Deep brain stimulation could be an alternative treatment for anxiety

Researchers at a Brazilian university observed a reduction in anxiety and panic after using this technique in experiments with rats.

By Karina Toledo  |  Agência FAPESP – Experiments with rats performed at the Federal University of São Paulo (UNIFESP) in Santos (on the coast of São Paulo State, Brazil) suggest that deep brain stimulation (DBS) could be an alternative for treating anxiety and panic disorders in people who do not respond to other therapeutic approaches.

The results of the research, which was supported by FAPESP, have been published in the journal Behavioural Brain Research.

“It’s important to emphasize that deep electrical stimulation is an invasive technique and therefore shouldn’t be the first choice for treating mental disorders. However, it can be an option for patients who don’t respond well to medication – between 30% and 40% in the case of anxiety disorders,” said Milena de Barros Viana, a professor in the Bioscience Department of the university’s Health & Society Institute (ISS-UNIFESP) and principal investigator for the study.

In humans, DBS is used to mitigate the symptoms of Parkinson’s disease, essential tremor, epilepsy and dystonia. Several research groups have also studied its potential for treating depression, chronic pain and obsessive-compulsive disorder, among other conditions.

In clinical use, DBS begins with a microsurgical procedure to implant small electrodes in deep areas of the brain. A neurostimulator is also implanted under the skin near the collarbone. The neurostimulator sends electrical impulses to the brain, modulating the activity of nervous structures.

Scientists do not yet know exactly how DBS works. One of the leading hypotheses, known as “depolarization block”, is that high-frequency stimulation blocks the emission of electrical signals by neurons in the stimulated area and its vicinity.

In the experiments conducted at UNIFESP, capillary (very thin) electrodes were microsurgically implanted in certain areas of the brains of male rats.

“In our study, we mainly stimulated the dorsal raphe nucleus located in the midbrain,” Viana explained. “Two regions of this nucleus, the lateral wings and the dorsal portion, have been associated with the modulation of panic and anxiety responses, respectively.”

Behavioral tests

The researchers used behavioral tests to evaluate the effect of deep electrical stimulation on the animals. After implanting the electrodes, they waited seven days to allow the rats to recover from the surgical procedure before starting the experiments.

On the day of the tests, the animals were connected to an external stimulator and received treatment for one hour. After stimulation, they were tested for anxiety in an elevated T-maze. 

The elevated T-maze is an apparatus derived from the elevated plus-maze, which consists of two arms with walls and two open arms. The T-maze has three arms, one of which is closed in by walls and is perpendicular to the other two, which are open. The apparatus is elevated 50 cm above the floor.

To evaluate behavior associated with generalized anxiety, rats are initially placed in the closed arm, Viana explained. “Rodents have an innate tendency to explore new spaces but an aversion to open spaces, because they use their whiskers, or vibrissae, to detect walls and assist with locomotion,” she said. 

Rats normally exit the closed arm to explore the open arms fairly soon after being placed in the maze, she continued. At the second or third attempt, they take longer to exit and often remain in the closed arm for the entire 300 seconds of the test.

“Their exploratory behavior is inhibited by what we call inhibitory avoidance of the open arms,” Viana said. “This has been characterized as an indicator of anxiety.”

To evaluate panic responses, the researchers placed the animals directly in the open space of the T-maze. “In this case, the expected response is one of escape from imminent danger, explosively defensive behavior characterized as a panic response. It’s different from the other case, in which the animal displays inhibitory behavior to avoid potential danger,” she said.

All the rats were submitted to surgery for electrode implantation, but only half received deep brain stimulation before the behavioral test. They were then divided into two groups: one was tested for inhibitory avoidance, which is relates to anxiety, and the other for the panic-related escape response.

“Considering the results obtained, we can say that stimulation of the dorsal region of the dorsal raphe nucleus had an anxiolytic effect [a reduction in the anxiety-related inhibitory avoidance response], while stimulation of the lateral wings of the dorsal raphe nucleus had a panicolytic effect [a reduction in the panic-related escape response],” Viana said. 

To find out whether any other brain regions were activated by deep electrical stimulation of the subnuclei of the dorsal raphe nucleus, the group investigated the effects of DBS on immunoreactivity to a protein called c-Fos.

“Immediate early genes are the first to be activated after stimulation,” Viana said. “They encode a family of proteins including c-Fos, which therefore serves as a marker of the regions activated by stimulation.”

This analysis showed that brain regions innervated by the dorsal raphe nucleus, including the prefrontal cortex and amygdala, are activated by DBS.

“We need to investigate in greater detail the mechanisms underlying the therapeutic effects of this technique. Our analysis of immunoreactivity to the protein c-Fos showed us which regions were activated but not which neuronal groups were activated in those regions. That’s what we’re trying to find out at the moment, through more detailed studies. Our main aim is to use DBS as a tool to understand the neurocircuitry involved in anxiety and panic responses,” Viana said.

The article “Deep brain stimulation of the dorsal raphe inhibits avoidance and escape reactions and activates forebrain regions related to the modulation of anxiety/panic” (https://doi.org/10.1016/j.bbr.2016.11.054), by Tatiana Wscieklica, Mariana S.C.F. Silva, Jéssica A. Lemes, Liana Melo-Thomas, Isabel C. Céspedes and Milena B. Viana, can be retrieved from: sciencedirect.com/science/article/pii/S0166432816307069.