Search

Cortical spreading depolarization (CSD), a slowly propagating wave of transient cellular depolarization, is a reliable cortical response to various brain insults (stroke, trauma, seizures) and underlying mechanism of migraine aura. Little is known about CSD effects on brain network activity. Using undirected (mutual information, MI) and directed (transfer entropy, TE) measures, we studied the dynamics of cross-hemispheric connectivity associated with the development of unilateral CSD in freely behaving rats and the involvement of inhibitory transmission in mechanisms of the coupling changes. We show that the development of CSD in the cortex of one hemisphere is followed by the transient loss of undirected functional connectivity (MI) between ipsilateral and contralateral cortical regions. The post-CSD functional disconnection of the hemispheres was accompanied by an increase in driving force from an unaffected contralateral cortex to an affected one (TE). Mild cortical disinhibition produced by pretreatment with an inhibitory receptor blocking agent (penthylenetetrazole) did not affect CSD but attenuated (MI) or eliminated (TE) the CSD-induced connectivity changes. The effects of CSD on functional connectivity in awake rodents were similar at the individual and group levels, suggesting that the described connectivity response may be a promising network biomarker of CSD occurrence in patients., Competing Interests: Competing Interests: The authors have declared that no competing interests exist., (© 2024 Massachusetts Institute of Technology.)

Functional connectivity analysis is gaining more interest due to its promising clinical applications. To study network mechanisms underlying seizure termination and postictal depression, we explore dynamics of interhemispheric functional connectivity near the offset of focal and bilateral seizures in the experimental model of reflex audiogenic epilepsy. In the model, seizures and spreading depression are induced by sound stimulation of genetically predisposed rodents. We characterize temporal evolution of seizure-associated coupling dynamics in the frontoparietal cortex during late ictal, immediate postictal and interictal resting states, using two measures applied to local field potentials recorded in awake epileptic rats. Signals were analyzed with mean phase coherence index in delta (1-4 Hz), theta (4-10 Hz) beta (10-25 Hz) and gamma (25-50 Hz) frequency bands and mutual information function. The study shows that reflex seizures elicit highly dynamic changes in interhemispheric functional coupling with seizure-, region- and frequency-specific patterns of increased and decreased connectivity during late ictal and immediate postictal periods. Also, secondary generalization of recurrent seizures (kindling) is associated with pronounced alterations in resting-state functional connectivity - an early wideband decrease and a subsequent beta-gamma increase. The findings show that intracortical functional connectivity is dynamically modified in response to seizures on short and long timescales, suggesting the existence of activity-dependent plastic network alterations that may promote or prevent seizure propagation within the cortex and underlie postictal behavioral impairments., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The role of the hippocampus (Hp) in absence epileptic networks and the effect of endocannabinoid system on this network remain enigmatic. Here, using adapted nonlinear Granger causality, we compared the differences in network strength in four intervals (baseline or interictal, preictal, ictal and postictal) in two hours before (Epoch 1) and six hours (epochs 2, 3 and 4) after the administration of three different doses of the endocannabinoid agonist WIN55,212-2 (WIN) or solvent. Local field potentials were recorded for eight hours in 23 WAG/Rij rats in the Frontal (FC), Parietal PC), Occipital Cortex (OC) and in the hippocampus (Hp). The four intervals were visually marked by an expert neurophysiologist and the strength of couplings between electrode pairs were calculated in both directions. Ictally, a strong decrease in coupling strength was found between Hp and FC, as well as a large increase bidirectionally between PC and FC and unidirectionally from FC and PC to OC, and from FC to Hp over all epochs. The highest dose of WIN increased the couplings strength from FC to Hp and from OC to PC during 4 and 2 hr respectively in all intervals, and decreased the FC to PC coupling strength postictally in epoch 2. A single rat showed generalized convulsive seizures after the highest dose: this rat shared not only coupling changes with the other rats in the same condition, but showed many more. WIN reduced SWD number in epoch 2 and 3, their mean duration increased in epochs 3 and 4. Conclusions:during SWDs FC and PC are strongly coupled and drive OC, while at the same time the influence of Hp to FC is diminished. The first is in agreement with the cortical focus theory, the latter demonstrates an involvement of the hippocampus in SWD occurrence and that ictally the hippocampal control of the cortico-thalamo-cortical system is lost. WIN causes dramatic network changes which have major consequences for the decrease of SWDs, the occurrence of convulsive seizures, and the normal cortico-cortical and cortico-hippocampal interactions., (Copyright © 2023 Elsevier B.V. All rights reserved.)

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.

Van der Pol oscillators and their generalizations are known to be a fundamental model in the theory of oscillations and their applications. Many objects of a different nature can be described using van der Pol-like equations under some circumstances; therefore, methods of reconstruction of such equations from experimental data can be of significant importance for tasks of model verification, indirect parameter estimation, coupling analysis, system classification, etc. The previously reported techniques were not applicable to time series with large measurement noise, which is usual in biological, climatological, and many other experiments. Here, we present a new approach based on the use of numerical integration instead of the differentiation and implicit approximation of a nonlinear dissipation function. We show that this new technique can work for noise levels up to 30% by standard deviation from the signal for different types of autonomous van der Pol-like systems and for ensembles of such systems, providing a new approach to the realization of the Granger-causality idea.

A mesoscale network model is proposed for the development of spike and wave discharges (SWDs) in the cortico-thalamo-cortical (C-T-C) circuit. It is based on experimental findings in two genetic models of childhood absence epilepsy-rats of WAG/Rij and GAERS strains. The model is organized hierarchically into two levels (brain structures and individual neurons) and composed of compartments for representation of somatosensory cortex, reticular and ventroposteriomedial thalamic nuclei. The cortex and the two thalamic compartments contain excitatory and inhibitory connections between four populations of neurons. Two connected subnetworks both including relevant parts of a C-T-C network responsible for SWD generation are modelled: a smaller subnetwork for the focal area in which the SWD generation can take place, and a larger subnetwork for surrounding areas which can be only passively involved into SWDs, but which is mostly responsible for normal brain activity. This assumption allows modeling of both normal and SWD activity as a dynamical system (no noise is necessary), providing reproducibility of results and allowing future analysis by means of theory of dynamical system theories. The model is able to reproduce most time-frequency changes in EEG activity accompanying the transition from normal to epileptiform activity and back. Three different mechanisms of SWD initiation reported previously in experimental studies were successfully reproduced in the model. The model incorporates also a separate mechanism for the maintenance of SWDs based on coupling analysis from experimental data. Finally, the model reproduces the possibility to stop ongoing SWDs with high frequency electrical stimulation, as described in the literature., Competing Interests: The authors have declared that no competing interests exist.

We propose a method for the reconstruction of time-delayed feedback systems having unobserved variables from scalar time series. The method is based on the modified initial condition approach, which allows one to significantly reduce the number of starting guesses for an unobserved variable with a time delay. The proposed method is applied to the reconstruction of the Lang-Kobayashi equations, which describe the dynamics of a single-mode semiconductor laser with external optical feedback. We consider the case where only the time series of laser intensity is observable and the other two variables of the model are hidden. The dependence of the quality of the system reconstruction on the accuracy of assignment of starting guesses for unobserved variables and unknown laser parameters is studied. The method could be used for testing the security of information transmission in laser-based chaotic communication systems.

Spike-wave discharges (SWDs) are the main manifestation of absence epilepsy. Their occurrence is dependent on the behavioral state, and they preferentially occur during unstable vigilance periods. The present study investigated whether the occurrence of SWDs can be predicted by the preceding behavioral state and whether this relationship is different between the light and the dark phases of the 24-h day. Twenty-four-hour (12:12 light/dark phases) electroencephalographic (EEG) recordings of 12 Wistar Albino Glaxo, originally bred in Rijswijk (WAG/Rij) rats, a well-known genetic model of absence epilepsy, were analyzed and transformed into sequences of 2-s length intervals of the following 6 possible states: active wakefulness (AW), passive wakefulness (PW), deep slow-wave sleep (DSWS), light slow-wave sleep (LSWS), rapid eye movement (REM) sleep, and SWDs, given discrete series of categorical data. Probabilities of all transitions between states and Shannon entropy of transitions were calculated for the light and dark phases separately and statistically analyzed. Common differences between the light and the dark phases were found regarding the time spent in AW, LSWS, DSWS, and SWDs. The most probable transitions were that AW was preceded and followed by PW and vice versa regardless of the phase of the photoperiod. A similar relationship was found for light and deep slow-wave sleep. The most probable transitions to and from SWDs were AW and LSWS, respectively, with these transition likelihoods being consistent across both circadian phases. The second most probable transitions around SWDs appeared more variable between light and dark. During the light phase, SWDs occurred around PW and participated exclusively in sleep initiation; in the dark phase, SWDs were seen on both, ascending and descending steps towards and from sleep. Conditional Shannon entropy showed that AW and DSWS are the most predictable events, while the possible prediction horizon of SWDs is not larger than 4 s and despite the higher occurrence of SWDs in the dark phase, did not differ between phases. It can be concluded that although SWDs show a stable, strong circadian rhythm with a peak in number during the dark phase, their occurrence cannot be reliably predicted by the preceding behavioral state, except at a very short time base., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Sensory information processing and higher cognitive functions rely on the interactions between thalamus and cortex. Many types of neurological and psychiatric disorders are accompanied or driven by alterations in the brain connectivity. In this study, putative changes in functional and effective corticocortical (CC), thalamocortical (TC), and corticothalamic (CT) connectivity during wakefulness and slow-wave sleep (SWS) in a model of thalamocortical dysrhythmia, TRIP8b -/- mice, and in control (wild-type or WT) mice are described. Coherence and nonlinear Granger causality (GC) were calculated for twenty 10 s length epochs of SWS and active wakefulness (AW) of each animal. Coherence was reduced between 4 and ca 20 Hz in the cortex and between cortex and thalamus during SWS compared with AW in WT but not in TRIP8b -/- mice. Moreover, TRIP8b -/- mice showed lower CT coherence during AW compared with WT mice; these differences were no longer present during SWS. Unconditional GC analysis also showed sleep-related reductions in TC and CT couplings in WT mice, while TRIP8b -/- mice showed diminished wake and enhanced sleep CC coupling and rather strong CT-directed coupling during wake and sleep, although smaller during sleep. Conditional GC coupling analysis confirmed the diminished CC and enhanced CT coupling in TRIP8b -/- mice. Our findings indicate that altered properties of hyperpolarization-activated cyclic nucleotide-gated cation channels, characterizing TRIP8b -/- mice, have clear effects on CC, TC, and CT networks. A more complete understanding of the function of the altered communication within these networks awaits detailed phenotyping of TRIP8b -/- mice aimed at specifics of sensory and attentional processes.

Purpose: The organization of neural networks and the mechanisms, which generate the highly stereotypical for absence epilepsy spike-wave discharges (SWDs) is heavily debated. Here we describe such a model which can both reproduce the characteristics of SWDs and dynamics of coupling between brain regions, relying mainly on properties of hierarchically organized networks of a large number of neuronal oscillators., Model: We used a two level mesoscale model. The first level consists of three structures: the nervus trigeminus serving as an input, the thalamus and the somatosensory cortex; the second level of a group of nearby situated neurons belonging to one of three modeled structures., Results: The model reproduces the main features of the transition from normal to epileptiformic activity and its spontaneous abortion: an increase in the oscillation amplitude, the emergence of the main frequency and its higher harmonics, and the ability to generate trains of seizures. The model was stable with respect to variations in the structure of couplings and to scaling. The analyzes of the interactions between model structures from their time series using Granger causality method showed that the model reproduced the preictal coupling increase detected previously from experimental data., Conclusion: SWDs can be generated by changes in network organization. It is proposed that a specific pathological architecture of couplings in the brain is necessary to allow the transition from normal to epileptiformic activity, next to by others modeled and reported factors referring to complex, intrinsic, and synaptic mechanisms., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

We propose a method for the recovery of coupling architecture and the parameters of elements in networks consisting of coupled oscillators described by delay-differential equations. For each oscillator in the network, we introduce an objective function characterizing the distance between the points of the reconstructed nonlinear function. The proposed method is based on the minimization of this objective function and the separation of the recovered coupling coefficients into significant and insignificant coefficients. The efficiency of the method is shown for chaotic time series generated by model equations of diffusively coupled time-delay systems and for experimental chaotic time series gained from coupled electronic oscillators with time-delayed feedback.

Purpose: Spike-and-wave discharges (SWDs) recorded in the cortical EEGs of WAG/Rij rats are the hallmark for absence epilepsy in this model. Although this type of epilepsy was long regarded as a form of primary generalized epilepsy, it is now recognized that there is an initiation zone - the perioral region of the somatosensory cortex. However, networks involved in spreading the seizure are not yet fully known. Previously, the dynamics of coupling between different layers of the perioral cortical region and between these zones and different thalamic nuclei was studied in time windows around the SWDs, using nonlinear Granger causality. The aim of the present study was to investigate, using the same method, the coupling dynamics between different regions of the cortex and between these regions and the hippocampus., Methods: Local field potentials were recorded in the frontal, parietal, and occipital cortices and in the hippocampus of 19 WAG/Rij rats. To detect changes in coupling reliably in a short time window, in order to provide a good temporal resolution, the innovative adapted time varying nonlinear Granger causality method was used. Mutual information function was calculated in addition to validate outcomes. Results of both approaches were tested for significance., Results: The SWD initiation process was revealed as an increase in intracortical interactions starting from 3.5s before the onset of electrographic seizure. The earliest preictal increase in coupling was directed from the frontal cortex to the parietal cortex. Then, the coupling became bidirectional, followed by the involvement of the occipital cortex (1.5s before SWD onset). There was no driving from any cortical region to hippocampus, but a slight increase in coupling from hippocampus to the frontoparietal cortex was observed just before SWD onset. After SWD onset, an abrupt drop in coupling in all studied pairs was observed. In most of the pairs, the decoupling rapidly disappeared, but driving force from hippocampus and occipital cortex to the frontoparietal cortex was reduced until the SWD termination., Conclusion: Involvement of multiple cortical regions in SWD initiation shows the fundamental role of corticocortical feedback loops, forming coupling architecture and triggering the generalized seizure. The results add to the ultimate aim to construct a complete picture of brain interactions preceding and accompanying absence seizures in rats., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose: Spike and wave discharges (SWDs), generated within cortico-thalamo-cortical networks, are the electroencephalographic biomarker of absence epilepsy. The current work aims to identify mechanisms of SWD initiation, maintenance and termination by the analyses of dynamics and directionality of mutual interactions between the neocortex and various functionally different thalamic nuclei., Methods: Local-field potential recordings of 16 male Wistar Albino Glaxo from Rijswijk (WAG/Rij) rats, equipped with electrodes targeting layer 4-6 of the somatosensory cortex, rostral and caudal reticular thalamic nuclei (rRTN and cRTN), ventro-posteromedial (VPM), anterior (ATN) and posterior (PO) thalamic nuclei, were obtained. 3s epochs prior to SWD onset, after SWD onset, prior to SWD offset and after SWD offset were analyzed with newly developed time-variant adapted nonlinear Granger causality., Results: A gradual increase in coupling toward SWD onset between cortico-cortical pairs appears as early as 2s preictally. Next first unidirectional increase in coupling is noticed in a restricted number of cortico-thalamic and thalamo-cortical channel pairs, which turn into bidirectional coupling approaching SWD onset, and a gradual increase of intrathalamic coupling. Seizure onset is characterized by a coupling decrease for more than a second in a majority of channel pairs, only the cortex kept driving the cRTN. Intrathalamically the cRTN drives the PO, VPM and ATN. Most channel pairs no longer show differences in coupling with baseline during SWD maintenance, a major exception is the unidirectional coupling between cortex and cRTN. Toward the end of SWDs, more and more channel pairs show an increase in often bidirectional coupling, this increase suddenly vanishes at SWD offset., Conclusion: The initiation of SWD is due to a gradual increase in intracortical coupling, followed by a selective increase in first unidirectional and later bidirectional coupling between the cortex and thalamus and also intrathalamically. Once the network is oscillating, coupling decreases in most of the channel pairs, although the cortex keeps its influence on the cRTN. The SWD is dampened by a gradual increase in coupling strength and in the number of channel pairs that influence each other; the latter might represent an endogenous brake of SWDs., (Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.)

Generalized spike and wave discharges (SWDs) are generated within the cortico-thalamo-cortical system, being an electroencephalographic sign of absence epilepsy. The current work aims to identify mechanisms of SWD initiation, maintenance and termination. Dynamics and directionality of mutual interactions between neocortex (occipital (OC) and frontal (FC) cortex) and thalamus (reticular (RTN) and ventral postero medial (VPM) thalamic nuclei) were investigated. SWD initiation process is revealed several seconds before seizure onset in interaction between all brain areas, except intrathalamic pair (RTN-VPM). This process begins at different moments relatively to SWD onset. The interaction increase is observed earlier and most obviously when thalamus and OC drive FC. The maintenance process (the first few seconds of SWD) is accompanied with high level interaction inside thalamus and increase of driving from thalamus to occipital cortex. Thus interaction from thalamus and occipital cortex to frontal cortex and influence to VPM occur to be below baseline level. At the SWD offset thalamo-cortical interactions were found to return to baseline level quickly.

We propose a method to recover from time series the parameters of coupled time-delay systems and the architecture of couplings between them. The method is based on a reconstruction of model delay-differential equations and estimation of statistical significance of couplings. It can be applied to networks composed of nonidentical nodes with an arbitrary number of unidirectional and bidirectional couplings. We test our method on chaotic and periodic time series produced by model equations of ensembles of diffusively coupled time-delay systems in the presence of noise, and apply it to experimental time series obtained from electronic oscillators with delayed feedback coupled by resistors.

Background: Advanced methods of signal analysis of the preictal and ictal activity dynamics characterizing absence epilepsy in humans with absences and in genetic animal models have revealed new and unknown electroencephalographic characteristics, that has led to new insights and theories., New Method: Taking into account that some network associations can be considered as nonlinear, an adaptive nonlinear Granger causality approach was developed and applied to analyze cortico-cortical, cortico-thalamic and intrathalamic network interactions from local field potentials (LFPs). The outcomes of adaptive nonlinear models, constructed based on the properties of electroencephalographic signal and on statistical criteria to optimize the number of coefficients in the models, were compared with the outcomes of linear Granger causality., Results: The nonlinear adaptive method showed statistically significant preictal changes in Granger causality in almost all pairs of channels, as well as ictal changes in cortico-cortical, cortico-thalamic and intrathalamic networks. Current results suggest rearrangement of interactions in the thalamo-cortical network accompanied the transition from preictal to ictal phase., Comparison With Existing Method(s): The linear method revealed no preictal and less ictal changes in causality., Conclusions: Achieved results suggest that this proposed adaptive nonlinear method is more sensitive than the linear one to dynamics of network properties. Since changes in coupling were found before the seizure-related increase of LFP signal amplitude and also based on some additional tests it seems likely that they were not spurious and could not result from signal to noise ratio change., (Copyright © 2014 Elsevier B.V. All rights reserved.)