Interaction of nucleus reuniens and entorhinal cortex projections in hippocampal field CA1 of the rat.

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.

Brain (Hyper)Excitability Revealed by Optimal Electrical Stimulation of GABAergic Interneurons.

BACKGROUND: Neurological disorders are often characterized by an excessive and prolonged imbalance between neural excitatory and inhibitory processes. An ubiquitous finding among these disorders is the disrupted function of inhibitory GABAergic interneurons. OBJECTIVE: The objective is to propose a novel stimulation procedure able to evaluate the efficacy of inhibition imposed by GABAergic interneurons onto pyramidal cells from evoked responses observed in local field potentials (LFPs). METHODS: Using a computational modeling approach combined with in vivo and in vitro electrophysiological recordings, we analyzed the impact of electrical extracellular, local, bipolar stimulation (ELBS) on brain tissue. We implemented the ELBS effects in a neuronal population model in which we can tune the excitation-inhibition ratio and we investigated stimulation-related parameters. Computer simulations led to sharp predictions regarding: i) the shape of evoked responses as observed in local field potentials, ii) the type of cells (pyramidal neurons and interneurons) contributing to these field responses and iii) the optimal tuning of stimulation parameters (intensity and frequency) to evoke meaningful responses. These predictions were tested in vivo (mouse). Neurobiological mechanisms were assessed in vitro (hippocampal slices). RESULTS: Appropriately-tuned ELBS allows for preferential activation of GABAergic interneurons. A quantitative neural network excitability index (NNEI) is proposed. It is computed from stimulation-induced responses as reflected in local field potentials. NNEI was used in four patients with focal epilepsy. Results show that it can readily reveal hyperexcitable brain regions. CONCLUSION: Well-tuned ELBS and NNEI can be used to locally probe brain regions and quantify the (hyper)excitability of the underlying brain tissue.

Connectivity and phase coherence in neural network models of interconnected Z(4)-bi-stable units.

A phenomenological neural network model with bi-stable oscillatory units is used to model up- and down-states. These states have been observed in vivo in biological neuronal systems and feature oscillatory, limit cycle type of behavior in the up-states. A network is formed by a set of interconnected units. Two different types of network layouts are considered in this work: networks with hierarchical connections and hubs and networks with random connections. The phase coherence between the different units is analyzed and compared to the connectivity distance between nodes. In addition the connectivity degree of a node is associated to the average phase coherence with all other units. The results show that we may be able to identify the set of hubs in a network based on the phase coherence estimates between the different nodes. If the network is very dense or randomly connected, the underlying network structure, however, can not be derived uniquely from the phase coherence.

Plasticity-modulated seizure dynamics for seizure termination in realistic neuronal models.

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.

Spatio-temporal dynamics of theta oscillations in hippocampal-entorhinal slices.

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.

Interactions between different EEG frequency bands and their effect on alpha-fMRI correlations.

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.

Short-lived brain state after cued motor imagery in naive subjects.

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.

A study of the brain's resting state based on alpha band power, heart rate and fMRI.

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.

Gene expression profile analysis of epilepsy-associated gangliogliomas.

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.

The hemodynamic response of the alpha rhythm: an EEG/fMRI study.

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.

Quantification of unidirectional nonlinear associations between multidimensional signals.

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.

Mu rhythm (de)synchronization and EEG single-trial classification of different motor imagery tasks.

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.

Epileptogenesis and rational therapeutic strategies.

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.

Correlating the alpha rhythm to BOLD using simultaneous EEG/fMRI: inter-subject variability.

Simultaneous recording of electroencephalogram/functional magnetic resonance images (EEG/fMRI) was applied to identify blood oxygenation level-dependent (BOLD) changes associated with spontaneous variations of the alpha rhythm, which is considered the hallmark of the brain resting state. The analysis was focused on inter-subject variability associated with the resting state. Data from 7 normal subjects are presented. Confirming earlier findings, three subjects showed a negative correlation between the BOLD signal and the average power time series within the alpha band (8--12 Hz) in extensive areas of the occipital, parietal and frontal lobes. In small thalamic areas, the BOLD signal was positively correlated with the alpha power. For subjects 3 and 4, who displayed two different states during the data acquisition time, it was shown that the corresponding correlation patterns were different, thus demonstrating the state dependency of the results. In subject 5, the changes in BOLD were observed mainly in the frontal and temporal lobes. Subject 6 only showed positive correlations, thus contradicting the negative BOLD alpha power cortical correlations that were found in most subjects. Results suggest that the resting state varies over subjects and, sometimes, even within one subject. As the resting state plays an important role in many fMRI experiments, the inter-subject variability of this state should be addressed when comparing fMRI results from different subjects.

What is magnetoencephalography and why it is relevant to neurosurgery?

Magnetoencephalography (MEG) is a relatively novel technique that allows the study of the dynamic properties of cortical activity. The functional localization of brain sources of MEG signals depends on the models used and it always has a certain degree of uncertainty. Nevertheless, MEG can be very useful in assisting the neurosurgeon in planning and carrying out brain surgery in, or around, eloquent brain areas, and in epilepsy surgery in pharmaco-resistant patients. The following three areas of application of MEG in neurosurgery are reviewed: (i) Presurgical functional localization of somatomotor eloquent cortex; (ii) Presurgical evaluation of epileptic patients. (iii) Functional localization of speech relevant brain areas. The performance of MEG in comparison with EEG and fMRI is discussed.

Removal of epileptogenic sequences from video material: the role of color.

BACKGROUND: After Pokémon viewing triggered an epidemic of seizures in Japan, many efforts have been made to design safety guidelines and systems to protect subjects with photosensitivity. The authors developed a new method based upon nonlinear diffusion techniques capable of filtering the epileptogenic content of a video sequence related to color without altering its spatial and luminance content. METHODS: The authors showed to 25 photosensitive patients (18 women, mean age: 22 years) the original Pokémon sequence and a modified one in an ABBA protocol using two television (TV) sets (100 and 50 Hz). RESULTS: Twenty-three patients had a photoparoxysmal response (PPR) according to Waltz classification with at least one of the scenes. The modified sequence triggered fewer and less severe PPRs than the original version in both TVs (p < 0.001). Original sequences elicited generalized PPRs in 56.5% of the trials for the 50 Hz TV and in 41.3% for the 100 Hz TV, whereas modified sequences elicited these responses in only 8.7% (50 Hz) and 4.3% (100 Hz TV) of the trials (p < 0.001). Sensitivity to the modified version on the 50 Hz TV correlated with pattern sensitivity (p < 0.05). CONCLUSION: Specific manipulations of the color modulation-depth could be enough to decrease dramatically the risk of triggering seizures in susceptible subjects exposed to provocative visual scenes. This new method can be implemented in protective devices able to filter out the epileptogenic video sequences in which color plays a fundamental role while leaving intact the spatial content, frequency, and average luminance.

Dynamics of non-convulsive epileptic phenomena modeled by a bistable neuronal network.

It is currently believed that the mechanisms underlying spindle oscillations are related to those that generate spike and wave (SW) discharges. The mechanisms of transition between these two types of activity, however, are not well understood. In order to provide more insight into the dynamics of the neuronal networks leading to seizure generation in a rat experimental model of absence epilepsy we developed a computational model of thalamo-cortical circuits based on relevant (patho)physiological data. The model is constructed at the macroscopic level since this approach allows to investigate dynamical properties of the system and the role played by different mechanisms in the process of seizure generation, both at short and long time scales. The main results are the following: (i) SW discharges represent dynamical bifurcations that occur in a bistable neuronal network; (ii) the durations of paroxysmal and normal epochs have exponential distributions, indicating that transitions between these two stable states occur randomly over time with constant probabilities; (iii) the probabilistic nature of the onset of paroxysmal activity implies that it is not possible to predict its occurrence; (iv) the bistable nature of the dynamical system allows that an ictal state may be aborted by a single counter-stimulus.

[The cortico-thalamic theory for generalised spike-wave discharges]. / Kortikotalamicheskaia teoriia proiskhozhdeniia generalizovannykh pik-volnovykh razriadov.

The origin of generalized absence epilepsy is still not known. In the last century, four theories have dominated the debate about the origin of the bilateral synchronous generalized spike-wave discharges associated with absence seizures: the "centrencephalic" theory [Penfield and Jasper], the "cortical" [Bancaud, Niedermeyer, Luders], the "cortico-reticular" theory [Gloor, Kostop[oulos, Avoli] and the "thalamic clock" theory [Buzsaki]. There is now some evidence that absence epilepsy, as studied in the WAG/Rij model, is a corticothalamic type of epilepsy. A new hypothesis is proposed which suggests that a cortical focus in the somatosensory cortex is driving the widespread corticothalamic networks during spontaneous absence seizures. This modern theory was given the name "hot spot' theory" [Meeren et al., 2002]. According to the present view three brain structures are critically involved and their integrity seems a minimal and sufficient condition for the occurrence of spike-wave discharges. Firstly, the reticular thalamic nucleus is involved and most likely its rostral pole. Secondly, the thalamocortical relay cells in the ventrobasal complex play a role and, thirdly and most importantly, the cerebral cortex with its epileptic zone. The zone in which the epileptic focus seems to be localised is located on the somato-sensory cortex, and more precisely in the area on which the peri-oral region including the upper lip, projects.

Long-term effects of temporal lobectomy on intelligence.

OBJECTIVE: To characterize the long-term effects of anterior temporal resection on intelligence. METHODS: Twenty-eight left temporal lobectomy (LTL) and 43 right temporal lobectomy (RTL) patients were followed at standard time points for at least 6 years after surgery. RESULTS: The average gain 6 years after operation was 3.6 Verbal IQ (VIQ) points and 10.3 Performance IQ (PIQ) points in LTL patients and 2.9 VIQ points and 7.7 PIQ points in RTL patients. A seizure-free outcome did not influence the increase in IQ, nor was the extent of resection related to IQ scores at the 6-year follow-up. Patients with exclusively mesial temporal sclerosis did not perform as well as patients with other pathologies, both before and after surgery. Major predictors of improved performance at 6 years were initial higher level of performance and lower age at surgery. Much of the observed improvement may be related to retest effects. CONCLUSIONS: The effects of epilepsy surgery on intelligence in the long term are limited. The largest gain in VIQ is seen from 2 to 6 years after surgery.