Epileptic Network Research Articles

Distribution of the Cannabinoid Receptor Type 1 in the Brain of the Genetically Audiogenic Seizure-Prone Hamster GASH/Sal.

The endocannabinoid system modulates epileptic seizures by regulating neuronal excitability. It has become clear that agonist activation of central type I cannabinoid receptors (CB1R) reduces epileptogenesis in pre-clinical animal models of epilepsy. The audiogenic seizure-prone hamster GASH/Sal is a reliable experimental model of generalized tonic-clonic seizures in response to intense sound stimulation. However, no studies hitherto had investigated CB1R in the GASH/Sal. Although the distribution of CB1R has been extensively studied in mammalian brains, their distribution in the Syrian golden hamster brain also remains unknown. The objective of this research is to determine by immunohistochemistry the differential distribution of CB1R in the brains of GASH/Sal animals under seizure-free conditions, by comparing the results with wild-type Syrian hamsters as controls. CB1R in the GASH/Sal showed a wide distribution in many nuclei of the central nervous system. These patterns of CB1R-immunolabeling are practically identical between the GASH/Sal model and control animals, varying in the intensity of immunostaining in certain regions, being slightly weaker in the GASH/Sal than in the control, mainly in brain regions associated with epileptic networks. The RT-qPCR analysis confirms these results. In summary, our study provides an anatomical basis for further investigating CB1R in acute and kindling audiogenic seizure protocols in the GASH/Sal model as well as exploring CB1R activation via exogenously administered cannabinoid compounds.

Connective profiles and antagonism between dynamic and static connectivity underlying generalized epilepsy.

This study aims to characterize the connective profiles and the coupling relationship between dynamic and static functional connectivity (dFC and sFC) in large-scale brain networks in patients with generalized epilepsy (GE). Functional, structural and diffuse MRI data were collected from 83 patients with GE and 106 matched healthy controls (HC). Resting-state BOLD time course was deconvolved to neural time course using a blind hemodynamic deconvolution method. Then, five connective profiles, including the structural connectivity (SC) and BOLD/neural time course-derived sFC/dFC networks, were constructed based on the proposed whole brain atlas. Network-level weighted correlation probability (NWCP) were proposed to evaluate the association between dFC and sFC. Both the BOLD signal and neural time course showed highly concordant findings and the present study emphasized the consistent findings between two functional approaches. The patients with GE showed hypervariability and enhancement of FC, and notably decreased SC in the subcortical network. Besides, increased dFC, weaker anatomic links, and complex alterations of sFC were observed in the default mode network of GE. Moreover, significantly increased SC and predominantly increased sFC were found in the frontoparietal network. Remarkably, antagonism between dFC and sFC was observed in large-scale networks in HC, while patients with GE showed significantly decreased antagonism in core epileptic networks. In sum, our study revealed distinct connective profiles in different epileptic networks and provided new clues to the brain network mechanism of epilepsy from the perspective of antagonism between dynamic and static functional connectivity.

Bad Timing for Epileptic Networks: Role of Temporal Dynamics in Seizures and Cognitive Deficits.

The precise coordination of neuronal activity is critical for optimal brain function. When such coordination fails, this can lead to dire consequences. In this review, I will present evidence that in epilepsy, failed coordination leads not only to seizures but also to alterations of the rhythmical patterns observed in the electroencephalogram and cognitive deficits. Restoring the dynamic coordination of epileptic networks could therefore both improve seizures and cognitive outcomes.

Regional and global resting-state functional MR connectivity in temporal lobe epilepsy: Results from the Epilepsy Connectome Project

Temporal lobe epilepsy (TLE) has been conceptualized as focal disease with a discrete neurobiological focus and can respond well to targeted resection or ablation. In contrast, the neuro-cognitive deficits resulting from TLE can be widespread involving regions beyond the primary epileptic network. We hypothesize that this seemingly paradoxical findings can be explained by differences in connectivity between the primary epileptic region which is hyper-connected and its secondary influence on global connectome organization. This hypothesis is tested using regional and global graph theory metrics where we anticipate that regional mesial-temporal hyperconnectivity will be found and correlate with seizure frequency while global networks will be disorganized and be more closely associated with neuro-cognitive deficits. Resting-state fMRI was used to examine temporal lobe regional connectivity and global functional connectivity from 102 patients with TLE and 55 controls. Connectivity matrices were calculated for subcortical volumes and cortical parcellations. Graph theory metrics (global clustering coefficient (GCC), degree, closeness) were compared between groups and in relation to neuropsychological profiles and disease covariates using permutation testing and causal analysis. In TLE there was a decrease in GCC (p = 0.0345) associated with a worse neuropsychological profile (p = 0.0134). There was increased connectivity in the left hippocampus/amygdala (degree p = 0.0103, closeness p = 0.0104) and a decrease in connectivity in the right lateral temporal lobe (degree p = 0.0186, closeness p = 0.0122). A ratio between the hippocampus/amygdala and lateral temporal lobe—temporal lobe connectivity ratio (TLCR) revealed differences between TLE and controls for closeness (left p = 0.00149, right p = 0.0494) and for degree on left p = 0.00169; with trend on right p = 0.0567. Causal analysis suggested that “Epilepsy Activity” (seizure frequency, anti-seizure medications) was associated with increase in TLCR but not in GCC, while cognitive decline was associated with decreased GCC. These findings support the hypothesis that in TLE there is hyperconnectivity in the hippocampus/amygdala and hypoconnectivity in the lateral temporal lobe associated with “Epilepsy Activity.” While, global connectome disorganization was associated with worse neuropsychological phenotype.

Neurovascular networks in epilepsy: Correlating ictal blood perfusion with intracranial electrophysiology

Perfusion patterns observed in Subtraction Ictal SPECT Co-registered to MRI (SISCOM) assist in focus localization and surgical planning for patients with medically intractable focal epilepsy. While the localizing value of SISCOM has been widely investigated, its relationship to the underlying electrophysiology has not been extensively studied and is therefore not well understood. In the present study, we set to investigate this relationship in a cohort of 70 consecutive patients who underwent ictal and interictal SPECT studies and subsequent stereo-electroencephalography (SEEG) monitoring for localization of the epileptogenic focus and surgical intervention. Seizures recorded during SEEG evaluation (SEEG seizures) were matched to semiologically-similar seizures during the preoperative ictal SPECT evaluation (SPECT seizures) by comparing the semiological changes in the course of each seizure. The spectral changes of the ictal SEEG with respect to interictal ones over 7 traditional frequency bands (0.1 to 150Hz) were analyzed at each SEEG site. Neurovascular (SEEG/SPECT) relations were assessed by comparing the estimated spectral power density changes of the SEEG at each site with the perfusion changes (SISCOM z-scores) estimated from the acquired SISCOM map at that site. Across patients, a significant correlation (p<0.05) was observed between spectral changes during the SEEG seizure and SISCOM perfusion z-scores. Brain sites with high perfusion z-score exhibited higher increased SEEG power in theta to ripple frequency bands with concurrent suppression in delta and theta frequency bands compared to regions with lower perfusion z-score. The dynamics of the correlation of SISCOM perfusion and SEEG spectral power from ictal onset to seizure end and immediate postictal period were also derived. Forty-six (46) of the 70 patients underwent resective epilepsy surgery. SISCOM z-score and power increase in beta to ripple frequency bands were significantly higher in resected than non-resected sites in the patients who were seizure-free following surgery. This study provides for the first time concrete evidence that both hyper-perfusion and hypo-perfusion patterns observed in SISCOM maps have strong electrophysiological underpinnings, and that integration of the information from SISCOM and SEEG can shed light on the location and dynamics of the underlying epileptic brain networks, and thus advance our anatomo-electro-clinical understanding and approaches to targeted diagnostic and therapeutic interventions.

Tracking Multisite Seizure Propagation Using Ictal High-Gamma Activity.

Spatial patterns of long-range seizure propagation in epileptic networks have not been well characterized. Here, we use ictal high-gamma activity (HGA) as a proxy of intense neuronal population firing to map the spatial evolution of seizure recruitment. Ictal HGA (80-150 Hz) was analyzed in 13 patients with 72 seizures recorded by stereotactic depth electrodes, using previously validated methods. Distinct spatial clusters of channels with the ictal high-gamma signature were identified, and seizure hubs were defined as stereotypically recruited nonoverlapping clusters. Clusters correlated with asynchronous seizure terminations to provide supportive evidence for independent seizure activity at these sites. The spatial overlap between seizure hubs and interictal ripples was compared. Ictal HGA was detected in 71% of seizures and 10% of implanted contacts, enabling tracking of contiguous and noncontiguous seizure recruitment. Multiple seizure hubs were identified in 54% of cases, including 43% of patients thought preoperatively to have unifocal epilepsy. Noncontiguous recruitment was associated with asynchronous seizure termination (odds ratio = 19.7; p = 0.029). Interictal ripples demonstrated greater spatial overlap with ictal HGA in cases with single seizure hubs compared with those with multiple hubs (100% vs. 66% per patient; p = 0.03). Ictal HGA may serve as a useful adjunctive biomarker to distinguish contiguous seizure spread from propagation to remote seizure sites. High-gamma sites were found to cluster in stereotyped seizure hubs rather than being broadly distributed. Multiple hubs were common even in cases that were considered unifocal.

Dysmorphic neurons as cellular source for phase-amplitude coupling in Focal Cortical Dysplasia Type II

ObjectiveReliable localization of the epileptogenic zone is necessary for successful epilepsy surgery. Neurophysiological biomarkers include ictal onsets and interictal spikes. Furthermore, the epileptic network shows oscillations with potential localization value and pathomechanistic implications. The cellular origin of such markers in invasive EEG in vivo remains to be clarified. MethodsIn the presented pilot study, surgical brain samples and invasive EEG recordings of seven patients with surgically treated Focal Cortical Dysplasia (FCD) type II were coregistered using a novel protocol. Dysmorphic neurons and balloon cells were immunohistochemically quantified. Evaluated markers included seizure onset, spikes, and oscillatory activity in delta, theta, gamma and ripple frequency bands, as well as sample entropy and phase-amplitude coupling between delta, theta, alpha and beta phase and gamma amplitude. ResultsCorrelations between histopathology and neurophysiology provided evidence for a contribution of dysmorphic neurons to interictal spikes, fast gamma activity and ripples. Furthermore, seizure onset and phase-amplitude coupling in areas with dysmorphic neurons suggests preserved connectivity is related to seizure initiation. Balloon cells showed no association. ConclusionsPhase-amplitude coupling, spikes, fast gamma and ripples are related to the density of dysmorphic neurons and localize the seizure onset zone. SignificanceThe results of our pilot study provide a new powerful tool to address the cellular source of abnormal neurophysiology signals to leverage current and novel biomarkers for the localization of epileptic activity in the human brain.

An Integrative Approach to Study Structural and Functional Network Connectivity in Epilepsy Using Imaging and Signal Data.

A key area of research in epilepsy neurological disorder is the characterization of epileptic networks as they form and evolve during seizure events. In this paper, we describe the development and application of an integrative workflow to analyze functional and structural connectivity measures during seizure events using stereotactic electroencephalogram (SEEG) and diffusion weighted imaging data (DWI). We computed structural connectivity measures using electrode locations involved in recording SEEG signal data as reference points to filter fiber tracts. We used a new workflow-based tool to compute functional connectivity measures based on non-linear correlation coefficient, which allows the derivation of directed graph structures to represent coupling between signal data. We applied a hierarchical clustering based network analysis method over the functional connectivity data to characterize the organization of brain network into modules using data from 27 events across 8 seizures in a patient with refractory left insula epilepsy. The visualization of hierarchical clustering values as dendrograms shows the formation of connected clusters first within each insulae followed by merging of clusters across the two insula; however, there are clear differences between the network structures and clusters formed across the 8 seizures of the patient. The analysis of structural connectivity measures showed strong connections between contacts of certain electrodes within the same brain hemisphere with higher prevalence in the perisylvian/opercular areas. The combination of imaging and signal modalities for connectivity analysis provides information about a patient-specific dynamical functional network and examines the underlying structural connections that potentially influences the properties of the epileptic network. We also performed statistical analysis of the absolute changes in correlation values across all 8 seizures during a baseline normative time period and different seizure events, which showed decreased correlation values during seizure onset; however, the changes during ictal phases were varied.

Neural functional connectivity in patients with periventricular nodular heterotopia-mediated epilepsy

Periventricular nodular heterotopia (PNH) is characterized by disabled neural migration and is usually associated with epilepsy. Despite awareness of PNH-related epilepsy, little is known about the brain-level underlying functional neural bases. Thus, we used functional magnetic resonance imaging (MRI) to examine the neurobiology of 42 subjects with PNH-related epilepsy and 42 sex- and age-matched healthy controls. Measurements of functional connectivity (FC) and whole-brain graph theory analysis of data in the resting state were performed to assess neurological organization and topology. PNH patients exhibited significantly higher FC in the parietal lobe, cingulum and thalamus, as well as significantly lower FC in frontoparietal, hippocampal, and precentral regions. Graph theory analysis identified no significant differences between patients and controls, while patients showed lower network global efficiency in the limbic and cerebellum network and occipital cortex. Seed-based FC analysis confirmed disruption of activities and interregional connectivity in remote epileptic networks of patients, which may point to underlying pathological mechanisms. The cerebellum and limbic system of patients showed altered topology, suggesting that these regions or hubs may contribute to whole-brain circuits in PNH and epilepsy.

Faciobrachial motor seizures: A more apt description?

Autoimmune encephalitis associated with antibodies against leucine-rich glioma inactivated protein (LGI1) is classically associated with brief, recurrent, contractions of facial and upper limb muscles, typically on the same side. Commonly described as 'faciobrachial dystonic seizures' (FBDS), these seizures have become the semiological hallmark of anti-LGI1 encephalitis. However, the facial and upper limb contractions observed in patients with anti-LGI1 encephalitis associated seizures are not always dystonic in nature. Here, we briefly highlight the case of a patient who was admitted to our institution with faciobrachial tonic-myoclonic seizures to emphasize the fact that faciobrachial seizures in anti-LGI1 encephalitis are not always dystonic. We also review the literature on the semiology of these seizures in patients diagnosed with anti-LGI1 encephalitis and propose a more apt description for this phenomenon. Our case as well as the literature highlights that in anti-LGI1 encephalitis the typical seizure semiology of faciobrachial distribution includes tonic, clonic, dystonic, and myoclonic activity in isolation or combination with or without plus features. Given that accurate labelling of clinical phenomenology enables a better understanding of the underlying epileptic networks and precise diagnosis, we would suggest a more inclusive term 'faciobrachial motor seizures' instead of 'faciobrachial dystonic seizures' to describe the typical seizure semiology of anti-LGI1 encephalitis. Based on the presence or absence of specific clinical features, these seizures can be further sub-classified as focal aware faciobrachial motor seizures, focal impaired awareness faciobrachial motor seizures or focal faciobrachial motor plus seizures (aware or impaired awareness).

Semi-automatic Extraction of Functional Dynamic Networks Describing Patient's Epileptic Seizures.

Intracranial electroencephalography (EEG) studies using stereotactic EEG (SEEG) have shown that during seizures, epileptic activity spreads across several anatomical regions from the seizure onset zone toward remote brain areas. A full and objective characterization of this patient-specific time-varying network is crucial for optimal surgical treatment. Functional connectivity (FC) analysis of SEEG signals recorded during seizures enables to describe the statistical relations between all pairs of recorded signals. However, extracting meaningful information from those large datasets is time consuming and requires high expertise. In the present study, we first propose a novel method named Brain-wide Time-varying Network Decomposition (BTND) to characterize the dynamic epileptogenic networks activated during seizures in individual patients recorded with SEEG electrodes. The method provides a number of pathological FC subgraphs with their temporal course of activation. The method can be applied to several seizures of the patient to extract reproducible subgraphs. Second, we compare the activated subgraphs obtained by the BTND method with visual interpretation of SEEG signals recorded in 27 seizures from nine different patients. As a whole, we found that activated subgraphs corresponded to brain regions involved during the course of the seizures and their time course was highly consistent with classical visual interpretation. We believe that the proposed method can complement the visual analysis of SEEG signals recorded during seizures by highlighting and characterizing the most significant parts of epileptic networks with their activation dynamics.

Synaptic Vesicles Dynamics in Neocortical Epilepsy.

Neuronal hyperexcitability often results from an unbalance between excitatory and inhibitory neurotransmission, but the synaptic alterations leading to enhanced seizure propensity are only partly understood. Taking advantage of a mouse model of neocortical epilepsy, we used a combination of photoconversion and electron microscopy to assess changes in synaptic vesicles pools in vivo. Our analyses reveal that epileptic networks show an early onset lengthening of active zones at inhibitory synapses, together with a delayed spatial reorganization of recycled vesicles at excitatory synapses. Proteomics of synaptic content indicate that specific proteins were increased in epileptic mice. Altogether, our data reveal a complex landscape of nanoscale changes affecting the epileptic synaptic release machinery. In particular, our findings show that an altered positioning of release-competent vesicles represent a novel signature of epileptic networks.

Electroclinical features of lateral and medial orbitofrontal epilepsy: a case series

To better understand the electroclinical features and epileptic network of lateral and medial orbitofrontal epilepsy (OFE). We evaluated four patients who had undergone epilepsy surgery. Epileptic foci in two patients originated from the lateral orbitofrontal cortex, and those in the other two originated from the medial orbitofrontal cortex, which was confirmed by stereoelectroencephalography (SEEG). Time-frequency spectrograms were also provided for assistance, and the change in high-frequency energy was superimposed on the 3D reconstructed brain with a colour code in order to more intuitively show the transfer of high-frequency energy as the seizure evolves. All patients underwent SEEG-guided radiofrequency thermocoagulation (RF-TC) or focal resection and achieved satisfactory results. Lateral OFE and medial OFE were relatively independent with regards to clinical symptoms and epileptic network, however, lateral OFE was likely to propagate to the dorsolateral frontal lobe, whereas medial OFE (gyrus rectus) was more likely to propagate to the medial temporal lobe or insular lobe with long duration. There were significant differences in duration (21.17 ± 11.5 vs. 127.22 ± 235.05) and early propagation time (7.92 ± 4.44 vs. 29.0 ± 33.47) between the two origins. A better understanding of the electroclinical features of lateral and medial OFE is helpful to understand their epileptic networks and perform accurate resections in order to protect the cognitive and behavioural functions of patients.

Reconfiguration of human evolving large-scale epileptic brain networks prior to seizures: an evaluation with node centralities

Previous research has indicated that temporal changes of centrality of specific nodes in human evolving large-scale epileptic brain networks carry information predictive of impending seizures. Centrality is a fundamental network-theoretical concept that allows one to assess the role a node plays in a network. This concept allows for various interpretations, which is reflected in a number of centrality indices. Here we aim to achieve a more general understanding of local and global network reconfigurations during the pre-seizure period as indicated by changes of different node centrality indices. To this end, we investigate—in a time-resolved manner—evolving large-scale epileptic brain networks that we derived from multi-day, multi-electrode intracranial electroencephalograpic recordings from a large but inhomogeneous group of subjects with pharmacoresistant epilepsies with different anatomical origins. We estimate multiple centrality indices to assess the various roles the nodes play while the networks transit from the seizure-free to the pre-seizure period. Our findings allow us to formulate several major scenarios for the reconfiguration of an evolving epileptic brain network prior to seizures, which indicate that there is likely not a single network mechanism underlying seizure generation. Rather, local and global aspects of the pre-seizure network reconfiguration affect virtually all network constituents, from the various brain regions to the functional connections between them.

Hippocampal adult-born granule cells drive network activity in a mouse model of chronic temporal lobe epilepsy

Temporal lobe epilepsy (TLE) is characterized by recurrent seizures driven by synchronous neuronal activity. The reorganization of the dentate gyrus (DG) in TLE may create pathological conduction pathways for synchronous discharges in the temporal lobe, though critical microcircuit-level detail is missing from this pathophysiological intuition. In particular, the relative contribution of adult-born (abGC) and mature (mGC) granule cells to epileptiform network events remains unknown. We assess dynamics of abGCs and mGCs during interictal epileptiform discharges (IEDs) in mice with TLE as well as sharp-wave ripples (SPW-Rs) in healthy mice, and find that abGCs and mGCs are desynchronized and differentially recruited by IEDs compared to SPW-Rs. We introduce a neural topic model to explain these observations, and find that epileptic DG networks organize into disjoint, cell-type specific pathological ensembles in which abGCs play an outsized role. Our results characterize identified GC subpopulation dynamics in TLE, and reveal a specific contribution of abGCs to IEDs.

Spatial and temporal dynamics of epileptic activity at sleep onset in the Encephalopathy with Status Epilepticus during slow sleep (ESES) after unilateral thalamic lesions

ObjectiveEncephalopathy with Status Epilepticus during slow Sleep (ESES) is a syndrome where neurocognitive impairment correlates with multifocal Electroencephalography (EEG) spikes increasing abruptly at sleep onset. Demonstration of a focal onset could provide important clues to unravel the mechanisms underlying the condition, but until know it has not been established. MethodsWe studied epileptic dynamics at sleep onset to assess its focal or diffuse features in five patients with perinatal thalamic hemorrhages lateralized to one hemisphere, using high resolution EEG. ResultsDynamical functional connectivity revealed the information flow in the epileptic network and identified primary sources of outflow, equated with cortical spike sources. We found that spikes with important activation originate in restricted cortical areas of the hemisphere with the lesion, spreading widely and quickly at onset of N2 sleep stage. ConclusionsPerinatal thalamic lesions have the potential to induce, years later, a regional onset of epileptic activity with features of ESES in a cortex without apparent structural lesion. Most widespread spike activity in the scalp results from secondary propagation. SignificancePerinatal thalamic lesions produce ESES with focal onset in a restricted cortical area of the hemisphere with the lesion, and prominent secondary propagation.

Changes of Ictal-Onset Epileptic Network Synchronicity in Childhood Absence Epilepsy: A Magnetoencephalography Study.

Objective: To further understand the mechanisms underlying epileptic network and the characteristics of individual specific network, we conducted a study on brain network by magnetoencephalography (MEG) focusing on patients with childhood absence epilepsy (CAE).Methods: The network connectivity of 22 patients was investigated with MEG at the source level. Network connectivity of spikes and slow waves was computed with accumulated source imaging (ASI) and correlation analysis. Time–frequency analysis was used to characterize the network changes during the ictal-onset period of each patient and the potential factors.Results: We found that spectral power increased at around 1 s and distributed at 2–4 Hz in all patients. Ictal spikes simultaneously showed elevation of network connectivity, predominantly excitatory connections, when generalized firing activity spread to the overall brain. High-frequency oscillations (HFOs) were prone to detect overexcited neuronal firing in certain focal areas.Conclusions: Personal network changes during ictal onset had unique features in the time range and parallel seizure rhythm uniformly in every patient. There was an important time point for generalized discharges of the epileptic network. Ictal spiking activity played an important role in the epileptic network synchronicity of childhood absence epilepsy. Frequency oscillations provided references for locating abnormal changes in neuromagnetic signals.

Electrical stimulation of the endopiriform nucleus attenuates epilepsy in rats by network modulation.

ObjectiveNeuromodulatory anterior thalamic deep brain stimulation (DBS) is an effective therapy for intractable epilepsy, but few patients achieve complete seizure control with thalamic DBS. Other stimulation sites may be considered for anti‐seizure DBS. We investigated bilateral low‐frequency stimulation of the endopiriform nuclei (LFS‐EPN) to control seizures induced by intracortically implanted cobalt wire in rats.MethodsChronic epilepsy was induced by cobalt wire implantation in the motor cortex unilaterally. Bipolar‐stimulating electrodes were implanted into the EPN bilaterally. Continuous electroencephalography (EEG) was recorded using electrodes placed into bilateral motor cortex and hippocampus CA1 areas. Spontaneous seizures were monitored by long‐term video‐EEG, and behavioral seizures were classified based on the Racine scale. Continuous 1‐Hz LFS‐EPN began on the third day after electrode implantation and was controlled by a multi‐channel stimulator. Stimulation continued until the rats had no seizures for three consecutive days.ResultsCompared with the control and sham stimulation groups, the LFS‐EPN group experienced significantly fewer seizures per day and the mean Racine score of seizures was lower due to fewer generalized seizures. Ictal discharges at the epileptogenic site had significantly reduced theta band power in the LFS‐EPN group compared to the other groups.InterpretationBilateral LFS‐EPN attenuates cobalt wire‐induced seizures in rats by modulating epileptic networks. Reduced ictal theta power of the EEG broadband spectrum at the lesion site may be associated with the anti‐epileptogenic mechanism of LFS‐EPN. Bilateral EPN DBS may have therapeutic applications in human partial epilepsies.

Transitions between neocortical seizure and non-seizure-like states and their association with presynaptic glutamate release

The transition between seizure and non-seizure states in neocortical epileptic networks is governed by distinct underlying dynamical processes. Based on the gamma distribution of seizure and inter-seizure durations, over time, seizures are highly likely to self-terminate; whereas, inter-seizure durations have a low chance of transitioning back into a seizure state. Yet, the chance of a state transition could be formed by multiple overlapping, unknown synaptic mechanisms. To identify the relationship between the underlying synaptic mechanisms and the chance of seizure-state transitions, we analyzed the skewed histograms of seizure durations in human intracranial EEG and seizure-like events (SLEs) in local field potential activity from mouse neocortical slices, using an objective method for seizure state classification. While seizures and SLE durations were demonstrated to have a unimodal distribution (gamma distribution shape parameter >1), suggesting a high likelihood of terminating, inter-SLE intervals were shown to have an asymptotic exponential distribution (gamma distribution shape parameter <1), suggesting lower probability of cessation. Then, to test cellular mechanisms for these distributions, we studied the modulation of synaptic neurotransmission during, and between, the in vitro SLEs. Using simultaneous local field potential and whole-cell voltage clamp recordings, we found a suppression of presynaptic glutamate release at SLE termination, as demonstrated by electrically- and optogenetically-evoked excitatory postsynaptic currents (EPSCs), and focal hypertonic sucrose application. Adenosine A1 receptor blockade interfered with the suppression of this release, changing the inter-SLE shape parameter from asymptotic exponential to unimodal, altering the chance of state transition occurrence with time. These findings reveal a critical role for presynaptic glutamate release in determining the chance of neocortical seizure state transitions.

Perampanel reduces paroxysmal depolarizing shift and inhibitory synaptic input in excitatory neurons to inhibit epileptic network oscillations.

Perampanel is a newly approved anticonvulsant uniquely targeting AMPA receptors, which mediate the most abundant form of excitatory synaptic transmission in the brain. However, the network mechanism underlying the anti-epileptic effect of the AMPAergic inhibition remains to be explored. The mechanism of perampanel action was studied with the basolateral amygdala network containing pyramidal-inhibitory neuronal resonators in seizure models of 4-aminopyridine (4-AP) and electrical kindling. Application of either 4-AP or electrical kindling to the basolateral amygdala readily induces AMPAergic transmission-dependent reverberating activities between pyramidal-inhibitory neuronal resonators, which are chiefly characterized by burst discharges in inhibitory neurons and corresponding recurrent inhibitory postsynaptic potentials in pyramidal neurons. Perampanel reduces post-kindling "paroxysmal depolarizing shift" especially in pyramidal neurons and, counterintuitively, eliminates burst activities in inhibitory neurons and inhibitory synaptic inputs onto excitatory pyramidal neurons to result in prevention of epileptiform discharges and seizure behaviours. Intriguingly, similar effects can be obtained with not only the AMPA receptor antagonist CNQX but also the GABAA receptor antagonist bicuculline, which is usually considered as a proconvulsant. Ictogenesis depends on the AMPA receptor-dependent recruitment of pyramidal-inhibitory neuronal network oscillations tuned by dynamic glutamatergic and GABAergic transmission. The anticonvulsant effect of perampanel then stems from disruption of the coordinated network activities rather than simply decreased neuronal excitability or excitatory transmission. Positive or negative modulation of epileptic network reverberations may be pro-ictogenic or anti-ictogenic, respectively, constituting a more applicable rationale for the therapy against seizures.