Researchers at the Escola Paulista de Medicina at the Federal University of São Paulo (Unifesp) have been investigating, through animal experiments, how high-frequency deep brain stimulation (DBS) can help control epilepsy – neurological disease characterized by abnormal and excessive electrical discharges in the brain that are recurrent, 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 a project developed with the support of the Fundação de Amparo à Pesquisa do Estado de São Paulo (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 changes the cell’s function and may be one of the factors responsible for the generation of epileptic seizures”, explains Luciene.
According to the expert, it was observed that increasing adenosine with deep brain stimulation promotes a reduction of the adenosine kinase enzyme and that there is also a reduction in seizures.
“We concluded 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. Luciene.
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, seizures are reduced throughout treatment. They don’t 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 strong evidence that it could be happening,” he points out.
According to Luciene, the discovery, in the long term, may 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 we have been doing so far”, explains the researcher.
Impacts of epilepsy
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 drugs. However, 30% of patients do not respond to medication and for them there are few alternatives, including resection surgery, which involves removing the region of the brain where epileptic seizures occur. 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.
The group from Unifesp 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. Many showed complete reversal of the condition between two and five years of treatment, with a significant improvement in quality of life, but it was still lacking 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 researcher. 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 regent within that circuit, which includes the hippocampus and other limbic structures that characterize temporal lobe epilepsy,” she says.
“If we modulate the activity of the thalamus, through deep brain stimulation, when it goes to talk to the cortex, it will inhibit this transmission of information. Epileptic seizures can generate responses of muscle contractions and even loss of consciousness. The crisis 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, can it happen that the person is having a hippocampal crisis and it doesn’t reach the cortex? He can. And that’s exactly what we’re trying to do, modulate neuronal activity so that it doesn’t spread through the cortex with sufficient intensity, preventing the patient from having these discharges or losing consciousness,” he says.
Next steps
In this next step, Luciene 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 DNA at a certain level in the epileptic rat, 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. Let’s do more complex analyzes of the DNA, to see what is actually changing. Whether this methylation or transmethylation will generate different proteins that will be transcribed, whether the DNA is changed or not after stimulation. But these are expensive experiments. Let’s submit other projects. It would be really cool if we had a product, maybe a patent”, says 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.
Source: CNN Brasil
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