When discomfort originates in the brain – understanding the neural structures opens better therapeutic opportunities for Parkinson’s disease

November 10, 2023 Reading time: 4 minutes.

New findings from the brain: Researchers have discovered in which area of ​​the brain discomfort and aversion arise. They discovered that activation of the subthalamic nucleus in mice caused intense discomfort. Since this brain area is stimulated therapeutically in Parkinson’s patients, the study may explain why depressive side effects sometimes occur when treating Parkinson’s disease. Therefore, this area of ​​the brain could also play a role in the development of depression. The findings could therefore lead to better treatments for Parkinson’s and other diseases.

In Parkinson’s disease, the brain area of ​​the thalamus (subthalamic nucleus), which controls voluntary movements and behavior, is overactive. Stimulating this area of ​​the brain with implanted electrodes “corrects” this and often eliminates the typical tremors and other motor complaints of this neurodegenerative disease in Parkinson’s patients. However, some patients experience side effects such as severe depression. A research group has now discovered why this is.

Researchers led by Gian Pietro Serra of Uppsala University have long used mice to study what happens when the thalamus is activated by deep brain stimulation. In a previous study, they found that mice whose thalamus was activated in this way tried to escape the stimulus.

Targeted activation of the subthalamic nucleus

Serra and his team have now examined in more detail why test mice find brain stimulation so apparently unpleasant. To do this, they used an optogenetics method to specifically stimulate the rat’s hypothalamic nucleus, but not any other brain tissue. They used light to activate or deactivate individual neurons in the brains of genetically modified mice that have light-sensitive proteins on their surfaces.

Using specific molecular markers, the researchers precisely distinguished the hypothalamic nucleus from the surrounding neural structures. This allowed them to examine how individual neurons in the mice’s brains were affected by light and how the mice behaved when the neurons were more or less active.

Mice avoid feeling tired

Experiments have shown that if the subthalamus is stimulated in mice, this obviously causes a distinct feeling of discomfort in the animals. They react with disgust or fear. The researchers realized this because the animals repeatedly groomed their facial fur, a behavior known from previous studies.

Surprisingly, the animals avoided the experimental situation not only while the subthalamic nucleus was activated, but also when this brain region was not activated in a subsequent trial. The researchers concluded that the mice remembered the discomfort they felt and avoided the situation as a precaution. Thus, the associations between the situation we were experiencing and negative emotions were strong enough to maintain the behavior.

“Our study shows that this area of ​​the brain is involved in aversion and avoidance behavior when stimulated,” explains lead author Asa Whalen McKenzie from Uppsala University. She and her colleagues have now pinpointed the place in the brain that causes discomfort and aversion: the subthalamic nucleus. They have also identified neural circuits that connect this area to the brain’s emotional system, which becomes active when a person is seriously ill.

Association with depression and Parkinson’s disease

According to the researchers, the feeling of aversion serves a biologically important function: it makes animals and us humans avoid things that make us feel guilty. However, it is also known from previous studies that strong activation of the brain’s aversion system can lead to depression in humans.

“The fact that the thalamus causes aversion and avoidance behavior is an important finding. “It expands our understanding of the brain’s emotional system and how brain activity can lead to psychological symptoms such as depression and apathy,” says Whalen-McKenzie. “It may also explain why such side effects occur.” “In people with Parkinson’s disease who are treated with deep brain stimulation.”

Hope for a refined treatment for Parkinson’s disease

These findings not only provide new insights into the loci of discomfort and aversion in the brain, but could also have practical medical use. “Now that we can show that the hypothalamus has a direct connection to aversion and is connected to the depression center in the brain, we can understand and explain these side effects neurobiologically when treating patients with Parkinson’s,” Serra says.

“Our study paves the way for improving the clinical accuracy of these treatments,” McKenzie explains. The goal is to treat the symptoms of the disease without causing serious side effects. This may also be useful in treating other diseases such as tremor, Tourette syndrome, obsessive-compulsive disorder and eating disorders, which are also treated by stimulating the thalamus. However, further studies are needed to uncover which neurons within the thalamus are involved in the observed avoidance behavior and depression. (Cell Reports, 2023; doi: 10.1016/j.celrep.2023.113328)

Source: Swedish Research Council

November 10, 2023 – Claudia Crabb