Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 53
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Sci Rep ; 11(1): 19025, 2021 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-34561483

RESUMO

The success of epilepsy surgery in patients with refractory epilepsy depends upon correct identification of the epileptogenic zone (EZ) and an optimal choice of the resection area. In this study we developed individualized computational models based upon structural brain networks to explore the impact of different virtual resections on the propagation of seizures. The propagation of seizures was modelled as an epidemic process [susceptible-infected-recovered (SIR) model] on individual structural networks derived from presurgical diffusion tensor imaging in 19 patients. The candidate connections for the virtual resection were all connections from the clinically hypothesized EZ, from which the seizures were modelled to start, to other brain areas. As a computationally feasible surrogate for the SIR model, we also removed the connections that maximally reduced the eigenvector centrality (EC) (large values indicate network hubs) of the hypothesized EZ, with a large reduction meaning a large effect. The optimal combination of connections to be removed for a maximal effect were found using simulated annealing. For comparison, the same number of connections were removed randomly, or based on measures that quantify the importance of a node or connection within the network. We found that 90% of the effect (defined as reduction of EC of the hypothesized EZ) could already be obtained by removing substantially less than 90% of the connections. Thus, a smaller, optimized, virtual resection achieved almost the same effect as the actual surgery yet at a considerably smaller cost, sparing on average 27.49% (standard deviation: 4.65%) of the connections. Furthermore, the maximally effective connections linked the hypothesized EZ to hubs. Finally, the optimized resection was equally or more effective than removal based on structural network characteristics both regarding reducing the EC of the hypothesized EZ and seizure spreading. The approach of using reduced EC as a surrogate for simulating seizure propagation can suggest more restrictive resection strategies, whilst obtaining an almost optimal effect on reducing seizure propagation, by taking into account the unique topology of individual structural brain networks of patients.

2.
Cereb Cortex ; 2021 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-34564728

RESUMO

Temporal lobe epilepsy (TLE) patients are at risk of memory deficits, which have been linked to functional network disturbances, particularly of integration of the default mode network (DMN). However, the cellular substrates of functional network integration are unknown. We leverage a unique cross-scale dataset of drug-resistant TLE patients (n = 31), who underwent pseudo resting-state functional magnetic resonance imaging (fMRI), resting-state magnetoencephalography (MEG) and/or neuropsychological testing before neurosurgery. fMRI and MEG underwent atlas-based connectivity analyses. Functional network centrality of the lateral middle temporal gyrus, part of the DMN, was used as a measure of local network integration. Subsequently, non-pathological cortical tissue from this region was used for single cell morphological and electrophysiological patch-clamp analysis, assessing integration in terms of total dendritic length and action potential rise speed. As could be hypothesized, greater network centrality related to better memory performance. Moreover, greater network centrality correlated with more integrative properties at the cellular level across patients. We conclude that individual differences in cognitively relevant functional network integration of a DMN region are mirrored by differences in cellular integrative properties of this region in TLE patients. These findings connect previously separate scales of investigation, increasing translational insight into focal pathology and large-scale network disturbances in TLE.

3.
Nat Commun ; 12(1): 4839, 2021 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-34376673

RESUMO

The ability to maintain a sequence of items in memory is a fundamental cognitive function. In the rodent hippocampus, the representation of sequentially organized spatial locations is reflected by the phase of action potentials relative to the theta oscillation (phase precession). We investigated whether the timing of neuronal activity relative to the theta brain oscillation also reflects sequence order in the medial temporal lobe of humans. We used a task in which human participants learned a fixed sequence of pictures and recorded single neuron and local field potential activity with implanted electrodes. We report that spikes for three consecutive items in the sequence (the preferred stimulus for each cell, as well as the stimuli immediately preceding and following it) were phase-locked at distinct phases of the theta oscillation. Consistent with phase precession, spikes were fired at progressively earlier phases as the sequence advanced. These findings generalize previous findings in the rodent hippocampus to the human temporal lobe and suggest that encoding stimulus information at distinct oscillatory phases may play a role in maintaining sequential order in memory.


Assuntos
Potenciais de Ação/fisiologia , Epilepsia/fisiopatologia , Aprendizagem/fisiologia , Neurônios/fisiologia , Ritmo Teta/fisiologia , Adolescente , Adulto , Epilepsia/diagnóstico , Feminino , Hipocampo/citologia , Hipocampo/fisiologia , Humanos , Masculino , Modelos Neurológicos , Neurônios/citologia , Estimulação Luminosa/métodos , Lobo Temporal/citologia , Lobo Temporal/fisiologia , Adulto Jovem
4.
Acta Neuropathol ; 142(4): 729-759, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34292399

RESUMO

Neuronal dysfunction due to iron accumulation in conjunction with reactive oxygen species (ROS) could represent an important, yet underappreciated, component of the epileptogenic process. However, to date, alterations in iron metabolism in the epileptogenic brain have not been addressed in detail. Iron-related neuropathology and antioxidant metabolic processes were investigated in resected brain tissue from patients with temporal lobe epilepsy and hippocampal sclerosis (TLE-HS), post-mortem brain tissue from patients who died after status epilepticus (SE) as well as brain tissue from the electrically induced SE rat model of TLE. Magnetic susceptibility of the presumed seizure-onset zone from three patients with focal epilepsy was compared during and after seizure activity. Finally, the cellular effects of iron overload were studied in vitro using an acute mouse hippocampal slice preparation and cultured human fetal astrocytes. While iron-accumulating neurons had a pyknotic morphology, astrocytes appeared to acquire iron-sequestrating capacity as indicated by prominent ferritin expression and iron retention in the hippocampus of patients with SE or TLE. Interictal to postictal comparison revealed increased magnetic susceptibility in the seizure-onset zone of epilepsy patients. Post-SE rats had consistently higher hippocampal iron levels during the acute and chronic phase (when spontaneous recurrent seizures are evident). In vitro, in acute slices that were exposed to iron, neurons readily took up iron, which was exacerbated by induced epileptiform activity. Human astrocyte cultures challenged with iron and ROS increased their antioxidant and iron-binding capacity, but simultaneously developed a pro-inflammatory phenotype upon chronic exposure. These data suggest that seizure-mediated, chronic neuronal iron uptake might play a role in neuronal dysfunction/loss in TLE-HS. On the other hand, astrocytes sequester iron, specifically in chronic epilepsy. This function might transform astrocytes into a highly resistant, pro-inflammatory phenotype potentially contributing to pro-epileptogenic inflammatory processes.

5.
J Neurosci ; 41(31): 6714-6725, 2021 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-34183446

RESUMO

An indispensable feature of episodic memory is our ability to temporally piece together different elements of an experience into a coherent memory. Hippocampal time cells-neurons that represent temporal information-may play a critical role in this process. Although these cells have been repeatedly found in rodents, it is still unclear to what extent similar temporal selectivity exists in the human hippocampus. Here, we show that temporal context modulates the firing activity of human hippocampal neurons during structured temporal experiences. We recorded neuronal activity in the human brain while patients of either sex learned predictable sequences of pictures. We report that human time cells fire at successive moments in this task. Furthermore, time cells also signaled inherently changing temporal contexts during empty 10 s gap periods between trials while participants waited for the task to resume. Finally, population activity allowed for decoding temporal epoch identity, both during sequence learning and during the gap periods. These findings suggest that human hippocampal neurons could play an essential role in temporally organizing distinct moments of an experience in episodic memory.SIGNIFICANCE STATEMENT Episodic memory refers to our ability to remember the what, where, and when of a past experience. Representing time is an important component of this form of memory. Here, we show that neurons in the human hippocampus represent temporal information. This temporal signature was observed both when participants were actively engaged in a memory task, as well as during 10-s-long gaps when they were asked to wait before performing the task. Furthermore, the activity of the population of hippocampal cells allowed for decoding one temporal epoch from another. These results suggest a robust representation of time in the human hippocampus.

6.
Neurology ; 96(21): e2639-e2652, 2021 05 25.
Artigo em Inglês | MEDLINE | ID: mdl-33910938

RESUMO

OBJECTIVE: To identify the molecular signaling pathways underlying sudden unexpected death in epilepsy (SUDEP) and high-risk SUDEP compared to control patients with epilepsy. METHODS: For proteomics analyses, we evaluated the hippocampus and frontal cortex from microdissected postmortem brain tissue of 12 patients with SUDEP and 14 with non-SUDEP epilepsy. For transcriptomics analyses, we evaluated hippocampus and temporal cortex surgical brain tissue from patients with mesial temporal lobe epilepsy: 6 low-risk and 8 high-risk SUDEP as determined by a short (<50 seconds) or prolonged (≥50 seconds) postictal generalized EEG suppression (PGES) that may indicate severely depressed brain activity impairing respiration, arousal, and protective reflexes. RESULTS: In autopsy hippocampus and cortex, we observed no proteomic differences between patients with SUDEP and those with non-SUDEP epilepsy, contrasting with our previously reported robust differences between epilepsy and controls without epilepsy. Transcriptomics in hippocampus and cortex from patients with surgical epilepsy segregated by PGES identified 55 differentially expressed genes (37 protein-coding, 15 long noncoding RNAs, 3 pending) in hippocampus. CONCLUSION: The SUDEP proteome and high-risk SUDEP transcriptome were similar to those in other patients with epilepsy in hippocampus and cortex, consistent with diverse epilepsy syndromes and comorbid conditions associated with SUDEP. Studies with larger cohorts and different epilepsy syndromes, as well as additional anatomic regions, may identify molecular mechanisms of SUDEP.


Assuntos
Córtex Cerebral/fisiopatologia , Epilepsia/fisiopatologia , Hipocampo/fisiopatologia , Morte Súbita Inesperada na Epilepsia , Adulto , Criança , Feminino , Perfilação da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Proteômica , Transdução de Sinais/fisiologia
7.
J Clin Invest ; 131(1)2021 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-33141761

RESUMO

Matrix metalloproteinases (MMPs) are synthesized by neurons and glia and released into the extracellular space, where they act as modulators of neuroplasticity and neuroinflammatory agents. Development of epilepsy (epileptogenesis) is associated with increased expression of MMPs, and therefore, they may represent potential therapeutic drug targets. Using quantitative PCR (qPCR) and immunohistochemistry, we studied the expression of MMPs and their endogenous inhibitors tissue inhibitors of metalloproteinases (TIMPs) in patients with status epilepticus (SE) or temporal lobe epilepsy (TLE) and in a rat TLE model. Furthermore, we tested the MMP2/9 inhibitor IPR-179 in the rapid-kindling rat model and in the intrahippocampal kainic acid mouse model. In both human and experimental epilepsy, MMP and TIMP expression were persistently dysregulated in the hippocampus compared with in controls. IPR-179 treatment reduced seizure severity in the rapid-kindling model and reduced the number of spontaneous seizures in the kainic acid model (during and up to 7 weeks after delivery) without side effects while improving cognitive behavior. Moreover, our data suggest that IPR-179 prevented an MMP2/9-dependent switch-off normally restraining network excitability during the activity period. Since increased MMP expression is a prominent hallmark of the human epileptogenic brain and the MMP inhibitor IPR-179 exhibits antiseizure and antiepileptogenic effects in rodent epilepsy models and attenuates seizure-induced cognitive decline, it deserves further investigation in clinical trials.

8.
Glia ; 68(1): 60-75, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31408236

RESUMO

Temporal lobe epilepsy (TLE) is a chronic neurological disease in humans, which is refractory to pharmacological treatment in about 30% of the patients. Reactive glial cells are thought to play a major role during the development of epilepsy (epileptogenesis) via regulation of brain inflammation and remodeling of the extracellular matrix (ECM). These processes can be regulated by microRNAs (miRs), a class of small non-coding RNAs, which can control entire gene networks at a post-transcriptional level. The expression of miRs is known to change dynamically during epileptogenesis. miR-132 is one of the most commonly upregulated miRs in animal TLE models with important roles shown in neurons. However, the possible role of miR-132 in glia remains largely unknown. The aim of this study was to characterize the cell-type specific expression of miR-132 in the hippocampus of patients with TLE and during epileptogenesis in a rat TLE model. Furthermore, the potential role of miR-132 was investigated by transfection of human primary cultured astrocytes that were stimulated with the cytokines IL-1ß or TGF-ß1. We showed an increased expression of miR-132 in the human and rat epileptogenic hippocampus, particularly in glial cells. Transfection of miR-132 in human primary astrocytes reduced the expression of pro-epileptogenic COX-2, IL-1ß, TGF-ß2, CCL2, and MMP3. This suggests that miR-132, particularly in astrocytes, represents a potential therapeutic target that warrants further in vivo investigation.


Assuntos
Astrócitos/metabolismo , Epilepsia do Lobo Temporal/metabolismo , MicroRNAs/biossíntese , Neuroglia/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Astrócitos/patologia , Células Cultivadas , Epilepsia do Lobo Temporal/genética , Epilepsia do Lobo Temporal/patologia , Feminino , Expressão Gênica , Hipocampo/metabolismo , Hipocampo/patologia , Humanos , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade , Neuroglia/patologia , Ratos , Ratos Sprague-Dawley , Adulto Jovem
9.
Neurobiol Dis ; 134: 104612, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31533065

RESUMO

Our understanding of mesial temporal lobe epilepsy (MTLE), one of the most common form of drug-resistant epilepsy in humans, is derived mainly from clinical, imaging, and physiological data from humans and animal models. High-throughput gene expression studies of human MTLE have the potential to uncover molecular changes underlying disease pathogenesis along with novel therapeutic targets. Using RNA- and small RNA-sequencing in parrallel, we explored differentially expressed genes in the hippocampus and cortex of MTLE patients who had undergone surgical resection and non-epileptic controls. We identified differentially expressed genes in the hippocampus of MTLE patients and differentially expressed small RNAs across both the cortex and hippocampus. We found significant enrichment for astrocytic and microglial genes among up-regulated genes, and down regulation of neuron specific genes in the hippocampus of MTLE patients. The transcriptome profile of the small RNAs reflected disease state more robustly than mRNAs, even across brain regions which show very little pathology. While mRNAs segregated predominately by brain region for MTLE and controls, small RNAs segregated by disease state. In particular, our data suggest that specific miRNAs (e.g., let-7b-3p and let-7c-3p) may be key regulators of multiple pathways related to MTLE pathology. Further, we report a strong association of other small RNA species with MTLE pathology. As such we have uncovered novel elements that may contribute to the establishment and progression of MTLE pathogenesis and that could be leveraged as therapeutic targets.


Assuntos
Epilepsia do Lobo Temporal/genética , Pequeno RNA não Traduzido/genética , Adulto , Idoso , Feminino , Perfilação da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Transcriptoma , Adulto Jovem
10.
Front Cell Neurosci ; 13: 315, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31354435

RESUMO

Group I metabotropic glutamate receptors (mGluRs) mediate a range of signaling and plasticity processes in the brain and are of growing importance as potential therapeutic targets in clinical trials for neuropsychiatric and neurodevelopmental disorders (NDDs). Fundamental knowledge regarding the functional effects of mGluRs upon pyramidal neurons and interneurons is derived largely from rodent brain, and their effects upon human neurons are predominantly untested. We therefore addressed how group I mGluRs affect microcircuits in human neocortex. We show that activation of group I mGluRs elicits action potential firing in Martinotti cells, which leads to increased synaptic inhibition onto neighboring neurons. Some other interneurons, including fast-spiking interneurons, are depolarized but do not fire action potentials in response to group I mGluR activation. Furthermore, we confirm the existence of group I mGluR-mediated depression of excitatory synapses in human pyramidal neurons. We propose that the strong increase in inhibition and depression of excitatory synapses onto layer 2/3 pyramidal neurons upon group I mGluR activation likely results in a shift in the balance between excitation and inhibition in the human cortical network.

11.
Brain Pathol ; 29(3): 351-365, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30303592

RESUMO

Oxidative stress (OS) occurs in brains of patients with epilepsy and coincides with brain inflammation, and both phenomena contribute to seizure generation in animal models. We investigated whether expression of OS and brain inflammation markers co-occurred also in resected brain tissue of patients with epileptogenic cortical malformations: hemimegalencephaly (HME), focal cortical dysplasia (FCD) and cortical tubers in tuberous sclerosis complex (TSC). Moreover, we studied molecular mechanisms linking OS and inflammation in an in vitro model of neuronal function. Untangling interdependency and underlying molecular mechanisms might pose new therapeutic strategies for treating patients with drug-resistant epilepsy of different etiologies. Immunohistochemistry was performed for specific OS markers xCT and iNOS and brain inflammation markers TLR4, COX-2 and NF-κB in cortical tissue derived from patients with HME, FCD IIa, IIb and TSC. Additionally, we studied gene expression of these markers using the human neuronal cell line SH-SY5Y in which OS was induced using H2 O2 . OS markers were higher in dysmorphic neurons and balloon/giant cells in cortex of patients with FCD IIb or TSC. Expression of OS markers was positively correlated to expression of brain inflammation markers. In vitro, 100 µM, but not 50 µM, of H2 O2 increased expression of TLR4, IL-1ß and COX-2. We found that NF-κB signaling was activated only upon stimulation with 100 µM H2 O2 leading to upregulation of TLR4 signaling and IL-1ß. The NF-κB inhibitor TPCA-1 completely reversed this effect. Our results show that OS positively correlates with neuroinflammation and is particularly evident in brain tissue of patients with FCD IIb and TSC. In vitro, NF-κB is involved in the switch to an inflammatory state after OS. We propose that the extent of OS can predict the neuroinflammatory state of the brain. Additionally, antioxidant treatments may prevent the switch to inflammation in neurons thus targeting multiple epileptogenic processes at once.


Assuntos
Malformações do Desenvolvimento Cortical/metabolismo , Malformações do Desenvolvimento Cortical/fisiopatologia , Estresse Oxidativo/fisiologia , Adolescente , Adulto , Encéfalo/metabolismo , Linhagem Celular , Córtex Cerebral/metabolismo , Criança , Pré-Escolar , Epilepsia Resistente a Medicamentos/metabolismo , Epilepsia/metabolismo , Feminino , Hemimegalencefalia , Humanos , Lactente , Recém-Nascido , Inflamação/metabolismo , Masculino , Malformações do Desenvolvimento Cortical do Grupo I , Pessoa de Meia-Idade , NF-kappa B/metabolismo , Neurônios/metabolismo , Convulsões/fisiopatologia , Transdução de Sinais , Esclerose Tuberosa
12.
Elife ; 72018 12 18.
Artigo em Inglês | MEDLINE | ID: mdl-30561325

RESUMO

It is generally assumed that human intelligence relies on efficient processing by neurons in our brain. Although grey matter thickness and activity of temporal and frontal cortical areas correlate with IQ scores, no direct evidence exists that links structural and physiological properties of neurons to human intelligence. Here, we find that high IQ scores and large temporal cortical thickness associate with larger, more complex dendrites of human pyramidal neurons. We show in silico that larger dendritic trees enable pyramidal neurons to track activity of synaptic inputs with higher temporal precision, due to fast action potential kinetics. Indeed, we find that human pyramidal neurons of individuals with higher IQ scores sustain fast action potential kinetics during repeated firing. These findings provide the first evidence that human intelligence is associated with neuronal complexity, action potential kinetics and efficient information transfer from inputs to output within cortical neurons.


Assuntos
Encéfalo/fisiologia , Inteligência , Células Piramidais/fisiologia , Potenciais de Ação , Adolescente , Adulto , Idoso , Simulação por Computador , Feminino , Humanos , Testes de Inteligência , Masculino , Pessoa de Meia-Idade , Modelos Neurológicos , Adulto Jovem
13.
Nat Commun ; 9(1): 4101, 2018 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-30291244

RESUMO

A variety of inhibitory pathways encompassing different interneuron types shape activity of neocortical pyramidal neurons. While basket cells (BCs) mediate fast lateral inhibition between pyramidal neurons, Somatostatin-positive Martinotti cells (MCs) mediate a delayed form of lateral inhibition. Neocortical circuits are under control of acetylcholine, which is crucial for cortical function and cognition. Acetylcholine modulates MC firing, however, precisely how cholinergic inputs affect cortical lateral inhibition is not known. Here, we find that cholinergic inputs selectively augment and speed up lateral inhibition between pyramidal neurons mediated by MCs, but not by BCs. Optogenetically activated cholinergic inputs depolarize MCs through activation of ß2 subunit-containing nicotinic AChRs, not muscarinic AChRs, without affecting glutamatergic inputs to MCs. We find that these mechanisms are conserved in human neocortex. Cholinergic inputs thus enable cortical pyramidal neurons to recruit more MCs, and can thereby dynamically highlight specific circuit motifs, favoring MC-mediated pathways over BC-mediated pathways.


Assuntos
Neurônios Colinérgicos/fisiologia , Interneurônios/fisiologia , Neocórtex/fisiologia , Inibição Neural , Células Piramidais/fisiologia , Adulto , Animais , Feminino , Humanos , Masculino , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade
14.
Epilepsia ; 59(10): 1931-1944, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30194729

RESUMO

OBJECTIVE: Because brain inflammation may contribute to the pathophysiology of temporal lobe epilepsy (TLE), we investigated the expression of various inflammatory markers of the innate and adaptive immune system in the epileptogenic human and rat hippocampus in relation to seizure activity and blood-brain barrier (BBB) dysfunction. METHODS: Immunohistochemistry was performed using various immune cell markers (for microglia, monocytes, macrophages, T lymphocytes, and dendritic cells) on hippocampal sections of drug-resistant TLE patients and patients who died after status epilepticus. The expression of these markers was also studied in the electrical post-status epilepticus rat model for TLE, during the acute, latent, and chronic epileptic phase. BBB dysfunction was assessed using albumin immunohistochemistry and the BBB tracer fluorescein. RESULTS: Monocyte infiltration, microglia, and perivascular macrophage activation were persistently increased in both epileptogenic human and rat hippocampus, whereas T lymphocytes and dendritic cells were not or were scarcely detected. In addition to this, increased expression of C-C motif ligand 2 (CCL2) and osteopontin was observed. In humans, the expression of CD68 and CCL2 was related to the duration of epilepsy and type of pathology. In rats, the expression of CD68, CCL2, and the perivascular macrophage marker CD163 was related to the duration of the initial insult and to the number of spontaneous seizures. Interestingly, the number of CD163-positive perivascular macrophages was also positively correlated to BBB dysfunction in chronic epileptic rats. SIGNIFICANCE: These data suggest a proepileptogenic role for monocytes/macrophages and other cells of the innate immune response, possibly via increased BBB leakage, and indicate that T cells and dendritic cells, which are closely associated with the adaptive immune response, are only sparsely infiltrated during epileptogenesis in the electrical post-status epilepticus rat model. Future studies should reveal the relative importance of these immune cells and whether specific manipulation can modify or prevent epileptogenesis.


Assuntos
Barreira Hematoencefálica/fisiopatologia , Epilepsia do Lobo Temporal , Sistema Imunitário/fisiopatologia , Estado Epiléptico , Animais , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Encéfalo/imunologia , Encéfalo/metabolismo , Citocinas/metabolismo , Progressão da Doença , Eletroencefalografia , Epilepsia do Lobo Temporal/complicações , Epilepsia do Lobo Temporal/imunologia , Epilepsia do Lobo Temporal/patologia , Feminino , Fluoresceína/metabolismo , Regulação da Expressão Gênica/imunologia , Humanos , Masculino , Osteopontina/metabolismo , Ratos , Ratos Sprague-Dawley , Estado Epiléptico/complicações , Estado Epiléptico/imunologia , Estado Epiléptico/patologia
15.
Front Neurol ; 9: 647, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30131762

RESUMO

Objective: Epilepsy surgery results in seizure freedom in the majority of drug-resistant patients. To improve surgery outcome we studied whether MEG metrics combined with machine learning can improve localization of the epileptogenic zone, thereby enhancing the chance of seizure freedom. Methods: Presurgical interictal MEG recordings of 94 patients (64 seizure-free >1y post-surgery) were analyzed to extract four metrics in source space: delta power, low-to-high-frequency power ratio, functional connectivity (phase lag index), and minimum spanning tree betweenness centrality. At the group level, we estimated the overlap of the resection area with the five highest values for each metric and determined whether this overlap differed between surgery outcomes. At the individual level, those metrics were used in machine learning classifiers (linear support vector machine (SVM) and random forest) to distinguish between resection and non-resection areas and between surgery outcome groups. Results: The highest values, for all metrics, overlapped with the resection area in more than half of the patients, but the overlap did not differ between surgery outcome groups. The classifiers distinguished the resection areas from non-resection areas with 59.94% accuracy (95% confidence interval: 59.67-60.22%) for SVM and 60.34% (59.98-60.71%) for random forest, but could not differentiate seizure-free from not seizure-free patients [43.77% accuracy (42.08-45.45%) for SVM and 49.03% (47.25-50.82%) for random forest]. Significance: All four metrics localized the resection area but did not distinguish between surgery outcome groups, demonstrating that metrics derived from interictal MEG correspond to expert consensus based on several presurgical evaluation modalities, but do not yet localize the epileptogenic zone. Metrics should be improved such that they correspond to the resection area in seizure-free patients but not in patients with persistent seizures. It is important to test such localization strategies at an individual level, for example by using machine learning or individualized models, since surgery is individually tailored.

16.
J Neuroinflammation ; 15(1): 211, 2018 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-30031401

RESUMO

BACKGROUND: Temporal lobe epilepsy (TLE) is a chronic neurological disease, in which about 30% of patients cannot be treated adequately with anti-epileptic drugs. Brain inflammation and remodeling of the extracellular matrix (ECM) seem to play a major role in TLE. Matrix metalloproteinases (MMPs) are proteolytic enzymes largely responsible for the remodeling of the ECM. The inhibition of MMPs has been suggested as a novel therapy for epilepsy; however, available MMP inhibitors lack specificity and cause serious side effects. We studied whether MMPs could be modulated via microRNAs (miRNAs). Several miRNAs mediate inflammatory responses in the brain, which are known to control MMP expression. The aim of this study was to investigate whether an increased expression of MMPs after interleukin-1ß (IL-1ß) stimulation can be attenuated by inhibition of the inflammation-associated miR-155. METHODS: We investigated the expression of MMP2, MMP3, MMP9, and MMP14 in cultured human fetal astrocytes after stimulation with the pro-inflammatory cytokine IL-1ß. The cells were transfected with miR-155 antagomiR, and the effect on MMP3 expression was investigated using real-time quantitative PCR and Western blotting. Furthermore, we characterized MMP3 and miR-155 expression in brain tissue of TLE patients with hippocampal sclerosis (TLE-HS) and during epileptogenesis in a rat TLE model. RESULTS: Inhibition of miR-155 by the antagomiR attenuated MMP3 overexpression after IL-1ß stimulation in astrocytes. Increased expression of MMP3 and miR-155 was also evident in the hippocampus of TLE-HS patients and throughout epileptogenesis in the rat TLE model. CONCLUSIONS: Our experiments showed that MMP3 is dynamically regulated by seizures as shown by increased expression in TLE tissue and during different phases of epileptogenesis in the rat TLE model. MMP3 can be induced by the pro-inflammatory cytokine IL-1ß and is regulated by miR-155, suggesting a possible strategy to prevent epilepsy via reduction of inflammation.


Assuntos
Astrócitos/metabolismo , Regulação da Expressão Gênica/fisiologia , Metaloproteinase 3 da Matriz/metabolismo , MicroRNAs/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Astrócitos/efeitos dos fármacos , Encéfalo/citologia , Encéfalo/metabolismo , Proteínas de Ligação ao Cálcio , Citocinas/genética , Citocinas/metabolismo , Citocinas/farmacologia , Proteínas de Ligação a DNA/metabolismo , Modelos Animais de Doenças , Estimulação Elétrica , Feminino , Feto , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Metaloproteinase 3 da Matriz/genética , MicroRNAs/genética , Proteínas dos Microfilamentos , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/metabolismo , Ratos , Estado Epiléptico/metabolismo , Estado Epiléptico/patologia
17.
Mol Cell Neurosci ; 89: 49-59, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29625180

RESUMO

An imbalance between production and clearance of soluble amyloid-ß (Aß) initiates the pathological process in sporadic Alzheimer's disease (AD). Aß-specific antibodies seemed promising as therapeutic option in AD mouse models. In patients, however, vascular side-effects and Aß-antibody complex-induced microglial and/or perivascular macrophage inflammatory responses were encountered. To prevent inflammatory reactions, we designed a single chain variable fragment (scFv-h3D6), based on monoclonal antibody bapineuzumab (mAb-h3D6), but lacking the Fc region. ScFv-h3D6 reduced Aß-oligomer burden and prevented AD-associated behavioral and cellular changes in 3xTg-AD mice. As scFv-h3D6 lacks the Fc-tail, it cannot enhance Fc-receptor mediated Aß clearance by microglia and probably exerts its beneficial effects in 3xTg-AD mice through other mechanisms. ScFv-h3D6 restored the increased apoE and apoJ levels in 3xTg-AD brains back to normal. ApoE and apoJ influence cholesterol transport, Aß aggregation and clearance, and their genetic variants are risk factors for sporadic AD. Astrocytes are constitutive scavengers of soluble Aß from the CNS. We previously found apoE and apoJ to inhibit Aß uptake by adult human astrocytes, in vitro, and thus to potentially protect astrocytes from Aß cytotoxicity. In the present study, scFv-h3D6 and mAb-h3D6 inhibited Aß-oligomer uptake by adult human astrocytes. ApoE- and apoJ- mimetic peptides (MP) affected Aß uptake as well as Aß-induced cytokine release similar to intact apoE and apoJ, without interfering with the strong inhibitory effects of scFv-h3D6 on Aß-oligomer uptake. These results suggest that combining Aß-specific scFv and apoE-MP, that inhibits Aß oligomer-induced cytokine release by astrocytes, could offer advantages over currently used therapeutics.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Apolipoproteínas E/química , Astrócitos/metabolismo , Fragmentos de Peptídeos/farmacologia , Anticorpos de Cadeia Única/farmacologia , Adolescente , Adulto , Peptídeos beta-Amiloides/imunologia , Anticorpos Monoclonais Humanizados/química , Anticorpos Monoclonais Humanizados/imunologia , Astrócitos/efeitos dos fármacos , Células Cultivadas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fragmentos de Peptídeos/imunologia , Fragmentos de Peptídeos/metabolismo , Anticorpos de Cadeia Única/imunologia
18.
Glia ; 66(5): 1082-1097, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29384235

RESUMO

Astrocytes are important mediators of inflammatory processes in the brain and seem to play an important role in several neurological disorders, including epilepsy. Recent studies show that astrocytes produce several microRNAs, which may function as crucial regulators of inflammatory pathways and could be used as therapeutic target. We aim to study which miRNAs are produced by astrocytes during IL-1ß mediated inflammatory conditions in vitro, as well as their functional role and to validate these findings in human epileptogenic brain tissue. Sequencing was used to assess miRNA and mRNA expression in IL-1ß-stimulated human fetal astrocyte cultures. miRNAs were overexpressed in cell cultures using miRNA mimics. Expression of miRNAs in resected brain tissue from patients with tuberous sclerosis complex or temporal lobe epilepsy with hippocampal sclerosis was examined using in situ hybridization. Two differentially expressed miRNAs were found: miR146a and miR147b, which were associated with increased expression of genes related to the immune/inflammatory response. As previously reported for miR146a, overexpression of miR147b reduced the expression of the pro-inflammatory mediators IL-6 and COX-2 after IL-1ß stimulation in both astrocyte and tuberous sclerosis complex cell cultures. miR146a and miR147b overexpression decreased proliferation of astrocytes and promoted neuronal differentiation of human neural stem cells. Similarly to previous evidence for miR146a, miR147b was increased expressed in astrocytes in epileptogenic brain. Due to their anti-inflammatory effects, ability to restore aberrant astrocytic proliferation and promote neuronal differentiation, miR146a and miR147b deserve further investigation as potential therapeutic targets in neurological disorders associated with inflammation, such as epilepsy.


Assuntos
Astrócitos/imunologia , Inflamação/metabolismo , MicroRNAs/metabolismo , Astrócitos/patologia , Encéfalo/imunologia , Encéfalo/patologia , Encéfalo/cirurgia , Diferenciação Celular/fisiologia , Proliferação de Células/fisiologia , Células Cultivadas , Ciclo-Oxigenase 2/metabolismo , Epilepsia do Lobo Temporal/metabolismo , Epilepsia do Lobo Temporal/patologia , Epilepsia do Lobo Temporal/cirurgia , Humanos , Inflamação/patologia , Interleucina-1beta , Interleucina-6/metabolismo , Células-Tronco Neurais/metabolismo , RNA Mensageiro/metabolismo , Esclerose Tuberosa/metabolismo , Esclerose Tuberosa/patologia , Esclerose Tuberosa/cirurgia
19.
N Engl J Med ; 377(17): 1648-1656, 2017 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-29069555

RESUMO

BACKGROUND: Detailed neuropathological information on the structural brain lesions underlying seizures is valuable for understanding drug-resistant focal epilepsy. METHODS: We report the diagnoses made on the basis of resected brain specimens from 9523 patients who underwent epilepsy surgery for drug-resistant seizures in 36 centers from 12 European countries over 25 years. Histopathological diagnoses were determined through examination of the specimens in local hospitals (41%) or at the German Neuropathology Reference Center for Epilepsy Surgery (59%). RESULTS: The onset of seizures occurred before 18 years of age in 75.9% of patients overall, and 72.5% of the patients underwent surgery as adults. The mean duration of epilepsy before surgical resection was 20.1 years among adults and 5.3 years among children. The temporal lobe was involved in 71.9% of operations. There were 36 histopathological diagnoses in seven major disease categories. The most common categories were hippocampal sclerosis, found in 36.4% of the patients (88.7% of cases were in adults), tumors (mainly ganglioglioma) in 23.6%, and malformations of cortical development in 19.8% (focal cortical dysplasia was the most common type, 52.7% of cases of which were in children). No histopathological diagnosis could be established for 7.7% of the patients. CONCLUSIONS: In patients with drug-resistant focal epilepsy requiring surgery, hippocampal sclerosis was the most common histopathological diagnosis among adults, and focal cortical dysplasia was the most common diagnosis among children. Tumors were the second most common lesion in both groups. (Funded by the European Union and others.).


Assuntos
Neoplasias Encefálicas/patologia , Encéfalo/patologia , Epilepsia/patologia , Hipocampo/patologia , Malformações do Desenvolvimento Cortical/patologia , Adulto , Fatores Etários , Idade de Início , Neoplasias Encefálicas/complicações , Criança , Bases de Dados como Assunto , Epilepsia/etiologia , Epilepsia/cirurgia , Europa (Continente) , Feminino , Humanos , Masculino , Malformações do Desenvolvimento Cortical/complicações , Lobo Temporal/patologia
20.
Epilepsia ; 58(8): 1462-1472, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28643873

RESUMO

OBJECTIVE: Inhibition of the mammalian target of rapamycin (mTOR) pathway reduces epileptogenesis in various epilepsy models, possibly by inhibition of inflammatory processes, which may include the proteasome system. To study the role of mTOR inhibition in the regulation of the proteasome system, we investigated (immuno)proteasome expression during epileptogenesis, as well as the effects of the mTOR inhibitor rapamycin. METHODS: The expression of constitutive (ß1, ß5) and immunoproteasome (ß1i, ß5i) subunits was investigated during epileptogenesis using immunohistochemistry in the electrical post-status epilepticus (SE) rat model for temporal lobe epilepsy (TLE). The effect of rapamycin was studied on (immuno)proteasome subunit expression in post-SE rats that were treated for 6 weeks. (Immuno)proteasome expression was validated in the brain tissue of patients who had SE or drug-resistant TLE and the effect of rapamycin was studied in primary human astrocyte cultures. RESULTS: In post-SE rats, increased (immuno)proteasome expression was detected throughout epileptogenesis in neurons and astrocytes within the hippocampus and piriform cortex and was most evident in rats that developed a progressive form of epilepsy. Rapamycin-treated post-SE rats had reduced (immuno)proteasome protein expression and a lower number of spontaneous seizures compared to vehicle-treated rats. (Immuno)proteasome expression was also increased in neurons and astrocytes within the human hippocampus after SE and in patients with drug-resistant TLE. In vitro studies using cultured human astrocytes showed that interleukin (IL)-1ß-induced (immuno)proteasome gene expression could be attenuated by rapamycin. SIGNIFICANCE: Because dysregulation of the (immuno)proteasome system is observed before the occurrence of spontaneous seizures in rats, is associated with progression of epilepsy, and can be modulated via the mTOR pathway, it may represent an interesting novel target for drug treatment in epilepsy.


Assuntos
Epilepsia do Lobo Temporal/induzido quimicamente , Epilepsia do Lobo Temporal/metabolismo , Regulação da Expressão Gênica/fisiologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Sirolimo/farmacologia , Serina-Treonina Quinases TOR/metabolismo , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Células Cultivadas , Modelos Animais de Doenças , Epilepsia do Lobo Temporal/patologia , Feto , Regulação da Expressão Gênica/efeitos dos fármacos , Proteína Glial Fibrilar Ácida/metabolismo , Hipocampo/metabolismo , Humanos , Interleucina-1beta/farmacologia , Masculino , Fosfopiruvato Hidratase/metabolismo , Subunidades Proteicas/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Fatores de Tempo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...