Detection of seizure onset in childhood absence epilepsy.

OBJECTIVE: This study aims to detect the seizure onset, in childhood absence epilepsy, as early as possible. Indeed, interfering with absence seizures with sensory simulation has been shown to be possible on the condition that the stimulation occurs soon enough after the seizure onset. METHODS: We present four variations (two supervised, two unsupervised) of an algorithm designed to detect the onset of absence seizures from 4 scalp electrodes, and compare their performance with that of a state-of-the-art algorithm. We exploit the characteristic shape of spike-wave discharges to detect the seizure onset. Their performance is assessed on clinical electroencephalograms from 63 patients with confirmed childhood absence epilepsy. RESULTS: The proposed approaches succeed in early detection of the seizure onset, contrary to the classical detection algorithm. Indeed, the results clearly show the superiority of the proposed methods for small delays of detection, under 750 ms from the onset. CONCLUSION: The performance of the proposed unsupervised methods is equivalent to that of the supervised ones. The use of only four electrodes makes the pipeline suitable to be embedded in a wearable device. SIGNIFICANCE: The proposed pipelines perform early detection of absence seizures, which constitutes a prerequisite for a closed-loop system.

Long-term Effect of Multichannel tDCS Protocol in Patients with Central Cortex Epilepsies Associated with Epilepsia Partialis Continua.

Epilepsia partialis continua (EPC) is a rare type of focal motor status epilepticus that causes continuous muscle jerking in a specific part of the body. Experiencing this type of seizure, along with other seizure types, such as focal motor seizures and focal to bilateral tonic-clonic seizures, can result in a disabling situation. Non-invasive brain stimulation methods like transcranial direct current stimulation (tDCS) show promise in reducing seizure frequency (SF) when medications are ineffective. However, research on tDCS for EPC and related seizures is limited. We evaluated personalized multichannel tDCS in drug-resistant EPC of diverse etiologies for long-term clinical efficacy We report three EPC patients undergoing a long-term protocol of multichannel tDCS. The patients received several cycles (11, 9, and 3) of five consecutive days of stimulation at 2 mA for 2 × 20 min, targeting the epileptogenic zone (EZ), including the central motor cortex with cathodal electrodes. The primary measurement was SF changes. In three cases, EPC was due to Rasmussen's Encephalitis (case 1), focal cortical dysplasia (case 2), or remained unknown (case 3). tDCS cycles were administered over 6 to 22 months. The outcomes comprised a reduction of at least 75% in seizure frequency for two patients, and in one case, a complete cessation of severe motor seizures. However, tDCS had no substantial impact on the continuous myoclonus characterizing EPC. No serious side effects were reported. Long-term application of tDCS cycles is well tolerated and can lead to a considerable reduction in disabling seizures in patients with various forms of epilepsy with EPC.

Improving Fast Ripples Recording With Model-Guided Design of Microelectrodes.

OBJECTIVE: Microelectrodes allow the recording of neural activities with a high spatial resolution. However, their small sizes result in high impedance causing high thermal noise and poor signal-to-noise ratio. In drug-resistant epilepsy, the accurate detection of Fast Ripples (FRs) can help in the identification of epileptogenic networks. Consequently, good-quality recordings are instrumental in improving surgical outcomes. In this work, we propose a novel model-based approach for the design of microelectrodes optimized for FRs recording. METHODS: A 3D microscale computational model was developed to simulate FRs generated in the hippocampus. It was coupled with a model of the Electrode-Tissue Interface that accounts for the biophysical properties of intracortical microelectrode. This hybrid model was used to analyze the microelectrode geometrical and physical characteristics and their impact on recorded FRs. For model validation, experimental signals (local field potentials, LFPs) were recorded from CA1 using different electrode materials: stainless steel, gold, and gold coated with poly(3,4-ethylene dioxythiophene)/Poly(styrene sulfonate) (Au:PEDOT/PSS). RESULTS: results indicated that a radius between 65 and 120 µm for a wire microelectrode is the most optimal for recording FRs. In addition, in silico and in vivo quantified results showed a possible improvement in FRs observability using PEDOT/PSS coated microelectrodes. CONCLUSION: the optimization of the design of microelectrodes for FRs recording can improve the observability and detectability of FRs which are a recognized marker of epileptogenicity. SIGNIFICANCE: This model-based approach can assist in the design of hybrid electrodes that can be used in the presurgical evaluation of epileptic patients with drug-resistant epilepsy.

Dynamic reshaping of functional brain networks during visual object recognition.

OBJECTIVE: Emerging evidence shows that the modular organization of the human brain allows for better and efficient cognitive performance. Many of these cognitive functions are very fast and occur in a sub-second time scale such as the visual object recognition. APPROACH: Here, we investigate brain network modularity while controlling stimuli meaningfulness and measuring a participant's reaction time. We particularly raised two questions: i) does the dynamic brain network modularity change during the recognition of meaningful and meaningless visual images? And (ii) is there a correlation between network modularity and the reaction time of the participants? To tackle these issues, we collected dense-electroencephalography (EEG, 256 channels) data from 20 healthy human subjects performing a cognitive task consisting of naming meaningful (tools, animals…) and meaningless (scrambled) images. Functional brain networks in both categories were estimated at the sub-second time scale using the EEG source connectivity method. By using multislice modularity algorithms, we tracked the reconfiguration of functional networks during the recognition of both meaningful and meaningless images. MAIN RESULTS: Results showed a difference in the module's characteristics of both conditions in term of integration (interactions between modules) and occurrence (probability on average of any two brain regions to fall in the same module during the task). Integration and occurrence were greater for meaningless than for meaningful images. Our findings revealed also that the occurrence within the right frontal regions and the left occipito-temporal can help to predict the ability of the brain to rapidly recognize and name visual stimuli. SIGNIFICANCE: We speculate that these observations are applicable not only to other fast cognitive functions but also to detect fast disconnections that can occur in some brain disorders.

Functional connectivity disruptions correlate with cognitive phenotypes in Parkinson's disease.

Cognitive deficits in Parkinson's disease are thought to be related to altered functional brain connectivity. To date, cognitive-related changes in Parkinson's disease have never been explored with dense-EEG with the aim of establishing a relationship between the degree of cognitive impairment, on the one hand, and alterations in the functional connectivity of brain networks, on the other hand. This study was aimed at identifying altered brain networks associated with cognitive phenotypes in Parkinson's disease using dense-EEG data recorded during rest with eyes closed. Three groups of Parkinson's disease patients (N = 124) with different cognitive phenotypes coming from a data-driven cluster analysis, were studied: G1) cognitively intact patients (63), G2) patients with mild cognitive deficits (46) and G3) patients with severe cognitive deficits (15). Functional brain networks were identified using a dense-EEG source connectivity method. Pairwise functional connectivity was computed for 68 brain regions in different EEG frequency bands. Network statistics were assessed at both global (network topology) and local (inter-regional connections) level. Results revealed progressive disruptions in functional connectivity between the three patient groups, typically in the alpha band. Differences between G1 and G2 (p < 0.001, corrected using permutation test) were mainly frontotemporal alterations. A statistically significant correlation (ρ = 0.49, p < 0.001) was also obtained between a proposed network-based index and the patients' cognitive score. Global properties of network topology in patients were relatively intact. These findings indicate that functional connectivity decreases with the worsening of cognitive performance and loss of frontotemporal connectivity may be a promising neuromarker of cognitive impairment in Parkinson's disease.

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.

Dynamic changes of depolarizing GABA in a computational model of epileptogenic brain: Insight for Dravet syndrome.

Abnormal reemergence of depolarizing GABAA current during postnatal brain maturation may play a major role in paediatric epilepsies, Dravet syndrome (DS) being among the most severe. To study the impact of depolarizing GABA onto distinct patterns of EEG activity, we extended a neural mass model as follows: one sub-population of pyramidal cells was added as well as two sub-populations of interacting interneurons, perisomatic-projecting interneurons (basket-like) with fast synaptic kinetics GABAA (fast, I1) and dendritic-projecting interneurons with slow synaptic kinetics GABAA (slow, I2). Basket-like cells were interconnected to reproduce mutual inhibition mechanisms (I1➔I1). The firing rate of interneurons was adapted to mimic the genetic alteration of voltage gated sodium channels found in DS patients, SCN1A(+/-). We implemented the "dynamic depolarizing GABAA" mediated post-synaptic potential in the model, as some studies reported that the chloride reversal potential can switch from negative to more positive value depending on interneuron activity. The "shunting inhibition" promoted by GABAA receptor activation was also implemented. We found that increasing the proportion of depolarizing GABAA mediated IPSP (I1➔I1 and I1➔P) only (i.e., other parameters left unchanged) was sufficient to sequentially switch the EEG activity from background to (1) interictal isolated polymorphic epileptic spikes, (2) fast onset activity, (3) seizure like activity and (4) seizure termination. The interictal and ictal EEG patterns observed in 4 DS patients were reproduced by the model via tuning the amount of depolarizing GABAA postsynaptic potential. Finally, we implemented the modes of action of benzodiazepines and stiripentol, two drugs recommended in DS. Both drugs blocked seizure-like activity, partially and dose-dependently when applied separately, completely and with a synergic effect when combined, as has been observed in DS patients. This computational modeling study constitutes an innovative approach to better define the role of depolarizing GABA in infantile onset epilepsy and opens the way for new therapeutic hypotheses, especially in Dravet syndrome.

Computational modeling of high frequency oscillations recorded with clinical intracranial macroelectrodes.

High Frequency Oscillations (HFOs) are a potential biomarker of epileptogenic regions. They have been extensively investigated in terms of automatic detection, classification and feature extraction. However, the mechanisms governing the generation of HFOs as well as the observability conditions on clinical intracranial macroelectrodes remain elusive. In this paper, we propose a novel physiologically-relevant macroscopic model for accurate simulation of HFOs as invasively recorded in epileptic patients. This model accounts for both the temporal and spatial properties of the cortical patch at the origin of epileptiform activity. Indeed, neuronal populations are combined with a 3D geometrical representation to simulate an extended epileptic source. Then, by solving the forward problem, the contributions of neuronal population signals are projected onto intracerebral electrode contacts. The obtained signals are qualitatively and quantitatively compared to real HFOs, and a relationship is drawn between macroscopic model parameters such as synchronization and spatial extent on the one hand, and HFO features such as the wave and fast ripple (200-600 Hz) components, on the other hand.

Energy deprivation transiently enhances rhythmic inhibitory events in the CA3 hippocampal network in vitro.

Oxygen glucose deprivation (OGD) leads to rapid suppression of synaptic transmission. Here we describe an emergence of rhythmic activity at 8 to 20 Hz in the CA3 subfield of hippocampal slice cultures occurring for a few minutes prior to the OGD-induced cessation of evoked responses. These oscillations, dominated by inhibitory events, represent network activity, as they were abolished by tetrodotoxin. They were also completely blocked by the GABAergic antagonist picrotoxin, and strongly reduced by the glutamatergic antagonist NBQX. Applying CPP to block NMDA receptors had no effect and neither did UBP302, an antagonist of GluK1-containing kainate receptors. The gap junction blocker mefloquine disrupted rhythmicity. Simultaneous whole-cell voltage-clamp recordings from neighboring or distant CA3 pyramidal cells revealed strong cross-correlation of the incoming rhythmic activity. Interneurons in the CA3 area received similar correlated activity. Interestingly, oscillations were much less frequently observed in the CA1 area. These data, together with the observation that the recorded activity consists primarily of inhibitory events, suggest that CA3 interneurons are important for generating these oscillations. This transient increase in inhibitory network activity during OGD may represent a mechanism contributing to the lower vulnerability to ischemic insults of the CA3 area as compared to the CA1 area.

Some aspects of the physiological role of ion channels in the nervous system.

Recent analyses of the genomes of several animal species, including man, have revealed that a large number of ion channels are present in the nervous system. Our understanding of the physiological role of these channels in the nervous system has followed the evolution of biophysical techniques during the last century. The observation and the quantification of the electrical events associated with the operation of the ionic channels has been, and still is, one of the best tools to analyse the various aspects of their contribution to nerve function. For this reason, we have chosen to use electrophysiological recordings to illustrate some of the main functions of these channels. The properties and the roles of Na+ and K+ channels in neuronal resting and action potentials are illustrated in the case of the giant axons of the squid and the cockroach. The nature and role of the calcium currents in the bursting behaviour of the neurons are illustrated for Aplysia giant neurons. The relationship between presynaptic calcium currents and synaptic transmission is shown for the squid giant synapse. The involvement of calcium channels in survival and neurite outgrowth of cultured neurons is exemplified using embryonic cockroach brain neurons. This same neuronal preparation is used to illustrate ion channel noise and single-channel events associated with the binding of agonists to nicotinic receptors. Some features of the synaptic activity in the central nervous system are shown, with examples from the cercal nerve giant-axon preparation of the cockroach. The interplay of different ion conductances involved in the oscillatory behaviour of the Xenopus spinal motoneurons is illustrated and discussed. The last part of this review deals with ionic homeostasis in the brain and the function of glial cells, with examples from Necturus and squids.

Properties and development of calcium currents in embryonic cockroach neurons.

In freshly dissociated neurons from embryonic cockroach (Periplaneta americana L.) brains, voltage-dependent calcium currents appear early in development (E14). Their intensity increases progressively during embryonic life until eclosion (E35). Their time course and voltage dependency are characteristic of high voltage activated (HVA) currents although a 10 mV shift of the I/V curve towards more negative potentials was observed between E18 and E23. Their sensitivity to omega-AgaTx-IVA and omega-CgTx-GVIA and insensitivity to both amiloride and isradipine indicate that the corresponding channels are of the P/Q and N types. These channels, as well as a small proportion of toxin-resistant (R) channels (about 20%), are blocked by mibefradil and verapamil. The physiological significance of these currents and their modifications during embryonic life is discussed.

omega-AgaIVA-sensitive (P/Q-type) and -resistant (R-type) high-voltage-activated Ba(2+) currents in embryonic cockroach brain neurons.

By means of the whole cell patch-clamp technique, the biophysical and pharmacological properties of voltage-dependent Ba(2+) currents (I(Ba)) were characterized in embryonic cockroach brain neurons in primary culture. I(Ba) was characterized by a threshold of approximately -30 mV, a maximum at approximately 0 mV, and a reversal potential near +40 mV. Varying the holding potential from -100 to -40 mV did not modify these properties. The steady-state, voltage-dependent activation and inactivation properties of the current were determined by fitting the corresponding curves with the Boltzmann equation and yielded V(0.5) of -10 +/- 2 (SE) mV and -30 +/- 1 mV, respectively. I(Ba) was insensitive to the dihydropyridine (DHP) agonist BayK8644 (1 microM) and antagonist isradipine (10 microM) but was efficiently and reversibly blocked by the phenylalkylamine verapamil in a dose-dependent manner (IC(50) = 170 microM). The toxin omega-CgTxGVIA (1 microM) had no significant effect on I(Ba). Micromolar doses of omega-CmTxMVIIC were needed to reduce the current amplitude significantly, and the effect was slow. At 1 microM, 38% of the peak current was blocked after 1 h. In contrast, I(Ba) was potently and irreversibly blocked by nanomolar concentrations of omega-AgaTxIVA in approximately 81% of the neurons. Approximately 20% of the current was unaffected after treatment of the neurons with high concentrations of the toxin (0. 4-1 microM). The steady-state dose-response relationship was fitted with a Hill equation and yielded an IC(50) of 17 nM and a Hill coefficient (n) of 0.6. A better fit was obtained with a combination of two Hill equations corresponding to specific (IC(50) = 9 nM; n = 1) and nonspecific (IC(50) = 900 nM; n = 1) omega-AgaTxIVA-sensitive components. In the remaining 19% of the neurons, concentrations >/=100 nM omega-AgaTxIVA had no visible effect on I(Ba). On the basis of these results, it is concluded that embryonic cockroach brain neurons in primary culture express at least two types of voltage-dependent, high-voltage-activated (HVA) calcium channels: a specific omega-AgaTxIVA-sensitive component and DHP-, omega-CgTxGVIA-, and omega-AgaTxIVA-resistant component related respectively to the P/Q- and R-type voltage-dependent calcium channels.