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Glut-1 transporter deficiency syndrome (GLUT1-DS) is a rare disorder caused by the mutation in SLC2A1 gene, which results in impaired glucose transport into the brain. It has a broad spectrum of phenotypic presentation ranging from cognitive decline, microcephaly, and refractory seizures to complex movement disorder. Recognition of this disorder is necessary as it is refractory to antiepileptic drugs (AEDs) and responds significantly to ketogenic diet. We report a case of 7-year-old girl who presented with paroxysmal eye movements in infancy with early-onset absence epilepsy (EOAE), which worsened in early morning and on fasting and was found to be refractory to four AEDs. She had mild developmental delay and subtle ataxia. Cerebrospinal fluid showed hypoglycorrhachia, and molecular analysis identified deletion in exon 4 of SLC2A1 gene (p.leu169del), thus confirming GLUT1-DS. She had a near-complete seizure control on ketogenic diet. Thus, GLUT1-DS should be suspected in all cases of refractory generalized seizures specially EOAE, especially if it worsens on fasting, is associated with development delay, positive family history, or paroxysmal movement disorder.

In this paper, we establish a cortical-thalamic-basal ganglia mean-field computational network that includes a newly determined direct glutamatergic thalamic-subthalamic projection. In this model, we consider the role of the thalamic-subthalamic projection and electromagnetic induction in regulating the spike and wave discharges (SWDs) during absence epilepsy, through numerical simulation. We observe that the thalamic-subthalamic projection can significantly inhibit SWDs, through two direct pallidothalamic inhibitory pathways. We find that the specific relay nuclei might be a potential target for deep brain stimulation in controlling absence seizures. Interestingly, electromagnetic induction from a memristor can assist the thalamic-subthalamic projection and external current stimulation in controlling SWDs. More importantly, electromagnetic induction can significantly reduce the side effects caused by external current stimulation. Since electromagnetic radiation is a non-invasive technique, our computational results theoretically confirm that it may be a safe and feasible means for clinical intervention in absence epilepsy.

A growing number of gain-of-function (GOF) BK channelopathies have been identified in patients with epilepsy and movement disorders. Nevertheless, the underlying pathophysiology and corresponding therapeutics remain obscure. Here, we utilized a knockin mouse model carrying human BK-D434G channelopathy to investigate the neuronal mechanism of BK GOF in the pathogenesis of epilepsy and dyskinesia. The BK-D434G mice manifest the clinical features of absence epilepsy and exhibit severe motor deficits and dyskinesia-like behaviors. The cortical pyramidal neurons and cerebellar Purkinje cells from the BK-D434G mice show hyperexcitability, which likely contributes to the pathogenesis of absence seizures and paroxysmal dyskinesia. A BK channel blocker, paxilline, potently suppresses BK-D434G–induced hyperexcitability and effectively mitigates absence seizures and locomotor deficits in mice. Our study thus uncovered a neuronal mechanism of BK GOF in absence epilepsy and dyskinesia. Our findings also suggest that BK inhibition is a promising therapeutic strategy for mitigating BK GOF-induced neurological disorders.

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.

In the present study, the effects of the acetylcholinesterase (AChE) enzyme inhibitor rivastigmine (RIVA) on spike-wave discharges (SWDs), memory impairment, anxiety-like behavior, and the transient receptor potential vanilloid 1 (TRPV1) gene expression were investigated in genetic absence epileptic Wistar Albino Glaxo/Rijswijk (WAG/Rij) rats. After tripolar electrodes were implanted on the WAG/Rij rats’ skulls, single doses of 0.125, 0.25, 0.5, 1, and 2 mg/kg RIVA were intraperitoneally (i.p.) administered, and electrocorticogram (ECoG) recordings of SWDs were recorded for three hours before and after injections. Additionally, once significant doses were determined in acute studies, WAG/Rij rats were administered low-dose (0.5 mg/kg) and high-dose (2 mg/kg) of RIVA for 21 consecutive days and SWDs were recorded. Learning-memory abilities (Y-maze test), anxiety-like behavior (elevated plus maze test), and TRPV1 gene expression were determined and compared in 8-month-old WAG/Rij and age-matched Wistar rats. Acute RIVA administration dose-dependently reduced the total number of SWDs and was even entirely inhibited at 1 and 2 mg/kg RIVA doses. On the other hand, long-term high-dose RIVA administration increased the total number of SWDs. Long-term high-dose RIVA treatment reduced learning-memory and anxiety-like behavior in WAG/Rij rats, while only anxiety-like behavior decreased in Wistar rats. TRPV1 gene expression increased in WAG/Rij rats and decreased in Wistar rats with long-term RIVA administration. These data indicate that the sudden increase of acetylcholine (ACh) causes a significant decrease in absence seizures. In contrast, prolonged maintenance of ACh elevation causes an increase in absence seizures, probably by altering the expression of channels such as TRPV1.

Aim The Genetic Absence Epilepsy Rats from Strasbourg (GAERS) are an inbred polygenic model of childhood absence epilepsy (CAE), which, as their non‐epileptic control (NEC) rats, are derived from Wistar rats. While the validity of GAERS in reproducing absence seizures is well established, its use as a model for CAE psychiatric comorbidities has been subject to conflicting findings. Differences in colonies, experimental procedures, and the use of diverse controls from different breeders may account for these disparities. Therefore, in this study, we compared GAERS, NEC, and Wistar bred in the same animal facility with commercially available Wistar (Cm Wistar) as a third control. Methods We performed hole board (HB) and elevated plus maze (EPM) tests that were analyzed with standard quantitative and T‐pattern analysis in male, age‐matched Cm Wistar and GAERS, NEC, and Wistar, bred under the same conditions, to rule out the influence of different housing factors and provide extra information on the structure of anxiety‐like behavior of GAERS rats. Results Quantitative analysis showed that GAERS and NEC had similar low anxiety‐like behavior when compared to Cm Wistar but not to Wistar rats, although a higher hole‐focused exploration was revealed in NEC. T‐pattern analysis showed that GAERS, NEC, and Wistar had a similar anxiety status, whereas GAERS and NEC exhibited major differences with Cm Wistar but not Wistar rats. EPM results indicated that GAERS and NEC also have similar low anxiety compared to Cm Wistar and/or Wistar rats. Nevertheless, the analysis of the T‐pattern containing open‐arm entry showed GAERS and Wistar to be less anxious than NEC and Cm Wistar rats. Conclusion To summarize, comorbid anxiety may not be present in male GAERS rats. This study also highlighted the importance of including a control Wistar group bred under the same conditions when evaluating their behavior, as using Wistar rats from commercial breeders can lead to misleading results. GAERS have been suggested as a model for studying childhood absence epilepsy (CAE)‐associated psychiatric comorbidities. GAERS, non‐epileptic control (NEC), and Wistar rats were compared, along with commercially available Wistar rats (Cm Wistar) as a control. Anxiety‐like behavior was evaluated using hole board (HB) and elevated plus maze (EPM) tests. T‐pattern analysis revealed similar anxiety status in GAERS, NEC, and Wistar rats, differing from Cm Wistars. EPM results showed lower anxiety levels in GAERS and Wistar rats compared to NEC rats and Cm Wistars. The study concluded that male GAERS rats from Malta colony lacked comorbid anxiety. It also highlighted the importance of using Wistar rats from the same breeding conditions to avoid misleading results.

A typical absence seizure is a generalized epileptic event characterized by a sudden, brief alteration of consciousness that serves as a hallmark for various generalized epilepsy syndromes. Distinguishing between similar interictal and ictal electroencephalographic (EEG) epileptiform patterns poses a challenge. However, quantitative EEG, particularly spectral analysis focused on EEG rhythms, shows potential for differentiation. This study was designed to investigate discernible differences in EEG spectral dynamics and entropy patterns during the pre-ictal and post-ictal periods compared to the interictal state. We analyzed 20 EEG ictal patterns from 11 patients with confirmed typical absence seizures, and assessed recordings made during the pre-ictal, post-ictal, and interictal intervals. Power spectral density (PSD) was used for the quantitative analysis that focused on the delta, theta, alpha , and beta bands. In addition, we measured EEG signal regularity using approximate (ApEn) and multi-scale sample entropy (MSE). Findings demonstrate a significant increase in delta and theta power in the pre-ictal and post-ictal intervals compared to the interictal interval, especially in the posterior brain region. We also observed a notable decrease in entropy in the pre-ictal and post-ictal intervals, with a more pronounced effect in anterior brain regions. These results provide valuable information that can potentially aid in differentiating epileptiform patterns in typical absence seizures. The implications of our findings are promising for precision medicine approaches to epilepsy diagnoses and patient management. In conclusion, our quantitative analysis of EEG data suggests that PSD and entropy measures hold promise as potential biomarkers for distinguishing ictal from interictal epileptiform patterns in patients with confirmed or suspected typical absence seizures.

Background Electromagnetic induction has recently been considered as an important factor affecting the activity of neurons. However, as an important form of intervention in epilepsy treatment, few people have linked the two, especially the related dynamic mechanisms have not been explained clearly. Methods Considering that electromagnetic induction has some brain area dependence, we proposed a modified two-compartment cortical thalamus model and set eight different key bifurcation parameters to study the transition mechanisms of epilepsy. We compared and analyzed the application and getting rid of memristors of single-compartment and coupled models. In particular, we plotted bifurcation diagrams to analyze the dynamic mechanisms behind abundant discharge activities, which mainly involved Hopf bifurcations (HB), fold of cycle bifurcations (LPC) and torus bifurcations (TR). Results The results show that the coupled model can trigger more discharge states due to the driving effect between compartments. Moreover, the most remarkable finding of this study is that the memristor shows two sides. On the one hand, it may reduce tonic discharges. On the other hand, it may cause new pathological states. Conclusions The work explains the control effect of memristors on different brain regions and lays a theoretical foundation for future targeted therapy. Finally, it is hoped that our findings will provide new insights into the role of electromagnetic induction in absence seizures.

In patients suffering absence epilepsy, recurring seizures can significantly decrease their quality of life and lead to yet untreatable comorbidities. Absence seizures are characterized by spike-and-wave discharges on the electroencephalogram associated with a transient alteration of consciousness. However, it is still unknown how the brain responds to external stimuli during and outside of seizures. This study aimed to investigate responsiveness to visual and somatosensory stimulation in Genetic Absence Epilepsy Rats from Strasbourg (GAERS), a well-established rat model for absence epilepsy. Animals were imaged under non-curarized awake state using a quiet, zero echo time, functional magnetic resonance imaging (fMRI) sequence. Sensory stimulations were applied during interictal and ictal periods. Whole-brain hemodynamic responses were compared between these two states. Additionally, a mean-field simulation model was used to explain the changes of neural responsiveness to visual stimulation between states. During a seizure, whole-brain responses to both sensory stimulations were suppressed and spatially hindered. In the cortex, hemodynamic responses were negatively polarized during seizures, despite the application of a stimulus. The mean-field simulation revealed restricted propagation of activity due to stimulation and agreed well with fMRI findings. Results suggest that sensory processing is hindered or even suppressed by the occurrence of an absence seizure, potentially contributing to decreased responsiveness during this absence epileptic process.

Motivated by the recent experimental findings that thalamic reticular nucleus (TRN) may be a pacemaker of absence seizures, we explore whether changes in the level of TRN activation can induce absence seizures by using a coupled thalamocortical model. We first simulate different firing states by considering the interaction of pathway between cortical excitatory pyramidal neuronal population (PY)–TRN and specific relay nucleus (SRN)–TRN. By simultaneously increasing the coupling strength of each of these pathways, we can reproduce the absence seizures, which indicates that epileptic seizures may be caused by activating the TRN. We further infer that the TRN may be an epileptogenic focus. Following this, different stimulation strategies, including deep brain stimulation, 1:0 coordinated reset stimulation (CRS) and 3:2 CRS, are applied in TRN. By qualitatively analyzing the efficacy of three different stimulation methods, we find that 3:2 CRS is a more effective and safe method to control absence seizures in the first compartment, for which we then further explore the impact of 3:2 CRS in the second compartment. The results show that the additional stimulation in the second compartment also can lead to a considerable decrease in the spike-and-wave discharges (SWD) oscillation region. Therefore, we conclude that TRN-3:2 CRS is an optimal electrical stimulation method for our modeling and simulation studies. Furthermore, we hope that these numerical simulation results can provide some references for the treatment of real epilepsy patients in the future.