Modulation of pacemaker channel function in a model of thalamocortical hyperexcitability by demyelination and cytokines.

A consensus is yet to be reached regarding the exact prevalence of epileptic seizures or epilepsy in multiple sclerosis (MS). In addition, the underlying pathophysiological basis of the reciprocal interaction among neuroinflammation, demyelination, and epilepsy remains unclear. Therefore, a better understanding of cellular and network mechanisms linking these pathologies is needed. Cuprizone-induced general demyelination in rodents is a valuable model for studying MS pathologies. Here, we studied the relationship among epileptic activity, loss of myelin, and pro-inflammatory cytokines by inducing acute, generalized demyelination in a genetic mouse model of human absence epilepsy, C3H/HeJ mice. Both cellular and network mechanisms were studied using in vivo and in vitro electrophysiological techniques. We found that acute, generalized demyelination in C3H/HeJ mice resulted in a lower number of spike-wave discharges, increased cortical theta oscillations, and reduction of slow rhythmic intrathalamic burst activity. In addition, generalized demyelination resulted in a significant reduction in the amplitude of the hyperpolarization-activated inward current (Ih) in thalamic relay cells, which was accompanied by lower surface expression of hyperpolarization-activated, cyclic nucleotide-gated channels, and the phosphorylated form of TRIP8b (pS237-TRIP8b). We suggest that demyelination-related changes in thalamic Ih may be one of the factors defining the prevalence of seizures in MS.

Spike-wave discharges in absence epilepsy: segregation of electrographic components reveals distinct pathways of seizure activity.

KEY POINTS: The major electrophysiological hallmarks of absence seizures are spike and wave discharges (SWDs), consisting of a sharp spike component and a slow wave component. In a widely accepted scheme, these components are functionally coupled and reflect an iterative progression of neuronal excitation during the spike and post-excitatory silence during the wave. In a genetic rat model of absence epilepsy, local pharmacological inhibition of the centromedian thalamus (CM) selectively suppressed the spike component, leaving self-contained waves in epidural recordings. Thalamic inputs induced activity in cortical microcircuits underlying the spike component, while intracortical oscillations generated the wave component. Based on these findings, we propose a model in which oscillatory waves provide adequate time windows for integration of thalamocortical inputs and feedback responses during generation of a synchronized SWD. ABSTRACT: Spike and wave discharges (SWDs) are the electrographic hallmark of absence seizures and the major diagnostic criterion for childhood absence epilepsy (CAE). In a widely accepted scheme, the alternating sequence of spikes and waves reflects an iterative progression of neuronal excitation during the spike component and post-excitatory silence during the wave component. Here we challenge this view by showing that these two components are not necessarily coupled. In a genetic rat model of CAE, self-contained waves occurred in motor cortex in synchrony with SWDs in the somatosensory system during blockade of afferent input from the thalamus. Current-source density analyses of multi-site local field potentials (LFPs) revealed layer-specific activity, in which thalamic inputs induced a sequence of cellular-synaptic events underlying the spike component, while intracortical oscillations generated the wave component. These findings indicate novel principles of SWDs, where oscillatory cortical waves provide adequate time windows for integration of thalamocortical inputs and feedback responses during generation of seizure activity.

The Hyperpolarization-Activated HCN4 Channel is Important for Proper Maintenance of Oscillatory Activity in the Thalamocortical System.

Hyperpolarization-activated cation channels are involved, among other functions, in learning and memory, control of synaptic transmission and epileptogenesis. The importance of the HCN1 and HCN2 isoforms for brain function has been demonstrated, while the role of HCN4, the third major neuronal HCN subunit, is not known. Here we show that HCN4 is essential for oscillatory activity in the thalamocortical (TC) network. HCN4 is selectively expressed in various thalamic nuclei, excluding the thalamic reticular nucleus. HCN4-deficient TC neurons revealed a massive reduction of Ih and strongly reduced intrinsic burst firing, whereas the current was normal in cortical pyramidal neurons. In addition, evoked bursting in a thalamic slice preparation was strongly reduced in the mutant mice probes. HCN4-deficiency also significantly slowed down thalamic and cortical oscillations during active wakefulness. Taken together, these results establish that thalamic HCN4 channels are essential for the production of rhythmic intrathalamic oscillations and determine regular TC oscillatory activity during alert states.

Feed-forward artificial neural network provides data-driven inference of functional connectivity.

We propose a new model-free method based on the feed-forward artificial neuronal network for detecting functional connectivity in coupled systems. The developed method which does not require large computational costs and which is able to work with short data trials can be used for analysis and reconstruction of connectivity in experimental multichannel data of different nature. We test this approach on the chaotic Rössler system and demonstrate good agreement with the previous well-known results. Then, we use our method to predict functional connectivity thalamo-cortical network of epileptic brain based on ECoG data set of WAG/Rij rats with genetic predisposition to absence epilepsy. We show the emergence of functional interdependence between cortical layers and thalamic nuclei after epileptic discharge onset.

Short-term depression of gap junctional coupling in reticular thalamic neurons of absence epileptic rats.

KEY POINTS: Gap junctional electrical coupling between neurons of the reticular thalamic nucleus (RTN) is critical for hypersynchrony in the thalamo-cortical network. This study investigates the role of electrical coupling in pathological rhythmogenesis in RTN neurons in a rat model of absence epilepsy. Rhythmic activation resulted in a Ca(2+) -dependent short-term depression (STD) of electrical coupling between pairs of RTN neurons in epileptic rats, but not in RTN of a non-epileptic control strain. Pharmacological blockade of gap junctions in RTN in vivo induced a depression of seizure activity. The STD of electrical coupling represents a mechanism of Ca(2+) homeostasis in RTN aimed to counteract excessive synchronization. ABSTRACT: Neurons in the reticular thalamic nucleus (RTN) are coupled by electrical synapses, which play a major role in regulating synchronous activity. This study investigates electrical coupling in RTN neurons from a rat model of childhood absence epilepsy, genetic absence epilepsy rats from Strasbourg (GAERS), compared with a non-epileptic control (NEC) strain, to assess the impact on pathophysiological rhythmogenesis. Whole-cell recordings were obtained from pairs of RTN neurons of GAERS and NEC in vitro. Coupling was determined by injection of hyperpolarizing current steps in one cell and monitoring evoked voltage responses in both activated and coupled cell. The coupling coefficient (cc) was compared under resting condition, during pharmacological interventions and repeated activation using a series of current injections. The effect of gap junctional coupling on seizure expression was investigated by application of gap junctional blockers into RTN of GAERS in vivo. At resting conditions, cc did not differ between GAERS and NEC. During repeated activation, cc declined in GAERS but not in NEC. This depression in cc was restored within 25 s and was prevented by intracellular presence of BAPTA in the activated but not in the coupled cell. Local application of gap junctional blockers into RTN of GAERS in vivo resulted in a decrease of spike wave discharge (SWD) activity. Repeated activation results in a short-term depression (STD) of gap junctional coupling in RTN neurons of GAERS, depending on intracellular Ca(2+) mechanisms in the activated cell. As blockage of gap junctions in vivo results in a decrease of SWD activity, the STD observed in GAERS is considered a compensatory mechanism, aimed to dampen SWD activity.

Termination of ongoing spike-wave discharges investigated by cortico-thalamic network analyses.

PURPOSE: While decades of research were devoted to study generation mechanisms of spontaneous spike and wave discharges (SWD), little attention has been paid to network mechanisms associated with the spontaneous termination of SWD. In the current study coupling-dynamics at the onset and termination of SWD were studied in an extended part of the cortico-thalamo-cortical system of freely moving, genetic absence epileptic WAG/Rij rats. METHODS: Local-field potential recordings of 16 male WAG/Rij rats, equipped with multiple electrodes targeting layer 4 to 6 of the somatosensory-cortex (ctx4, ctx5, ctx6), rostral and caudal reticular thalamic nucleus (rRTN & cRTN), ventral postero medial (VPM), anterior- (ATN) and posterior (Po) thalamic nucleus, were obtained. Six seconds lasting pre-SWD->SWD, SWD->post SWD and control periods were analyzed with time-frequency methods, and between-region interactions were quantified with frequency-resolved Granger Causality (GC) analysis. RESULTS: Most channel pairs showed increases in GC lasting from onset to offset of the SWD. While for most thalamo-thalamic pairs a dominant coupling direction was found during the complete SWD, most cortico-thalamic pairs only showed a dominant directional drive (always from cortex to thalamus) during the first 500ms of SWD. Channel pair ctx4-rRTN showed a longer lasting dominant cortical drive, which stopped 1.5sec prior to SWD offset. This early decrease in directional coupling was followed by an increase in directional coupling from cRTN to rRTN 1sec prior to SWD offset. For channel pairs ctx5-Po and ctx6-Po the heightened cortex->thalamus coupling remained until 1.5sec following SWD offset, while the thalamus->cortex coupling for these pairs stopped at SWD offset. CONCLUSION: The high directional coupling from somatosensory cortex to the thalamus at SWD onset is in good agreement with the idea of a cortical epileptic focus that initiates and entrains other brain structures into seizure activity. The decrease of cortex to rRTN coupling as well as the increased coupling from cRTN to rRTN preceding SWD termination demonstrates that SWD termination is a gradual process that involves both cortico-thalamic as well as intrathalamic processes. The rostral RTN seems to be an important resonator for SWD and relevant for maintenance, while the cRTN might inhibit this oscillation. The somatosensory cortex seems to attempt to reinitiate SWD following its offset via its strong coupling to the posterior thalamus.

Epilepsy-related functional brain network alterations are already present at an early age in the GAERS rat model of genetic absence epilepsy.

Introduction: Genetic Absence Epilepsy Rats from Strasbourg (GAERS) represent a model of genetic generalized epilepsy. The present longitudinal study in GAERS and age-matched non-epileptic controls (NEC) aimed to characterize the epileptic brain network using two functional measures, resting state-functional magnetic resonance imaging (rs-fMRI) and manganese-enhanced MRI (MEMRI) combined with morphometry, and to investigate potential brain network alterations, following long-term seizure activity. Methods: Repeated rs-fMRI measurements at 9.4 T between 3 and 8 months of age were combined with MEMRI at the final time point of the study. We used graph theory analysis to infer community structure and global and local network parameters from rs-fMRI data and compared them to brain region-wise manganese accumulation patterns and deformation-based morphometry (DBM). Results: Functional connectivity (FC) was generally higher in GAERS when compared to NEC. Global network parameters and community structure were similar in NEC and GAERS, suggesting efficiently functioning networks in both strains. No progressive FC changes were observed in epileptic animals. Network-based statistics (NBS) revealed stronger FC within the cortical community, including regions of association and sensorimotor cortex, and with basal ganglia and limbic regions in GAERS, irrespective of age. Higher manganese accumulation in GAERS than in NEC was observed at 8 months of age, consistent with higher overall rs-FC, particularly in sensorimotor cortex and association cortex regions. Functional measures showed less similarity in subcortical regions. Whole brain volumes of 8 months-old GAERS were higher when compared to age-matched NEC, and DBM revealed increased volumes of several association and sensorimotor cortex regions and of the thalamus. Discussion: rs-fMRI, MEMRI, and volumetric data collectively suggest the significance of cortical networks in GAERS, which correlates with an increased fronto-central connectivity in childhood absence epilepsy (CAE). Our findings also verify involvement of basal ganglia and limbic regions. Epilepsy-related network alterations are already present in juvenile animals. Consequently, this early condition seems to play a greater role in dynamic brain function than chronic absence seizures.

Anti-epileptogenesis: Electrophysiology, diffusion tensor imaging and behavior in a genetic absence model.

The beneficial effects of chronic and early pharmacological treatment with ethosuximide on epileptogenesis were studied in a genetic absence epilepsy model comorbid for depression. It was also investigated whether there is a critical treatment period and treatment length. Cortical excitability in the form of electrical evoked potentials, but also to cortico-thalamo-cortical network activity (spike-wave discharges, SWD and afterdischarges), white matter changes representing extra cortico-thalamic functions and depressive-like behavior were investigated. WAG/Rij rats received either ethosuximide for 2 months (post natal months 2-3 or 4-5), or ethosuximide for 4 months (2-5) in their drinking water, while control rats drank plain water. EEG measurements were made during treatment, and 6 days and 2 months post treatment. Behavioral test were also done 6 days post treatment. DTI was performed ex vivo post treatment. SWD were suppressed during treatment, and 6 days and 2 months post treatment in the 4 month treated group, as well as the duration of AD elicited by cortical electrical stimulation 6 days post treatment. Increased fractional anisotropy in corpus callosum and internal capsula on DTI was found, an increased P8 evoked potential amplitude and a decreased immobility in the forced swim test. Shorter treatments with ETX had no large effects on any parameter. Chronic ETX has widespread effects not only within but also outside the circuitry in which SWD are initiated and generated, including preventing epileptogenesis and reducing depressive-like symptoms. The treatment of patients before symptom onset might prevent many of the adverse consequences of chronic epilepsy.

The Metabotropic Glutamate 5 Receptor in Sleep and Wakefulness: Focus on the Cortico-Thalamo-Cortical Oscillations.

Sleep is an essential innate but complex behaviour which is ubiquitous in the animal kingdom. Our knowledge of the distinct neural circuit mechanisms that regulate sleep and wake states in the brain are, however, still limited. It is therefore important to understand how these circuits operate during health and disease. This review will highlight the function of mGlu5 receptors within the thalamocortical circuitry in physiological and pathological sleep states. We will also evaluate the potential of targeting mGlu5 receptors as a therapeutic strategy for sleep disorders that often co-occur with epileptic seizures.

The dynamics of cortico-thalamo-cortical interactions at the transition from pre-ictal to ictal LFPs in absence epilepsy.

PURPOSE: Generalized spike and wave discharges (SWD) are generated within the cortico-thalamo-cortical system. However the exact interactions between cortex and different thalamic nuclei needed for the generation and maintenance of SWD are still to be elucidated. This study aims to shed more light on these interactions via multisite cortical and thalamic local-field-potential recordings. METHODS: WAG/Rij rats were equipped with multiple electrodes targeting layers 4 to 6 of the somatosensory-cortex, rostral and caudal RTN, VPM, anterior (ATN)- and posterior (Po) thalamic nucleus. The maximal-association-strength between signals was calculated for pre-ictal→ictal transition periods and in control periods using non-linear-association-analysis. Dynamics of changes in coupling-direction and time-delays between channels were analyzed. RESULTS: Earliest and strongest increases in coupling-strength were seen between cortical layers 5/6 and Po. Other thalamic nuclei became later involved in SWD activity. During the first 500ms of SWDs the cortex guided most thalamic nuclei while cortex and Po kept a bidirectional crosstalk. Most thalamic nuclei started to guide the Po until the end of the SWD. While the rostral RTN showed increased coupling with Po, the caudal RTN decoupled. Instead, it directed its activity to the rostral RTN. CONCLUSIONS: Next to the focal cortical instigator zone of SWDs, the Po seems crucial for their occurrence. This nucleus shows early increases in coupling and is the only nucleus which keeps a bidirectional crosstalk to the cortex within the first 500ms of SWDs. Other thalamic nuclei seem to have only a function in SWD maintenance. Rostral and caudal-RTN have opposite roles in SWD occurrence.

The role of thalamic nuclei in genetic generalized epilepsies.

There is no doubt on the participation of the thalamus in the various types of genetic generalized epilepsies as evidenced by multiple non-invasive imaging studies in humans as well as invasive studies in animal models of GGE. Based on human and mostly animal data gathered in early 2000 a so called 'three compartment model' on seizure generation was proposed conceptualizing the existence of a hyperexcitable cortical seizure onset zone providing excitation to relay cells of the relay thalamus and the inhibitory reticular thalamic nucleus (RTn). The interplay of corticothalamic excitation and feedforward inhibition via RTn is supposed to entrain thalamic relay neurons into synchronous, oscillatory activity for SWD sustainment. With the emergence of more fine-tuned experimental techniques and analyses, however, it becomes apparent that this model is too simplistic as the thalamus cannot be regarded as unity. Rather, different thalamic nuclei, being integrated in different thalamocortical and other subcortical subloops, need to be differentiated, which take over different functions for seizure generation, generalization and maintenance. Moreover, these networks are not necessarily the same for different classes of patients with GGE and can even be antagonistic between seizure types. This review will summarize data concerning different nuclei and their participation in GGE in order to extend this model and create a more detailed concept on seizure generation, generalization and maintenance.

Thalamo-Cortical and Thalamo-Thalamic Coupling During Sleep and Wakefulness in Rats.

Introduction: The thalamus, a heterogeneous brain structure, is involved in the generation of sleep-related thalamo-cortical oscillations. Higher order nuclei might possess a distinct function compared with first-order nuclei in brain communication. Here it is investigated whether this distinction can also be found during the process of falling asleep and deepening of slow-wave sleep. Methods: A nonlinear version of Granger causality was used to describe changes in directed network activity between the somatosensory cortex and rostral reticular thalamic nucleus (rRTN) and caudal reticular thalamic nucleus (cRTN), the higher order posterior (PO)- and anterior-thalamic nuclei (ATN), and the first-order ventral posteromedial thalamic nucleus (VPM) as assessed in local field potential recordings acquired during passive wakefulness (PW), light slow-wave sleep (LSWS), and deep slow-wave sleep (DSWS) in freely behaving rats. Surrogate statistics was used to assess significance. Results: Decreases in cortico-thalamo-cortical couplings were found. In contrast, multiple increases in intrathalamic couplings were observed. In particular, the rRTN increased its inhibition on the ATN from PW to LSWS, and this was further strengthened from LSWS to DSWS. The cRTN increased its coupling to VPM and PO from PW to LSWS, but the coupling from cRTN to VPM weakened at the transition from LSWS to DSWS, while its coupling to PO strengthened. Furthermore, intra-RTN coupling from PW to LSWS was differently changed compared with the change from LSWS to DSWS. Discussion: It can be inferred that higher order (ATN and PO) and first-order nuclei (VPM) are differentially inhibited during DSWS, which might be relevant for a proper functioning of sleep-related processes. Impact statement The functionally heterogeneous thalamus is affected by the different sleep/wake states. Changes in directed functional coupling between the thalamus and cortex and between functional different thalamic nuclei during the process of falling asleep and deepening to slow-wave sleep were investigated. It was revealed that the rostral and caudal subparts of the reticular thalamic nucleus, constituting the major source of intrathalamic inhibition, decouple from each other and show different coupling profiles with other thalamic nuclei. Specifically, higher order nuclei were found to be more inhibited than first-order nuclei during deep slow-wave sleep. These differences might be relevant for a proper coordination of sleep-related processes such as housekeeping, forgetting of irrelevant information, and consolidation of episodic memory.

Seizure Prediction in Genetic Rat Models of Absence Epilepsy: Improved Performance through Multiple-Site Cortico-Thalamic Recordings Combined with Machine Learning.

Seizure prediction is the grand challenge of epileptology. However, effort was devoted to prediction of focal seizures, while generalized seizures were regarded as stochastic events. Long-lasting local field potential (LFP) recordings containing several hundred generalized spike and wave discharges (SWDs), acquired at eight locations in the cortico-thalamic system of absence epileptic rats, were iteratively analyzed in all possible combinations of either two or three recording sites, by a wavelet-based algorithm, calculating the product of the wavelet-energy signaling increases in synchronicity. Sensitivity and false alarm rate of prediction were compared between various combinations, and wavelet spectra of true and false positive predictions were fed to a random forest machine learning algorithm to further differentiate between them. Wavelet analysis of intracortical and cortico-thalamic LFP traces showed a significantly smaller number of false alarms compared with intrathalamic combinations, while predictions based on recordings in Layers IV, V, and VI of the somatosensory-cortex significantly outreached all other combinations in terms of prediction sensitivity. In 24-h out-of-sample recordings of nine Genetic Absence Epilepsy Rats from Strasbourg (GAERS), containing diurnal fluctuations of SWD occurrence, classification of true and false positives by the trained random forest further reduced the false alarm rate by 71%, although at some trade-off between false alarms and sensitivity of prediction, as reflected in relatively low F1 score values. Results provide support for the cortical-focus theory of absence epilepsy and allow the conclusion that SWDs are predictable to some degree. The latter paves the way for the development of closed-loop SWD prediction-prevention systems. Suggestions for a possible translation to human data are outlined.

Neandertal introgression and accumulation of hypomorphic mutations in the neuropeptide S (NPS) system promote attenuated functionality.

The neuropeptide S (NPS) system plays an important role in fear and fear memory processing but has also been associated with allergic and inflammatory diseases. Genes for NPS and its receptor NPSR1 are found in all tetrapods. Compared to non-human primates, several non-synonymous single-nucleotide polymorphisms (SNPs) occur in both human genes that collectively result in functional attenuation, suggesting adaptive mechanisms in a human context. To investigate historic and geographic origins of these hypomorphic mutations and explore genetic signs of selection, we analyzed ancient genomes and worldwide genotype frequencies of four prototypic SNPs in the NPS system. Neandertal and Denisovan genomes contain exclusively ancestral alleles for NPSR1 while all derived alleles occur in ancient genomes of anatomically modern humans, indicating that they arose in modern Homo sapiens. Worldwide genotype frequencies for three hypomorphic NPSR1 SNPs show significant regional homogeneity but follow a gradient towards increasing derived allele frequencies that supports an out-of-Africa scenario. Increased density of high-frequency polymorphisms around the three NPSR1 loci suggests weak or possibly balancing selection. A hypomorphic mutation in the NPS precursor, however, was detected at high frequency in Eurasian Neandertal genomes and shows genetic signatures indicating that it was introgressed into the human gene pool, particularly in Southern Europe, by interbreeding with Neandertals. We discuss potential evolutionary scenarios including behavior and immune-based natural selection.

Retrosplenial Cortex Contributes to Network Changes during Seizures in the GAERS Absence Epilepsy Rat Model.

Resting state-fMRI was performed to explore brain networks in Genetic Absence Epilepsy Rats from Strasbourg and in nonepileptic controls (NEC) during monitoring of the brain state by simultaneous optical Ca2+-recordings. Graph theoretical analysis allowed for the identification of acute and chronic network changes and revealed preserved small world topology before and after seizure onset. The most prominent acute change in network organization during seizures was the segregation of cortical regions from the remaining brain. Stronger connections between thalamic with limbic regions compared with preseizure state indicated network regularization during seizures. When comparing between strains, intrathalamic connections were prominent in NEC, on local level represented by higher thalamic strengths and hub scores. Subtle differences were observed for retrosplenial cortex (RS), forming more connections beyond cortex in epileptic rats, and showing a tendency to lateralization during seizures. A potential role of RS as hub between subcortical and cortical regions in epilepsy was supported by increased numbers of parvalbumin-positive (PV+) interneurons together with enhanced inhibitory synaptic activity and neuronal excitability in pyramidal neurons. By combining multimodal fMRI data, graph theoretical methods, and electrophysiological recordings, we identified the RS as promising target for modulation of seizure activity and/or comorbidities.

Regional specificity of cortico-thalamic coupling strength and directionality during waxing and waning of spike and wave discharges.

Spike-wave discharges (SWDs) on the EEG during absence epilepsy are waxing and waning stages of corticothalamic hypersynchrony. While the somatosensory cortex contains an epileptic focus, the role of thalamic nuclei in SWD generation is debated. Here we assess the contribution of distinct thalamic nuclei through multiple-site unit recordings in a genetic rat model of absence epilepsy and cross-correlation analysis, revealing coupling strength and directionality of neuronal activity at high temporal resolution. Corticothalamic coupling increased and decreased during waxing and waning of SWD, respectively. A cortical drive on either sensory or higher order thalamic nuclei distinguished between onset and offset of SWD, respectively. Intrathalamic coupling steadily increased during maintained SWD activity, peaked at SWD offset, and subsequently displayed a sharp decline to baseline. The peak in intrathalamic coupling coincided with a sharp increase in coupling strength between reticular thalamic nucleus and somatosensory cortex. This increased influence of the inhibitory reticular thalamic nucleus is suggested to serve as a break for SWD activity. Overall, the data extend the cortical focus theory of absence epilepsy by identifying a regionally specific cortical lead over distinct thalamic nuclei, particularly also during waning of generalized epileptic discharges, thereby revealing a potential window and location for intervention.

Statistical Properties and Predictability of Extreme Epileptic Events.

The use of extreme events theory for the analysis of spontaneous epileptic brain activity is a relevant multidisciplinary problem. It allows deeper understanding of pathological brain functioning and unraveling mechanisms underlying the epileptic seizure emergence along with its predictability. The latter is a desired goal in epileptology which might open the way for new therapies to control and prevent epileptic attacks. With this goal in mind, we applied the extreme event theory for studying statistical properties of electroencephalographic (EEG) recordings of WAG/Rij rats with genetic predisposition to absence epilepsy. Our approach allowed us to reveal extreme events inherent in this pathological spiking activity, highly pronounced in a particular frequency range. The return interval analysis showed that the epileptic seizures exhibit a highly-structural behavior during the active phase of the spiking activity. Obtained results evidenced a possibility for early (up to 7 s) prediction of epileptic seizures based on consideration of EEG statistical properties.

Increasing Human Performance by Sharing Cognitive Load Using Brain-to-Brain Interface.

Brain-computer interfaces (BCIs) attract a lot of attention because of their ability to improve the brain's efficiency in performing complex tasks using a computer. Furthermore, BCIs can increase human's performance not only due to human-machine interactions, but also thanks to an optimal distribution of cognitive load among all members of a group working on a common task, i.e., due to human-human interaction. The latter is of particular importance when sustained attention and alertness are required. In every day practice, this is a common occurrence, for example, among office workers, pilots of a military or a civil aircraft, power plant operators, etc. Their routinely work includes continuous monitoring of instrument readings and implies a heavy cognitive load due to processing large amounts of visual information. In this paper, we propose a brain-to-brain interface (BBI) which estimates brain states of every participant and distributes a cognitive load among all members of the group accomplishing together a common task. The BBI allows sharing the whole workload between all participants depending on their current cognitive performance estimated from their electrical brain activity. We show that the team efficiency can be increased due to redistribution of the work between participants so that the most difficult workload falls on the operator who exhibits maximum performance. Finally, we demonstrate that the human-to-human interaction is more efficient in the presence of a certain delay determined by brain rhythms. The obtained results are promising for the development of a new generation of communication systems based on neurophysiological brain activity of interacting people. Such BBIs will distribute a common task between all group members according to their individual physical conditions.

Modulation of Hyperpolarization-Activated Inward Current and Thalamic Activity Modes by Different Cyclic Nucleotides.

The hyperpolarization-activated inward current, Ih, plays a key role in the generation of rhythmic activities in thalamocortical (TC) relay neurons. Cyclic nucleotides, like 3',5'-cyclic adenosine monophosphate (cAMP), facilitate voltage-dependent activation of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels by shifting the activation curve of Ih to more positive values and thereby terminating the rhythmic burst activity. The role of 3',5'-cyclic guanosine monophosphate (cGMP) in modulation of Ih is not well understood. To determine the possible role of the nitric oxide (NO)-sensitive cGMP-forming guanylyl cyclase 2 (NO-GC2) in controlling the thalamic Ih, the voltage-dependency and cGMP/cAMP-sensitivity of Ih was analyzed in TC neurons of the dorsal part of the lateral geniculate nucleus (dLGN) in wild type (WT) and NO-GC2-deficit (NO-GC2-/-) mice. Whole cell voltage clamp recordings in brain slices revealed a more hyperpolarized half maximal activation (V1/2) of Ih in NO-GC2-/- TC neurons compared to WT. Different concentrations of 8-Br-cAMP/8-Br-cGMP induced dose-dependent positive shifts of V1/2 in both strains. Treatment of WT slices with lyase enzyme (adenylyl and guanylyl cyclases) inhibitors (SQ22536 and ODQ) resulted in further hyperpolarized V1/2. Under current clamp conditions NO-GC2-/- neurons exhibited a reduction in the Ih-dependent voltage sag and reduced action potential firing with hyperpolarizing and depolarizing current steps, respectively. Intrathalamic rhythmic bursting activity in brain slices and in a simplified mathematical model of the thalamic network was reduced in the absence of NO-GC2. In freely behaving NO-GC2-/- mice, delta and theta band activity was enhanced during active wakefulness (AW) as well as rapid eye movement (REM) sleep in cortical local field potential (LFP) in comparison to WT. These findings indicate that cGMP facilitates Ih activation and contributes to a tonic activity in TC neurons. On the network level basal cGMP production supports fast rhythmic activity in the cortex.