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Harnessing the Brain’s Plasticity to Acquire Epilepsy Resilience

A specific neuronal stimulation paradigm has successfully converted a rat’s brain to a seizure-resistant state, opening up the possibility of cultivating epilepsy resistance in humans.

Plaguing around 50 million people worldwide, epilepsy is considered to be one of the most common neurological diseases and involves the repeated occurrence of spontaneous seizures. While people suffering from the disease could live seizure-free with the correct diagnosis and treatment, studies have shown that only 65 per cent of patients can manage their symptoms with medications. Moreover, lifetime symptomatic therapy using anti-seizure drugs could cause severe side effects. This leaves invasive surgical removals of disease-causing lesions in the brain the only radical cure for epilepsy.

In a recent study led by Professor Ko Matsui from the Super-network Brain Physiology Lab at Tohoku University, scientists have reported on a simulation paradigm used on experimental animals that could potentially promote resilience to epilepsy. Contrary to previous research that showed that frequent seizure-evoking stimulation to the brain could lead to epileptogenesis and epileptic brain conditions, their current study has found that repeated stimulation induced a significant decrease in the seizure response to the stimulus.

“Our brain has an infinite ability for plasticity,” explained Matsui. “If an epileptic state can be created, we must query whether it is also conceivable to reverse the transition or to override the existing hyper-excitable circuit with an additional suppressive system.”

Leveraging optogenetics technology, first author of the study Dr. Yoshiteru Shimoda, Matsui and colleagues induced neuronal stimulation in rat brain that prompted the release of the endogenous inhibitory transmitter adenosine from glial cells. With continued stimulation, the rat’s brain was converted to a hyperexcitable state which was strongly resistant to seizures. Furthermore, histochemical analyses revealed that the moderate activation of astrocytes coincided with the acquisition of resilience. When the scientists administered an adenosine A1 receptor antagonist, they discovered that the brain was instantly reverted to a hyperexcitable state, demonstrating that hyperexcitability is suppressed by adenosine.

Although the optogenetic technology used in their study, which involves genetically expressing light-sensitive proteins in neurons to control moderate neuron-to-glial signalling at will, would be difficult to apply to human patients, the study’s findings have opened up the possibility of cultivating epilepsy resistance in the brain without exogenous drug administration.

“Although epileptogenesis, unfortunately, could not be reversed, we showed we could invoke the homeostatic nature of the brain circuit to contain hyper-excitation,” said Matsui optimistically.

Importantly, their findings suggest that it may be possible to suppress epileptic seizures by increasing endogenous adenosine. However, to do this, a normal brain must first be transformed to a hyperexcitable state in a process known as kindling. Further research will be needed to develop a kindling-free approach to translate such resilience-enhancing stimulation methods to clinical practice.

“Despite clinical use being a long way off, it is possible to imagine a future where a therapeutic strategy can directly target glial cells and enable the creation of an epileptic resistant state,” continued Matsui. [APBN]

Source: Shimoda et al. (2022). Optogenetic stimulus-triggered acquisition of seizure resistance. Neurobiology of Disease, 163, 105602.