Disruption of neocortical synchronisation during slow-wave sleep in the rotenone model of Parkinson's disease.

Parkinson's disease motor dysfunctions are associated with improperly organised neural oscillatory activity. The presence of such disruption at the early stages of the disease in which altered sleep is one of the main features could be a relevant predictive feature. Based on this, we aimed to investigate the neocortical synchronisation dynamics during slow-wave sleep (SWS) in the rotenone model of Parkinson's disease. After rotenone administration within the substantia nigra pars compacta, one group of male Wistar rats underwent sleep-wake recording. Considering the association between SWS oscillatory activity and memory consolidation, another group of rats underwent a memory test. The fine temporal structure of synchronisation dynamics was evaluated by a recently developed technique called first return map. We observed that rotenone administration decreased the time spent in SWS and altered the power spectrum within different frequency bands, whilst it increased the transition rate from a synchronised to desynchronised state. This neurotoxin also increased the probability of longer and decreased the probability of shorter desynchronisation events. At the same time, we observed impairment in object recognition memory. These findings depict an electrophysiological fingerprint represented by a disruption in the typical oscillatory activity within the neocortex at the early stages of Parkinson's disease, concomitant with a decrease in the time spent in SWS and impairment in recognition memory.

Early postnatal environmental enrichment restores neurochemical and functional plasticities of the cerebral cortex and improves learning performance in hidden-prenatally-malnourished young-adult rats.

Moderate reduction of dietary protein (from 25% to 8% casein) in pregnant rats, calorically compensated by carbohydrates, gives rise to 'hidden prenatal malnutrition' (HPM) in the offspring since it does not alter body and brain weights of pups at birth. However, this dietary treatment leads to decreased ß-adrenoceptor signaling and brain derived neurotrophic factor (BDNF) levels in the pup' brain, altogether with defective cortical long-term potentiation (LTP) and lowered visuospatial memory performance. Since early postnatal environmental enrichment (EE) has been shown to exert plastic effects on the developing brain and neuroprotection both on cognition and on structural properties of the neocortex, in the present study we addressed the question of whether early postnatal EE during the lactation period could exert compensatory changes in the expression of ®-adrenergic receptors and BDNF in the neocortex of HPM rats, and if these effects are associated with an improvement or even a restore of both neocortical LTP in vivo and cognitive performance induced by HPM. The results obtained show that EE restored ß-adrenoceptor density, BDNF expression and the ability to support LTP at prefrontal and occipital cortices of HPM rats. Besides, EE improved learning performance in visuospatial and operant conditioning tasks. The latter support the notion that adequate maternal protein nutrition during pregnancy is required for proper brain development and function. Further, the results highlight the role of environmental enrichment during early postnatal life in increasing later brain plasticity and exerting neuroprotection against brain deficits induced by prenatal malnutrition.

Mirror Neurons Modeled Through Spike-Timing-Dependent Plasticity are Affected by Channelopathies Associated with Autism Spectrum Disorder.

Mirror neurons fire action potentials both when the agent performs a certain behavior and watches someone performing a similar action. Here, we present an original mirror neuron model based on the spike-timing-dependent plasticity (STDP) between two morpho-electrical models of neocortical pyramidal neurons. Both neurons fired spontaneously with basal firing rate that follows a Poisson distribution, and the STDP between them was modeled by the triplet algorithm. Our simulation results demonstrated that STDP is sufficient for the rise of mirror neuron function between the pairs of neocortical neurons. This is a proof of concept that pairs of neocortical neurons associating sensory inputs to motor outputs could operate like mirror neurons. In addition, we used the mirror neuron model to investigate whether channelopathies associated with autism spectrum disorder could impair the modeled mirror function. Our simulation results showed that impaired hyperpolarization-activated cationic currents (Ih) affected the mirror function between the pairs of neocortical neurons coupled by STDP.

Transplantation of inhibitory precursor cells from medial ganglionic eminence produces distinct responses in two different models of acute seizure induction.

Medial ganglionic eminence (MGE) is one of the sources of inhibitory interneurons during development. Following transplantation in postnatal developing brain, MGE cells can increase local inhibition suggesting a possible protection to GABAergic dysfunction in brain disorders, such as epilepsy. Since it has been shown that MGE-derived cells harvested as neurospheres are able to suppress seizures, it might be important to investigate whether these protective effects would change in different seizure models. Here, we used pentylenetetrazole-(PTZ) and maximal electroshock (MES)-induced seizure models to test whether the transplantation of MGE cells would increase the threshold to trigger acute seizures. When transplanted into the neocortex (layers 3-4) of neonatal mice (postnatal days 3-4), MGE cells were able to survive and were mainly found in piriform cortex, fimbria, and ventricular wall regions. Additionally, the number of GFP+ cells found in the brains of mice induced with PTZ and MES differed significantly and suggests proliferation and larger survival rate of MGE-transplanted cells after PTZ, but not MES-induced seizures. Following transplantation, there was a reduction in the number of animals presenting mild and severe seizures induced by PTZ. Furthermore, MGE-cell transplantation was able to increase threshold to seizures induced by PTZ, but was not able to prevent seizure spread induced by MES.

Mild thiamine deficiency and chronic ethanol consumption modulate acetylcholinesterase activity change and spatial memory performance in a water maze task.

Chronic thiamine deficiency may be responsible for pathologic changes in the brains of alcoholics, and subclinical episodes of this vitamin deficiency may cause cumulative brain damage. In the present work, the chronic effects of ethanol and its association to a mild thiamine deficiency episode (subclinical model) on neocortical and hippocampal acetylcholinesterase activity were assessed along with their possible association to spatial cognitive dysfunction. The results indicate that in the beginning of the neurodegenerative process, before the appearance of brain lesions, chronic ethanol consumption reverses the effects of mild thiamine deficiency on both spatial cognitive performance and acetylcholinesterase activity without having significant effects on any morphometric parameter.

Neocortical atrophy in Machado-Joseph disease: a longitudinal neuroimaging study.

BACKGROUND/PURPOSE: Previous imaging studies in the Machado-Joseph disease (MJD/SCA3) have mostly concentrated on the cerebellum and brainstem. Our goal was to perform a whole brain longitudinal evaluation. METHODS: We included 45 patients and 51 controls, who underwent two brain magnetic resonance imaging and magnetic resonance spectroscopy (mean interval of 12.5 ± 1.5 months). We used voxel-based morphometry (VBM) and the MarsBar analysis toolbox to extract grey matter density (GMD) values from regions of interest. We used a linear regression model and a general linear model to correlate GMD with clinical markers, and paired t-test for the longitudinal evaluation. RESULTS: We observed decreased GMD (P < .01) at frontal, parietal, temporal and occipital lobes, subcortical grey matter, cerebellum, and brainstem. White matter atrophy was restricted to the cerebellum. Age, CAG, and disease duration predicted GMD in different areas, but age and CAG were the most important predictors. The longitudinal analysis failed to demonstrate changes. Changes in regions other than the cerebellum appeared to contribute significantly to the final International Cooperative Ataxia Rating Scale score. CONCLUSION: We confirmed cortical involvement in MJD/SCA3. The most important factors in predicting GMD were age and CAG. The lack of progression of atrophy may indicate floor effect and/or short duration of follow-up.

Diagnostic methods for extra-temporal neocortical focal epilepsies: present and future.

The progress of epilepsies diagnosis has been great, but, amongst the diagnostic detailing that demand research, one of the most important is the essential lateralization and localization of epileptogenic zone, considered as the cerebral cortex region, that removed, will result in a free state of seizures. The present study aims to analyze the possible uses of proton spectroscopy for clinical and pre-surgical evaluation of focal extratemporal epilepsies, since this group presents the highest difficulty degree for lateralizing and locating epileptogenic zones. In almost all cases, a non invasive diagnosis can be performed using routine electroencephalography, video-electroencephalography - considered as gold standard, and magnetic resonance imaging. However, when the results of these exams are contradictory, some patients need invasive techniques, as the intra-cranial video-EEG, using deep electrodes, sub-dural strip and grid, that are associated with increased diagnostic cost and risk of complications, as cerebral hemorrhages and intra-cranial infections. Proton spectroscopy appears as a possibility, given its capacity to evaluate cerebral metabolism, by N-acetyl-aspartate (NAA), creatine (Cre) and choline (Cho) concentrations, amongst other metabolites. This non invasive method may provide time reduction of this evaluation and reliable level improvement for this topographical diagnosis.

Diagnostic methods for extra-temporal neocortical focal epilepsies: present and future / Métodos diagnósticos das epilepsias focais neocorticais extratemporais: presente e futuro

The progress of epilepsies diagnosis has been great, but, amongst the diagnostic detailing that demand research, one of the most important is the essential lateralization and localization of epileptogenic zone, considered as the cerebral cortex region, that removed, will result in a free state of seizures. The present study aims to analyze the possible uses of proton spectroscopy for clinical and pre-surgical evaluation of focal extratemporal epilepsies, since this group presents the highest difficulty degree for lateralizing and locating epileptogenic zones. In almost all cases, a non invasive diagnosis can be performed using routine electroencephalography, video-electroencephalography - considered as gold standard, and magnetic resonance imaging. However, when the results of these exams are contradictory, some patients need invasive techniques, as the intra-cranial video-EEG, using deep electrodes, sub-dural strip and grid, that are associated with increased diagnostic cost and risk of complications, as cerebral hemorrhages and intra-cranial infections. Proton spectroscopy appears as a possibility, given its capacity to evaluate cerebral metabolism, by N-acetyl-aspartate (NAA), creatine (Cre) and choline (Cho) concentrations, amongst other metabolites. This non invasive method may provide time reduction of this evaluation and reliable level improvement for this topographical diagnosis.

Tem sido grande o progresso no diagnóstico das epilepsias, mas dentre os detalhamentos diagnósticos a exigir pesquisas, estão a lateralização e a localização precisas da zona epileptogênica, considerada como a região do córtex cerebral que, removida, irá resultar num estado livre de crises. Por meio de revisão da literatura, o objetivo deste estudo é expor e analisar os métodos diagnósticos das epilepsias neocorticais extratemporais, dadas as características que as tornam mais complexas do que as epilepsias temporais visto que estas apresentam o maior grau de dificuldade para lateralização e localização das zonas epileptogênicas. Na maior parte dos casos, o diagnóstico pode ser firmado de forma não invasiva, empregando-se a eletrencefalografia de superfície, a vídeo-eletrencefalografia, considerada o padrão-ouro, e a imagem por ressonância magnética. No entanto, quando os resultados dessas investigações são contraditórios, alguns pacientes necessitam de técnicas invasivas, como o vídeo-EEG intracraniano, utilizando eletrodos profundos, placas ou estrias subdurais, que se associam ao aumento do custo diagnóstico e do risco de complicações, como as hemorragias cerebrais e as infecções intracranianas. A espectroscopia de prótons surge como uma possibilidade, dada sua capacidade de avaliar o metabolismo cerebral, por meio das alterações de N-acetil aspartato (NAA), creatina (Cr) e colina (Co), dentre outros metabólitos. Esse método não invasivo pode reduzir o tempo de avaliação e melhorar o nível de confiança desse diagnóstico topográfico.

Allopregnanolone effects on astrogliosis induced by hypoxia in organotypic cultures of striatum, hippocampus, and neocortex.

UNLABELLED: Perinatal asphyxia occurs in approximately 0.3% full-term newborn babies, and this percentage has not decreased despite medical advances. There are now evidences indicating that neurosteroids are important in neurodevelopment showing neuroprotective effects. We studied the potential protective effect of allopregnanolone (Allo) in vitro using organotypic cultures from neocortex, striatum, and hippocampus. Immunocytochemistry and confocal microscopy showed an increase of the glial fibrillary acidic protein (GFAP) signal in the studied brain areas after hypoxia. Western blot studies supported these results (hippocampus, 193%; neocortex, 306%; and striatum, 231%). Twenty-four-hour pretreatment with Allo showed different effects at the brain areas studied. In the hippocampus and the neocortex, 24-h pretreatment with Allo 5x10(-6) M showed to be neuroprotective as there was a significant decrease of the GFAP signal compared to control cultures exposed to hypoxia. Pretreatment with 5x10(-8) M Allo attenuated the astrogliosis response in the hippocampus and the neocortex in a nonsignificant way. Allo pretreatment at all doses did not show to affect the astrogliosis triggered by hypoxia in the striatum. Cell survival was analyzed by measuring LDH. After 1 h of hypoxia, all cultures showed a nonsignificant increase of LDH, which was greater after 24 h of hypoxia (hippocampus, 180%; striatum-cortex co-cultures, 140%). LDH levels have no changes by Allo pretreatment before hypoxia. CONCLUSION: 24 h pretreatment with 5x10(-6) M of Allo does not change neuronal viability but it prevents astrogliosis induced by hypoxia in the hippocampus and the neocortex.

Microscopic mild focal cortical dysplasia in temporal lobe dual pathology: an electrocorticography study.

BACKGROUND: Associations between electrophysiological and histological findings might provide an insight into the epileptogenicity of mild focal cortical dysplasia (FCD) in patients with temporal lobe epilepsy (TLE) and a dual pathology. SUBJECTS AND METHODS: A total of 22 patients with pharmacoresistant TLE were included in the study, 16 of them with histologically confirmed hippocampal sclerosis (HS) associated with neocortical temporal mild Palmini Type-I FCD subtypes and 6 with HS. Intraoperative electrocorticography (ECoG) recordings were analysed for epileptiform discharge frequency and morphology. Associations between histological, and electrocorticography pattern findings in these patients were analysed. Electroclinical outcomes in these patients were also evaluated. RESULTS: Neocortical areas with mild Palmini Type-I FCD showed a significantly higher spike frequency (SF) recorded in the inferior temporal gyrus than those neocortical areas in patients with HS. There was a tendency to higher spike frequency and lower amplitude in neocortical areas with histopathologic subtype IB FCD in relation with IA during intraoperative ECoG. Post-SF excision and amplitude were significantly lower during neocortical post-excision intraoperative ECoG than during neocortical pre-excision recording. There was no difference found in the clinical outcome between patients with and without FCD. CONCLUSIONS: Intraoperative electrocorticographic interictal spike frequency recorded in the neocortical inferior temporal gyrus may help to characterize the histopathologic subtypes of mild Palmini Type-I FCD in patients with temporal lobe epilepsy (TLE) and a dual pathology. Our data support the epileptogenicity of neocortical mild FCD in TLE and assessments of ECoG patterns are relevant to determine the extent of the resection in these patients which can influence the electroclinical outcome.

Mild cognitive deficits associated to neocortical microgyria in mice with genetic deletion of cellular prion protein.

The cellular prion protein (PrP(C)) has been implicated with the modulation of neuronal apoptosis, adhesion, neurite outgrowth and maintenance which are processes involved in the neocortical development. Malformations of cortical development (MCD) are frequently associated with neurological conditions including mental retardation, autism, and epilepsy. Here we investigated the behavioral performance of female adult PrP(C)-null mice (Prnp(0/0)) and their wild-type controls (Prnp(+/+)) presenting unilateral polymicrogyria, a MCD experimentally induced by neonatal freeze-lesion in the right hemisphere. Injured mice from both genotypes presented similar locomotor activity but Prnp(0/0) mice showed a tendency to increase anxiety-related responses when compared to Prnp(+/+) animals. Additionally, injured Prnp(0/0) mice have a poorer performance in the social recognition task than sham-operated and Prnp(+/+) injured ones. Moreover the step-down inhibitory avoidance task was not affected by the procedure or the genotype of the animals. These data suggest that the genetic deletion of PrP(C) confers increased susceptibility to short-term social memory deficits induced by neonatal freezing model of polymicrogyria in mice.

AMPA receptor activation reduces epileptiform activity in the rat neocortex.

We have previously reported that topical application of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) to the rat neocortex prevents the effects of a subsequent application of N-methyl-d-aspartic acid (NMDA). Activation of NMDA receptors is involved in the pathogenesis of epileptic activity. Therefore, we examined if topically applied AMPA could affect changes in the somatosensory evoked potentials (SEPs) and electrocorticogram (ECoG) epileptic spikes caused by bicuculline. AMPA (50 microM) prevented the epileptiform activity to a level that was comparable to that caused by diazepam (3 mg/kg i.p.) or clomethiazole (100 mg/kg i.p.). Also, the epileptiform activity was suppressed by the AMPAR antagonist, CNQX, or the blocker of AMPAR desensitization, cyclothiazide. In the hippocampal slice, bicuculline-induced changes in the population spike potentials recorded from the CA1 cells were not affected by AMPA. We conclude that in the complex neuronal network of the rat neocortex, epileptiform activity can be suppressed in a variety of strategies that target the AMPA receptors: (1) blocking AMPA receptors, (2) promoting an apparent desensitization of AMPA receptors (possibly on the pyramidal neurons) or (3) reducing an apparent desensitization of AMPA receptors (possibly on the inhibitory GABA-ergic interneurons).

Mild prenatal protein malnutrition increases alpha2C-adrenoceptor density in the cerebral cortex during postnatal life and impairs neocortical long-term potentiation and visuo-spatial performance in rats.

Mild reduction in the protein content of the mother's diet from 25 to 8% casein, calorically compensated by carbohydrates, does not alter body and brain weights of rat pups at birth, but leads to significant enhancements in the concentration and release of cortical noradrenaline during early postnatal life. Since central noradrenaline and some of its receptors are critically involved in long-term potentiation (LTP) and memory formation, this study evaluated the effect of mild prenatal protein malnutrition on the alpha2C-adrenoceptor density in the frontal and occipital cortices, induction of LTP in the same cortical regions and the visuo-spatial memory. Pups born from rats fed a 25% casein diet throughout pregnancy served as controls. At day 8 of postnatal age, prenatally malnourished rats showed a threefold increase in neocortical alpha2C-adrenoceptor density. At 60 days-of-age, alpha2C-adrenoceptor density was still elevated in the neocortex, and the animals were unable to maintain neocortical LTP and presented lower visuo-spatial memory performance. Results suggest that overexpression of neocortical alpha2C-adrenoceptors during postnatal life, subsequent to mild prenatal protein malnutrition, could functionally affect the synaptic networks subserving neocortical LTP and visuo-spatial memory formation.

Damage, reorganization, and abnormal neocortical hyperexcitability in the pilocarpine model of temporal lobe epilepsy.

PURPOSE: Clinical, neuropathological, and electrophysiological data have shown that limbic structures are involved in the pathogenesis of temporal lobe epilepsy (TLE). In most cases, limbic-originated seizures frequently spread to extrahippocampal areas. It is unclear whether such distant circuitries, especially the neocortex, exhibit abnormal electrophysiology as consequences of a chronic epileptogenic process. The present research studied neuropathological abnormalities and in vitro electrophysiological properties of sensorimotor neocortex in pilocarpine-treated epileptic rats. METHODS: Adult epileptic animals showing six to seven seizures/week and saline-injected rats were selected for neurohistology. Coronal sections were sampled throughout the anteroposterior extent of the diencephalon and stained with cresyl violet (Nissl). Immunocytochemistry (ICC) was performed using anti-neurofilament (SMI-311) antibody. Extracellular (layer II/III) and intracellular (layer V) recordings were performed in coronal sensorimotor neocortical slices. Several electrophysiological aspects were examined such as evoked responses, intrinsic properties, and firing patterns of layer V pyramidal cells. RESULTS: Nissl staining showed a significant decrease of cortical thickness in epileptic rats when compared with controls, particularly in superficial layers (II-IV). Such abnormalities were also revealed by SMI-311 staining. SMI-311-labeled dendrite arborizations were more complex in layers I-II of epileptic rats. Epileptic rats manifested several abnormalities in extracellular field responses including hyperresponsiveness and presence of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)-mediated polysynaptic activity. Although no significant changes were observed concerning passive intrinsic properties, it was possible to detect a higher proportion of bursting neurons distributed in layer V (60%) of epileptic rats compared with 22% in control slices. CONCLUSIONS: Taken together, our findings indicate damage, reorganization, and chronic hyperexcitability of sensorimotor neocortex in experimental TLE.

Disruption of astroglial interlaminar processes in Alzheimer's disease.

A palisade of long, interlaminar astroglial processes in supragranular layers of the cerebral cortex is characteristic of adult individuals of anthropoid species. In the present study, this distinctive cytoarchitectonic feature was analyzed in tissue deriving from the neocortex of cases affected by Alzheimer's disease (n=14) and age-matched control cases (n=10). Samples of different cortical areas, and in particular prefrontal, temporal and striate fields, were analyzed. Astroglia was labeled by glial fibrillary acidic protein immunoreactivity, that allowed a clear distinction between the classical, stellate intralaminar astroglia and the interlaminar glial processes. The occurrence and relative density of neuritic plaques were ascertained in the same specimens with Bielchowsky staining. In most cortical regions of cases diagnosed as severe Alzheimer's disease by the donor institutions, interlaminar astroglia was found to be markedly altered or absent, and replaced by hypertrophic intralaminar astrocytes. Cases diagnosed as milder or uncertain Alzheimer's disease showed a less consistent involvement of the interlaminar glial palisade. Alterations of the interlaminar palisade in the cortex affected by Alzheimer's disease did not strictly correlate with the density of neuritic plaques in the examined specimens. The findings indicate that loss/severe disruption of the interlaminar palisade of astroglial processes is part of the array of neuropathological changes occurring in the cerebral cortex during Alzheimer's disease. In addition, our data indicate that different types of neocortical astrocytes (namely intralaminar and interlaminar astrocytes) respond differently to the pathobiology of Alzheimer's disease in the neocortex, inasmuch as interlaminar processes tend to disappear while intralaminar processes become reactive.

[A new formulation of death: definition, criteria and diagnostic tests]. / Una nueva formulación de la muerte: definición, criterio y pruebas diagnósticas.

OBJECTIVE: To present a new formulation of human death based on neurological considerations. DEVELOPMENT: One of the reasons there is still controversy over a new formulation of human death which is acceptable to society, is that many authors do not suitably integrate three fundamental aspects which should be included in such a formulation: definition, criteria and diagnostic tests. We review the physiopathological mechanisms for generation of consciousness and discuss the three fundamental criteria presented by different authors in recent decades: the whole encephalum, brainstem death and neocortical criteria. We conclude that there are major contradictions in the three criteria with regard to satisfactory integration of the elements, definition, criteria and diagnostic tests. We therefore present a new formulation of human death. DEFINITION: irreversible loss of consciousness, since this gives the essential human attributes, and is the most integrating function of the organism. CRITERIA: cortico-subcortical connections for the generation of both components of consciousness (capacity and content). DIAGNOSTIC TESTS: no waking response to stimuli (capacity), no cognitive nor affective functions (content). CONCLUSIONS: We present a new formulation of human death on a neurological basis which permits satisfactory integration of the three fundamental elements, definition, criteria and diagnostic tests, and so offers a suitable starting point from which man may start to understand death.