The research objective is to identify changes that occur in the motor neuron in the pre-symptomatic stage of the disease
Unicamp researchers developed a mathematical model that allows them to simulate on a computer the changes that occur in the motor neurons of patients with amyotrophic lateral sclerosis (ALS) – the disease that killed British physicist Stephen Hawking.
Characterized by a condition of progressive muscular paralysis, ALS is caused by genetic mutations – inherited or not – that impair the production or activity of an enzyme called SOD1 (copper-zinc superoxide dismutase), responsible for protecting nerve cells from toxic by-products. of metabolism. This condition leads to the degeneration and death of motor neurons, responsible for innervating skeletal muscles and controlling voluntary movements.
The main objective of the group coordinated by the teacher Leonardo Abdala, head of the Neuroengineering Research Laboratory at the Faculty of Electrical and Computer Engineering at Unicamp, is to understand the molecular mechanisms associated with neuronal degeneration – identifying, for example, possible changes in the functioning of proteins permeable to ions such as calcium, sodium and potassium (the ion channels) that can affect the neuron's response and, consequently, the control of muscle strength.
“We used a computer simulator to search, at a pre-symptomatic stage of the disease, for a biological marker, that is, a biophysical phenomenon that occurs in the membrane of the motor neuron and affects the cell's electrical activity and the control of muscle strength. This would open the way for the study of pharmacological interventions capable of reversing or alleviating the problem”, said Elias, who is also director of the Center for Biomedical Engineering at Unicamp.
As Elias explained, in mammals there are two types of motor neurons: upper and lower. In the brain, the upper motor neuron sends electrical impulses that travel to the lower motor neurons, located along the spinal cord and brain stem. These impulses are conducted to the muscles, which transform them into movements.
During the masters by Débora Elisa da Costa Matoso, a mathematical model was developed capable of simulating the dynamics of a lower motor neuron – both in a healthy condition and in an ALS condition. To do this, the group was based on data obtained through experiments with rodents published in the scientific literature.
“There is no data available from human patients, only from mouse models genetically modified to reproduce a condition similar to ALS. To validate the model, we simulated the same experiments carried out with animals in laboratories. We observed results compatible with those obtained in vivo e vitro, which suggests that the model is capable of representing what happens to the lower motor neuron throughout the progression of the disease in the mouse,” he said.
Using computer simulations, the group is mainly studying what happens in three ion channels: one permeable to sodium ions, which is normally located in the cell body of the neuron, another permeable to calcium, which is usually located in the dendritic branches, and one third potassium channel found in both the cell body and dendrite.
According to Elias, the results have suggested that the potassium channel is fundamental in explaining some important changes observed in the dynamics of the lower motor neuron – although there is little data from animal experiments capable of corroborating this finding.
“The only medication currently available to treat ALS, Riluzole, acts on persistent sodium channels. If we can show with the model that other ion channels are also involved in this degeneration process, we will open up space for new research to be carried out with animals to test new pharmacological interventions”, said Elias.
Now, during the doctorate, Matoso intends to develop a complete model of the neuromuscular system to investigate how biophysical mechanisms that alter motor neuron dynamics influence force generation at an early stage of the disease.
“In parallel, we intend to carry out experiments in partnership with groups that have access to ALS patients to try to collect as much data as possible and, thus, validate the model under development. In a second stage of the research, we will compare the simulation results with the experimental ones, seeking perspectives for clinical and pharmacological interventions”, he said.
Furthermore, Elias entered into a partnership with a BRAINN team coordinated by professor Li Li Min to study the effect of different neuromodulation techniques (application of electrical currents, transcranial magnetic stimulation and focused ultrasound) in controlling the strength of patients who have suffered a cerebrovascular accident (CVA), those with Parkinson's or cerebellar ataxia (a group of diseases that affects movement control).
Brain Congress
Results of Elias' line of research were presented on April 10, in Campinas, during the 5th Brain Congress – event held by the Brazilian Institute of Neurosciences and Neurotechnology (BRAINN), one of the CEPIDs financed by FAPESP.
One of the international highlights of the event was researcher John A. Detre, professor at the University of Pennsylvania, in the United States. He presented a talk on the use of functional imaging technologies, including magnetic resonance imaging (MRI) and optical imaging, to study brain function in healthy individuals and in patients with a variety of clinical disorders, such as stroke, epilepsy, neurodegenerative disease and migraine.
“In an adult, the brain uses about 20% of blood flow, although it corresponds to only 2% of body mass. Because blood flow and metabolism are closely coupled, we can use flow measurement to study many aspects of brain function. For this we use functional imaging techniques”, explained Detre to FAPESP Agency.
Among the national highlights of the program was Roberto Lent, director of the Institute of Biomedical Sciences at the Federal University of Rio de Janeiro (ICB-UFRJ), who presented studies on neuroplasticity – the ability of the nervous system to shape itself, at a structural and functional level , throughout neuronal development and when subject to environmental interference.
“This environmental interference can be a disease, a conversation between people or an educational action. When a teacher teaches something, he changes the student's brain and this is a form of plasticity. In my laboratory we deal with long-distance plasticity, which is the ability to change and alter the most important brain pathways,” said Lent.
As a study model, the UFRJ group uses an important communication pathway between the left and right hemispheres of the brain known as the corpus callosum, formed by 200 million nerve fibers.
“The corpus callosum changes in various situations, such as, for example, after a traumatic amputation of one of the limbs. It is common in these cases for the person to develop phantom limb syndrome. She feels pain, itching and anomalous positions of an arm that no longer exists, for example. This is the result of the reorganization of the brain, in particular this great avenue that is the corpus callosum,” she said.
The congress program also included the round table “BRAIN(N): past, present and future” which, among other topics, discussed ways to increase the impact and optimize resources in neuroscience research carried out in Brazil. In addition to Lent and Detre, Fernando Cendes, coordinator of BRAINN, Canadian researcher Richard Frayne (University of Calgary) and the scientific director of FAPESP, Carlos Henrique de Brito Cruz, participated.