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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.
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
3.
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.

4.
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.

5.
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
6.
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.

7.
Cell Rep Med ; 1(7): 100101, 2020 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-33103128

RESUMO

Tumor-educated platelets (TEPs) are potential biomarkers for cancer diagnostics. We employ TEP-derived RNA panels, determined by swarm intelligence, to detect and monitor glioblastoma. We assessed specificity by comparing the spliced RNA profile of TEPs from glioblastoma patients with multiple sclerosis and brain metastasis patients (validation series, n = 157; accuracy, 80%; AUC, 0.81 [95% CI, 0.74-0.89; p < 0.001]). Second, analysis of patients with glioblastoma versus asymptomatic healthy controls in an independent validation series (n = 347) provided a detection accuracy of 95% and AUC of 0.97 (95% CI, 0.95-0.99; p < 0.001). Finally, we developed the digitalSWARM algorithm to improve monitoring of glioblastoma progression and demonstrate that the TEP tumor scores of individual glioblastoma patients represent tumor behavior and could be used to distinguish false positive progression from true progression (validation series, n = 20; accuracy, 85%; AUC, 0.86 [95% CI, 0.70-1.00; p < 0.012]). In conclusion, TEPs have potential as a minimally invasive biosource for blood-based diagnostics and monitoring of glioblastoma patients.

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.
Adv Sci (Weinh) ; 6(11): 1900163, 2019 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-31179222

RESUMO

Distinguishing tumors from normal brain cells is important but challenging in glioma surgery due to the lack of clear interfaces between the two. The ability of label-free third harmonic generation (THG) microscopy in combination with automated image analysis to quantitatively detect glioma infiltration in fresh, unprocessed tissue in real time is assessed. The THG images reveal increased cellularity in grades II-IV glioma samples from 23 patients, as confirmed by subsequent hematoxylin and eosin histology. An automated image quantification workflow is presented for quantitative assessment of the imaged cellularity as a reflection of the degree of glioma invasion. The cellularity is validated in three ways: 1) Quantitative comparison of THG imaging with fluorescence microscopy of nucleus-stained samples demonstrates that THG reflects the true tissue cellularity. 2) Thresholding of THG cellularity differentiates normal brain from glioma infiltration, with 96.6% sensitivity and 95.5% specificity, in nearly perfect (93%) agreement with pathologists. 3) In one patient, a good correlation between THG cellularity and preoperative magnetic resonance and positron emission tomography imaging is demonstrated. In conclusion, quantitative real-time THG microscopy accurately assesses glioma infiltration in ex vivo human brain samples, and therefore holds strong potential for improving the accuracy of surgical resection.

12.
J Craniofac Surg ; 30(2): 408-411, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30676441

RESUMO

Polymethyl methacrylate (PMMA), an easily moldable and economical synthetic resin, has been used since the 1940s. In addition, PMMA has good mechanical properties and is one of the most biocompatible alloplastic materials currently available. The PMMA can serve as a spacer and as a delivery vehicle for antibiotics. Prior studies have indicated that no significant differences in infection rates exist between autologous and acrylic cranioplasty. Although inexpensive, the free-hand cranioplasty technique often yields unsatisfactory cosmetic results. In the present study, the application of a recently developed, economic modality for the perioperative application, and molding of PMMA to ensure a precise fit in 16 patients using computer-aided design, computer-aided manufacturing, and rapid prototyping was described.The mean defect size was 102.0 ±â€Š26.4 cm. The mean volume of PMMA required to perform the cranioplasty procedure was 51 mL. The cost of PMMA was approximately 6 Euro (&OV0556;) per mL. The costs of fabricating the implants varied from 119.8 &OV0556; to 1632.0 &OV0556; with a mean of 326.4 &OV0556; ±â€Š371.6. None of the implants required removal during the follow-up period.


Assuntos
Materiais Biocompatíveis/uso terapêutico , Polimetil Metacrilato/uso terapêutico , Próteses e Implantes/economia , Desenho de Prótese/economia , Procedimentos Cirúrgicos Reconstrutivos/métodos , Crânio/cirurgia , Adulto , Materiais Biocompatíveis/economia , Desenho Assistido por Computador , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Período Perioperatório , Polimetil Metacrilato/economia
13.
Neurosurgery ; 85(2): E304-E313, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-30423155

RESUMO

BACKGROUND: Preoperative interpretation of resectability of diffuse nonenhancing glioma is primarily based on individual surgical expertise. OBJECTIVE: To compare the accuracy and precision between observed resections and preoperative estimates of neurosurgeons and a resection probability map (RPM). We hypothesize that the RPM estimates is as good as senior neurosurgeons. METHODS: A total of 234 consecutive patients were included from 2 centers, who had resective surgery with functional mapping between 2006 and 2012 for a supra-tentorial nonenhancing glioma. Extent of resection (EOR) and residual tumor volume (RTV) were segmented and an RPM was constructed in standard brain space. Three junior and three senior neurosurgeons estimated EOR and RTV, blinded for postoperative results. We determined the agreement between the estimates and calculated the diagnostic accuracy of the neurosurgeons and the RPM to predict the observed resections. RESULTS: Preoperative estimates of resection results by junior and senior neurosurgeons were significantly biased towards overestimation of EOR (4.2% and 11.2%) and underestimation of RTV (4.3 and 9.0 mL), whereas estimates of the RPM were unbiased (-2.6% and -.2 mL, respectively). The limits of agreement were wide for neurosurgeons and for the RPM. The RPM was significantly more accurate in identifying patients in whom an EOR >40% was observed than neurosurgeons. CONCLUSION: Neurosurgeons estimate preoperative resectability before surgery of a nonenhancing glioma rather accurate-with a small bias-and imprecise-with wide limits of agreement. An RPM provides unbiased resectability estimates, which can be useful for surgical decision-making, planning, and education.


Assuntos
Mapeamento Encefálico/normas , Neoplasias Encefálicas/cirurgia , Glioma/cirurgia , Procedimentos Neurocirúrgicos/métodos , Adulto , Idoso , Mapeamento Encefálico/métodos , Competência Clínica/normas , Feminino , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Neoplasia Residual/patologia , Carga Tumoral
14.
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
15.
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
16.
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
17.
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
18.
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.

19.
Neuroimage Clin ; 19: 758-766, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30009129

RESUMO

In some patients with medically refractory epilepsy, EEG with intracerebrally placed electrodes (stereo-electroencephalography, SEEG) is needed to locate the seizure onset zone (SOZ) for successful epilepsy surgery. SEEG has limitations and entails risk of complications because of its invasive character. Non-invasive magnetoencephalography virtual electrodes (MEG-VEs) may overcome SEEG limitations and optimize electrode placement making SOZ localization safer. Our purpose was to assess whether interictal activity measured by MEG-VEs and SEEG at identical anatomical locations were comparable, and whether MEG-VEs activity properties could determine the location of a later resected brain area (RA) as an approximation of the SOZ. We analyzed data from nine patients who underwent MEG and SEEG evaluation, and surgery for medically refractory epilepsy. MEG activity was retrospectively reconstructed using beamforming to obtain VEs at the anatomical locations corresponding to those of SEEG electrodes. Spectral, functional connectivity and functional network properties were obtained for both, MEG-VEs and SEEG time series, and their correlation and reliability were established. Based on these properties, the approximation of the SOZ was characterized by the differences between RA and non-RA (NRA). We found significant positive correlation and reliability between MEG-VEs and SEEG spectral measures (particularly in delta [0.5-4 Hz], alpha2 [10-13 Hz], and beta [13-30 Hz] bands) and broadband functional connectivity. Both modalities showed significantly slower activity and a tendency towards increased broadband functional connectivity in the RA compared to the NRA. Our findings show that spectral and functional connectivity properties of non-invasively obtained MEG-VEs match those of invasive SEEG recordings, and can characterize the SOZ. This suggests that MEG-VEs might be used for optimal SEEG planning and fewer depth electrode implantations, making the localization of the SOZ safer and more successful.


Assuntos
Mapeamento Encefálico/métodos , Encéfalo/fisiopatologia , Epilepsia Resistente a Medicamentos/fisiopatologia , Convulsões/fisiopatologia , Adolescente , Adulto , Eletroencefalografia , Feminino , Humanos , Magnetoencefalografia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto Jovem
20.
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
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