Researchers identify seizure-associated depolarization as cause of post-ictal symptoms

People with temporal lobe epilepsy in particular often wander around aimlessly and unconsciously after a seizure. Researchers at the University Hospital Bonn (UKB), the University of Bonn, and the German Center for Neurodegenerative Diseases (DZNE) have identified a neurobiological mechanism that could be responsible for this so-called post-ictal wandering and potentially other postictal symptoms. According to their hypothesis, epileptic seizures are not directly responsible for post-ictal symptoms, but rather seizure-associated depolarization waves, also known as spreading depolarization (SD). The results of the studies have now been published in the journal Science Translational Medicine.

In everyday clinical practice, symptoms are regularly observed after epileptic seizures, known as "post-ictal symptoms", which, in contrast to the usually short duration of seizures, typically last several minutes to hours. Besides symptoms such as impaired speech and language comprehension, a state of disorientation may occur. This wandering about, known in technical terms as postictal wandering, can sometimes be life-threatening if, for example, the affected unconscious person runs onto the street. "Postictal symptoms are traditionally referred to the preceding epileptic seizure. However, it is unclear whether there is actually a direct neurobiological connection or whether the symptoms are based on another pathology," says corresponding author Prof. Michael Wenzel from the Dept. of Epileptology at the UKB, who is also a member of the Transdisciplinary Research Area (TRA) "Life & Health" at the University of Bonn.

Brain waves paralyze neural network

The Bonn research team initially wanted to better understand the development of epilepsy as a result of an initial acute disease-in this case, viral encephalitis, an inflammation of the brain caused by viruses. To do this, they used modern cellular-resolution fluorescence microscopy in combination with electrophysiology and optogenetics in a mouse model, which allows them to study network dynamics and the communication of different brain cell types in the living brain with high resolution over a period of months. "In doing so, we accidentally discovered a network phenomenon in the hippocampus-a structure relevant to epilepsy located inside the temporal lobe-that could explain postictal symptoms but, surprisingly, does not represent seizures themselves," says first author Bence Mitlasóczki, a doctoral student at the University of Bonn in Prof. Wenzel's research group at the UKB.

The observed phenomenon consists of slow depolarization waves, which are mainly known from neurological disorders such as migraine or acute brain injuries. This so-called spreading depolarization (SD) causes the collapse of the neuronal membrane potential and the failure of the affected network for minutes to hours. The structures in the inner region of the temporal lobe, such as the hippocampus, may be more sensitive to SD during epileptic seizures than the multisensory and motor part of the cerebral cortex, known as the neocortex.

This could also explain why postictal symptoms are most commonly observed in temporal lobe epilepsy."

Bence Mitlasóczki, Doctoral Student, University of Bonn

In addition, SD waves are filtered out in standard clinical EEGs in epileptology because they are so slow. "As a result, SDs have been 'invisible' in clinical EEGs for decades, which is an important reason why the strictly seizure-related concept of postictal symptoms persists, even though this may not be accurate," states Prof. Wenzel.

Seizure-associated SD in depth electrode recordings from people with epilepsy

In addition, the Bonn researchers found evidence that seizure-associated SDs also exist in deep regions of the human brain. To do this, they used a special feature of pre-surgical diagnostics at the UKB for people with difficult-to-treat epilepsy, which tests whether a local seizure focus can be surgically removed. As part of the study, the research team initially examined some participants using the electrodes implanted for diagnosis with additional microwire bundles – which were established by the working group led by co-author Prof. Florian Mormann at the UKB – to determine whether local SD can also be detected deep in the human brain as soon as the EEG bandwidth is extended beyond the international standard, thus enabling very slow potential fluctuations to be recorded.

The conclusion of the Bonn researchers is that epileptic seizures, although assumed to be the cause for decades, may not be the direct cause of postictal symptoms. "Our hypothesis is that local seizure-associated SD is a key factor in epilepsy that has been massively understudied to date," says co-author Prof. Heinz Beck from the UKB and DZNE. He is a spokesperson for the Transdisciplinary Research Area (TRA) "Life & Health" and a member of the ImmunoSensation Cluster of Excellence at the University of Bonn. The results point to a possible general role of SD in a variety of different postictal disorders, which now need to be investigated further. "In addition, our results require a review of previous studies which, because SD was filtered out, related effects and effect sizes to epileptic seizures, even though this may not be the case," says Prof. Wenzel. "Finally, our study could stimulate a discussion on whether the international EEG standard needs to be expanded to make SD directly visible in clinical EEG as well."