A drawing of the human brain showing the thalamus and cortex relative to other structures. The<unk>  pattern seen during an absence seizure is the result of a bilateral synchronous firing of neurons ranging from the neocortex (part of the cerebral cortex) to the thalamus, along the thalamocortical network. The EEG<unk> ” of the<unk>  complex corresponds to the depolarization of the neuronal membrane potential, also called a paroxysmal depolarizing shift (PDS). The initial understanding behind the mechanism of the PDS was that it was caused by a very large EPSP (excitatory postsynaptic potential) in the absence of synaptic inhibition, which relayed the action potentials in the neurons by triggering activation of voltage-gated channels. The voltage-gated sodium channels cause transitory sodium current into the cell, which generates the action potential. The voltage-gated calcium channels also have some effect on the depolarization of the cell, but the effect is minimal compared to the sodium channels. However, the increasing concentration of intracellular calcium leads to greater activation of calcium-activated potassium channels. These calcium-activated potassium channels, along with the voltage-gated potassium channels, contribute to the repolarization and hyperpolarization of the membrane. In an epileptic seizure, there are periods of a sustained depolarization, which cause a train of action potentials followed by a repolarization and hyperpolarization phase. The train of action potentials constitutes the<unk> ” phase, and the repolarization and hyperpolarization constitute the “wave” phase. Although there is evidence for the generation of a large EPSP, many studies have shown that synaptic inhibition remains functional during the generation of these types of paroxysmal depolarizing shifts. Also, it has been shown that a decrease in the inhibitory activity does not affect neocortical kindling. Therefore, the theory that<unk>  activity is caused by a giant EPSP due to the decrease or the absence of IPSPs (inhibitory postsynaptic potentials) is not accepted as a general mechanism for epileptic activity. Many studies have shown that the inhibitory postsynaptic signaling is actually increased during these epileptic attacks. The activation of postsynaptic GABAA receptors leads to an increase in the intracellular chloride concentration, which in non-epileptic situations would lead to an IPSP. However, in seizure-related depolarizing shifts, there is a substantial activation of postsynaptic GABAA receptors, which leads to an even larger concentration of intracellular chloride concentration. This change in ion concentration gradient causes the GABAA inhibitory current to surpass the reversal potential, leading to an efflux of the chloride ions. This leads to a decreased amplitude or even reversed polarity of the IPSPs. Metabotropic glutamate receptors (mGluRs) in the thalamocortical network have also shown to display some role in the generation of<unk>  discharges <unk> Ds) associated with absence epilepsy. The different subtypes of mGlu receptors have a modulatory role on either excitatory or inhibitory synaptic transmission. There are conflicting hypotheses for the function of the many mGlu receptors with regards to epileptic seizures, however the role of the mGlu4 receptor is undisputed in the generation of<unk> Ds, shown in animal models. In one study, knockout mice lacking mGlu4 receptors showed a disruption of glutamate and GABA release in the thalamocortical network and were resistant to absence seizures induced by low doses of pentylenetetrazole. Another study showed that bilateral injection of a mGlu4 receptor antagonist into the nRT (thalamic reticular nucleus) of normal mice protected against pentylenetetrazole induced seizures. Also, WAG/Rij rats show an increased expression of mGlu4 receptors in the nRT when compared to a control group of normal rats. These studies show that an increase in the expression and/or activity of mGlu4 receptors is associated with<unk>  discharges seen in absence seizures. This link between mGlur4 receptors and<unk> Ds has led to the search for a selective mGlu4 receptor antagonist (which will block these receptors) as a potential new drug for the treatment of absence epilepsy. Initiation factors The use of animal models, such as cats, for studying<unk>  discharges, has provided useful data for studying epilepsy in humans. One method of inducing a seizure in a cat is to inject penicillin into the cortical region of the brain. The<unk>  discharges seen in feline generalized penicillin epilepsy (FGPE) are very similar to the<unk>  discharges of a human absence seizure. The use of rats has also been a common method for studying the<unk>  phenomenon. The Genetic Absence Epilepsy Rats from Strasbourg (GAERS) and the inbred Wistar Albino Glaxo rats from Rijswijk (WAG/Rij) are the two main strains of rats that have been used in studies. The rats from these two strains show spontaneously occurring absence seizures that consist of typical<unk>  activity seen on an EEG. Rat genetic models have given data showing that the expression of absence seizures involves both the thalamic and cortical networks. In both models, electrophysiological data showed that<unk> s are initiated in the somatosensory cortex and then spread rapidly to the motor cortex and thalamic nuclei. Using in vivo intracellular recordings, it was found in the GAERS that<unk>  are initiated in layer 5/6 neurons of the somatosensory cortex. These neurons, show a distinctive hyperactivity associated with a membrane depolarization. They are suggested to lead the firing of distant cortical cells during the epileptic discharge. Another possible initiation pattern tested in rats suggested the thalamocortical (TC) loop is involved in the initiation of<unk>  oscillations under certain conditions. In this study, relay and reticular thalamic neurons of epileptic and non-epileptic rats were dual extracellularly recorded and juxtacellularly labeled. Medium oscillations (5–9 Hz) in both types of rats were noted to occur randomly in an unsynchronized pattern in relay and reticular neurons. However, spontaneous<unk>  discharges were observed in epileptic rats when the medium oscillations became synchronized, suggesting a dependence of the two. However, since medium ranged oscillations only developed into<unk>  discharges spontaneously, genetic factors also seem to contribute to the initiation of synchronized oscillations. These genetic factors may contribute to<unk>  oscillations by decreasing the action potential threshold in reticular cells, making them more excitable and potentially easier to initiate synchronized firing. Another study has shown that these medium oscillations have led to<unk>  discharges. The activity of the primary and secondary cortical regions, as well as the adjacent insular cortex were recorded using an EEG and where applied with electrical stimulation. The findings here showed that the onset of<unk>  discharged were followed by 5–9 Hz oscillations in these cortical regions as well. Genetic/developmental factors Elongator Protein Complex 4 (ELP4) has been identified as a key component in the transcription of genes known to regulate the actin cytoskeleton, cell motility and migration of neurons. Research on ELP4 has been linked the gene to a centrotemporal sharp<unk>  phenotype. Hypotheses have been made that a mutation in the non-coding region of the ELP4 gene may interfere with elongo-mediated gene interaction, specifically during the developmental stages of the cortical region. This mutation may be responsible for a predisposition to<unk>  discharges, as well as other neurodevelopmental disorders. Another study revealed that glucose may also be relevant to<unk>  occurrence in mice that contained a knock-in of the human GABA(A) γ2(R43Q) mutation, which has been known to be a genetic factor involved in the causation of absence epilepsy. These absence seizure prone mice were injected with insulin to lower blood glucose levels by 40%. This reduction in blood glucose led to double the occurrence of<unk>  activity. Similar to the insulin effect, overnight fasting, where blood glucose levels were reduced by 35% also showed this double in occurrence. This model concludes that low glucose levels could be a potential trigger for absence seizures, and could be an environmental risk factor for humans.
Spike-and-wave
Cyclic alternating pattern
Delta wave
Oak wilt
Infradian rhythm
Alpha wave
Apex beat
Mu wave