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1.
Neurobiol Dis ; 134: 104628, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31669732

RESUMO

Cardiorespiratory dysfunction during or after seizures may contribute to sudden unexpected death in epilepsy. Disruption of lower brainstem cardiorespiratory systems by seizures is postulated to impair respiratory and cardiac function. Here, we explore the effects of brainstem seizures and stimulation on cardiorespiratory function using a rat model of intrahippocampal 4-aminopyridine (4-AP)-induced acute recurrent seizures. Cardiac and respiratory monitoring together with local field potential recordings from hippocampus, contralateral parietal cortex and caudal dorsomedial brainstem, were conducted in freely moving adult male Wistar rats. Seizures were induced by intrahippocampal injection of 4-AP. Increased respiratory rate but unchanged heart rate occurred during hippocampal and secondarily generalized cortical seizures. Status epilepticus without brainstem seizures increased respiratory and heart rates, whereas status epilepticus with intermittent brainstem seizures induced repeated episodes of cardiorespiratory depression leading to death. Respiratory arrest occurred prior to asystole which was the terminal event. Phenytoin (100 mg/kg, intraperitoneal injection), administered after 4-AP intrahippocampal injection, terminated brainstem seizures and the associated cardiorespiratory depression, preventing death in five of six rats. Focal electrical stimulation of the caudal dorsomedial brainstem also suppressed cardiorespiratory rates. We conclude that in our model, brainstem seizures were associated with respiratory depression followed by cardiac arrest, and then death. We hypothesize this model shares mechanisms in common with the classic sudden unexpected death in epilepsy (SUDEP) syndrome associated with spontaneous seizures.

2.
IEEE J Transl Eng Health Med ; 7: 2000203, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31497409

RESUMO

OBJECTIVE: To investigate the feasibility of improving the performance of an EEG-based multistate classifier (MSC) previously proposed by our group. RESULTS: Using the random forest (RF) classifiers on the previously reported dataset of patients, but with three improvements to classification logic, the specificity of our alarm algorithm improves from 82.4% to 92.0%, and sensitivity from 87.9% to 95.2%. DISCUSSION: The MSC could be a useful approach for seizure-monitoring both in the clinic and at home. METHODS: Three improvements to the MSC are described. Firstly, an additional check using RF outputs is made prior to alarm to confirm increasing probability of a seizure onset state. Secondly, a post-alarm detection horizon that accounts for the seizure state duration is implemented. Thirdly, the alarm decision window is kept constant.

3.
Neurobiol Dis ; 130: 104488, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31181283

RESUMO

The human brain, largely accepted as the most complex biological system known, is still far from being understood in its parts or as a whole. More specifically, biological mechanisms of epileptic states and state transitions are not well understood. Here, we explore the concept of the epilepsy as a manifestation of a multistate network composed of coupled oscillatory units. We also propose that functional coupling between neuroglial elements is a dynamic process, characterized by temporal changes both at short and long time scales. We review various experimental and modelling data suggesting that epilepsy is a pathological manifestation of such a multistate network - both when viewed as a coupled oscillatory network, and as a system of multistate stable state attractors. Based on a coupled oscillators model, we propose a significant role for glial cells in modulating hyperexcitability of the neuroglial networks of the brain. Also, using these concepts, we explain a number of observable phenomena such as propagation patterns of bursts within a seizure in the isolated intact hippocampus in vitro, postictal generalized suppression in human encephalographic seizure data, and changes in seizure susceptibility in epileptic patients. Based on our conceptual model we propose potential clinical applications to estimate brain closeness to ictal transition by means of active perturbations and passive measures during on-going activity.

4.
J Vis Exp ; (143)2019 01 19.
Artigo em Inglês | MEDLINE | ID: mdl-30735161

RESUMO

Controlling seizures remains a challenging issue for the medical community. To make progress, researchers need a way to extensively study seizure dynamics and investigate its underlying mechanisms. Acute seizure models are convenient, offer the ability to perform electrophysiological recordings, and can generate a large volume of electrographic seizure-like (ictal) events. The promising findings from acute seizure models can then be advanced to chronic epilepsy models and clinical trials. Thus, studying seizures in acute models that faithfully replicate the electrographic and dynamical signatures of a clinical seizure will be essential for making clinically relevant findings. Studying ictal events in acute seizure models prepared from human tissue is also important for making findings that are clinically relevant. The key focus in this paper is on the cortical 4-AP model due to its versatility in generating ictal events in both in vivo and in vitro studies, as well as in both mouse and human tissue. The methods in this paper will also describe an alternative method of seizure induction using the Zero-Mg2+ model and provide a detailed overview of the advantages and limitations of the epileptiform-like activity generated in the different acute seizure models. Moreover, by taking advantage of commercially available optogenetic mouse strains, a brief (30 ms) light pulse can be used to trigger an ictal event identical to those occurring spontaneously. Similarly, 30 - 100 ms puffs of neurotransmitters (Gamma-Amino Butyric Acid or glutamate) can be applied to the human tissue to trigger ictal events that are identical to those occurring spontaneously. The ability to trigger ictal events on-demand in acute seizure models offers the newfound ability to observe the exact sequence of events that underlie seizure initiation dynamics and efficiently evaluate potential anti-seizure therapies.


Assuntos
Convulsões/patologia , Potenciais de Ação/efeitos dos fármacos , Animais , Bumetanida , Modelos Animais de Doenças , Humanos , Magnésio/farmacologia , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Pirimidinas
5.
Ann Clin Transl Neurol ; 6(1): 167-173, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30656195

RESUMO

A patient with pilomotor seizures post anti-LGI1 limbic encephalitis, refractory to immunotherapy and anti-epileptic drugs, was investigated with electroencephalography and magnetoencephalography. Seizures occurred daily (14.9 ± 4.9/day), with catamenial exacerbation, inducible by hyperventilation. Anterior temporal ictal onsets were heralded (by ~15 sec) by high amplitude ipsilateral electromagnetic infraslow activity. The catamenial/ventilatory sensitivity and the infraslow activity (reflecting glial depolarization) suggested an ionic, CO 2/pH-related glioneuronal mechanism. Furosemide decreased seizure frequency by ~33%. Acetazolamide led to immediate seizure freedom, but lost efficacy with daily treatment. A cycling acetazolamide regimen (2 days on, 4 days off) plus low-dose topiramate maintained >95% reduction (0.5 ± 0.9/day) in seizures.


Assuntos
Acetazolamida/uso terapêutico , Anticonvulsivantes/uso terapêutico , Encéfalo/efeitos dos fármacos , Encéfalo/fisiopatologia , Encefalite Límbica/complicações , Convulsões/tratamento farmacológico , Adulto , Autoanticorpos , Eletroencefalografia , Feminino , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/imunologia , Encefalite Límbica/imunologia , Magnetoencefalografia , Convulsões/etiologia , Convulsões/fisiopatologia , Resultado do Tratamento
6.
J Neurosci ; 39(13): 2430-2440, 2019 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-30696731

RESUMO

Ischemic stroke is responsible for a large number of neurological deficits including memory impairment. Deep brain stimulation (DBS), a well established therapeutic modality for the treatment of movement disorders, has recently shown potential beneficial effects on memory in animals and patients with Alzheimer's disease. Here, we test DBS for its ability to improve memory impairments by stimulating the entorhinal cortex (EC) in a rat model of global ischemia (GI). Two weeks after GI, adult male rats received high-frequency EC DBS for 1 h, and animals were assessed for changes in locomotor activity, learning, and memory 6 weeks later. GI produced spatial memory impairment that was ameliorated by DBS, with no difference between the group that received DBS for GI (GI-DBS ON group) and nonstroke control groups. Although GI led to a dramatic CA1 neuronal loss that could not be rescued with DBS, stimulation attenuated the reduction of CA1 synaptophysin expression after GI. Further, in vitro slice recordings showed a restoration of typical evoked synaptic dendritic fields in GI-DBS ON animals, indicating that the DBS-induced memory rescue is associated with increased synaptophysin expression and enhanced synaptic function. These results suggest that DBS may ameliorate the functional consequences of cerebral ischemia and point to be a potential new therapeutic approach.SIGNIFICANCE STATEMENT Deep brain stimulation (DBS) is remarkably effective in treating Parkinson's disease and is currently under investigation for the treatment of neuropsychiatric disorders including Alzheimer's disease. Until now, DBS has not been examined for its cognitive benefits in the context of hypoxic-ischemic injuries. Here, we investigated the effect of DBS in a rat model of global ischemia (GI) that mimics the neurological consequences occurring after a cardiac arrest. We show that DBS rescues memory deficits induced by GI and produces changes in synaptic activity in the hippocampus. Novel approaches to improve neurological outcomes after stroke are urgently needed; therefore, the present study highlights a possible role for DBS in the treatment of cognitive impairment associated with ischemia.

7.
Neurosci Lett ; 695: 71-75, 2019 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-28886985

RESUMO

Pannexin-1 (Panx1) expression is raised in several animal seizure models and in resected human epileptic brain tissue, suggesting relevance to epilepsy. Multiple factors that are characteristic of seizures are thought to regulate Panx1 channel opening, including elevated levels of extracellular K+. Panx1, when open, 1) releases ATP, glutamate, and other metabolites into the extracellular medium, and 2) may depolarize the membrane due to a channel reversal potential around 0mV. Resultant ATP release from stimulated Panx1 can activate purinergic receptors, including P2X7 receptors. Glutamate and other signaling molecules released by Panx1 opening may have both excitatory and inhibitory actions on seizure generation. This review examines the critical and complex roles of Panx1 channels in epilepsy, which could provide a basis for future therapeutics.


Assuntos
Conexinas/metabolismo , Epilepsia/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Animais , Humanos , Neurônios/metabolismo , Receptores Purinérgicos P2X7/metabolismo
8.
Biomed Opt Express ; 9(11): 5615-5634, 2018 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-30460150

RESUMO

Single-frame blood flow maps from laser speckle contrast imaging (LSCI) contain high spatiotemporal variation that obscures high spatial-frequency vascular features, making precise image registration for signal amplification challenging. In this work, novel bivariate standardized moment filters (BSMFs) were used to provide stable measures of vessel edge location, permitting more robust LSCI registration. Relatedly, BSMFs enabled the stable reconstruction of vessel edges from sparsely distributed blood flow map outliers, which were found to retain most of the temporal dynamics. Consequently, data discarding and BSMF-based reconstruction enable efficient real-time quantitative LSCI data compression. Smaller LSCI-kernels produced log-normal blood flow distributions, enhancing sparse-to-dense inference.

9.
Front Mol Neurosci ; 11: 338, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30271324

RESUMO

Although epidemiological evidence suggests significant sex and gender-based differences in stroke risk and recovery, females have been widely under-represented in preclinical stroke research. The neurovascular sequelae of brain ischemia in females, in particular, are largely uncertain. We set out to address this gap by a multimodal in vivo study of neurovascular recovery from endothelin-1 model of cortical focal-stroke in sham vs. ovariectomized female rats. Three weeks post ischemic insult, sham operated females recapitulated the phenotype previously reported in male rats in this model, of normalized resting perfusion but sustained peri-lesional cerebrovascular hyperreactivity. In contrast, ovariectomized (Ovx) females showed reduced peri-lesional resting blood flow, and elevated cerebrovascular responsivity to hypercapnia in the peri-lesional and contra-lateral cortices. Electrophysiological recordings showed an attenuation of theta to low-gamma phase-amplitude coupling in the peri-lesional tissue of Ovx animals, despite relative preservation of neuronal power. Further, this chronic stage neuronal network dysfunction was inversely correlated with serum estradiol concentration. Our pioneering data demonstrate dramatic differences in spontaneous recovery in the neurovascular unit between Ovx and Sham females in the chronic stage of stroke, underscoring the importance of considering hormonal-dependent aspects of the ischemic sequelae in the development of novel therapeutic approaches and patient recruitment in clinical trials.

10.
Stroke ; 49(9): 2173-2181, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30354983

RESUMO

Background and Purpose- Recent evidence suggests great potential of metabolically targeted interventions for treating neurological disorders. We investigated the use of the endogenous ketone body ß-hydroxybutyrate (BHB) as an alternate metabolic substrate for the brain in the acute phase of ischemia because postischemic hyperglycemia and brain glucose metabolism elevation compromise functional recovery. Methods- We delivered BHB (or vehicle) 1 hour after ischemic insult induced by cortical microinjection of endothelin-1 in sensorimotor cortex of rats. Two days after ischemic insult, the rats underwent multimodal characterization of the BHB effects. We examined glucose uptake on 2-Deoxy-d-glucose chemical exchange saturation transfer magnetic resonance imaging, cerebral hemodynamics on continuous arterial spin labeling magnetic resonance imaging, resting-state field potentials by intracerebral multielectrode arrays, Neurological Deficit Score, reactive oxygen species production, and astrogliosis and neuronal death. Results- When compared with vehicle-administered animals, BHB-treated cohort showed decreased peri-infarct neuronal glucose uptake which was associated with reduced oxidative stress, diminished astrogliosis and neuronal death. Functional examination revealed ameliorated neuronal functioning, normalized perilesional resting perfusion, and ameliorated cerebrovascular reactivity to hypercapnia, suggesting improved functioning. Cellular and functional recovery of the neurogliovascular unit in the BHB-treated animals was associated with improved performance on the withdrawal test. Conclusions- We characterize the effects of the ketone body BHB administration at cellular and system levels after focal cortical stroke. The results demonstrate that BHB curbs the peri-infarct glucose-metabolism driven production of reactive oxygen species and astrogliosis, culminating in improved neurogliovascular and functional recovery.


Assuntos
Ácido 3-Hidroxibutírico/farmacologia , Astrócitos/efeitos dos fármacos , Isquemia Encefálica/metabolismo , Encéfalo/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Ácido 3-Hidroxibutírico/metabolismo , Acetoacetatos/metabolismo , Animais , Astrócitos/patologia , Glicemia/metabolismo , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Encéfalo/patologia , Isquemia Encefálica/diagnóstico por imagem , Isquemia Encefálica/patologia , Morte Celular/efeitos dos fármacos , Circulação Cerebrovascular , Modelos Animais de Doenças , Fenômenos Eletrofisiológicos , Endotelina-1 , Hemodinâmica , Imagem por Ressonância Magnética , Espectroscopia de Ressonância Magnética , Microinjeções , Neurônios/patologia , Ratos , Espécies Reativas de Oxigênio/metabolismo , Córtex Sensório-Motor
11.
Front Cell Neurosci ; 12: 278, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30210302

RESUMO

The hippocampal circuitry is widely recognized as susceptible to ischemic injury and seizure generation. However, hippocampal contribution to acute non-convulsive seizures (NCS) in models involving middle cerebral artery occlusion (MCAO) remains to be determined. To address this, we occluded the middle cerebral artery in adult C57 black mice and monitored electroencephalographic (EEG) discharges from hippocampal and neocortical areas. Electrographic discharges in the absence of convulsive motor behaviors were observed within 90 min following occlusion of the middle cerebral artery. Hippocampal discharges were more robust than corresponding cortical discharges in all seizure events examined, and hippocampal discharges alone or with minimal cortical involvement were also observed in some seizure events. Seizure development was associated with ipsilateral hippocampal injuries as determined by subsequent histological examinations. We also introduced hypoxia-hypoglycemia episodes in mouse brain slices and examined regional hyperexcitable responses ex vivo. Extracellular recordings showed that the hippocampal CA3 region had a greater propensity for exhibiting single/multiunit activities or epileptiform field potentials following hypoxic-hypoglycemic (HH) episodes compared to the CA1, dentate gyrus, entorhinal cortical (EC) or neocortical regions. Whole-cell recordings revealed that CA3 pyramidal neurons exhibited excessive excitatory postsynaptic currents, attenuated inhibitory postsynaptic currents and intermittent or repetitive spikes in response to HH challenge. Together, these observations suggest that hippocampal discharges, possibly as a result of CA3 circuitry hyperexcitability, are a major component of acute NCS in a mouse model of MCAO.

12.
IEEE Trans Biomed Eng ; 65(11): 2440-2449, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29993471

RESUMO

OBJECTIVE: This work proposes a machine-learning based system for a scalp EEG that flags an alarm in advance of a clinical seizure onset. METHODS: EEG recordings from 12 patients with drug resistant epilepsy were marked by an expert neurologist for clinical seizure onset. Scalp EEG recordings consisted of 56 seizures and 9.67 h of interictal periods. Data from six patients were reserved for testing, and the rest was split into training and testing sets. A global spatial average of a cross-frequency coupling (CFC) index, , was extracted in 2 s windows, and used as the feature for the machine learning. A multistage state classifier (MSC) based on random forest algorithms was trained and tested on these data. Training was conducted to classify three states: interictal baseline, and segments prior to and following EG onset. Classifier performance was assessed using a receiver-operating characteristic (ROC) analysis. RESULTS: The MSC produced an alarm 45 16 s in advance of a clinical seizure onset across seizures from the 12 patients. It performed with a sensitivity of 87.9%, a specificity of 82.4%, and an area-under-the-ROC of 93.4%. On patients for whom it received training, performance metrics increased. Performance metrics did not change when the MSC used reduced electrode ring configurations. CONCLUSION: Using the scalp , the MSC produced an alarm in advance of a clinical seizure onset for all 12 patients. Patient-specific training improved the specificity of classification. SIGNIFICANCE: The MSC is noninvasive, and demonstrates that CFC features may be suitable for use in a home-based seizure monitoring system.


Assuntos
Eletroencefalografia/métodos , Aprendizado de Máquina , Couro Cabeludo/fisiologia , Convulsões/diagnóstico , Processamento de Sinais Assistido por Computador , Humanos , Curva ROC , Convulsões/fisiopatologia
13.
Front Mol Neurosci ; 11: 135, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29780304

RESUMO

Pannexins (Panx) are integral membrane proteins, with Panx1 being the best-characterized member of the protein family. Panx1 is implicated in sensory processing, and knockout (KO) animal models have become the primary tool to investigate the role(s) of Panx1 in sensory systems. Extending previous work from our group on primary olfaction, the expression patterns of Panxs in the vomeronasal organ (VNO), an auxiliary olfactory sense organ with a role in reproduction and social behavior, were compared. Using qRT-PCR and Immunohistochemistry (IHC), we confirmed the loss of Panx1, found similar Panx2 expression levels in both models, and a significant upregulation of Panx3 in mice with a global ablation of Panx1. Specifically, Panx3 showed upregulated expression in nerve fibers of the non-sensory epithelial layer in juvenile and adult KO mice and in the sensory layer of adults, which overlaps with Panx1 expression areas in WT populations. Since both social behavior and evoked ATP release in the VNO was not compromised in KO animals, we hypothesized that Panx3 could compensate for the loss of Panx1. This led us to compare Panx1 and Panx3 channels in vitro, demonstrating similar dye uptake and ATP release properties. Outcomes of this study strongly suggest that Panx3 may functionally compensate for the loss of Panx1 in the VNO of the olfactory system, ensuring sustained chemosensory processing. This finding extends previous reports on the upregulation of Panx3 in arterial walls and the skin of Panx1 KO mice, suggesting that roles of Panx1 warrant uncharacterized safeguarding mechanisms involving Panx3.

14.
Neurobiol Dis ; 109(Pt A): 102-116, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29024712

RESUMO

Activation of γ-aminobutyric acid (GABAA) receptors have been associated with the onset of epileptiform events. To investigate if a causal relationship exists between GABAA receptor activation and ictal event onset, we activated inhibitory GABAergic networks in the superficial layer (2/3) of the somatosensory cortex during hyperexcitable conditions using optogenetic techniques in mice expressing channelrhodopsin-2 in all GABAergic interneurons. We found that a brief 30ms light pulse reliably triggered either an interictal-like event (IIE) or ictal-like ("ictal") event in the in vitro cortical 4-Aminopyridine (4-AP) slice model. The link between light pulse and epileptiform event onset was lost following blockade of GABAA receptors with bicuculline methiodide. Additionally, recording the chronological sequence of events following a light pulse in a variety of configurations (whole-cell, gramicidin-perforated patch, and multi-electrode array) demonstrated an initial hyperpolarization followed by post-inhibitory rebound spiking and a subsequent slow depolarization at the transition to epileptiform activity. Furthermore, the light-triggered ictal events were independent of the duration or intensity of the initiating light pulse, suggesting an underlying regenerative mechanism. Moreover, we demonstrated that brief GABAA receptor activation can initiate ictal events in the in vivo 4-AP mouse model, in another common in vitro model of epileptiform activity, and in neocortical tissue resected from epilepsy patients. Our findings reveal that the synchronous activation of GABAergic interneurons is a robust trigger for ictal event onset in hyperexcitable cortical networks.


Assuntos
Neurônios GABAérgicos/fisiologia , Interneurônios/fisiologia , Convulsões/fisiopatologia , Córtex Somatossensorial/fisiopatologia , 4-Aminopiridina/administração & dosagem , Potenciais de Ação , Animais , Modelos Animais de Doenças , Epilepsia do Lobo Temporal/fisiopatologia , Feminino , GABAérgicos/administração & dosagem , Antagonistas de Receptores de GABA-A/administração & dosagem , Humanos , Masculino , Camundongos Endogâmicos C57BL , Neocórtex/fisiopatologia , Optogenética , Células Piramidais/fisiologia , Receptores de GABA-A/fisiologia , Convulsões/induzido quimicamente , Ácido gama-Aminobutírico/administração & dosagem , Ácido gama-Aminobutírico/fisiologia
15.
J Neurochem ; 144(5): 669-679, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-28777881

RESUMO

Alzheimer's disease (AD) is pathologically characterized by amyloid-ß peptide (Aß) accumulation, neurofibrillary tangle formation, and neurodegeneration. Preclinical studies on neuronal impairments associated with progressive amyloidosis have demonstrated some Aß-dependent neuronal dysfunction including modulation of gamma-aminobutyric acid-ergic signaling. The present work focuses on the early stage of disease progression and uses TgF344-AD rats that recapitulate a broad repertoire of AD-like pathologies to investigate the neuronal network functioning using simultaneous intracranial recordings from the hippocampus (HPC) and the medial prefrontal cortex (mPFC), followed by pathological analyses of gamma-aminobutyric acid (GABAA ) receptor subunits α1, α5, and δ, and glutamic acid decarboxylases (GAD65 and GAD67). Concomitant to amyloid deposition and tau hyperphosphorylation, low-gamma band power was strongly attenuated in the HPC and mPFC of TgF344-AD rats in comparison to those in non-transgenic littermates. In addition, the phase-amplitude coupling of the neuronal networks in both areas was impaired, evidenced by decreased modulation of theta band phase on gamma band amplitude in TgF344-AD animals. Finally, the gamma coherence between HPC and mPFC was attenuated as well. These results demonstrate significant neuronal network dysfunction at an early stage of AD-like pathology. This network dysfunction precedes the onset of cognitive deficits and is likely driven by Aß and tau pathologies. This article is part of the Special Issue "Vascular Dementia".


Assuntos
Doença de Alzheimer/fisiopatologia , Hipocampo/fisiopatologia , Neurônios/fisiologia , Córtex Pré-Frontal/fisiopatologia , Doença de Alzheimer/patologia , Animais , Ondas Encefálicas , Modelos Animais de Doenças , Feminino , Glutamato Descarboxilase/metabolismo , Hipocampo/metabolismo , Hipocampo/patologia , Masculino , Vias Neurais/fisiopatologia , Placa Amiloide/metabolismo , Córtex Pré-Frontal/patologia , Ratos Endogâmicos F344 , Ratos Transgênicos , Receptores de GABA-A/metabolismo
16.
Int J Mol Sci ; 18(11)2017 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-29143800

RESUMO

Epilepsy afflicts up to 1.6% of the population and the mechanisms underlying the appearance of seizures are still not understood. In past years, many efforts have been spent trying to understand the mechanisms underlying the excessive and synchronous firing of neurons. Traditionally, attention was pointed towards synaptic (dys)function and extracellular ionic species (dys)regulation. Recently, novel clinical and preclinical studies explored the role of brain metabolism (i.e., glucose utilization) of seizures pathophysiology revealing (in most cases) reduced metabolism in the inter-ictal period and increased metabolism in the seconds preceding and during the appearance of seizures. In the present review, we summarize the clinical and preclinical observations showing metabolic dysregulation during epileptogenesis, seizure initiation, and termination, and in the inter-ictal period. Recent preclinical studies have shown that 2-Deoxyglucose (2-DG, a glycolysis blocker) is a novel therapeutic approach to reduce seizures. Furthermore, we present initial evidence for the effectiveness of 2-DG in arresting 4-Aminopyridine induced neocortical seizures in vivo in the mouse.


Assuntos
Metabolismo Energético , Neurônios/metabolismo , Animais , Modelos Animais de Doenças , Humanos , Convulsões/etiologia , Convulsões/metabolismo , Convulsões/fisiopatologia
17.
Epilepsia ; 58(9): 1637-1644, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28691204

RESUMO

OBJECTIVE: Sudden unexplained death in epilepsy is the leading cause of death in young adult epilepsy patients, typically occurring during the early postictal period, presumably resulting from brainstem and cardiorespiratory dysfunction. We hypothesized that ictal discharges in the brainstem disrupt the cardiorespiratory network, causing mortality. To study this hypothesis, we chose an animal model comprising focal unilateral hippocampal injection of 4-aminopyridine (4-AP), which produced focal recurrent hippocampal seizures with secondary generalization in awake, behaving rats. METHODS: We studied ictal and interictal intracranial electrographic activity (iEEG) in 23 rats implanted with a custom electrode array into the hippocampus, the contralateral cortex, and brainstem. The hippocampal electrodes contained a cannula to administer the potassium channel blocker and convulsant (4-AP). iEEG was recorded continuously before, during, and after seizures induced by 4-AP infusion into the hippocampus. RESULTS: The control group (n = 5) was monitored for 2-3 months, and the weekly baseline iEEG recordings showed long-term stability. The low-dose group (1 µL 4-AP, 40 mm, n = 5) exhibited local electrographic seizures without spread to the contralateral cerebral cortex or brainstem. The high-dose group (5 µL 4-AP, 40 mm, n = 3) had several hippocampal electrographic seizures, which spread contralaterally and triggered brainstem discharges within 40 min, and were associated with violent motor seizures followed by dyspnea and respiratory arrest, with cortical and hippocampal iEEG flattening. The group that received high-dose 4-AP without brainstem implantation (n = 5) had similar seizure-related respiratory difficulties. Finally, five rats that received high-dose 4-AP without EEG recording also developed violent motor seizures with postictal respiratory arrest. Following visualized respiratory arrest in groups III, IV, and V, manual respiratory resuscitation was successful in five of 13 animals. SIGNIFICANCE: These studies show that hippocampal seizure activity can spread or trigger brainstem epileptiform discharges that may cause mortality, possibly mediated by respiratory network dysfunction.


Assuntos
4-Aminopiridina/farmacologia , Tronco Encefálico/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Convulsões/induzido quimicamente , Animais , Eletroencefalografia/efeitos dos fármacos , Masculino , Ratos , Ratos Wistar , Recidiva , Convulsões/mortalidade
18.
Biomed Opt Express ; 8(2): 873-889, 2017 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-28270990

RESUMO

We developed a multi-modal brain imaging system to investigate the relationship between blood flow, blood oxygenation/volume, intracellular calcium and electrographic activity during acute seizure-like events (SLEs), both before and after pharmacological intervention. Rising blood volume was highly specific to SLE-onset whereas blood flow was more correlated with all eletrographic activity. Intracellular calcium spiked between SLEs and at SLE-onset with oscillation during SLEs. Modified neurovascular and ionic SLE responses were observed after intervention and the interval between SLEs became shorter and more inconsistent. Comparison of artery and vein pulsatile flow suggest proximal interference and greater vascular leakage prior to intervention.

19.
Neuroimage ; 146: 869-882, 2017 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-27664828

RESUMO

Brain plasticity following focal cerebral ischaemia has been observed in both stroke survivors and in preclinical models of stroke. Endogenous neurovascular adaptation is at present incompletely understood yet its potentiation may improve long-term functional outcome. We employed longitudinal MRI, intracranial array electrophysiology, Montoya Staircase testing, and immunofluorescence to examine function of brain vessels, neurons, and glia in addition to forelimb skilled reaching during the subacute stage of ischemic injury progression. Focal ischemic stroke (~100mm3 or ~20% of the total brain volume) was induced in adult Sprague-Dawley rats via direct injection of endothelin-1 (ET-1) into the right sensori-motor cortex, producing sustained impairment in left forelimb reaching ability. Resting perfusion and vascular reactivity to hypercapnia in the peri-lesional cortex were elevated by approximately 60% and 80% respectively seven days following stroke. At the same time, the normal topological pattern of local field potential (LFP) responses to peripheral somatosensory stimulation was abolished and the average power of spontaneous LFP activity attenuated by approximately 50% relative to the contra-lesional cortex, suggesting initial response attenuation within the peri-infarct zone. By 21 days after stroke, perilesional blood flow resolved, but peri-lesional vascular reactivity remained elevated. Concomitantly, the LFP response amplitudes increased with distance from the site of ET-1 injection, suggesting functional remodelling from the core of the lesion to its periphery. This notion was further buttressed by the lateralization of spontaneous neuronal activity: by day 21, the average ipsi-lesional power of spontaneous LFP activity was almost twice that of the contra-lesional cortex. Over the observation period, the peri-lesional cortex exhibited increased vascular density, along with neuronal loss, astrocytic activation, and recruitment and activation of microglia and macrophages, with neuronal loss and inflammation extending beyond the peri-lesional cortex. These findings highlight the complex relationship between neurophysiological state and behaviour and provide evidence of highly dynamic functional changes in the peri-infarct zone weeks following the ischemic insult, suggesting an extended temporal window for therapeutic interventions.


Assuntos
Isquemia Encefálica/fisiopatologia , Encéfalo/irrigação sanguínea , Encéfalo/fisiopatologia , Córtex Somatossensorial/irrigação sanguínea , Córtex Somatossensorial/fisiopatologia , Acidente Vascular Cerebral/fisiopatologia , Remodelação Vascular , Animais , Encéfalo/metabolismo , Isquemia Encefálica/induzido quimicamente , Isquemia Encefálica/complicações , Ondas Encefálicas , Encefalite/complicações , Encefalite/metabolismo , Endotelina-1/administração & dosagem , Hipercapnia/fisiopatologia , Imagem por Ressonância Magnética , Masculino , Destreza Motora , Neuroglia/metabolismo , Neurônios/metabolismo , Estimulação Física , Ratos Sprague-Dawley , Recuperação de Função Fisiológica , Córtex Sensório-Motor/efeitos dos fármacos , Acidente Vascular Cerebral/induzido quimicamente , Acidente Vascular Cerebral/complicações , Percepção do Tato/fisiologia
20.
Neurobiol Dis ; 101: 1-7, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28007587

RESUMO

Extracellular potassium concentration, [K+]o, is a major determinant of neuronal excitability. In the healthy brain, [K+]o levels are tightly controlled. During seizures, [K+]o increases up to 15mM and is thought to cause seizures due to its depolarizing effect. Although astrocytes have been suggested to play a key role in the redistribution (or spatial buffering) of excess K+ through Connexin-43 (Cx43)-based Gap Junctions (GJs), the relation between this dynamic regulatory process and seizure generation remains unknown. Here we contrasted the role of astrocytic GJs and hemichannels by studying the effect of GJ and hemichannel blockers on [K+]o regulation in vivo. [K+]o was measured by K+-sensitive microelectrodes. Neuronal excitability was estimated by local field potential (LFP) responses to forepaw stimulation and changes in the power of resting state activity. Starting at the baseline [K+]o level of 1.61±0.3mM, cortical microinjection of CBX, a broad spectrum connexin channel blocker, increased [K+]o to 11±3mM, Cx43 GJ/hemichannel blocker Gap27 increased it from 1.9±0.7 to 9±1mM. At these [K+]o levels, no seizures were observed. Cx43 hemichannel blockade with TAT-Gap19 increased [K+]o by only ~1mM. Microinjection of 4-aminopyridine, a known convulsant, increased [K+]o to ~10mM and induced spontaneously recurring seizures, whereas direct application of K+ did not trigger seizure activity. These findings are the first in vivo demonstration that astrocytic GJs are major determinants for the spatial buffering of [K+]o and that an increase in [K+]o alone does not trigger seizures in the neocortex.


Assuntos
Astrócitos/metabolismo , Junções Comunicantes/metabolismo , Neocórtex/metabolismo , Potássio/metabolismo , Animais , Astrócitos/efeitos dos fármacos , Cátions Monovalentes/metabolismo , Conexina 43/antagonistas & inibidores , Conexina 43/metabolismo , Potenciais Somatossensoriais Evocados/efeitos dos fármacos , Potenciais Somatossensoriais Evocados/fisiologia , Junções Comunicantes/efeitos dos fármacos , Camundongos , Neocórtex/efeitos dos fármacos , Canais de Potássio/metabolismo , Convulsões/metabolismo
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