A spike is a spike: On the universality of spike features in four epilepsy models.

OBJECTIVE: Frequency properties of the EEG characteristics of different seizure types including absence seizures have been described for various rodent models of epilepsy. However, little attention has been paid to the frequency properties of individual spike-wave complexes (SWCs), the constituting elements characterizing the different generalized seizure types. Knowledge of their properties is not only important for understanding the mechanisms underlying seizure generation but also for the identification of epileptiform activity in various seizure types. Here, we compared the frequency properties of SWCs in different epilepsy models. METHODS: A software package was designed and used for the extraction and frequency analysis of SWCs from long-term EEG of four spontaneously seizing, chronic epilepsy models: a post-status epilepticus model of temporal lobe epilepsy, a lateral fluid percussion injury model of post-traumatic epilepsy, and two genetic models of absence epilepsy-GAERS and rats of the WAG/Rij strain. The SWCs within the generalized seizures were separated into fast (three-phasic spike) and slow (mostly containing the wave) components. Eight animals from each model were used (32 recordings, 104 510 SWCs in total). A limitation of our study is that the recordings were hardware-filtered (high-pass), which could affect the frequency composition of the EEG. RESULTS: We found that the three-phasic spike component was similar in all animal models both in time and frequency domains, their amplitude spectra showed a single expressed peak at 18-20 Hz. The slow component showed a much larger variability across the rat models. SIGNIFICANCE: Despite differences in the morphology of the epileptiform activity in different models, the frequency composition of the spike component of single SWCs is identical and does not depend on the particular epilepsy model. This fact may be used for the development of universal algorithms for seizure detection applicable to different rat models of epilepsy. PLAIN LANGUAGE SUMMARY: There is a large variety between people with epilepsy regarding the clinical manifestations and the electroencephalographic (EEG) phenomena accompanying the epileptic seizures. Here, we show that one of the EEG signs of epilepsy, an epileptic spike, is universal, since it has the same shape and frequency characteristics in different animal models of generalized epilepsies, despite differences in recording sites and location.

Molecular Mechanisms Underlying the Generation of Absence Seizures: Identification of Potential Targets for Therapeutic Intervention.

Understanding the molecular mechanisms underlying the generation of absence seizures is crucial for developing effective, patient-specific treatments for childhood absence epilepsy (CAE). Currently, one-third of patients remain refractive to the antiseizure medications (ASMs), previously called antiepileptic drugs (AEDs), available to treat CAE. Additionally, these ASMs often produce serious side effects and can even exacerbate symptoms in some patients. Determining the precise cellular and molecular mechanisms directly responsible for causing this type of epilepsy has proven challenging as they appear to be complex and multifactorial in patients with different genetic backgrounds. Aberrant neuronal activity in CAE may be caused by several mechanisms that are not fully understood. Thus, dissecting the causal factors that could be targeted in the development of precision medicines without side effects remains a high priority and the ultimate goal in this field of epilepsy research. The aim of this review is to highlight our current understanding of potential causative mechanisms for absence seizure generation, based on the latest research using cutting-edge technologies. This information will be important for identifying potential targets for future therapeutic intervention.

Huperzine A suppresses absence seizures in the genetic absence epilepsy rat from Strasbourg (GAERS) model of genetic generalized epilepsy with absence seizures.

OBJECTIVE: We evaluated huperzine A treatment in the Genetic Absence Epilepsy Rat from Strasbourg (GAERS) model of genetic generalized epilepsy (GGE) with absence seizures. METHODS: Adult male GAERS (N = 15) were implanted with EEG recording electrodes 10 days before receiving study drug. Each animal received the following six treatments as a single, intraperitoneal dose, 7 days apart (in random order): huperzine A (0.3, 1.0, or 3.0 mg/kg), two periods of vehicle (0.9% NaCl), or ethosuximide (100 mg/kg) as a positive control. Electroencephalograms (EEGs) were acquired for 24 h before and after each treatment and analyzed for seizure activity during the 90-min period immediately post-treatment, including 30-min intervals at 30, 60, and 90 min. Additional analyses evaluated seizure activity over the 24-h post-treatment period using 60-min intervals at 6, 12, and 24 h. The cumulative 24-h periods before and after each administered treatment were also compared. RESULTS: Two-way ANOVA showed a treatment difference [F(91,182) = 3.592, p < 0.0001] on the number of seizures over the first 90-min post-treatment (primary outcome); Tukey's post hoc analyses showed that, compared to vehicle, huperzine A (3.0 mg/kg) significantly reduced seizures in the 30-min (p = 0.02) and 60-min (p = 0.001) intervals, and ethosuximide significantly reduced seizures at all measured time intervals except the 1-h blocks at 12 and 24 h. Huperzine A 3.0 mg/kg and ethosuximide significantly reduced seizures during the cumulative 24-h post-treatment period relative to pretreatment baseline. While huperzine A 3.0 mg/kg did not differ significantly from ethosuximide at any time point, the study was not designed to evaluate non-inferiority. The only adverse event after huperzine A or ethosuximide was mild, dose-dependent sedation. SIGNIFICANCE: Huperzine A potently suppressed absence-like seizures in GAERS, albeit with a shorter duration of action relative to ethosuximide, showing promise for clinical efficacy in GGE. PLAIN LANGUAGE SUMMARY: This study looked at how huperzine A affects seizures in rats with similar abnormal brain activity as seen in humans with absence epilepsy. Rats received different treatments, placebo (i.e., saline solution), huperzine A, and ethosuximide. Ethosuximide is considered a gold standard treatment for absence epilepsy. We recorded brain activity to measure seizures before and after each treatment. We found that huperzine A (3.0 mg/kg) reduced seizures soon after treatment, like ethosuximide. Both treatments appeared safe, causing only mild sleepiness. The study shows that huperzine A could be a good new treatment for a type of absence epilepsy.

The "Twin Peaks" method of automated Spike-Wave detection: A two-step, two-criteria Matlab application.

BACKGROUND: There are many automated spike-wave discharge detectors, but the known weaknesses of otherwise good methods and the varying working conditions of different research groups (mainly the access to hardware and software) invite further exploration into alternative approaches. NEW METHOD: The algorithm combines two criteria, one in the time-domain and one in the frequency-domain, exploiting morphological asymmetry and the presence of harmonics, respectively. The time-domain criterion is additionally adjusted by normal modelling between the first and second iterations. RESULTS: We report specificity, sensitivity and accuracy values for 20 recordings from 17 mature, male WAG/Rij rats. In addition, performance was preliminary tested with different hormones, pharmacological injections and species (mice) in a smaller sample. Accuracy and specificity were consistently above 91 %. The number of automatically detected spike-wave discharges was strongly correlated with the numbers derived from visual inspection. Sensitivity varied more strongly than specificity, but high values were observed in both rats and mice. COMPARISON WITH EXISTING METHODS: The algorithm avoids low-voltage movement artifacts, displays a lower false positive rate than many predecessors and appears to work across species, i.e. while designed initially with data from the WAG/Rij rat, the algorithm can pick up seizure activity in the mouse of considerably lower inter-spike frequency. Weaknesses of the proposed method include a lower sensitivity than several predecessors. CONCLUSION: The algorithm excels in being a selective and flexible (based on e.g. its performance across rats and mice) spike-wave discharge detector. Future work could attempt to increase the sensitivity of this approach.

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

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

The role of HCN channels on the effects of T-type calcium channels and GABAA receptors in the absence epilepsy model of WAG/Rij rats.

In this study we used ivabradine (IVA), a hyperpolarization-activated cyclic nucleotide-gated (HCN) channel blocker, to identify its effect on spike-wave discharges (SWDs); and aimed to determine the role of IVA on the effects of T-type calcium channel blocker NNC 55-0396, GABAA receptor agonist muscimol and antagonist bicuculline in male WAG/Rij rats. After tripolar electrodes for electrocorticogram (ECoG) recordings were placed on the WAG/Rij rats' skulls, 5, 10, and 20 mg/kg IVA were intraperitoneally administered for 7 consecutive days and ECoG recordings were obtained on days 0th, 3rd, 6th, and 7th for three hours before and after injections. While acute injection of 5, 10, and 20 mg/kg IVA did not affect the total number and the mean duration of SWDs, subacute administration (7 days) of IVA decreased the SWDs parameters 24 hours after the 7th injection. Interestingly, when IVA was administered again 24 hours after the 6th IVA injection, it increased the SWDs parameters. Western-blot analyses showed that HCN1 and HCN2 expressions decreased and HCN4 increased in the 5-month-old WAG/Rij rats compared to the 1-month-old WAG/Rij and 5-month-old native Wistar rats, while subacute IVA administration increased the levels of HCN1 and HCN2 channels, except HCN4. Subacute administration of IVA reduced the antiepileptic activity of NNC, while the proepileptic activity of muscimol and the antiepileptic activity of bicuculline were abolished. It might be suggested that subacute IVA administration reduces absence seizures by changing the HCN channel expressions in WAG/Rij rats, and this affects the T-type calcium channels and GABAA receptors.

Encefalopatías epilépticas y del desarrollo. ¿Que hay de nuevo? / Developmental and epileptic encephalopathy. What is new?

Resumen Este artículo no tiene como objetivo el presentar una descripción detallada de cada una de las encefalopatías epilépticas y del desarrollo, sino más bien discutir cam bios recientes en la terminología y criterios diagnósticos de ciertas encefalopatías, en base a una revisión actua lizada de los últimos 10 años. Se analizan cambios importantes en definiciones de síndromes específicos y nuevos tratamientos que han demostrado eficacia en el manejo de crisis convulsivas en estos pacientes. En conclusión: Las nuevas terapias de modulación genética, contribuirán no solo a reducir la carga de crisis epilépticas, sino también a mejorar el pronóstico cognitivo, y por lo tanto la calidad de vida.

Abstract It is not the intend of this article to present a de tailed description of each developmental and epileptic encephalopathy, but to discuss recent changes in the terminology and diagnostic criteria of specific disorders, based on an updated review of the last 10 years. Important changes in the definitions of specific syn dromes and new treatments that have shown efficacy in the management of seizures in these patients are analyzed. In conclusion: New gene modulation therapy will likely improve not only seizure frequency, but also cog nitive outcome and therefore quality of life.

[Developmental and epileptic encephalopathy. What is new?] / Encefalopatías epilépticas y del desarrollo. ¿Qué hay de nuevo?

It is not the intend of this article to present a detailed description of each developmental and epileptic encephalopathy, but to discuss recent changes in the terminology and diagnostic criteria of specific disorders, based on an updated review of the last 10 years. Important changes in the definitions of specific syndromes and new treatments that have shown efficacy in the management of seizures in these patients are analyzed. In conclusion: New gene modulation therapy will likely improve not only seizure frequency, but also cognitive outcome and therefore quality of life.

Este artículo no tiene como objetivo el presentar una descripción detallada de cada una de las encefalopatías epilépticas y del desarrollo, sino más bien discutir cambios recientes en la terminología y criterios diagnósticos de ciertas encefalopatías, en base a una revisión actualizada de los últimos 10 años. Se analizan cambios importantes en definiciones de síndromes específicos y nuevos tratamientos que han demostrado eficacia en el manejo de crisis convulsivas en estos pacientes. En conclusión: Las nuevas terapias de modulación genética, contribuirán no solo a reducir la carga de crisis epilépticas, sino también a mejorar el pronóstico cognitivo, y por lo tanto la calidad de vida.

Spike and wave discharges detection in genetic absence epilepsy rat from Strasbourg and patients with genetic generalized epilepsy.

OBJECTIVE: Generalised spike and wave discharges (SWDs) are pathognomonic EEG signatures for diagnosing absence seizures in patients with Genetic Generalized Epilepsy (GGE). The Genetic Absence Epilepsy Rats from Strasbourg (GAERS) is one of the best-validated animal models of GGE with absence seizures. METHODS: We developed an SWDs detector for both GAERS rodents and GGE patients with absence seizures using a neural network method. We included 192 24-hour EEG sessions recorded from 18 GAERS rats, and 24-hour scalp-EEG data collected from 11 GGE patients. RESULTS: The SWDs detection performance on GAERS showed a sensitivity of 98.01% and a false positive (FP) rate of 0.96/hour. The performance on GGE patients showed 100% sensitivity in five patients, while the remaining patients obtained over 98.9% sensitivity. Moderate FP rates were seen in our patients with 2.21/hour average FP. The detector trained within our patient cohort was validated in an independent dataset, TUH EEG Seizure Corpus (TUSZ), that showed 100% sensitivity in 11 of 12 patients and 0.56/hour averaged FP. CONCLUSIONS: We developed a robust SWDs detector that showed high sensitivity and specificity for both GAERS rats and GGE patients. SIGNIFICANCE: This detector can assist researchers and neurologists with the time-efficient and accurate quantification of SWDs.

Epilepsy in a mouse model of GNB1 encephalopathy arises from altered potassium (GIRK) channel signaling and is alleviated by a GIRK inhibitor.

De novo mutations in GNB1, encoding the Gß1 subunit of G proteins, cause a neurodevelopmental disorder with global developmental delay and epilepsy, GNB1 encephalopathy. Here, we show that mice carrying a pathogenic mutation, K78R, recapitulate aspects of the disorder, including developmental delay and generalized seizures. Cultured mutant cortical neurons also display aberrant bursting activity on multi-electrode arrays. Strikingly, the antiepileptic drug ethosuximide (ETX) restores normal neuronal network behavior in vitro and suppresses spike-and-wave discharges (SWD) in vivo. ETX is a known blocker of T-type voltage-gated Ca2+ channels and G protein-coupled potassium (GIRK) channels. Accordingly, we present evidence that K78R results in a gain-of-function (GoF) effect by increasing the activation of GIRK channels in cultured neurons and a heterologous model (Xenopus oocytes)-an effect we show can be potently inhibited by ETX. This work implicates a GoF mechanism for GIRK channels in epilepsy, identifies a new mechanism of action for ETX in preventing seizures, and establishes this mouse model as a pre-clinical tool for translational research with predicative value for GNB1 encephalopathy.

Alpha2 Adrenergic Modulation of Spike-Wave Epilepsy: Experimental Study of Pro-Epileptic and Sedative Effects of Dexmedetomidine.

In the present report, we evaluated adrenergic mechanisms of generalized spike-wave epileptic discharges (SWDs), which are the encephalographic hallmarks of idiopathic generalized epilepsies. SWDs link to a hyper-synchronization in the thalamocortical neuronal activity. We unclosed some alpha2-adrenergic mechanisms of sedation and provocation of SWDs in rats with spontaneous spike-wave epilepsy (WAG/Rij and Wistar) and in control non-epileptic rats (NEW) of both sexes. Dexmedetomidine (Dex) was a highly selective alpha-2 agonist (0.003-0.049 mg/kg, i.p.). Injections of Dex did not elicit de novo SWDs in non-epileptic rats. Dex can be used to disclose the latent form of spike-wave epilepsy. Subjects with long-lasting SWDs at baseline were at high risk of absence status after activation of alpha2- adrenergic receptors. We create the concept of alpha1- and alpha2-ARs regulation of SWDs via modulation of thalamocortical network activity. Dex induced the specific abnormal state favorable for SWDs-"alpha2 wakefulness". Dex is regularly used in clinical practice. EEG examination in patients using low doses of Dex might help to diagnose the latent forms of absence epilepsy (or pathology of cortico-thalamo-cortical circuitry).

Alpha2-Adrenergic Receptors as a Pharmacological Target for Spike-Wave Epilepsy.

Spike-wave discharges are the hallmark of idiopathic generalized epilepsy. They are caused by a disorder in the thalamocortical network. Commercially available anti-epileptic drugs have pronounced side effects (i.e., sedation and gastroenterological concerns), which might result from a low selectivity to molecular targets. We suggest a specific subtype of adrenergic receptors (ARs) as a promising anti-epileptic molecular target. In rats with a predisposition to absence epilepsy, alpha2 ARs agonists provoke sedation and enhance spike-wave activity during transitions from awake/sedation. A number of studies together with our own observations bring evidence that the sedative and proepileptic effects require different alpha2 ARs subtypes activation. Here we introduce a new concept on target pharmacotherapy of absence epilepsy via alpha2B ARs which are presented almost exclusively in the thalamus. We discuss HCN and calcium channels as the most relevant cellular targets of alpha2 ARs involved in spike-wave activity generation.

Investigating the mechanism of action of ginkgolides and bilobalide on absence seizures in male WAG/Rij rats.

The effects of a single and multiple doses of ginkgolide A, B, C, and bilobalide, active components of Ginkgo biloba extract (EGb 761), on absence seizures were investigated in male WAG/Rij rats, a genetic animal model of absence epilepsy. Furthermore, the interactions of ginkgolide A together with NMDA receptor antagonist MK-801, AMPA/kainate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), or L-type calcium channel blocker nicardipine were studied to figure out how ginkgolide A affects spike-wave discharges (SWDs) in the brain. The experiments were done using 6-8-month-old male WAG/Rij rats with infusion cannula and EEG electrode implanted. Ginkgolide A, B, C, and bilobalide were administered intraperitoneally for 7 days at a dose of 6 mg/kg. In interaction groups, 6 µg ginkgolide A was injected intracerebroventricularly in combination with MK-801 (10 µg), CNQX (1 µg), and nicardipine (50 µg) for 7 days. EEG was recorded from animals at the baseline, first dose, and seventh dose periods for 4 h. Ginkgolide A (p = .028), C (p = .046), and bilobalide (p = .043) significantly increased the frequency of SWDs in WAG/Rij rats. Ginkgolide A injected into the lateral ventricle with MK-801 (p = .046), CNQX (p = .043), and nicardipine (p = .046) significantly increased the number of SWDs after seventh dose. Finally, the EGb 761-related increase in absence epilepsy was determined to be caused by ginkgolide A, C, and bilobalide. All three receptor antagonists/channel blockers do not inhibit the pro-absence effect of ginkgolide A. The findings revealed that ginkgolide A's pro-absence effect is mediated by brain circuits other than ionotropic glutamate receptors or L-type calcium channels.

Sleep slow-wave oscillations trigger seizures in a genetic epilepsy model of Dravet syndrome.

Sleep is the preferential period when epileptic spike-wave discharges appear in human epileptic patients, including genetic epileptic seizures such as Dravet syndrome with multiple mutations including SCN1A mutation and GABAA receptor γ2 subunit Gabrg2Q390X mutation in patients, which presents more severe epileptic symptoms in female patients than male patients. However, the seizure onset mechanism during sleep still remains unknown. Our previous work has shown that the sleep-like state-dependent homeostatic synaptic potentiation can trigger epileptic spike-wave discharges in one transgenic heterozygous Gabrg2+/Q390X knock-in mouse model.1 Here, using this heterozygous knock-in mouse model, we hypothesized that slow-wave oscillations themselves in vivo could trigger epileptic seizures. We found that epileptic spike-wave discharges in heterozygous Gabrg2+/Q390X knock-in mice exhibited preferential incidence during non-rapid eye movement sleep period, accompanied by motor immobility/facial myoclonus/vibrissal twitching and more frequent spike-wave discharge incidence appeared in female heterozygous knock-in mice than male heterozygous knock-in mice. Optogenetically induced slow-wave oscillations in vivo significantly increased epileptic spike-wave discharge incidence in heterozygous Gabrg2+/Q390X knock-in mice with longer duration of non-rapid eye movement sleep or quiet-wakeful states. Furthermore, suppression of slow-wave oscillation-related homeostatic synaptic potentiation by 4-(diethylamino)-benzaldehyde injection (i.p.) greatly attenuated spike-wave discharge incidence in heterozygous knock-in mice, suggesting that slow-wave oscillations in vivo did trigger seizure activity in heterozygous knock-in mice. Meanwhile, sleep spindle generation in wild-type littermates and heterozygous Gabrg2+/Q390X knock-in mice involved the slow-wave oscillation-related homeostatic synaptic potentiation that also contributed to epileptic spike-wave discharge generation in heterozygous Gabrg2+/Q390X knock-in mice. In addition, EEG spectral power of delta frequency (0.1-4 Hz) during non-rapid eye movement sleep was significantly larger in female heterozygous Gabrg2+/Q390X knock-in mice than that in male heterozygous Gabrg2+/Q390X knock-in mice, which likely contributes to the gender difference in seizure incidence during non-rapid eye movement sleep/quiet-wake states of human patients. Overall, all these results indicate that slow-wave oscillations in vivo trigger the seizure onset in heterozygous Gabrg2+/Q390X knock-in mice, preferentially during non-rapid eye movement sleep period and likely generate the sex difference in seizure incidence between male and female heterozygous Gabrg2+/Q390X knock-in mice.

GABAergic synaptic transmission and cortical oscillation patterns in the primary somatosensory area of a valproic acid rat model of autism spectrum disorder.

Autism spectrum disorder (ASD) is characterized by impaired social communication and interaction associated with repetitive or stereotyped behaviour. Prenatal valproic acid (VPA) exposure in rodents is a commonly used model of ASD. Resveratrol (RSV) has been shown to prevent interneuronal and behavioural impairments in the VPA model. We investigated the effects of prenatal VPA exposure and RSV on the GABAergic synaptic transmission, brain oscillations and on the genic expression of interneuron-associated transcription factor LHX6 in the primary somatosensory area (PSSA). Prenatal VPA exposure decreased the sIPSC and mIPSC frequencies and the sIPSC decay kinetics onto layers 4/5 pyramidal cells of PSSA. About 40% of VPA animals exhibited absence-like spike-wave discharge (SWD) events associated with behaviour arrest and increased power spectrum density of delta, beta and gamma cortical oscillations. VPA animals had reduced LHX6 expression in PSSA, but VPA animals treated with RSV had no changes on synaptic inhibition or LHX6 expression in the PSSA. SWD events associated with behaviour arrest and the abnormal increment of cortical oscillations were also absent in VPA animals treated with RSV. These findings provide new venues to investigate the role of both RSV and VPA in the pathophysiology of ASD and highlight the VPA animal model as an interesting tool to investigate pathways related to the aetiology and possible future therapies to this neuropsychiatric disorder.

Spike-wave discharges in Sprague-Dawley rats reflect precise intra- and interhemispheric synchronization of somatosensory cortex.

Spike-wave discharges (SWDs) are among the most prominent electrical signals recordable from the rat cerebrum. Increased by inbreeding, SWDs have served as an animal model of human genetic absence seizures. Yet, SWDs are ubiquitous in inbred and outbred rats, suggesting they reflect normal brain function. We hypothesized that SWDs represent oscillatory neural ensemble activity underlying sensory encoding. To test this hypothesis, we simultaneously mapped SWDs from wide areas (8 × 8 mm) of both hemispheres in anesthetized rats, using 256-electrode epicortical arrays that covered primary and secondary somatosensory, auditory and visual cortex bilaterally. We also recorded the laminar pattern of SWDs with linear microelectrode arrays. We compared the spatial and temporal organization of SWDs to somatosensory-evoked potentials (SEPs), as well as auditory- and visual-evoked potentials (AEPs and VEPs) to examine similarities and/or differences between sensory-evoked and spontaneous oscillations in the same animals. We discovered that SWDs are confined to the facial representation of primary and secondary somatosensory cortex (SI and SII, respectively), areas that are preferentially engaged during environmental exploration in the rat. Furthermore, these oscillations exhibit highly synchronized bilateral traveling waves in SI and SII, simultaneously forming closely matched spread patterns in both hemispheres. We propose that SWDs could reflect a previously unappreciated capacity for rat somatosensory cortex to perform precise spatial and temporal analysis of rapidly changing sensory input at the level of large neural ensembles synchronized both within and between the cerebral hemispheres.NEW & NOTEWORTHY We simultaneously mapped electrocortical SWDs from both cerebral hemispheres of Sprague-Dawley rats and discovered that they reflect systematic activation of the facial representation of somatosensory cortex. SWDs form mirror spatiotemporal patterns in both hemispheres that are precisely aligned in both space and time. Our data suggest that SWDs may reflect a substrate by which large neural ensembles perform precise spatiotemporal processing of rapidly changing somatosensory input.

Absence-like Seizures, Cortical Oscillations Abnormalities and Decreased Anxiety-like Behavior in Wistar Audiogenic Rats with Cortical Microgyria.

Wistar Audiogenic Rats (WAR) is an inbred rodent strain susceptible to acute auditory stimulation-induced seizures. However, spontaneous epileptic seizures (SES) and their associated electroencephalogram (EEG) abnormalities have not been reported in WAR kindled animals. The same is true for naïve WARs (without sound-induced seizures). An approach to increment epileptogenesis and SES is to use a second insult to be added to the genetic background. Here, we used adult naïve WARs with microgyria induced by neonatal cortical freeze-lesion (FL) to evaluate the occurrence of SES and the modification in cortical oscillation patterns and behavior. The neonatal cortical FL was performed in Wistar and naïve WARs (Wis-FL and WAR-FL). Sham animals were used as controls (Wistar-S and WAR-S). Video-EEG recordings and behavioral tasks were performed during adulthood. Surprisingly, spike-waive discharges (SWD) events associated with behavior arrest were detected in WAR-S rats. Those events increased in duration and number in WAR-FL animals. The EEG quantitative analysis showed decreased power of cortical delta, theta and beta oscillations in WAR-S, decreased power of cortical fast gamma (FG) oscillations in WARs, independent of microgyria, and decreased interhemispheric synchrony for delta and FG with stronger coupling in delta and theta-FG oscillations in FL animals. The WARs, regardless of microgyria, had reduced locomotor activity, but only WAR-FL animals had reduced anxiety-like behavior. Microgyria in naïve WARs intensified SWD events associated with behavior arrest that could reflect absence-like seizures and abnormal cortical oscillations, and reduced anxiety-like behavior indicating that WAR-FL could be a reliable model to study epileptogenesis.

Blood-brain barrier targeted delivery of lacosamide-conjugated gold nanoparticles: Improving outcomes in absence seizures.

OBJECTIVE: Most currently available antiepileptics are not fully effective in the prevention of seizures in absence epilepsy owing to the presence of blood-brain barrier (BBB). We aimed to test whether binding an antiepileptic drug, lacosamide (LCM), to glucose-coated gold nanoparticles (GNPs) enables efficient brain drug delivery to suppress the epileptic activity in WAG/Rij rats with absence epilepsy. METHODS: In these animals, intracranial-EEG recording, behavioral test, in vivo imaging of LCM and LCM-GNP conjugate distribution in the brain, inductively coupled plasma mass spectrometry analysis, immunofluorescence staining of glucose transporter (Glut)- 1, glial fibrillary acidic protein (GFAP), and p-glycoprotein (P-gp) and electron microscopy were performed. RESULTS: Lacosamide-GNP conjugates decreased the amplitude and frequency of spike-wave-like discharges (SWDs) and alleviated the anxiety-like behavior as assessed by EEG and elevated plus-maze test, respectively (p < 0.01). The in vivo imaging system results showed higher levels of fluorescein dye tagged to LCM-GNP in the brain during the 5-day injection period (p < 0.01). Immunofluorescence staining displayed decreased P-gp, Glut-1, and GFAP expression by LCM-GNP conjugate treatment predominantly in the cerebral cortex suggesting a potential functionality of this brain region in the modulation of neuronal activity in our experimental setting (p < 0.01). SIGNIFICANCE: We suggest that the conjugation of LCM to GNPs may provide a novel approach for efficient brain drug delivery in light of the effectiveness of our strategy not only in suppressing the seizure activity but also in decreasing the need to use high dosages of the antiepileptics to reduce the frequently encountered side effects in drug-resistant epilepsy.

Characteristics of Epileptiform Spike-wave Discharges and Chronic Histopathology in Controlled Cortical Impact Model of Sprague-Dawley Rats.

Post-traumatic epilepsy (PTE) is a serious complication that can occur following traumatic brain injury (TBI). Sustained secondary changes after TBI promote the process of PTE. Here, we aim to evaluate changes in behavior, electrocorticogram, and histomorphology in rats following chronic TBI models. We observed intensive 7-8 Hz spike-wave-discharges (SWDs) at frontal recording sites and quantified them in SD rats with different degrees of TBI and compared them with age-matched sham rats to evaluate the association between SWDs and injury severity. Notably, although SWDs were even presented in the sham group, the number and duration of events were much lower than those in the TBI groups. SWDs have numerous similarities to absence seizures, such as abrupt onset, termination, and lack of postictal suppression, which may be the nonconvulsive characteristics of PTE. Retigabine, a novel antiepileptic drug, is ineffective in reducing SWDs. In addition, we examined chronic histopathological changes in TBI rats. Rats subjected to moderate and severe TBI exhibited significantly impaired neurological function, which was accompanied by marked cortical injury, hippocampus deformation, reactive gliosis, and mossy fiber sprouting. Long-term progressive structural changes in the brain are one of the characteristics of epileptogenesis after TBI. Our study provided the potential value of epileptiform SWDs in reflecting the nonconvulsive characteristic of PTE and highlighted the vital role of chronic pathological changes, such as reactive gliosis, in promoting the epileptogenesis following TBI.

Whisker trimming during infanthood modifies the development of spike-wave discharges and behavioral sequences in IntelliCage impulsivity paradigm in adult WAG/Rij rats.

Whisker system in rats undergoes rapid development during the first postnatal weeks. Neonatal whisker trimming increases excitability in the somatosensory cortex and affects exploratory behavior at adult ages. WAG/Rij rats are genetically predisposed to develop absence seizures in adulthood, and whisker trimming during three postnatal weeks aggravates epileptic activity in these rats. It is assumed that behavioral performance in adult WAG/Rij rats is influenced (1) by absence epilepsy and (2) by whisker trimming during the short period around the onset of active whisker movements, PN9-16. We examined the effect of whisker trimming in WAG/Rij rats during PN9-16 on spike-wave discharges (SWD, EEG hallmark of absence epilepsy). We found that 77% of WAG/Rij rats showed pronounced SWD (epileptic phenotype), and the rest did not (non-epileptic phenotype). At the age of 5 m, epileptic trimmed rats showed more SWD than epileptic control rats. Age-related increase of SWD was found only in the control group, suggesting that whisker trimming during PN9-16 led to an earlier maturation of SWD. Goal-directed behavior was examined in all rats at the age of 4-4.5 m using IntelliCage impulsivity paradigm. In order to optimize the analysis of behavioral data, we combined several Python packages into a single processing pipeline. Early life whisker trimming altered behavioral sequences and strategy of exploration in adulthood, suggesting reduced whisker sensitivity in the trimmed rats. Epileptic WAG/Rij rats at 4-4.5 months showed only a slight learning impairment during later stages of IntelliCage impulsivity paradigm, which may be associated with the early stage of development of SWD.