
Front Neurol ; 7: 130, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27559330

RESUMEN

Narcolepsy with cataplexy is a rare, but important differential diagnosis for daytime sleepiness and atonic paroxysms in an adolescent. A recent increase in incidence in the pediatric age group probably linked to the use of the Pandemrix influenza vaccine in 2009, has increased awareness that different environmental factors can "trigger" narcolepsy with cataplexy in a genetically susceptible population. Here, we describe the case of a 13-year-old boy with narcolepsy following yellow fever vaccination. He carries the HLA DQB1*0602 haplotype strongly associated with narcolepsy and cataplexy. Polysomnography showed rapid sleep onset with rapid eye movement (REM) latency of 47 min, significant sleep fragmentation and a mean sleep latency of 1.6 min with sleep onset REM in four out of four nap periods. Together with the clinical history, these findings are diagnostic of narcolepsy type 1. The envelope protein E of the yellow fever vaccine strain 17D has significant amino acid sequence overlap with both hypocretin and the hypocretin receptor 2 receptors in protein regions that are predicted to act as epitopes for antibody production. These findings raise the question whether the yellow fever vaccine strain may, through a potential molecular mimicry mechanism, be another infectious trigger for this neuro-immunological disorder.

19.
Neurol Genet ; 2(2): e56, 2016 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-27123475

RESUMEN

OBJECTIVE: To identify shared genes and pathways between common absence epilepsy (AE) subtypes (childhood absence epilepsy [CAE], juvenile absence epilepsy [JAE], and unclassified absence epilepsy [UAE]) that may indicate common mechanisms for absence seizure generation and potentially a diagnostic continuum. METHODS: We used high-density single-nucleotide polymorphism arrays to analyze genome-wide rare copy number variation (CNV) in a cohort of 144 children with AEs (95 CAE, 26 UAE, and 23 JAE). RESULTS: We identified CNVs that are known risk factors for AE in 4 patients, including 3x 15q11.2 deletion. We also expanded the phenotype at 4 regions more commonly identified in other neurodevelopmental disorders: 1p36.33 duplication, 1q21.1 deletion, 22q11.2 duplication, and Xp22.31 deletion and duplication. Fifteen patients (10.5%) were found to carry rare CNVs that disrupt genes associated with neuronal development and function (8 CAE, 2 JAE, and 5 UAE). Four categories of protein are each disrupted by several CNVs: (1) synaptic vesicle membrane or vesicle endocytosis, (2) synaptic cell adhesion, (3) synapse organization and motility via actin, and (4) gap junctions. CNVs within these categories are shared across the AE subtypes. CONCLUSIONS: Our results have reinforced the complex and heterogeneous nature of the AEs and their potential for shared genetic mechanisms and have highlighted several pathways that may be important in epileptogenesis of absence seizures.

20.
Neuropsychologia ; 50(5): 810-5, 2012 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-22285903

RESUMEN

Historically, most theoretical accounts of hemispheric specialisation have proposed a single underlying factor that leads to left hemisphere language and right hemisphere visuospatial processing in the majority of people. More recently empirical evidence has started to challenge this view, suggesting lateralisation of language and visuospatial attention are independent. However, so far studies did not control for a possible confound, task difficulty. For this study, 20 healthy right-handed volunteers underwent functional laterality assessment using functional transcranial Doppler ultrasound (fTCD). We assessed laterality using both a word generation task and a novel variation of the visuospatial landmark task that can be adjusted along two dimensions of difficulty (temporal and spatial). The visuospatial laterality measures were highly intercorrelated and unaffected by task difficulty. Furthermore, there was no correlation between visuospatial and verbal lateralisation within individuals - neither qualitatively (in direction of lateralisation), nor quantitatively (in laterality index size). These results substantiate a growing body of evidence suggesting multiple independent biases leading to the hemispheric lateralisation of different cognitive domains, thus further questioning previously accepted models of laterality development and evolution.


Asunto(s)
Atención/fisiología , Corteza Cerebral/diagnóstico por imagen , Dominancia Cerebral/fisiología , Lenguaje , Ultrasonografía Doppler Transcraneal , Percepción Visual/fisiología , Adulto , Mapeo Encefálico , Circulación Cerebrovascular , Femenino , Humanos , Masculino , Pruebas Neuropsicológicas , Vocabulario , Adulto Joven
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