While it might seem that the neurons become “exhausted” after the near-constant firing involved in a seizure, the ability of the neuron to carry an action potential following a seizure is not decreased. Neurons of the brain fire normally when stimulated, even after long periods of<unk> s epilepticus. Furthermore, the sodium gradient that allows the axon potential to be propagated is so large in comparison to the tiny number of ions that are let through each channel with each signal that it is highly unlikely that this gradient could be ‘used up’ by high activity during a seizure. Instead, there are four major hypotheses regarding what cellular and molecular mechanisms could cause the observed<unk>  systems: neurotransmitter depletion, changes in receptor concentration, active inhibition, and cerebral bloodflow changes. It is likely that these may in fact interact or more than one theory may contribute to<unk>  symptoms. Neurotransmitters Neurotransmitters must be present in the axon terminal and then exocytosed into the synaptic cleft in order to propagate the signal to the next neuron. While neurotransmitters are not typically a limiting factor in neuronal signaling rates, it is possible that with extensive firing during seizures neurotransmitters could be used up faster than new ones could be synthesized in the cell and transported down the axon. There is currently no direct evidence for neurotransmitter depletion following seizures. Receptor concentration In studies that stimulate seizures by subjecting rats to electroshock, seizures are followed by unconsciousness and slow waves on an electroencephalogram (EEG), signs of<unk>  catalepsy. Administering the opiate antagonist naloxone immediately reverses this<unk> , providing evidence that increased responsiveness or concentration of the opiate receptors may be occurring during seizures and may be partially responsible for the weariness humans experience following a seizure. When humans were given naloxone in-between seizures, researchers observed increased activity on their EEGs, suggesting that opioid receptors may also be upregulated during human seizures. To provide direct evidence for this, Hammers et al. did positron emission tomography (PET) scanning of radiolabelled ligands before, during, and after spontaneous seizures in humans. They found that opioid receptors were upregulated in the regions near the focus of the seizure during the ictal phase, gradually returning to baseline availability during the<unk>  phase. Hammers notes that cerebral bloodflow after a seizure can not account for the increase in PET activity observed. Regional bloodflow can increase by as much as 70-80% after seizures but normalizes after 30 minutes. The shortest<unk>  interval in their study was 90 minutes and none of the patients had seizures during the scanning. It has been predicted that a decrease in opioid activity following a seizure could cause withdrawal symptoms, contributing to<unk>  depression. The opioid receptor connection with mitigating seizures has been disputed, and opioids have been found to have different functions in different regions of the brain, having both proconvulsive and anticonvulsive effects. Active inhibition It is possible that seizures cease spontaneously, but it is much more probable that some changes in the brain create inhibitory signals that serve to tamp down the overactive neurons and effectively end the seizure. Opioid peptides have been shown to be involved in the<unk>  and are at times anticonvulsive, and adenosine has also been implicated as a molecule potentially involved in terminating seizures. Evidence for the theory of active inhibition lies in the<unk>  refractory period, a period of weeks or even months following a series of seizures in which seizures cannot be induced (using animal models and a technique called kindling, in which seizures are induced with repeated electrical stimulation). Leftover inhibitory signals are the most likely explanation for why there would be a period in which the threshold for provoking a second seizure is high, and lowered excitability may also explain some of the<unk>  symptoms. Inhibitory signals could be through GABA receptors (both fast and slow IPSPs), calcium-activated potassium receptors (which give rise to afterhyperpolarization), hyperpolarizing pumps, or other changes in ion channels or signal receptors. These changes would likely have a residual effect for a short time after successfully ending the high activity of neurons, perhaps actively inhibiting normal firing during the time after the seizure has ended. However, most of these changes would be expected to last for seconds (in the case of IPSP and AHP) or maybe minutes (in the case of hyperpolarized pumps), but cannot account for the fog that lasts for hours after a seizure. While not an example of active inhibition, acidosis of the blood could aid in ending the seizure and also depress neuron firing following its conclusion. As muscles contract during tonic-clonic seizures they outpace oxygen supplies and go into anaerobic metabolism. With continued contractions under anaerobic conditions, the cells undergo lactic acidosis, or the production of lactic acid as a metabolic byproduct. This acidifies the blood (higher H+ concentration, lower pH), which has many impacts on the brain. For one, “hydrogen ions compete with other ions at the ion channel associated with N-methyl-d-aspartate (NMDA). This competition may partially attenuate NMDA receptor and channel mediated hyperexcitability after seizures.” It is unlikely that these effects would be long-lasting, but by decreasing the effectiveness of NMDA-type glutamate receptors, high H+ concentrations could increase the threshold needed to excite the cell, inhibiting the seizure and potentially slowing neuronal signaling after the event. Cerebral bloodflow Cerebral autoregulation typically ensures that the correct amount of blood reaches the various regions of the brain to match the activity of the cells in that region. In other words, perfusion typically matches metabolism in all organs; especially in the brain, which gets the highest priority. However, following a seizure it has been shown that sometimes cerebral blood flow is not proportionate to metabolism. While cerebral blood flow didn’t change in the mouse hippocampus (the foci of seizures in this model) during or after seizures, increases in relative glucose uptake were observed in the region during the ictal and early<unk>  periods. Animal models are difficult for this type of study because each type of seizure model produces a unique pattern of perfusion and metabolism. Thus, in different models of epilepsy, researchers have had differing results as to whether or not metabolism and perfusion become uncoupled. Hosokawa’s model used EL mice, in which seizures begin in the hippocampus and present similarly to the behaviors observed in human epileptic patients. If humans show similar uncoupling of perfusion and metabolism, this would result in hypoperfusion in the affected area, a possible explanation for the confusion and ‘fog’ patients experience following a seizure. It is possible that these changes in blood flow could be a result of poor autoregulation following a seizure, or it could, in fact, be yet another factor involved in stopping seizures.
Postictal state
Window period
Nightmare
Postdrome
Twilight sleep
Nightscout
Free-running sleep
Sleep onset