Wave Discharges Research Articles

Transition dynamics and optogenetic control of epileptiform activity in a modified mean filed model of human cortex

Physiological experiments have shown that inhibitory interneurons can induce and maintain epileptiform activities, and different interneuron subtypes may be responsible for different types of seizures. Here we aim to link these electrophysiological experimental phenomena with theoretical dynamic mechanisms based on an improved Liley mean field model. Fascinatingly, the number of synapses between inhibitory neural populations can induce a rich state transition. Typically, the system will experience normal rhythm discharges, multispike discharges, spike wave discharges (SWD), generalized periodic discharges (GPD), the beta band oscillation, and eventually return to the normal state. Interestingly, the transition process can also be reversed. Meanwhile, disinhibition circuits can cause more epileptiform activities after taking into account the delay of synaptic information transmission. Furthermore, we are committed to designing different control strategies for epileptiform activities. As we expected, both deep brain stimulation and optogenetic technology can destroy or even eliminate pathological waves. It is need to emphasis that the cell type specificity of optogenetic regulation allows it to precisely target inhibitory neural populations, which is agree with experiment. Particularly, three different optogenetic regulatory strategies targeting inhibitory neural populations are modeled and proposed, of which the intermittent is designed to save energy. These modeling results reproduce the experimental phenomena and more significantly, help understand the mechanism of epilepsy to guide the clinical practice.

Regulating absence seizures by tri-phase delay stimulation applied to globus pallidus internal.

In this paper, a reduced globus pallidus internal (GPI)-corticothalamic (GCT) model is developed, and a tri-phase delay stimulation (TPDS) with sequentially applying three pulses on the GPI representing the inputs from the striatal D1 neurons, subthalamic nucleus (STN), and globus pallidus external (GPE), respectively, is proposed. The GPI is evidenced to control absence seizures characterized by 2 Hz-4 Hz spike and wave discharge (SWD). Hence, based on the basal ganglia-thalamocortical (BGCT) model, we firstly explore the triple effects of Dl-GPI, GPE-GPI, and STN-GPI pathways on seizure patterns. Then, using the GCT model, we apply the TPDS on the GPI to potentially investigate the alternative and improved approach if these pathways to the GPI are blocked. The results show that the striatum D1, GPE, and STN can indeed jointly and significantly affect seizure patterns. In particular, the TPDS can effectively reproduce the seizure pattern if the D1-GPI, GPE-GPI, and STN-GPI pathways are cut off. In addition, the seizure abatement can be obtained by well tuning the TPDS stimulation parameters. This implies that the TPDS can play the surrogate role similar to the modulation of basal ganglia, which hopefully can be helpful for the development of the brain-computer interface in the clinical application of epilepsy.

INSTABILITIES OF SUPERSONIC COMBUSTION AT PLASMA-BASED FLAMEHOLDING

Two types of supersonic combustion instabilities identified in a M = 2 reacting flow at direct injection of gaseous hydrocarbon fuel and quasi-direct-current (Q-DC) plasma assistance have been considered: a global instability triggered by a mechanism of flow-combustion-plasma coupling and a fast instability of a thermoacoustic nature. The experiments were performed at SBR-50 supersonic combustion facility at variable conditions: pressureP0 = 1-4 bar, temperature T0 = 300-750 K, and fuel mass flow rate m‘ = 1-8.5 g/s. Diagnostics includedpressure measurements, filtered fast camera imaging, schlieren visualization, and spectroscopic observations. The global instability develops with a characteristic time of about 10 ms and is related to the interaction of the combustion-based separation zone with the reflected shock wave (SW) and electric discharge. It is shown that this instability could be effectively controlled by electrical discharge power. The thermoacoustic instability is developed with a characteristic time less than 1 ms. The analysis of pressure data reveals a resonant acoustic wave presence in the combustion zone between the fuel injection ports and the test section diffuser.

Effects of amplitude modulated discharge on growth of nanoparticles in TEOS/O2/Ar capacitively coupled plasma

We investigate the effects of the amplitude modulation (AM) discharge method on the growth of nanoparticles and the relation between growth of nanoparticles and plasma generation in tetraethylorthosilicate (TEOS)/O2/Ar plasma. The laser-light scattering (LLS) intensity, which is proportional to the density and the sixth power of the size of nanoparticles in the Rayleigh scattering regime, decreases by 18% at an AM level of 10% and by 60% at an AM level of 50%. On the other hand, the ArI emission intensity, which is roughly proportional to plasma density, is higher than that for the continuous wave discharge. Thus, AM discharges suppress growth of nanoparticles in TEOS plasma. We have shown oscillations of the axial electric field Ez with the AM frequency for AM discharge by electric field measurement using an electro-optic probe. We have discussed that these fluctuations of Ez mainly lead to the vertical oscillation of the levitation position of nanoparticles trapped in the plasma sheath boundary region by taking into account the force balance equation in the axial direction on these negatively charged nanoparticles.

Electroencephalography-functional magnetic resonance imaging of epileptiform discharges: Noninvasive investigation of the whole brain.

Simultaneous electroencephalography-functional magnetic resonance imaging (EEG-fMRI) is a unique and noninvasive method for investigating epileptic activity. Interictal epileptiform discharge-related EEG-fMRI provides cortical and subcortical blood oxygen level-dependent (BOLD) signal changes specific to epileptic discharges. As a result, EEG-fMRI has revealed insights into generators and networks involved in epileptic activity in different types of epilepsy, demonstrating-for instance-the implication of the thalamus in human generalized spike and wave discharges and the role of the default mode network in absences and focal epilepsy, and has suggested a mechanism for the cortico-subcortical interactions in Lennox-Gastaut syndrome discharges. EEG-fMRI can find deep sources of epileptic activity not available to scalp EEG or magnetoencephalography, and provides critical new information to delineate the epileptic focus when considering surgical treatment or electrode implantation. In recent years, methodological advances, such as artifact removal and automatic detection of events, have rendered this method easier to implement, and its clinical potential has since been established by evidence of the impact of BOLD response on clinical decision-making and of the relationship between concordance of BOLD responses with extent of resection and surgical outcome. This review presents the recent developments in EEG-fMRI methodology and EEG-fMRI studies in different types of epileptic disorders as follows: EEG-fMRI acquisition, gradient and pulse artifact removal, statistical analysis, clinical applications, presurgical evaluation, altered physiological state in generalized genetic epilepsy, and pediatric EEG-fMRI studies.

Characterizing the neurological phenotype of the hyperinsulinism hyperammonemia syndrome

BackgroundHyperinsulinism hyperammonemia (HI/HA) syndrome is caused by activating mutations in GLUD1, encoding glutamate dehydrogenase (GDH). Atypical absence seizures and neuropsychological disorders occur at high rates in this form of hyperinsulinism. Dysregulated central nervous system (CNS) glutamate balance, due to GDH overactivity in the brain, has been hypothesized to play a role. This study aimed to describe the neurologic phenotype in HI/HA syndrome and investigate CNS glutamate levels using glutamate weighted chemical exchange saturation transfer magnetic resonance imaging (GluCEST MRI). In this cross-sectional study, 12 subjects with HI/HA syndrome had plasma ammonia measurement, self- or parent-completed neurocognitive assessments, electroencephalogram (EEG), and GluCEST MRI at 7 T performed. GluCEST MRI measures were compared to a historic reference population of 10 healthy adults.ResultsSubjects were five males and seven females with median age of 25.5 years. Seventy-five percent of subjects reported a history of neurodevelopmental problems and 42% had neurocognitive assessment scores outside the normal range. Fifty percent had interictal EEG findings of generalized, irregular spike and wave discharges. Higher variability in hippocampal GluCEST asymmetry (p = 0.002), and in peak hippocampal GluCEST values (p = 0.008), was observed in HI/HA subjects (n = 9 with interpretable MRI) compared to the healthy reference population (n = 10).ConclusionsThe high prevalence of abnormal neurocognitive assessment scores and interictal EEG findings observed highlights the importance of longitudinal neuropsychological assessment for individuals with HI/HA syndrome. Our findings demonstrate the potential application of GluCEST to investigate persistent knowledge gaps in the mechanisms underlying the unique neurophenotype of this disorder.

0830 A Pediatric Case of Myoclonic Seizures Precipitating Central Sleep Apnea And Sequences of Periodic Breathing During Sleep

Abstract Introduction Myoclonic seizures are known to be influenced by the sleep-wake cycle. Although myoclonic seizures have been shown to alter sleep architecture, little is known about their influence on sleep-disordered breathing. Report of Cases: A 7-year-old male with a history of generalized epilepsy of unknown etiology with absence as well as myoclonic seizures, poor impulse control, and fine motor delay was referred for restless sleep and frequent nocturnal awakenings. A routine electroencephalography (EEG) performed 33 months prior to presentation, at an outside institution, reportedly showed 3.0 Hz generalized frontally dominant spike and wave discharges lasting less than two seconds. Video EEG (vEEG) revealed diffuse bilateral poly-spike and slow wave discharges, predominantly during sleep, and myoclonic seizures with abrupt whole-body jerks. Polysomnography, at this time, was characterized by mild central sleep apnea (AHI: 3.7; OAHI: 0.0; CAI: 2.8; REM AHI: 14.4). His lamotrigine dosing was increased to from 1.8 mg/kg/day to 3.6 mg/kg/day, at presentation, with seizure control for three months but he developed a recurrence of myoclonic seizures in the setting of sleep deprivation. A repeat vEEG was similar to previous findings and his lamotrigine was increased further and clobazam was added. Due to worsening behaviors, clobazam was discontinued and a weaning plan for lamotrigine was formulated. Repeat polysomnography demonstrated worsening central sleep apnea (AHI: 18.3, OAHI: 2.3), without hypoventilation, characterized by sequences of periodic breathing that occurred in conjunction with myoclonic seizures. The majority of seizure-induced periodic breathing episodes were observed during a one-hour period of NREM sleep near the end of the study. Stereotyped epileptiform activity occurred in conjunction with a resumption of hyperventilatory respirations following apneic events. The increased respiratory drive, however, did not appear to be clinically epileptic in nature as the epileptiform activity either preceded or trailed the respirations. A variable REM and then NREM predominance of central events on successive polysomnograms further suggests that his central events are not intrinsic but that they are precipitated by epileptiform activity. Zonisamide, an anticonvulsant with carbonic anhydrase inhibitory properties was initiated and is being titrated to therapeutic goal. Conclusion This case illustrates an unusual presentation of myoclonic seizure-induced periodic breathing during sleep. Support (If Any) Cincinnati Children’s Research Foundation.

4-Phenylbutyrate restored γ-aminobutyric acid uptake and reduced seizures in SLC6A1 patient variant-bearing cell and mouse models.

We have studied the molecular mechanisms of variants in solute carrier Family 6 Member 1 associated with neurodevelopmental disorders, including various epilepsy syndromes, autism and intellectual disability. Based on functional assays of solute carrier Family 6 Member 1 variants, we conclude that partial or complete loss of γ-amino butyric acid uptake due to reduced membrane γ-amino butyric acid transporter 1 trafficking is the primary aetiology. Importantly, we identified common patterns of the mutant γ-amino butyric acid transporter 1 protein trafficking from biogenesis, oligomerization, glycosylation and translocation to the cell membrane across variants in different cell types such as astrocytes and neurons. We hypothesize that therapeutic approaches to facilitate membrane trafficking would increase γ-amino butyric acid transporter 1 protein membrane expression and function. 4-Phenylbutyrate is a Food and Drug Administration-approved drug for paediatric use and is orally bioavailable. 4-Phenylbutyrate shows promise in the treatment of cystic fibrosis. The common cellular mechanisms shared by the mutant γ-amino butyric acid transporter 1 and cystic fibrosis transmembrane conductance regulator led us to hypothesize that 4-phenylbutyrate could be a potential treatment option for solute carrier Family 6 Member 1 mutations. We examined the impact of 4-phenylbutyrate across a library of variants in cell and knockin mouse models. Because γ-amino butyric acid transporter 1 is expressed in both neurons and astrocytes, and γ-amino butyric acid transporter 1 deficiency in astrocytes has been hypothesized to underlie seizure generation, we tested the effect of 4-phenylbutyrate in both neurons and astrocytes with a focus on astrocytes. We demonstrated existence of the mutant γ-amino butyric acid transporter 1 retaining wildtype γ-amino butyric acid transporter 1, suggesting the mutant protein causes aberrant protein oligomerization and trafficking. 4-Phenylbutyrate increased γ-amino butyric acid uptake in both mouse and human astrocytes and neurons bearing the variants. Importantly, 4-phenylbutyrate alone increased γ-amino butyric acid transporter 1 expression and suppressed spike wave discharges in heterozygous knockin mice. Although the mechanisms of action for 4-phenylbutyrate are still unclear, with multiple possibly being involved, it is likely that 4-phenylbutyrate can facilitate the forward trafficking of the wildtype γ-amino butyric acid transporter 1 regardless of rescuing the mutant γ-amino butyric acid transporter 1, thus increasing γ-amino butyric acid uptake. All patients with solute carrier Family 6 Member 1 variants are heterozygous and carry one wildtype allele, suggesting a great opportunity for treatment development leveraging wildtype protein trafficking. The study opens a novel avenue of treatment development for genetic epilepsy via drug repurposing.

Opto‐ and Chemogenetic Dissection of Ictal Apnea Neural Circuitry

Sudden Unexpected Death in Epilepsy (SUDEP) is defined as the sudden, unexpected and unexplained death of a person with epilepsy and accounts for between 8 and 17% of epilepsy‐related deaths, rising to 50% for patients with refractory epilepsy. In a mouse model of SUDEP, we have recently shown that death is due to seizure‐induced respiratory arrest. In addition, apnea is initiated during the tonic phase and tonic respiratory muscle contraction is a possible mechanism of apnea. In the present study, we explore 1) whether tonic activity of the inspiratory rhythm generator in the brainstem and/or 2) upper motor neuron activity in the motor cortex drives ictal apnea.We recorded video, electrocorticogram (ECoG), electrocardiogram (ECG), and breathing via whole body plethysmography in adult mice carrying the human SCN8A encephalopathy mutation p.Asn1768Asp (N1768D; “D/+ mice”) during audiogenic seizures. This mutation was identified from a patient that died from SUDEP and D/+ mice have severe convulsive seizures with apnea and many suffer seizure‐induced death.To test the hypothesis that tonic activity from the inspiratory oscillator results in apnea, we implanted fiberoptic ferrules bilaterally into the Bötzinger Complex (BötC) of mice that express Channelrhodopsin2 (ChR2) under the vesicular GABA transporter (VGAT; “VGAT‐ChR2” mice) that were crossed with D/+ mice (Fig. 1A & B). The goal of the experiment is to photostimulate BötC during ictal apnea to inhibit tonic inspiratory activity and produce expiration (Fig. 1C). Seizures were evoked using a 15 kHz pure tone, as we have done before (Fig. 1D). Trains of light pulses (50 ms pulses, 5 mW of 473 nm light) were evoked repetitively during ictal apnea (Fig. 1E & F). However, this did not recover normal breathing rhythm and apnea duration was no different for any photostimulation paradigm versus control (p = 0.7892, F = 0.1747, One‐Way ANOVA; Fig. 1G). Although breathing was not affected during seizures, the effects on baseline breathing were substantial; for example, inspiration was inhibited for a full 10 second photostimulation train (Fig. 1H).To test the necessity of ictal activity from upper motor neurons in the motor cortex are required for generating ictal apnea, we expressed iDREADD receptors in cortical excitatory neurons of D/+ mice and injected CNO i.p. prior to inducing seizures with a 15 kHz pure tone (Fig. 2A). Under control conditions, seizures presented with the usual tonic phase apnea and spike wave discharges (SWDs) in the motor cortex (Fig. 2B). CNO was able to robustly inhibit the SWDs, but the tonic phase and apnea were not affected (Figs. 2C‐E). The effect of 3 mg/kg CNO on ECoG power was significantly greater than the effect on apnea (p = 0.0059, paired t‐test).In sum, we found that the core inspiratory oscillator circuitry in the brainstem is likely bypassed to create tonic inspiratory activity. Furthermore, inhibition of cortical upper motor neurons has no effect on apnea. Thus, our interpretation is that other pools of upper motor neurons must drive the tonic inspiratory activity and apnea.

Contributions of Magnetoencephalography to Understanding Mechanisms of Generalized Epilepsies: Blurring the Boundary Between Focal and Generalized Epilepsies?

According to the latest operational 2017 ILAE classification of epileptic seizures, the generalized epileptic seizure is still conceptualized as “originating at some point within and rapidly engaging, bilaterally distributed networks.” In contrast, the focal epileptic seizure is defined as “originating within networks limited to one hemisphere.” Hence, one of the main concepts of “generalized” and “focal” epilepsy comes from EEG descriptions before the era of source localization, and a presumed simultaneous bilateral onset and bi-synchrony of epileptiform discharges remains a hallmark for generalized seizures. Current literature on the pathophysiology of generalized epilepsy supports the concept of a cortical epileptogenic focus triggering rapidly generalized epileptic discharges involving intact corticothalamic and corticocortical networks, known as the cortical focus theory. Likewise, focal epilepsy with rich connectivity can give rise to generalized spike and wave discharges resulting from widespread bilateral synchronization. Therefore, making this key distinction between generalized and focal epilepsy may be challenging in some cases, and for the first time, a combined generalized and focal epilepsy is categorized in the 2017 ILAE classification. Nevertheless, treatment options, such as the choice of antiseizure medications or surgical treatment, are the reason behind the importance of accurate epilepsy classification. Over the past several decades, plentiful scientific research on the pathophysiology of generalized epilepsy has been conducted using non–invasive neuroimaging and postprocessing of the electromagnetic neural signal by measuring the spatiotemporal and interhemispheric latency of bi-synchronous or generalized epileptiform discharges as well as network analysis to identify diagnostic and prognostic biomarkers for accurate diagnosis of the two major types of epilepsy. Among all the advanced techniques, magnetoencephalography (MEG) and multiple other methods provide excellent temporal and spatial resolution, inherently suited to analyzing and visualizing the propagation of generalized EEG activities. This article aims to provide a comprehensive literature review of recent innovations in MEG methodology using source localization and network analysis techniques that contributed to the literature of idiopathic generalized epilepsy in terms of pathophysiology and clinical prognosis, thus further blurring the boundary between focal and generalized epilepsy.

Closed-loop controller based on reference signal tracking for absence seizures

Absent epilepsy is a kind of refractory epilepsy, which is characterized by 2–4 Hz spike and wave discharges (SWDs) in electroencephalogram. Open-loop deep brain stimulation (DBS) targeting the thalamic reticular nucleus (TRN) is an effective method to treat absent epilepsy by eliminating SWDs in the brain. Compared with open-loop DBS, closed-loop DBS has been recognized by researchers for its advantages of significantly inhibiting seizures and having fewer side effects. Since traditional trial-and-error methods for adjusting closed-loop controller parameters are too dependent on the experience of doctors, in this paper we designed two proportional integral (PI) controllers based on the basal ganglia-cortical-thalamic model, whose PI parameters are calculated from the stability of the system. The two PI controllers can automatically adjust the frequency and amplitude of DBS respectively according to the change of the firing rate detected by substantia nigra pars reticulata (SNr). The parameters of the PI controller are calculated based on the Routh-Hurwitz stability criterion of a linear system which transformed by the original system using controlled auto-regressive (CAR) model and recursive least squares (RLS) method. Numerical simulation results show that both PI controllers significantly destroy the SWDs of the cerebral cortex and restore it to the other two normal discharge modes according to the different target firing rate, which supplies a promising brain stimulation strategy.

GABAB - and GABAA -receptor-mediated regulation of Up and Down states across development.

Slow oscillations, the hallmark of non-REM sleep, and their cellular counterpart, Up and Down states (UDSs), are considered a signature of cortical dynamics that reflect the intrinsic network organization. Although previous studies have explored the role of inhibition in regulating UDSs, little is known about whether this role changes with maturation. This is surprising since both slow oscillations and UDSs exhibit significant age-dependent alterations. To elucidate the developmental impact of GABAB and GABAA receptors on UDS activity, we conducted simultaneous local field potentials and intracellular recordings ex vivo, in brain slices of young and adult male mice, using selective blockers, CGP55845 and a non-saturating concentration of gabazine, respectively. Blockade of both GABAB and GABAA signalling showed age-differentiated functions. CGP55845 caused an increase in Down state duration in young animals, but a decrease in adults. Gabazine evoked spike and wave discharges in both ages; however, while young networks became completely epileptic, adults maintained the ability to generate UDSs. Furthermore, voltage clamp recordings of miniature inhibitory postsynaptic currents revealed that gabazine selectively blocks phasic currents, particularly involving postsynaptic mechanisms. The latter exhibit clear maturational changes, suggesting a different subunit composition of GABAA receptors in young vs. adult animals. Indeed, subsequent local field potential recordings under diazepam (nanomolar or micromolar concentrations) revealed that mechanisms engaging the drug's classical binding site, mediated by α1-subunit-containing GABAA receptors, make a bigger contribution to Up state initiation in young networks compared to adults. Taken together, these findings help clarify the mechanisms that underlie the maturation of cortical network activity and enhance our understanding regarding the emergence of neurodevelopmental disorders. KEY POINTS: Slow oscillations, the EEG hallmark of non-REM sleep, and their cellular counterpart, Up and Down states (UDSs), are considered the default activity of the cerebral cortex and reflect the underlying neural connectivity. GABAB - and GABAA -receptor-mediated inhibition play a major role in regulating UDS activity. Although slow oscillations and UDSs exhibit significant alterations as a function of age, it is unknown how developmental changes in inhibition contribute to the developmental profile of this activity. In this study, we reveal for the first time age-dependent effects of GABAB and GABAA signalling on UDSs. We also document the differential subunit composition of postsynaptic GABAA receptors in young and adult animals, highlighting the α1-subunit as a major component of the age-differentiated regulation of UDSs. These findings help clarify the mechanisms that underlie the maturation of cortical network activity, and enhance our understanding regarding the emergence of neurodevelopmental disorders.

STUDY OF MODIFIED PERFORATED BREAKWATER AS RENEWABLE ENERGY DEVICE

Aim: This study investigates to determine the influence of wave steepness, relative freeboard, and breaker parameters on overtopping discharge at a perforated breakwater. Methodology and results: The research method used was using both a numerical model simulations on three-dimensional computational fluid dynamics (CFD) modelling software namely FLOW-3D; and empirical equation computation. The evaluation of both approaches were performed for understanding the characteristics of wave discharge that overtopping the perforated breakwater. The experimental results of modified perforated breakwater revealed that the lowest slope possible with the highest porosity possible can generate the highest value of dimensionless overtopping discharge for wave energy harvesting. Conclusion, significance and impact study: The findings of this study formulated the optimum slope and porosity to the highest wave energy harvested. Further studies recommend that data collection from onsite trials of modified perforated breakwater are performed.

440 Modulating decreases in Superior Colliculus activity through optogenetic activation attenuates seizures in the WAG/Rij genetic model of Absence Epilepsy

OBJECTIVES/GOALS: While anti-seizure medications are effective, nearly one third of patients have seizures that go untreated. Prior studies using evoked seizure models have shown that activation of the Superior Colliculus (SC) display anti-seizure effects. Here we monitored and modulated the DLSC to suppress spontaneous seizures in a genetic model of epilepsy. METHODS/STUDY POPULATION: WAG/Rij rats (4 months old) were employed as study subjects. Animals were surgically prepared for virus injection (ChR2 excitatory opsin, or control vector), fiber optic implantation and cortical EEG for optogenetic studies. For In vivo electrophysiology, animals were implanted with a 16 wire multi-electrode array into the DLSC. In optogenetic experiments, we compared the efficacy of continuous neuromodulation to that of on-demand neuromodulation (real time detection of seizures) paradigms on a within-subject basis. We compared three stimulation frequencies on a within-subject basis (5, 20, 100 Hz). We quantified the number and duration of each spike wave discharge (SWD) during each two-hour-long trial. Electrode array single units were sorted and analyzed for activity before, during and after seizures. RESULTS/ANTICIPATED RESULTS: In vivo electrophysiology found there to be a significant decrease in single unit activity leading up to the start of SWDs. Interestingly, on-demand neuromodulation was effective in both females and males – where the greatest reduction in seizure duration was under 100 Hz light delivery. As expected, male and female animals injected with a control vector did not show a reduction in seizures in response to light delivery. In the open-loop (continuous) stimulation paradigm, optogenetic activation of the DLSC was without effect on the number or duration of SWDs at any of the frequencies examined. DISCUSSION/SIGNIFICANCE: SC activity is significantly decreased prior to the start of seizures. Furthermore, activation of the SC displays anti-seizure effects in a model of spontaneous seizures. A striking difference between open and closed-loop neuromodulation approaches underscores the importance of stimulation paradigm in determining therapeutic effect.

Effect of Sleep on Epileptic Discharges in Patients with Idiopathic Generalized Epilepsy.

Background. It is known that sleep and sleep deprivation affect the EEG findings, onset, frequency and semiology of the seizures. Generalized spike and wave discharges were found more common in drowsiness and sleep states, especially in childhood and juvenile absence epilepsy syndromes. Aim. In this study we aimed to show the effects of short sleep on the interictal and ictal discharges of the patients with genetic generalized epileptic seizures and to show the effects of treatment on the discharges during awake and sleep states. Method. 37 patients (29 females and 8 males) with a diagnosis of genetic generalized epilepsy syndrome were included. All the patients were investigated with video-EEG recording during awake, sleep and post sleep states. Epileptic discharges were counted manually. Discharge numbers and their relation with triggers were analyzed to see the difference between different vigilance states. Results. Number of ictal discharges is found to be increased after sleep. There was no difference in the control EEGs, which were taken under treatment. Conclusion. Sleep is a trigger of epileptic discharges in ictal nature, but an effective antiepileptic treatment prevents this effect.

Mechanism analysis for excitatory interneurons dominating poly-spike wave and optimization of electrical stimulation.

In addition to inhibitory interneurons, there exist excitatory interneurons (EINs) in the cortex, which mainly have excitatory projections to pyramidal neurons. In this study, we improve a thalamocortical model by introducing EIN, investigate the dominant role of EIN in generating spike and slow wave discharges (SWDs), and consider a non-rectangular pulse to control absence seizures. First, we display here that the improved model can reproduce typical SWDs of absence seizures. Moreover, we focus on the function of EIN by means of bifurcation analysis and find that EIN can induce transition behaviors under Hopf-type and fold limit cycle bifurcations. Specifically, the system has three stable solutions composing a tri-stable region. In this region, there are three attraction basins, which hints that external stimulation can drive the system trajectory from one basin to another, thereby eliminating abnormal oscillations. Furthermore, we compare the increasing ramp with rectangular pulse and optimize stimulation waveforms from the perspective of electrical charges input. The controlling role of the single increasing ramp to absence seizures is remarkable and the optimal stimulus parameters have been found theoretically. This work provides a computational model containing EIN and a theoretical basis for future physiological experiments and clinical research studies.

The adjustment mechanism of the spike and wave discharges in thalamic neurons: a simulation analysis.

Different from many previous theoretical studies, this paper explores the regulatory mechanism of the spike and wave discharges (SWDs) in the reticular thalamic nucleus (TRN) by a dynamic computational model. We observe that the SWDs appears in the TRN by changing the coupling weights and delays in the thalamocortical circuit. The abundant poly-spikes wave discharges is also induced when the delay increases to large enough. These discharges can be inhibited by tuning the inhibitory output from the basal ganglia to the thalamus. The mechanisms of these waves can be explained in this model together with simulation results, which are different from the mechanisms in the cortex. The TRN is an important target in treating epilepsy, and the results may be a theoretical evidence for experimental study in the future.

HP17: Electroencephalography patterns on two case studies of absence status epilepticus in adults

Two cases of Absence Status Epilepticus (ASE), in two patients of different ages, within two different clinical contexts, and with two different Electroencephalogram (EEG) patterns. I describe here, two female patients, 30 years old (case report one) and 76 years old (case report two) that were diagnosed with ASE after prolonged EEG (260 hours and 20.5 hours, respectively) had been performed. In these cases, the clinical manifestation of ASE was different, with the cardinal symptom being memory loss in case report one and confusion in case report two. Furthermore, the EEG pattern of each patient was different as well. In case report one there were very frequent runs of high amplitude, at times sharpened, slow activity over frontal or fronto-temporal regions and bursts of 1-2Hz generalised spike/polyspike and slow wave. Conversely, in case report two there were continuous 2-3Hz generalised spike and slow wave discharges for approximately 30 hour. EEG is the gold standard technique for the diagnosis of ASE, however, it can still present variable electrographic patterns that sometimes may cast doubt on whether it constitutes a definite ASE in particular it can be difficult to ascertain whether the pattern seen is ictal or interictal, especially when clinical signs are subtle. These two cases illustrate the difficulties in diagnosis and the range of presentations of ASE.

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

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

Successful use of perampanel in GABRA1-related myoclonic epilepsy with photosensitivity.

Pathogenic variants in gamma-aminobutyric acid type A receptor subunit alpha1 (GABRA1) is a protein coding gene that has been associated with a broad phenotypic spectrum of epilepsies. These have ranged from mild generalized forms to early-onset severe epileptic encephalopathies. Both in mild and in severe forms, tonic-clonic and myoclonic seizures with generalized spike and wave discharges and photoparoxysmal responses are common clinical manifestations. We present the case of a 14-year-old girl referred to our clinic with uncontrolled epilepsy. She was found to carry a heterozygous variant (c.335G>A) in GABRA1, already described in the literature and classified as "pathogenic" according to ACMG guidelines. The patient showed severe drug resistance with seizures often triggered by photic stimulation. The introduction of perampanel therapy led to overall reduction of the focal and generalized myoclonic seizures and complete clinical control of the light-triggered seizures. To our knowledge this is the first report of perampanel efficacy in photosensitive epilepsy, and in particular in the presence of a GABRA1 variant. New evidence is needed to confirm our findings in this case.