RESUMEN
Chagas disease is a life-threatening infection caused by a variety of genetically diverse strains of the protozoan parasite Trypanosoma cruzi The current treatment (benznidazole and nifurtimox) is unsatisfactory, and potential alternatives include inhibitors of sterol 14α-demethylase (CYP51), the cytochrome P450 enzyme essential for the biosynthesis of sterols in eukaryotes and the major target of clinical and agricultural antifungals. Here we performed a comparative investigation of two protozoon-specific CYP51 inhibitors, VNI and its CYP51 structure-based derivative VFV, in the murine models of infection caused by the Y strain of T. cruzi The effects of different treatment regimens and drug delivery vehicles were evaluated in animals of both genders, with benznidazole serving as the reference drug. Regardless of the treatment scheme or delivery vehicle, VFV was more potent in both genders, causing a >99.7% peak parasitemia reduction, while the VNI values varied from 91 to 100%. Treatments with VNI and VFV resulted in 100% animal survival and 0% natural relapse after the end of therapy, though, except for the 120-day treatment schemes with VFV, relapses after three cycles of immunosuppression were observed in each animal group, and quantitative PCR analysis revealed a very light parasite load in the blood samples (sometimes below or near the detection limit, which was 1.5 parasite equivalents/ml). Our studies support further investigations of this class of compounds, including their testing against other T. cruzi strains and in combination with other drugs.
Asunto(s)
Inhibidores de 14 alfa Desmetilasa/farmacología , Enfermedad de Chagas/tratamiento farmacológico , Sistema Enzimático del Citocromo P-450/química , Imidazoles/farmacología , Oxadiazoles/farmacología , Tripanocidas/farmacología , Trypanosoma cruzi/efectos de los fármacos , Inhibidores de 14 alfa Desmetilasa/química , Animales , Enfermedad de Chagas/inmunología , Enfermedad de Chagas/parasitología , Ciclofosfamida/efectos adversos , Sistema Enzimático del Citocromo P-450/genética , Sistema Enzimático del Citocromo P-450/metabolismo , Modelos Animales de Enfermedad , Esquema de Medicación , Femenino , Expresión Génica , Humanos , Imidazoles/química , Inmunosupresores/efectos adversos , Masculino , Ratones , Modelos Moleculares , Nitroimidazoles/farmacología , Oxadiazoles/química , Carga de Parásitos , Recurrencia , Análisis de Supervivencia , Tripanocidas/química , Trypanosoma cruzi/enzimología , Trypanosoma cruzi/genética , Trypanosoma cruzi/crecimiento & desarrolloRESUMEN
The nucleus reuniens (RE) and entorhinal cortex (EC) provide monosynaptic excitatory inputs to the apical dendrites of pyramidal cells and to interneurons with dendrites in stratum lacunosum moleculare (LM) of hippocampal field CA1. However, whether the RE and EC inputs interact at the cellular level is unknown. In this electrophysiological in vivo study, low-frequency stimulation was used to selectively activate each projection at its origin; field excitatory postsynaptic potentials (fEPSPs) were recorded in CA1. We applied (1) paired pulses to RE or EC, (2) combined paired pulses to RE and EC, and (3) simultaneously paired pulses to RE/EC. The main findings are that: (a) stimulation of either RE- or EC-evoked subthreshold fEPSPs, displaying paired pulse facilitation (PPF), (b) subthreshold fEPSPs evoked by combined stimulation did not display heterosynaptic PPF, and (c) simultaneous stimulation of RE/EC resulted in enhanced subthreshold fEPSPs in proximal LM displaying a nonlinear interaction. CSD analyses of RE/EC-evoked depth profiles revealed a nonlinear enlargement of the 'LM sink-radiatum source' configuration and the appearance of an additional small sink-source pair close to stratum pyramidale, likely reflecting (peri)somatic inhibition. The nonlinear interaction between both inputs indicates that RE and EC axons form synapses, at least partly, onto the same dendritic compartments of CA1 pyramidal cells. We propose that low-frequency activation of the RE-CA1 input facilitates the entorhinal-hippocampal dialogue, and may synchronize the neocortical-hippocampal slow oscillation which is relevant for hippocampal-dependent memory consolidation.
Asunto(s)
Región CA1 Hipocampal/fisiología , Corteza Entorrinal/fisiología , Potenciales Postsinápticos Excitadores/fisiología , Vía Perforante/citología , Sinapsis/fisiología , Animales , Axones/fisiología , Masculino , Núcleos Talámicos de la Línea Media/fisiología , Células Piramidales/fisiología , Ratas WistarRESUMEN
Arylimidamides (AIAs) have been shown to have considerable biological activity against intracellular pathogens, includingTrypanosoma cruzi, which causes Chagas disease. In the present study, the activities of 12 novel bis-AIAs and 2 mono-AIAs against different strains ofT. cruziin vitroandin vivowere analyzed. The most active wasm-terphenyl bis-AIA (35DAP073), which had a 50% effective concentration (EC50) of 0.5 µM for trypomastigotes (Y strain), which made it 26-fold more effective than benznidazole (Bz; 13 µM). It was also active against the Colombiana strain (EC50= 3.8 µM). Analysis of the activity against intracellular forms of the Tulahuen strain showed that this bis-AIA (EC50= 0.04 µM) was about 100-fold more active than Bz (2 µM). The trypanocidal effect was dissociated from the ability to trigger intracellular lipid bodies within host cells, detected by oil red labeling. Both an active compound (35DAP073) and an inactive compound (26SMB060) displayed similar activation profiles. Due to their high selectivity indexes, two AIAs (35DAP073 and 35DAP081) were moved toin vivostudies, but because of the results of acute toxicity assays, 35DAP081 was excluded from the subsequent tests. The findings obtained with 35DAP073 treatment of infections caused by the Y strain revealed that 2 days of therapy induced a dose-dependent action, leading to 96 to 46% reductions in the level of parasitemia. However, the administration of 10 daily doses in animals infected with the Colombiana strain resulted in toxicity, preventing longer periods of treatment. The activity of the combination of 0.5 mg/kg of body weight/day 35DAP073 with 100 mg/kg/day Bz for 10 consecutive days was then assayed. Treatment with the combination resulted in the suppression of parasitemia, the elimination of neurological toxic effects, and survival of 100% of the animals. Quantitative PCR showed a considerable reduction in the parasite load (60%) compared to that achieved with Bz or the amidine alone. Our results support further investigations of this class with the aim of developing novel alternatives for the treatment of Chagas disease.
Asunto(s)
Amidas/farmacología , Enfermedad de Chagas/tratamiento farmacológico , Parasitemia/tratamiento farmacológico , Compuestos de Terfenilo/farmacología , Tripanocidas/farmacología , Trypanosoma cruzi/efectos de los fármacos , Amidas/síntesis química , Amidinas/farmacología , Animales , Enfermedad de Chagas/mortalidad , Enfermedad de Chagas/parasitología , Modelos Animales de Enfermedad , Esquema de Medicación , Cálculo de Dosificación de Drogas , Sinergismo Farmacológico , Quimioterapia Combinada , Femenino , Ratones , Nitroimidazoles/farmacología , Carga de Parásitos , Parasitemia/mortalidad , Parasitemia/parasitología , Pruebas de Sensibilidad Parasitaria , Relación Estructura-Actividad , Análisis de Supervivencia , Compuestos de Terfenilo/síntesis química , Tripanocidas/síntesis química , Trypanosoma cruzi/crecimiento & desarrolloRESUMEN
The lack of translation between preclinical assays and clinical trials for novel therapies for Chagas disease (CD) indicates a need for more feasible and standardized protocols and experimental models. Here, we investigated the effects of treatment with benznidazole (Bz) and with the potent experimental T. cruzi CYP51 inhibitor VNI in mouse models of Chagas disease by using different animal genders and parasite strains and employing distinct types of therapeutic schemes. Our findings confirm that female mice are less vulnerable to the infection than males, show that male models are less susceptible to treatment with both Bz and VNI, and thus suggest that male models are much more suitable for selection of the most promising antichagasic agents. Additionally, we have found that preventive protocols (compound given at 1 dpi) result in higher treatment success rates, which also should be avoided during advanced steps of in vivo trials of novel anti-T. cruzi drug candidates. Another consideration is the relevance of immunosuppression methods in order to verify the therapeutic profile of novel compounds, besides the usefulness of molecular diagnostic tools (quantitative PCR) to ascertain compound efficacy in experimental animals. Our study aims to contribute to the development of more reliable methods and decision gates for in vivo assays of novel antiparasitic compounds in order to move them from preclinical to clinical trials for CD.
Asunto(s)
Inhibidores de 14 alfa Desmetilasa/farmacología , Enfermedad de Chagas/tratamiento farmacológico , Imidazoles/farmacología , Oxadiazoles/farmacología , Parasitemia/tratamiento farmacológico , Tripanocidas/farmacología , Trypanosoma cruzi/efectos de los fármacos , Animales , Enfermedad de Chagas/inmunología , Enfermedad de Chagas/parasitología , Enfermedad de Chagas/patología , Sistema Enzimático del Citocromo P-450/genética , Sistema Enzimático del Citocromo P-450/metabolismo , Modelos Animales de Enfermedad , Esquema de Medicación , Evaluación Preclínica de Medicamentos/métodos , Femenino , Expresión Génica , Inmunosupresores/farmacología , Masculino , Ratones , Nitroimidazoles/farmacología , Parasitemia/inmunología , Parasitemia/parasitología , Parasitemia/patología , Factores Sexuales , Resultado del Tratamiento , Trypanosoma cruzi/enzimología , Trypanosoma cruzi/genéticaRESUMEN
Phosphodiesterase-9 (PDE9) specifically hydrolyzes cyclic GMP, and was detected in human corpus cavernosum. However, no previous studies explored the selective PDE9 inhibition with BAY 73-6691 in corpus cavernosum relaxations. Therefore, this study aimed to characterize the PDE9 mRNA expression in mice corpus cavernosum, and investigate the effects of BAY 73-6691 in endothelium-dependent and -independent relaxations, along with the nitrergic corpus cavernosum relaxations. Male mice received daily gavage of BAY 73-6691 (or dimethylsulfoxide) at 3 mg kg(-1) per day for 21 days. Relaxant responses to acetylcholine (ACh), nitric oxide (NO) (as acidified sodium nitrite; NaNO2 solution), sildenafil and electrical-field stimulation (EFS) were obtained in corpus cavernosum in control and BAY 73-6691-treated mice. BAY 73-6691 was also added in vitro 30 min before construction of concentration-responses and frequency curves. PDE9A and PDE5 mRNA expression was detected in the mice corpus cavernosum in a similar manner. In vitro addition of BAY 73-6691 neither itself relaxed mice corpus cavernosum nor changed the NaNO2, sildenafil and EFS-induced relaxations. However, in mice treated chronically with BAY 73-6691, the potency (pEC50) values for ACh, NaNO2 and sildenafil were significantly greater compared with control group. The maximal responses (Emax) to NaNO2 and sildenafil were also significantly greater in BAY 73-6691-treated mice. BAY 73-6691 treatment also significantly increased the magnitude and duration of the nitrergic corpus cavernosum relaxations (8-32 Hz). In conclusion, murine corpus cavernosum expresses PDE9 mRNA. Prolonged PDE9 inhibition with BAY 73-6691 amplifies the NO-cGMP-mediated cavernosal responses, and may be of therapeutic value for erectile dysfunction.
Asunto(s)
3',5'-AMP Cíclico Fosfodiesterasas/antagonistas & inhibidores , GMP Cíclico/fisiología , Óxido Nítrico/fisiología , Pene/enzimología , Pene/fisiología , Pirazoles/farmacología , Pirimidinas/farmacología , 3',5'-AMP Cíclico Fosfodiesterasas/genética , 3',5'-AMP Cíclico Fosfodiesterasas/fisiología , Animales , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 5/genética , Estimulación Eléctrica , Masculino , Ratones , Ratones Endogámicos C57BL , Relajación Muscular/efectos de los fármacos , Óxido Nítrico/farmacología , Inhibidores de Fosfodiesterasa/farmacología , Piperazinas/farmacología , Purinas/farmacología , ARN Mensajero/análisis , Transducción de Señal/efectos de los fármacos , Citrato de Sildenafil , Sulfonas/farmacologíaRESUMEN
The most important quest of cognitive neuroscience may be to unravel the mechanisms by which the brain selects, links, consolidates, and integrates new information into its neuronal network, while preventing saturation to occur. During the past decade, neuroscientists working within several disciplines have observed an important involvement of the specific types of brain oscillations that occur during sleep--the cortical slow oscillations; during the resting state--the fMRI resting state networks including the default-mode network (DMN); and during task performance--the performance modulations that link as well to modulations in electroencephalography or magnetoencephalography frequency content. Understanding the role of these slow oscillations thus appears to be essential for our fundamental understanding of brain function. Brain activity is characterized by oscillations occurring in spike frequency, field potentials or blood oxygen level-dependent functional magnetic resonance imaging signals. Environmental stimuli, reaching the brain through our senses, activate or inactivate neuronal populations and modulate ongoing activity. The effect they sort is to a large extent determined by the momentary state of the slow endogenous oscillations of the brain. In the absence of sensory input, as is the case during rest or sleep, brain activity does not cease. Rather, its oscillations continue and change with respect to their dominant frequencies and coupling topography. This chapter briefly introduces the topics that will be addressed in this dedicated volume of Progress in Brain Research on slow oscillations and sets the stage for excellent papers discussing their molecular, cellular, network physiological and cognitive performance aspects. Getting to know about slow oscillations is essential for our understanding of plasticity, memory, brain structure from synapse to DMN, cognition, consciousness, and ultimately for our understanding of the mechanisms and functions of sleep and vigilance.
Asunto(s)
Encéfalo/fisiología , Corteza Cerebral/anatomía & histología , Corteza Cerebral/fisiología , Neuronas/fisiología , Fases del Sueño/fisiología , Sueño/fisiología , HumanosRESUMEN
In previous studies we showed that autonomous absence seizure generation and termination can be explained by realistic neuronal models eliciting bi-stable dynamics. In these models epileptic seizures are triggered either by external stimuli (reflex epilepsies) or by internal fluctuations. This scenario predicts exponential distributions of the duration of the seizures and of the inter-ictal intervals. These predictions were validated in rat models of absence epilepsy, as well as in a few human cases. Nonetheless, deviations from the predictions with respect to seizure duration distributions remained unexplained. The objective of the present work is to implement a simple but realistic computational model of a neuronal network including synaptic plasticity and ionic current dynamics and to explore the dynamics of the model with special emphasis on the distributions of seizure and inter-ictal period durations. We use as a basis our lumped model of cortical neuronal circuits. Here we introduce 'activity dependent' parameters, namely post-synaptic voltage-dependent plasticity, as well as a voltage-dependent hyperpolarization-activated current driven by slow and fast activation conductances. We examine the distributions of the durations of the seizure-like model activity and the normal activity, described respectively by the limit cycle and the steady state in the dynamics. We use a parametric γ-distribution fit as a quantifier. Our results show that autonomous, activity-dependent membrane processes can account for experimentally obtained statistical distributions of seizure durations, which were not explainable using the previous model. The activity-dependent membrane processes that display the strongest effect in accounting for these distributions are the hyperpolarization-dependent cationic (I(h)) current and the GABAa plastic dynamics. Plastic synapses (NMDA-type) in the interneuron population show only a minor effect. The inter-ictal statistics retain their consistency with the experimental data and the previous model.
Asunto(s)
Epilepsia Tipo Ausencia/fisiopatología , Redes Neurales de la Computación , Plasticidad Neuronal/fisiología , Convulsiones/fisiopatología , Algoritmos , Animales , Canales Catiónicos Regulados por Nucleótidos Cíclicos/fisiología , Canales Regulados por Nucleótidos Cíclicos Activados por Hiperpolarización , Potenciación a Largo Plazo , Potenciales de la Membrana/fisiología , Modelos Neurológicos , N-Metilaspartato/fisiología , Canales de Potasio/fisiología , Células Piramidales/fisiología , Ratas , Sinapsis/fisiología , Ácido gamma-Aminobutírico/fisiologíaRESUMEN
In EEG/fMRI correlation studies it is common to consider the fMRI BOLD as filtered version of the EEG alpha power. Here the question is addressed whether other EEG frequency components may affect the correlation between alpha and BOLD. This was done comparing the statistical parametric maps (SPMs) of three different filter models wherein either the free or the standard hemodynamic response functions (HRF) were used in combination with the full spectral bandwidth of the EEG. EEG and fMRI were co-registered in a 30 min resting state condition in 15 healthy young subjects. Power variations in the delta, theta, alpha, beta and gamma bands were extracted from the EEG and used as regressors in a general linear model. Statistical parametric maps (SPMs) were computed using three different filter models, wherein either the free or the standard hemodynamic response functions (HRF) were used in combination with the full spectral bandwidth of the EEG. Results show that the SPMs of different EEG frequency bands, when significant, are very similar to that of the alpha rhythm. This is true in particular for the beta band, despite the fact that the alpha harmonics were discarded. It is shown that inclusion of EEG frequency bands as confounder in the fMRI-alpha correlation model has a large effect on the resulting SPM, in particular when for each frequency band the HRF is extracted from the data. We conclude that power fluctuations of different EEG frequency bands are mutually highly correlated, and that a multi frequency model is required to extract the SPM of the frequency of interest from EEG/fMRI data. When no constraints are put on the shapes of the HRFs of the nuisance frequencies, the correlation model looses so much statistical power that no correlations can be detected.
Asunto(s)
Encéfalo/fisiología , Electroencefalografía , Imagen por Resonancia Magnética , Adulto , Ritmo alfa , Femenino , Humanos , Modelos Lineales , MasculinoRESUMEN
Theta oscillations (4-12 Hz) are associated with learning and memory and are found in the hippocampus and the entorhinal cortex (EC). The spatio-temporal organization of rhythmic activity in the hippocampal-EC complex was investigated in vitro. The voltage sensitive absorption dye NK3630 was used to record the changes in aggregated membrane voltage simultaneously from the neuronal networks involved. Oscillatory activity at 7.0 Hz (range, 5.8-8.2) was induced in the slice with the muscarinic agonist carbachol (75-100 microM) in the presence of bicuculline (5 microM). Time relations between all recording sites were analyzed using cross-correlation functions which revealed systematic phase shifts in the theta oscillation recorded from the different entorhinal and hippocampal subregions. These phase shifts could be interpreted as propagation delays. The oscillation propagates over the slice in a characteristic spatio-temporal sequence, where the entorhinal cortex leads, followed by the subiculum and then the dentate gyrus (DG), to finally reach the CA3 and the CA1 area. The delay from dentate gyrus to the CA3 area was 12.4 +/- 1.1 ms (mean +/- s.e.m.) and from the CA3 to the CA1 region it was 10.9 +/- 1.9 ms. The propagation delays between the hippocampal subregions resemble the latencies of electrically evoked responses in the same subregions. Removing the entorhinal cortex from the slice changed the spatiotemporal pattern into a more clustered pattern with higher local synchrony. We conclude that in the slice, carbachol-induced theta oscillations are initiated in the entorhinal cortex. The EC could serve to control the information flow through the neuronal network in the subregions of the hippocampus by synchronizing and/or entraining their responses to external inputs.
Asunto(s)
Relojes Biológicos/fisiología , Corteza Entorrinal/fisiología , Potenciales Evocados/fisiología , Hipocampo/fisiología , Dinámicas no Lineales , Animales , Bicuculina/farmacología , Relojes Biológicos/efectos de los fármacos , Mapeo Encefálico , Carbacol/farmacología , Agonistas Colinérgicos/farmacología , Potenciales Evocados/efectos de los fármacos , Agonistas del GABA/farmacología , Antagonistas del GABA/farmacología , Técnicas In Vitro , Masculino , Muscimol/farmacología , Vías Nerviosas/fisiología , Ratas , Ratas Wistar , Análisis Espectral , Factores de Tiempo , Imagen de Colorante Sensible al Voltaje/métodosRESUMEN
Multi-channel electroencephalography recordings have shown that a visual cue, indicating right hand, left hand or foot motor imagery, can induce a short-lived brain state in the order of about 500 ms. In the present study, 10 able-bodied subjects without any motor imagery experience (naive subjects) were asked to imagine the indicated limb movement for some seconds. Common spatial filtering and linear single-trial classification was applied to discriminate between two conditions (two brain states: right hand vs. left hand, left hand vs. foot and right hand vs. foot). The corresponding classification accuracies (mean +/- SD) were 80.0 +/- 10.6%, 83.3 +/- 10.2% and 83.6 +/- 8.8%, respectively. Inspection of central mu and beta rhythms revealed a short-lasting somatotopically specific event-related desynchronization (ERD) in the upper mu and/or beta bands starting approximately 300 ms after the cue onset and lasting for less than 1 s.
Asunto(s)
Señales (Psicología) , Potenciales Evocados/fisiología , Imaginación/fisiología , Movimiento/fisiología , Desempeño Psicomotor/fisiología , Percepción Visual/fisiología , Adulto , Mapeo Encefálico , Electroencefalografía , Pie/fisiología , Lateralidad Funcional/fisiología , Mano/fisiología , Humanos , Pruebas Neuropsicológicas , Estimulación Luminosa , Factores de Tiempo , Adulto JovenRESUMEN
Considering that there are several theoretical reasons why fMRI data is correlated to variations in heart rate, these correlations are explored using experimental resting state data. In particular, the possibility is discussed that the "default network", being a brain area that deactivates during non-specific general tasks, is a hemodynamic effect caused by heart rate variations. Of fifteen healthy controls ECG, EEG and fMRI were co-registered. Slice time dependent heart rate regressors were derived from the ECG data and correlated to fMRI using a linear correlation analysis where the impulse response is estimated from the data. It was found that in most subjects substantial correlations between heart rate variations and fMRI exist, both within the brain and at the ventricles. The brain areas with high correlation to heart rate are different from the "default network" and the response functions deviate from the canonical hemodynamic response function. Furthermore, a general negative correlation was found between heart beat intervals (reverse of heart rate) and alpha power. We interpret this finding by assuming that subject's state varies between drowsiness and wakefulness. Finally, given this large correlation, we re-examined the contribution of heart rate variations to earlier reported fMRI/alpha band correlations, by adding heart rate regressors as confounders. It was found that inclusion of these confounders most often had a negligible effect. From its strong correlation to alpha power, we conclude that the heart rate variations contain important physiological information about subject's resting state. However, it does not provide a full explanation of the behaviour of the "default network". Its application as confounder in fMRI experiments is a relatively small computational effort, but may have a substantial impact in paradigms where heart rate is controlled by the stimulus.
Asunto(s)
Ritmo alfa/métodos , Encéfalo/fisiología , Frecuencia Cardíaca/fisiología , Imagen por Resonancia Magnética/métodos , Modelos Cardiovasculares , Modelos Neurológicos , Descanso/fisiología , Adulto , Simulación por Computador , Femenino , Humanos , MasculinoRESUMEN
OBJECTIVE: EEG coherence is decreased in Alzheimer's disease (AD), suggesting decreased interaction between brain areas. Nonlinear EEG analysis in AD points to decreased complexity of brain dynamics, implicating increased interaction. To clarify these apparently paradoxical findings from linear and nonlinear analysis, we calculated global coherence and global correlation dimension (D2), a nonlinear measure, in the EEG of patients with probable AD and controls. Our hypothesis is that these measures are related to each other when calculated in a comparable way. METHODS: From 15 patients with probable AD (mean age 63.1 years; SD 6.3) and 21 age-matched controls with subjective memory complaints (mean age 62.8; SD 12.0), band filtered EEG data were analysed in six frequency bands. For each frequency band average coherence and multichannel D2 were determined. RESULTS: ANOVA for repeated measures showed for D2 an interaction between band and group, but not for coherence. In the beta band and upper alpha band, D2 was higher in patients with probable AD compared to controls, while global coherence tended to be lower in these frequency bands in patients with probable AD. In the frequency range from theta to beta, coherence and D2 were inversely correlated without group differences. CONCLUSIONS: When calculated in comparable ways, global correlation dimension and coherence are related measures. In AD, these measures change especially in the higher frequency ranges, both pointing to decreased functional cortical connectivity. SIGNIFICANCE: Both global coherence and global correlation dimension seem to measure global connectivity, but nonlinear measures may be more sensitive. In AD, connectivity measures are not equally impaired in all frequency ranges, possibly reflecting differentiated affection of the dynamical processes responsible for the different frequency bands.
Asunto(s)
Enfermedad de Alzheimer/fisiopatología , Encéfalo/fisiopatología , Electroencefalografía , Femenino , Humanos , Masculino , Persona de Mediana Edad , Dinámicas no LinealesRESUMEN
UNLABELLED: This study explores differences in cognitive outcome after a standard resection (SR) or tailored (TR) in 100 patients with left temporal lobe epilepsy, controlling for extent in the three lateral gyri. Comparing preoperative to 6-month postoperative performance on a battery of intelligence, language and verbal memory tests revealed the following: a differential effect of the procedure was found for digit span, a short-term memory and attention task, the SR group showing a gain and the TR group a loss postoperatively. This could be explained by a rather large improvement of the SR group with below average resection sizes in the superior temporal gyrus (STG) (<2.8 cm), which small resections are nearly absent in TR resections. Effect of larger extent on the STG in the SR group was related to a decrease in verbal intelligence and a tendency in auditory comprehension which poses a risk in 'large' standard resections. Differences in extent of resection on the other gyri did not cause differences in effects on language functioning or verbal memory. CONCLUSIONS: In standard anterior temporal lobe resections only (without intraoperative language mapping) up to a limit of 4.5 cm, large resections on the STG pose a risk for declining on verbal IQ and auditory comprehension. In general, tailored resections (with language mapping) result in decline on a task measuring short-term memory and attention.
Asunto(s)
Lobectomía Temporal Anterior/efectos adversos , Trastornos del Conocimiento/etiología , Epilepsia del Lóbulo Temporal/cirugía , Trastornos de la Memoria/etiología , Plasticidad Neuronal , Lóbulo Temporal/cirugía , Adaptación Fisiológica , Adolescente , Adulto , Lobectomía Temporal Anterior/métodos , Atención , Niño , Epilepsia del Lóbulo Temporal/complicaciones , Epilepsia del Lóbulo Temporal/fisiopatología , Femenino , Lateralidad Funcional , Humanos , Pruebas de Inteligencia , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Recuperación de la Función , Estudios Retrospectivos , Lóbulo Temporal/patología , Lóbulo Temporal/fisiopatología , Resultado del TratamientoRESUMEN
Gangliogliomas (GG) constitute the most frequent tumor entity in young patients undergoing surgery for intractable epilepsy. The histological composition of GG, with the presence of dysplastic neurons, corroborates their maldevelopmental origin. However, their histogenesis, the pathogenetic relationship with other developmental lesions, and the molecular alterations underlying the epileptogenicity of these tumors remain largely unknown. We performed gene expression analysis using the Affymetrix Gene Chip System (U133 plus 2.0 array). We used GENMAPP and the Gene Ontology database to identify global trends in gene expression data. Our analysis has identified various interesting genes and processes that are differentially expressed in GG when compared with normal tissue. The immune and inflammatory responses were the most prominent processes expressed in GG. Several genes involved in the complement pathway displayed a high level of expression compared with control expression levels. Higher expression was also observed for genes involved in cell adhesion, extracellular matrix and proliferation processes. We observed differential expression of genes as cyclin D1 and cyclin-dependent kinases, essential for neuronal cell cycle regulation and differentiation. Synaptic transmission, including GABA receptor signaling was an under-expressed process compared with control tissue. These data provide some suggestions for the molecular pathogenesis of GG. Furthermore, they indicate possible targets that may be investigated in order to dissect the mechanisms of epileptogenesis and possibly counteract the epileptogenic process in these developmental lesions.
Asunto(s)
Neoplasias Encefálicas/complicaciones , Neoplasias Encefálicas/genética , Epilepsia/complicaciones , Epilepsia/genética , Ganglioglioma/complicaciones , Ganglioglioma/genética , Perfilación de la Expresión Génica , Adulto , Adhesión Celular/efectos de los fármacos , Proteínas del Sistema Complemento/biosíntesis , Proteínas del Sistema Complemento/genética , Cartilla de ADN , Matriz Extracelular/metabolismo , Regulación Neoplásica de la Expresión Génica , Humanos , Inmunohistoquímica , Inflamación/patología , Masculino , Persona de Mediana Edad , Neovascularización Patológica/genética , Neovascularización Patológica/patología , Análisis de Secuencia por Matrices de Oligonucleótidos , ARN Neoplásico/biosíntesis , ARN Neoplásico/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal/fisiología , Transmisión Sináptica/fisiología , Fijación del Tejido , Proteínas Wnt/biosíntesis , Ácido gamma-Aminobutírico/fisiologíaRESUMEN
We investigated the involvement of the complement cascade during epileptogenesis in a rat model of temporal lobe epilepsy (TLE), and in the chronic epileptic phase in both experimental as well as human TLE. Previous rat gene expression analysis using microarrays indicated prominent activation of the classical complement pathway which peaked at 1 week after SE in CA3 and entorhinal cortex. Increased expression of C1q, C3 and C4 was confirmed in CA3 tissue using quantitative PCR at 1 day, 1 week and 3-4 months after status epilepticus (SE). Upregulation of C1q and C3d protein expression was confirmed mainly to be present in microglia and in a few hippocampal neurons. In human TLE with hippocampal sclerosis, astroglial, microglial and neuronal (5/8 cases) expression of C1q, C3c and C3d was observed particularly within regions where neuronal cell loss occurs. The membrane attack protein complex (C5b-C9) was predominantly detected in activated microglial cells. The persistence of complement activation could contribute to a sustained inflammatory response and could destabilize neuronal networks involved.
Asunto(s)
Proteínas del Sistema Complemento/inmunología , Encefalitis/inmunología , Epilepsia del Lóbulo Temporal/inmunología , Gliosis/inmunología , Hipocampo/inmunología , Regulación hacia Arriba/inmunología , Adolescente , Adulto , Anciano , Animales , Astrocitos/inmunología , Astrocitos/metabolismo , Complemento C1q/genética , Complemento C1q/inmunología , Complemento C1q/metabolismo , Complemento C3c/genética , Complemento C3c/inmunología , Complemento C3c/metabolismo , Complemento C3d/genética , Complemento C3d/inmunología , Complemento C3d/metabolismo , Complemento C5b/genética , Complemento C5b/inmunología , Complemento C5b/metabolismo , Proteínas del Sistema Complemento/genética , Proteínas del Sistema Complemento/metabolismo , Modelos Animales de Enfermedad , Encefalitis/genética , Encefalitis/fisiopatología , Epilepsia del Lóbulo Temporal/genética , Epilepsia del Lóbulo Temporal/fisiopatología , Femenino , Gliosis/genética , Gliosis/fisiopatología , Hipocampo/patología , Hipocampo/fisiopatología , Humanos , Masculino , Microglía/inmunología , Microglía/metabolismo , Persona de Mediana Edad , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Estado Epiléptico/genética , Estado Epiléptico/inmunología , Estado Epiléptico/fisiopatología , Regulación hacia Arriba/genéticaRESUMEN
In this paper, we present a rigorous, general definition of the nonlinear association index, known as h2. Proving equivalence between different definitions we show that the index measures the best dynamic range of any nonlinear map between signals. We present also a construction for removing the influence of one signal from another, providing, thus, the basis of an independent component analysis. Our definition applies to arbitrary multidimensional vector-valued signals and depends on an aperture function. In this way, the bin-related classic definition of h2 can be generalized. We show that upon choosing suitable aperture functions the bin-related intuitive definition can be deduced. Special attention is dedicated to the direction of the association index that in general is taken in only one sense. We show that for linearly coupled signals high associations are always bidirectional. As a consequence, high asymmetric nonlinear associations are indicators of nonlinear relations, possibly critical, between the dynamic systems underlying the measured signals. We give a simple simulated example to illustrate this property. As a potential clinical application, we show that unidirectional associations between electroencephalogram (EEG) and electromyogram (EMG) recorded from patient with pharmacologically intractable epilepsy can be used to study the cortical involvement in the generation of motor seizures.
Asunto(s)
Algoritmos , Encéfalo/fisiopatología , Diagnóstico por Computador/métodos , Electroencefalografía/métodos , Electromiografía/métodos , Epilepsia Parcial Motora/diagnóstico , Epilepsia Parcial Motora/fisiopatología , Inteligencia Artificial , Preescolar , Simulación por Computador , Femenino , Humanos , Modelos Neurológicos , Dinámicas no Lineales , Procesamiento de Señales Asistido por Computador , Estadística como AsuntoRESUMEN
EEG was recorded during fMRI scanning of 16 normal controls in resting condition with eyes closed. Time variations of the occipital alpha band amplitudes were correlated to the fMRI signal variations to obtain insight into the hemodynamic correlates of the EEG alpha activity. Contrary to earlier studies, no a priori assumptions were made on the expected shape of the alpha band response function (ARF). The ARF of different brain regions and subjects were explored and compared. It was found that: (1) the ARF of the thalamus is mainly positive. (2) The ARFs at the occipital and left and right parietal points are similar in amplitude and timing. (3) The peak time of the thalamus is a few seconds earlier than that of occipital and parietal cortex. (4) No systematic BOLD activity was found preceding the alpha band activity, although in the two subjects with the strongest alpha band power such correlation was present. (5) There is a strong and immediate positive correlation at the eyeball, and a strong negative correlation at the back of the eye. Furthermore, it was found that in one subject the cortical ARF was positive, contrary to the other subjects. Finally, a cluster analysis of the observed ARF, in combination with a Modulated Sine Model (MSM) fit to the estimated ARF, revealed that within the cortex the ARF peak time shows a spatial pattern that may be interpreted as a traveling wave. The spatial pattern of alpha band response function represents the combined effect of local differences in electrical alpha band activity and local differences in the hemodynamic response function (HRF) onto these electrical activities. To disentangle the contributions of both factors, more advanced integration of EEG inverse modeling and hemodynamic response modeling is required in future studies.
Asunto(s)
Ritmo alfa/métodos , Mapeo Encefálico/métodos , Encéfalo/irrigación sanguínea , Encéfalo/fisiología , Circulación Cerebrovascular/fisiología , Imagen por Resonancia Magnética/métodos , Adulto , Velocidad del Flujo Sanguíneo/fisiología , Femenino , Humanos , Masculino , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
OBJECTIVE: To assess the long-term effects of temporal lobe epilepsy surgery on verbal memory. METHODS: We assessed verbal memory performance as measured by a verbal learning test ("15 Words Test," a Dutch adaptation of Rey's Auditory Verbal Learning Test) before surgery and at three specific times after surgery: 6 months, 2 years, and 6 years in 85 patients (34 left temporal lobe [LTL] vs. 51 right temporal lobe [RTL]). An amygdalo-hippocampectomy and a neocortical temporal resection between 2.5 and 8 cm were carried out in all patients. RESULTS: LTL patients showed an ongoing memory decline for consolidation and acquisition of verbal material (both 2/3 SDs) for up to 2 years after surgery. RTL patients at first showed a gain in both memory acquisition and consolidation, which vanished in the long term. Breaking the group up into a mesiotemporal (MTS) group and a non-MTS group showed clear differences. The group with pure MTS showed an overall lower verbal memory performance than the group without pure MTS, in the LTL group more pronounced than in the RTL group. After surgery, both pathology groups showed an ongoing decline for up to 2 years, but the degree of decline was greater for the LTL patients with MTS compared with the non-MTS group. Becoming and remaining seizure-free after surgery does not result in a better performance in the long term. Predictors of postoperative verbal memory performance at 6 years after surgery were side of surgery, preoperative memory score, and age. CONCLUSIONS: The results provide evidence for a dynamic decline of verbal memory functions up to 2 years after left temporal lobectomy, which then levels off.
Asunto(s)
Lobectomía Temporal Anterior/estadística & datos numéricos , Epilepsia del Lóbulo Temporal/epidemiología , Epilepsia del Lóbulo Temporal/cirugía , Trastornos de la Memoria/epidemiología , Complicaciones Posoperatorias/epidemiología , Medición de Riesgo/métodos , Aprendizaje Verbal , Adulto , Niño , Epilepsia del Lóbulo Temporal/diagnóstico , Femenino , Estudios de Seguimiento , Humanos , Incidencia , Estudios Longitudinales , Masculino , Trastornos de la Memoria/diagnóstico , Recuerdo Mental , Países Bajos/epidemiología , Pronóstico , Factores de Riesgo , Resultado del TratamientoRESUMEN
The understanding of neurobiological mechanisms of epileptogenesis is essential for rational approaches for a possible disease modification as well as treatment of underlying causes of the epilepsies. More effort is necessary to translate results from basic investigations into new approaches for clinical research and to better understand a relationship with findings from clinical studies. The following report is a condensed synapsis in which molecular mechanisms of epileptogenesis, pharmacological modulation of epileptogenesis, evidence based therapy, refractoriness and prediction of outcome is provided in order to stimulate further collaborative international research.
Asunto(s)
Anticonvulsivantes/uso terapéutico , Epilepsia/tratamiento farmacológico , Epilepsia/fisiopatología , Emparejamiento Cromosómico/fisiología , Medicina Basada en la Evidencia , Humanos , Pronóstico , Resultado del TratamientoRESUMEN
We studied the reactivity of EEG rhythms (mu rhythms) in association with the imagination of right hand, left hand, foot, and tongue movement with 60 EEG electrodes in nine able-bodied subjects. During hand motor imagery, the hand mu rhythm blocked or desynchronized in all subjects, whereas an enhancement of the hand area mu rhythm was observed during foot or tongue motor imagery in the majority of the subjects. The frequency of the most reactive components was 11.7 Hz +/- 0.4 (mean +/- SD). While the desynchronized components were broad banded and centered at 10.9 Hz +/- 0.9, the synchronized components were narrow banded and displayed higher frequencies at 12.0 Hz +/- 1.0. The discrimination between the four motor imagery tasks based on classification of single EEG trials improved when, in addition to event-related desynchronization (ERD), event-related synchronization (ERS) patterns were induced in at least one or two tasks. This implies that such EEG phenomena may be utilized in a multi-class brain-computer interface (BCI) operated simply by motor imagery.