Study reveals how deep brain stimulation helps control epilepsy

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Researchers at the Escola Paulista de Medicina at the Federal University of São Paulo (EPM-Unifesp) have been investigating, through animal experiments, how high-frequency deep brain stimulation (DBS) can help control epilepsy — a neurological disease characterized by abnormal and excessive electrical surges in the brain that recur, causing seizures. Recent results have been published in the journal Brain Stimulation.

Coordinated by Professor Luciene Covolan, the study showed that stimulation of the anterior nucleus of the thalamus through electrodes implanted in the central part of the brain is capable of suppressing epileptic seizures in the long term by increasing the production of adenosine – a substance resulting from the energy metabolism of cells and which plays an important role in the communication process between neurons.

The article is the result of the project “Contribution of adenosine to the anti-epileptogenic role of deep brain stimulation in the anterior nucleus of the thalamus”, developed with the support of Fapesp.

The research continues now, in a new stage, in partnership with Rutgers University, in the United States.

“When a person has epilepsy, they have excess adenosine kinase [ADK] in the brain. This enzyme methylates the DNA of neurons—a biochemical modification [adição de um grupo metil à molécula] that alters gene expression.

Basically, this alters the cell’s function and may be one of the factors responsible for the generation of epileptic seizures.

So, when we see that increasing adenosine with deep brain stimulation leads to a reduction in the adenosine kinase enzyme, we see that there is also a reduction in these crises.

We conclude that it is possible that a kind of reprogramming of the neurons involved in the epileptic circuits is taking place.

Our hypothesis is that, by stimulating the anterior nucleus of the thalamus, the increase in adenosine and the reduction in adenosine kinase lead to attenuation and even remission of crises in some cases, by acting on the transmethylation of the DNA present in the cells of these brain circuits”, he explains. Covolan.

The hypothesis being tested in the experimental model, with rodents, is that the brain tissue may be undergoing changes in the DNA.

“The effect of treating epileptic seizures with deep brain stimulation has a progressive improvement character, that is, the seizures are reduced throughout the treatment. They do not stop abruptly. This indicates that adenosine may be acting beyond the simple binding with its receptors, in several other mechanisms. One of them, for example, would be the stabilization of the electrical potential of neuronal membranes. This is a mechanism that we still have to investigate further, but there is a strong indication that it may be happening”, highlights.

According to Covolan, the discovery is important because, in the long term, it can help to develop less invasive treatments for patients who do not have an indication for surgery.

“We understand that this adenosine mechanism works as if we were teaching the cell to return to normal. If we are right, we can, for example, start thinking about strategies and treatments for epilepsy itself and not just for the reduction of seizures, as been doing so far”, explains the researcher to Agência Fapesp.

Epilepsy currently affects more than 50 million people worldwide and about 3 million Brazilians, according to the World Health Organization (WHO).

About 70% of cases are controlled with the use of appropriate medications, however, 30% do not respond to medication and for them there are few alternatives, including resection surgery, which involves removing the region of the brain in which the epileptic seizures occur. happen.

When this area is well defined in the patient, the probability of long-term control is reasonably high. However, this does not always happen. In some patients, it is not possible to know where the attacks begin or, even if it is known, it is sometimes not possible to succeed with this technique.

That’s why the Unifesp group tries, through experiments with rodents, to understand how it would be possible to open other fronts of treatment for epilepsy, especially that of the temporal lobe, which affects 30% of people with the disease.

Surgery for the implantation of electrodes that perform deep brain stimulation was recently approved in the United States and Brazil as an alternative treatment option for patients who no longer respond to drug treatment.

Despite clinical studies showing that a significant number of them have reduced seizures, the mechanism of action is still poorly studied.

“In 2010, an important clinical finding by another group of researchers showed that epileptic patients who underwent this surgery and had electrodes implanted in the anterior nucleus of the thalamus had a progressive reduction in seizures over the years of stimulation. between two and five years of treatment, with a significant improvement in quality of life, but we still needed to understand how and why this was happening”, he emphasizes.

Role of the thalamus in epilepsy

The thalamus is a kind of “on and off” switch for our actions. It is located in a central position in the brain, which receives information from all sensory pathways and distributes it to the cortex. It also makes important connections between systems involved in the generation and propagation of limbic epileptic seizures.

Whenever an epileptic seizure starts (in a cortical region), necessarily, this information passes instantly through the thalamus and is distributed throughout the circuit, returning to the cerebral cortex from where the manifestations in the patient arise. It is for this reason that he was chosen for the Unifesp study, according to Professor Covolan.

“What we are trying to do, when we investigate what happens in deep brain stimulation, is to prevent this information from the epileptic seizure that happened in a specific point in the brain from reaching other areas, so that the seizure does not spread”, explains the study coordinator.

According to the scientist, the clinical manifestation of the epileptic seizure is related to the area of ​​the brain where it is generated. The seizure may be rapid or prolonged; with or without alteration of consciousness; with motor, sensory or sensory phenomena; single or in clusters; when the person is awake or during sleep, for example. And it all depends on where it originates in the brain.

“It’s like an orchestra, your nervous system prepares you to give an answer. And the thalamus would be the conductor within this circuit, which includes the hippocampus and other limbic structures that characterize temporal lobe epilepsy”, explains Covolan.

“If we modulate the activity of the thalamus, through deep brain stimulation, when it goes to talk to the cortex it will inhibit this passage of information. Epileptic seizures can generate responses of muscle contractions and even lose consciousness. it will only have motor expression, for example, if it reaches the motor cortex, which will give the spinal cord neurons the order for the muscles to contract or not. So, it may happen that the person is having a hippocampus crisis and he does not arrive to the cortex? You can. And that’s exactly what we’re trying to do, modulate neuronal activity so that it doesn’t spread through the cortex with enough intensity, preventing the patient from having these discharges or losing consciousness”, he explains.

Next steps

In this next step, Covolan says that the researchers want to understand, among other issues, how the methylation of the DNA of neurons is being carried out after the reduction of adenosine kinase, that is, this process of change in cell function.

“We saw that adenosine kinase decreased, which methylated the DNA at a certain level in the epileptic mouse, but I am now doing tests to measure this methylation exactly”, he ponders.

In addition, it is also necessary to understand, from now on, that new substances or drugs could be developed to help the treatment of patients, given that they were able to better understand the mechanism of action of deep brain stimulation in epilepsy.

“We are doing a systematic review of experimental models of epilepsy that use deep brain stimulation and analyzing a lot of data. We are going to do more complex analyzes of the DNA, to see what is actually changing. If this methylation or transmethylation is going to generate different proteins that will be transcribed, whether the DNA is changed or not after stimulation. But these are high-cost experiments. We are going to submit other projects. It would be very cool if we had a product, perhaps a patent”, comments the researcher.

Christiane Gimenes, Maria Luiza Motta Pollo and Eduardo Diaz, from the Unifesp Department of Physiology, as well as Eric Hargreaves, from Jersey Shore University Medical Center, and Detlev Boison, from Robert Wood Johnson Medical School, at Rutgers University, also participated in the research.

The article Deep brain stimulation of the anterior thalamus attenuates PTZ kindling with concomitant reduction of adenosine kinase expression in rats can be read at: www.brainstimjrnl.com/article/S1935-861X(22)00099-7/fulltext.

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