Deriving theoretical phase locking values of a coupled cortico-thalamic neural mass model using center manifold reduction

Cognitive functions such as sensory processing and memory processes lead to phase synchronization in the electroencephalogram or local field potential between different brain regions. There are a lot of computational researches deriving phase locking values (PLVs), which are an index of phase synchronization intensity, from neural models. However, these researches derive PLVs numerically. To the best of our knowledge, there have been no reports on the derivation of a theoretical PLV. In this study, we propose an analytical method for deriving theoretical PLVs from a cortico-thalamic neural mass model described by a delay differential equation. First, the model for generating neural signals is transformed into a normal form of the Hopf bifurcation using center manifold reduction. Second, the normal form is transformed into a phase model that is suitable for analyzing synchronization phenomena. Third, the Fokker–Planck equation of the phase model is derived and the phase difference distribution is obtained. Finally, the PLVs are calculated from the stationary distribution of the phase difference. The validity of the proposed method is confirmed via numerical simulations. Furthermore, we apply the proposed method to a working memory process, and discuss the neurophysiological basis behind the phase synchronization phenomenon. The results demonstrate the importance of decreasing the intensity of independent noise during the working memory process. The proposed method will be of great use in various experimental studies and simulations relevant to phase synchronization, because it enables the effect of neurophysiological changes on PLVs to be analyzed from a mathematical perspective.     

Functional connectivity between prefrontal cortex and striatum estimated by phase locking value

The interplay between the prefrontal cortex (PFC) and striatum has an important role in cognitive processes. To investigate interactive functions between the two areas in reward processing, we recorded local field potentials (LFPs) simultaneously from the two areas of two monkeys performing a reward prediction task (large reward vs small reward). The power of the LFPs was calculated in three frequency bands: the beta band (15–29 Hz), the low gamma band (30–49 Hz), and the high gamma band (50–100 Hz). We found that both the PFC and striatum encoded the reward information in the beta band. The reward information was also found in the high gamma band in the PFC, not in the striatum. We further calculated the phase-locking value (PLV) between two LFP signals to measure the phase synchrony between the PFC and striatum. It was found that significant differences occurred between PLVs in different task periods and in different frequency bands. The PLVs in small reward condition were significant higher than that in large reward condition in the beta band. In contrast, the PLVs in the high gamma band were stronger in large reward trials than in small trials. These results suggested that the functional connectivity between the PFC and striatum depended on the task periods and reward conditions. The beta synchrony between the PFC and striatum may regulate behavioral outputs of the monkeys in the small reward condition.     

Experimental observation of increased fluctuations in an order parameter before epochs of extended brain synchronization

The identification of epileptic seizure precursors has potential clinical relevance. It is conjectured that seizures may be represented by dynamical bifurcations and that an adequate order parameter to characterize brain dynamics is the phase difference in the oscillatory activity of neural systems. In this study, the critical point hypothesis that seizures, or more generally periods of widespread high synchronization, represent bifurcations is empirically tested by monitoring the growth of fluctuations in the putative order parameter of phase differences between magnetoencephalographic and electroencephalographic signals in nearby brain regions in patients with epilepsy and normal subjects during hyperventilation. Implications of the results with regard to epileptic phenomena are discussed.     

Optogenetically Induced Seizure and the Longitudinal Hippocampal Network Dynamics

Epileptic seizure is a paroxysmal and self-limited phenomenon characterized by abnormal hypersynchrony of a large population of neurons. However, our current understanding of seizure dynamics is still limited. Here we propose a novel in vivo model of seizure-like afterdischarges using optogenetics, and report on investigation of directional network dynamics during seizure along the septo-temporal (ST) axis of hippocampus. Repetitive pulse photostimulation was applied to the rodent hippocampus, in which channelrhodopsin-2 (ChR2) was expressed, under simultaneous recording of local field potentials (LFPs). Seizure-like afterdischarges were successfully induced after the stimulation in both W-TChR2V4 transgenic (ChR2V-TG) rats and in wild type rats transfected with adeno-associated virus (AAV) vectors carrying ChR2. Pulse frequency at 10 and 20 Hz, and a 0.05 duty ratio were optimal for afterdischarge induction. Immunohistochemical c-Fos staining after a single induced afterdischarge confirmed neuronal activation of the entire hippocampus. LFPs were recorded during seizure-like afterdischarges with a multi-contact array electrode inserted along the ST axis of hippocampus. Granger causality analysis of the LFPs showed a bidirectional but asymmetric increase in signal flow along the ST direction. State space presentation of the causality and coherence revealed three discrete states of the seizure-like afterdischarge phenomenon: 1) resting state; 2) afterdischarge initiation with moderate coherence and dominant septal-to-temporal causality; and 3) afterdischarge termination with increased coherence and dominant temporal-to-septal causality. A novel in vivo model of seizure-like afterdischarge was developed using optogenetics, which was advantageous in its reproducibility and artifact-free electrophysiological observations. Our results provide additional evidence for the potential role of hippocampal septo-temporal interactions in seizure dynamics in vivo. Bidirectional networks work hierarchically along the ST hippocampus in the genesis and termination of epileptic seizures.     

A Transient Upregulation of Glutamine Synthetase in the Dentate Gyrus Is Involved in Epileptogenesis Induced by Amygdala Kindling in the Rat

Reduction of glutamine synthetase (GS) function is closely related to established epilepsy, but little is known regarding its role in epileptogenesis. The present study aimed to elucidate the functional changes of GS in the brain and its involvement in epileptogenesis using the amygdala kindling model of epilepsy induced by daily electrical stimulation of basolateral amygdala in rats. Both expression and activity of GS in the ipsilateral dentate gyrus (DG) were upregulated when kindled seizures progressed to stage 4. A single dose of L-methionine sulfoximine (MSO, in 2 µl), a selective GS inhibitor, was administered into the ipsilateral DG on the third day following the first stage 3 seizure (just before GS was upregulated). It was found that low doses of MSO (5 or 10 µg) significantly and dose-dependently reduced the severity of and susceptibility to evoked seizures, whereas MSO at a high dose (20 µg) aggravated kindled seizures. In animals that seizure acquisition had been successfully suppressed with 10 µg MSO, GS upregulation reoccurred when seizures re-progressed to stage 4 and re-administration of 10 µg MSO consistently reduced the seizures. GLN at a dose of 1.5 µg abolished the alleviative effect of 10 µg MSO and deleterious effect of 20 µg MSO on kindled seizures. Moreover, appropriate artificial microRNA interference (1 and 1.5×10⁶ TU/2 µl) of GS expression in the ipsilateral DG also inhibited seizure progression. In addition, a transient increase of GS expression and activity in the cortex was also observed during epileptogenesis evoked by pentylenetetrazole kindling. These results strongly suggest that a transient and region-specific upregulation of GS function occurs when epilepsy develops into a certain stage and eventually promotes the process of epileptogenesis. Inhibition of GS to an adequate degree and at an appropriate timing may be a potential therapeutic approach to interrupting epileptogenesis.     

Epileptic seizures in a heterogeneous excitatory network with short-term plasticity

Epilepsy involves a diverse group of abnormalities, including molecular and cellular disorders. These abnormalities prove to be associated with the changes in local excitability and synaptic dynamics. Correspondingly, the epileptic processes including onset, propagation and generalized seizure may be related with the alterations of excitability and synapse. In this paper, three regions, epileptogenic zone (EZ), propagation area and normal region, were defined and represented by neuronal population model with heterogeneous excitability, respectively. In order to describe the synaptic behavior that the strength was enhanced and maintained at a high level for a short term under a high frequency spike train, a novel activity-dependent short-term plasticity model was proposed. Bifurcation analysis showed that the presence of hyperexcitability could increase the seizure susceptibility of local area, leading to epileptic discharges first seen in the EZ. Meanwhile, recurrent epileptic activities might result in the transition of synaptic strength from weak state to high level, augmenting synaptic depolarizations in non-epileptic neurons as the experimental findings. Numerical simulation based on a full-connected weighted network could qualitatively demonstrate the epileptic process that the propagation area and normal region were successively recruited by the EZ. Furthermore, cross recurrence plot was used to explore the synchronization between neuronal populations, and the global synchronization index was introduced to measure the global synchronization. Results suggested that the synchronization between the EZ and other region was significantly enhanced with the occurrence of seizure. Interestingly, the desynchronization phenomenon was also observed during seizure initiation and propagation as reported before. Therefore, heterogeneous excitability and short-term plasticity are believed to play an important role in the epileptic process. This study may provide novel insights into the mechanism of epileptogenesis.     

Exposure to Mozart music reduces cognitive impairment in pilocarpine-induced status epilepticus rats

Patients with temporal lobe epilepsy (TLE) often display cognitive deficits. However, current epilepsy therapeutic interventions mainly aim at how to reduce the frequency and degree of epileptic seizures. Recovery of cognitive impairment is not attended enough, resulting in the lack of effective approaches in this respect. In the pilocarpine-induced temporal lobe epilepsy rat model, memory impairment has been classically reported. Here we evaluated spatial cognition changes at different epileptogenesis stages in rats of this model and explored the effects of long-term Mozart music exposure on the recovery of cognitive ability. Our results showed that pilocarpine rats suffered persisting cognitive impairment during epileptogenesis. Interestingly, we found that Mozart music exposure can significantly enhance cognitive ability in epileptic rats, and music intervention may be more effective for improving cognitive function during the early stages after Status epilepticus. These findings strongly suggest that Mozart music may help to promote the recovery of cognitive damage due to seizure activities, which provides a novel intervention strategy to diminish cognitive deficits in TLE patients.     

Targeting brain and peripheral plasticity of the lipidome in acute kainic acid-induced epileptic seizures in mice via quantitative mass spectrometry

Epilepsy is a highly common chronic neurological disorder, manifested in many different types, affecting ~ 1% of the worldwide human population. The molecular mechanisms of epileptogenesis have not yet been clarified, and pharmacoresistance exhibited by 30–40% of epilepsy patients remains a major obstacle in medical care. Growing evidence indicates a role of lipid signalling pathways in epileptogenesis, thus lipid signals emerge as potential biomarkers for the onset and evolving course of the epileptic disorder, as well as potential therapeutic agents and targets. For this purpose, we applied a lipidomic strategy to unravel lipid alterations in brain regions, periphery tissues and plasma that are specific for acute epileptic seizures in mice at 1 h after seizure induction by systemic kainic acid injection as compared to vehicle controls. Specifically, levels of (i) selected phospholipids and sphingomyelins, (ii) the endocannabinoids anandamide (AEA) and 2-arachidonoyl glycerol (2-AG), and the endocannabinoid-related compounds oleoylethanolamide (OEA) and palmitoylethanolamide (PEA), (iii) arachidonic acid (AA), (iv) selected eicosanoids, and (v) fatty acyl content of lipidome were determined in pulverized tissues from six brain regions of kainic acid induced epileptic seizure models and vehicle controls: hypothalamus, hippocampus, thalamus, striatum, cerebellum and cerebral cortex, and from peripheral organs, such as heart and lungs, and in plasma. Alterations in lipid levels after acute epileptic seizures as compared to non-seizure controls were found to be brain region- and periphery tissue-specific, including specific plasma lipid correlates, highlighting their value as marker candidates in translational research studies, and/or drug discovery and response monitoring.     

Mechanisms regulating GABAergic inhibitory transmission in the basolateral amygdala: implications for epilepsy and anxiety disorders

Summary. The amygdala, a temporal lobe structure that is part of the limbic system, has long been recognized for its central role in emotions and emotional behavior. Pathophysiological alterations in neuronal excitability in the amygdala are characteristic features of certain psychiatric illnesses, such as anxiety disorders and depressive disorders. Furthermore, neuronal excitability in the amygdala, and, in particular, excitability of the basolateral nucleus of the amygdala (BLA) plays a pivotal role in the pathogenesis and symptomatology of temporal lobe epilepsy. Here, we describe two recently discovered mechanisms regulating neuronal excitability in the BLA, by modulating GABAergic inhibitory transmission. One of these mechanisms involves the regulation of GABA release via kainate receptors containing the GluR5 subunit (GluR5KRs). In the rat BLA, GluR5KRs are present on both somatodendritic regions and presynaptic terminals of GABAergic interneurons, and regulate GABA release in an agonist concentration-dependent, bidirectional manner. The relevance of the GluR5KR function to epilepsy is suggested by the findings that GluR5KR agonists can induce epileptic activity, whereas GluR5KR antagonists can prevent it. Further support for an important role of GluR5KRs in epilepsy comes from the findings that antagonism of GluR5KRs is a primary mechanism underlying the antiepileptic properties of the anticonvulsant topiramate. Another mechanism regulating neuronal excitability in the BLA by modulating GABAergic synaptic transmission is the facilitation of GABA release via presynaptic α_1A adrenergic receptors. This mechanism may significantly underlie the antiepileptic properties of norepinephrine. Notably, the α_1A adrenoceptor-mediated facilitation of GABA release is severely impaired by stress. This stress-induced impairment in the noradrenergic facilitation of GABA release in the BLA may underlie the hyperexcitability of the amygdala in certain stress-related affective disorders, and may explain the stress-induced exacerbation of seizure activity in epileptic patients.     

Disrupted Ipsilateral Network Connectivity in Temporal Lobe Epilepsy

ObjectiveThe current practice under which patients with refractory epilepsy are surgically treated is based mainly on the identification of specific cortical areas, mainly the epileptogenic zone, which is believed to be responsible for generation of seizures. A better understanding of the whole epileptic network and its components and properties is required before more effective and less invasive therapies can be developed. The aim of the present study was to partially characterize the evolution of the functional network during the preictal-ictal transition in partial seizures in patients with temporal lobe epilepsy (TLE).MethodsScalp and foramen ovale (FOE) recordings from twenty-two TLE patients were analyzed under the complex network perspective. The density of links, average path length, average clustering coefficient, and modularity were calculated during the preictal and the ictal stages. Both linear–Pearson correlation–and non-linear–phase synchronization–measures were used as proxies of functional connectivity between the electrode locations areas. The transition from one stage to the other was evaluated in the whole network and in the mesial sub-networks. The results were compared with a voltage-dependent measure, namely, the spectral entropy.ResultsChanges in the global functional network during the transition from the preictal to the ictal stage show, in the linear case, that in sixteen cases (72.7%) the density of the links increased during the seizure, with a decrease in the average path length in fifteen cases (68.1%). There was also a preictal and ictal imbalance in functional connectivity during both stages (77.2% to 86.3%). The SE dropped during the seizure in 95.4% of the cases, but did not show any tendency towards lateralization. When using the nonlinear measure of functional connectivity, the phase synchronization, similar results were obtained.ConclusionsIn TLE patients, the transition to the ictal stage is accompanied by increasing global synchronization and a more ordered spectral content of the signals, indicated by lower spectral entropy. The interictal connectivity imbalance (lower ipsilateral connectivity) is sustained during the seizure, irrespective of any appreciable imbalance in the spectral entropy of the mesial recordings.     

Changes in the electrical activity of the medial septal region, piriform cortex and amygdala during epileptogenesis in the model of temporal lobe epilepsy

Local field potentials (EEGs) in the medial septal area, amygdala and piriform cortex were recorded in waking guinea pigs in the control and during epileptogenesis in the model of chronic temporal lobe epilepsy (lithium-pilocarpin model of status epilepticus). Analysis of changes in rhythmical activity and interstructural relations was carried out at different stages of epileptogenesis. Increased frequency of rhythmic activity in delta, theta, and alphabands was observed during epileptogenesis. Correlation relations between the activities of the medical septum with the piriform cortex and amygdala clearly decreased to 5 months after development of status epilepticus. Changes in the frequency of oscillations and structural correlations developed in time from two months on and reached a maximum 5 months after the status epilepticus development. It point to intensification of the pathological changes during formation of the epileptic focus. A possible role of the observed EEG changes in the formation of a pathological centre is discussed.     

Mosaic genomes of the six major primate lentivirus lineages revealed by phylogenetic analyses

To clarify the origin and evolution of the primate lentiviruses (PLVs), which include human immunodeficiency virus types 1 and 2 as well as their simian relatives, simian immunodeficiency viruses (SIVs), isolated from several host species, we investigated the phylogenetic relationships among the six supposedly nonrecombinant PLV lineages for which the full genome sequences are available. Employing bootscanning as an exploratory tool, we located several regions in the PLV genome that seem to have uncertain or conflicting phylogenetic histories. Phylogeny reconstruction based on distance and maximum-likelihood algorithms followed by a number of statistical tests confirms the existence of at least five putative recombinant fragments in the PLV genome with different clustering patterns. Split decomposition analysis also shows that phylogenetic relationships among PLVs may be better represented by network-based graphs, such as the ones produced by SplitsTree. Our findings not only imply that the six so-called pure PLV lineages have in fact mosaic genomes but also make more unlikely the hypothesis of cospeciation of SIVs and their simian hosts.     

Dynamic Network Drivers of Seizure Generation,Propagation and Termination in Human Neocortical Epilepsy

The epileptic network is characterized by pathologic, seizure-generating ‘foci’ embedded in a web of structural and functional connections. Clinically, seizure foci are considered optimal targets for surgery. However, poor surgical outcome suggests a complex relationship between foci and the surrounding network that drives seizure dynamics. We developed a novel technique to objectively track seizure states from dynamic functional networks constructed from intracranial recordings. Each dynamical state captures unique patterns of network connections that indicate synchronized and desynchronized hubs of neural populations. Our approach suggests that seizures are generated when synchronous relationships near foci work in tandem with rapidly changing desynchronous relationships from the surrounding epileptic network. As seizures progress, topographical and geometrical changes in network connectivity strengthen and tighten synchronous connectivity near foci—a mechanism that may aid seizure termination. Collectively, our observations implicate distributed cortical structures in seizure generation, propagation and termination, and may have practical significance in determining which circuits to modulate with implantable devices.     

Synchronization regulation in a model of coupled neural masses

A model of coupled neural masses can generate seizure-like events and dynamics similar to those observed during interictal to ictal transitions and thus can be used for theoretical study of the control of epileptic seizures. In an effort to understand the mechanisms underlying epileptic seizures and how to avoid them, we added a control input to this model. Epileptic seizures are always accompanied by hypersynchronous firing of neurons, so research on synchronization among cortical areas is significant for seizure control. In this study, principal component analysis (PCA) was used to identify synchronization clusters composed of several neural masses. A method for calculating the synchronization cluster strength and participation rate is presented. The synchronization cluster strength can be used to identify synchronization clusters and the participation rate can be employed to identify neural masses that participate in the clusters. Each synchronization cluster is controlled as a whole using a proportional-integral-derivative (PID) controller. We illustrate these points using coupled neural mass models of synchronization to show their responses to increased (between node) coupling with and without control. Experiment results indicated that PID control can effectively regulate synchronization between neural masses and has the potential for seizure prevention.     

Impairment of Cognitive Function and Synaptic Plasticity Associated with Alteration of Information Flow in Theta and Gamma Oscillations in Melamine-Treated Rats

Changes of neural oscillations at a variety of physiological rhythms are effectively associated with cognitive performance. The present study investigated whether the directional indices of neural information flow (NIF) could be used to symbolize the synaptic plasticity impairment in hippocampal CA3-CA1 network in a rat model of melamine. Male Wistar rats were employed while melamine was administered at a dose of 300 mg/kg/day for 4 weeks. Behavior was measured by the Morris water maze(MWM)test. Local field potentials (LFPs) were recorded before long-term potentiation (LTP) induction. Generalized partial directed coherence (gPDC) and phase-amplitude coupling conditional mutual information (PAC_CMI) were used to measure the unidirectional indices in both theta and low gamma oscillations (LG, ∼30–50 Hz). Our results showed that melamine induced the cognition deficits consistent with the reduced LTP in CA1 area. Phase locking values (PLVs) showed that the synchronization between CA3 and CA1 in both theta and LG rhythms was reduced by melamine. In both theta and LG rhythms, unidirectional indices were significantly decreased in melamine treated rats while a similar variation trend was observed in LTP reduction, implying that the effects of melamine on cognitive impairment were possibly mediated via profound alterations of NIF on CA3-CA1 pathway in hippocampus. The results suggested that LFPs activities at these rhythms were most likely involved in determining the alterations of information flow in the hippocampal CA3-CA1 network, which might be associated with the alteration of synaptic transmission to some extent.     

Protective Effect of Resveratrol against Kainate-induced Temporal Lobe Epilepsy in Rats

Resveratrol (Res) is a phytoalexin produced naturally by several plants, which has multi functional effects such as neuroprotection, anti-inflammatory, and anti-cancer. The present study was to evaluate a possible anti-epileptic effect of Res against kainate-induced temporal lobe epilepsy (TLE) in rat. We performed behavior monitoring, intracranial electroencepholography (IEEG) recording, histological analysis, and Western blotting to evaluate the anti-epilepsy effect of Res in kainate-induced epileptic rats. Res decreased the frequency of spontaneous seizures and inhibited the epileptiform discharges. Moreover, Res could protect neurons against kainate-induced neuronal cell death in CA1 and CA3a regions and depressed mossy fiber sprouting, which are general histological characteristics both in TLE patients and animal models. Western blot revealed that the expression level of kainate receptors (KARs) in hippocampus was reduced in Res-administrated rats compared to that in epileptic ones. These results suggest that Res is a potent anti-epilepsy agent, which protects against epileptogenesis and progression of the kainate-induced TLE animal. The authors Z. Wu and Q. Xu contributed equally to this work.     

Dynamic Imaging of Coherent Sources Reveals Different Network Connectivity Underlying the Generation and Perpetuation of Epileptic Seizures

The concept of focal epilepsies includes a seizure origin in brain regions with hyper synchronous activity (epileptogenic zone and seizure onset zone) and a complex epileptic network of different brain areas involved in the generation, propagation, and modulation of seizures. The purpose of this work was to study functional and effective connectivity between regions involved in networks of epileptic seizures. The beginning and middle part of focal seizures from ictal surface EEG data were analyzed using dynamic imaging of coherent sources (DICS), an inverse solution in the frequency domain which describes neuronal networks and coherences of oscillatory brain activities. The information flow (effective connectivity) between coherent sources was investigated using the renormalized partial directed coherence (RPDC) method. In 8/11 patients, the first and second source of epileptic activity as found by DICS were concordant with the operative resection site; these patients became seizure free after epilepsy surgery. In the remaining 3 patients, the results of DICS / RPDC calculations and the resection site were discordant; these patients had a poorer post-operative outcome. The first sources as found by DICS were located predominantly in cortical structures; subsequent sources included some subcortical structures: thalamus, Nucl. Subthalamicus and cerebellum. DICS seems to be a powerful tool to define the seizure onset zone and the epileptic networks involved. Seizure generation seems to be related to the propagation of epileptic activity from the primary source in the seizure onset zone, and maintenance of seizures is attributed to the perpetuation of epileptic activity between nodes in the epileptic network. Despite of these promising results, this proof of principle study needs further confirmation prior to the use of the described methods in the clinical praxis.     

Discrepancies of Notch 1 receptor during development of chronic seizures

The critical role of Notch signaling has been shown in the pathogenesis of some neurological disorders including schizophrenia, epilepsy and Alzheimer’s disease. This study was aimed to evaluate the role of Notch 1 receptor in epileptogenesis as well as seizure characteristics. The animals were divided into three groups of sham, early stage and end stage. In sham group: Normal saline was injected intraperitoneally (ip) in the same as protocol of pentylenetetrazol (PTZ) injection. PTZ was injected (ip) every 48 hr over a period of 1 week in the group of early stage and over a period of 4 weeks in the end stage. The gene expression as well as distribution of Notch 1 receptor was assessed in the parietal cortex and hippocampus. In addition, the effect of agonist or antagonist of Notch 1 receptor was assessed on the epileptic discharges induced by PTZ injection. The gene expression of Notch 1 decreased in the hippocampus significantly in the end-stage group compared with sham, and early groups. Furthermore, distribution of Notch 1 receptor increased in the somatosensory cortex and decreased in the CA1 hippocampal area in the end-stage group. Intraventricular microinjection of Notch 1 agonist significantly increased the amplitude as well as frequency of spikes and decreased the latency of first epileptic discharges. Our findings illustrate the critical role of Notch signalling as a potential pathway in the epileptogenesis during development of chronic seizures.