A circuit that runs from the prefrontal cortex near the front of the brain to a deeper brain structure called the insular cortex appears to mediate the antidepressant effects of a newer form of transcranial magnetic stimulation (TMS), according to a study led by Weill Cornell Medicine investigators. The discovery could lead to more effective TMS treatment of depression.

In the study, published May 7 in Cell, the researchers developed mice whose brains can be stimulated artificially in a prefrontal region to mimic the antidepressant effect of a widely used – but not well understood – TMS technique. The researchers showed that this antidepressant effect in the mice depends heavily on the indirect stimulation of a connected region, the insular cortex.

“We’re excited about this work because it advances our understanding of the antidepressant effects of TMS, and points to more effective ways of delivering this therapy,” said study senior author Dr. Conor Liston, the Robert Michels, M.D. Professor of Psychiatry in the Department of Psychiatry and a professor of neuroscience in the Feil Family Brain and Mind Research Institute at Weill Cornell Medicine. Shane B. Johnson, Devin Rocks and Laura Chalencon, postdoctoral associates in psychiatry at the time of the study, were co-first authors of the study.

Depression is one of the most commonly diagnosed illnesses in the modern world, and its prevalence has been increasing in recent decades. In the United States alone, tens of millions of people are treated for depression annually, according to the National Institute of Mental Health. Selective serotonin reuptake inhibitors are the most common antidepressant treatments but can take weeks to work and frequently have side effects.

TMS treatments, though requiring clinic visits, are more targeted, have few if any side effects, and are increasingly used for patients who do not respond to drug therapy. Accelerated intermittent theta-burst stimulation (aiTBS), one new TMS protocol, has been found to reduce or abolish depression symptoms in many patients after only a few days of treatment. But exactly how TMS works and how it could be optimized have been notoriously difficult to study.

“There’s a lot of variation in how you can deliver TMS, which makes it very hard to test systematically in humans,” said Liston, who is also a psychiatrist at NewYork-Presbyterian/Weill Cornell Medical Center. “The variables include the duration of treatment in each session, the specific pulse rhythm, the interval between sessions and the specific brain area targeted, among others.”

The researchers developed a mouse model to explore and optimize aiTBS. The optogenetic mouse model allows the researchers to use light pulses to stimulate specific groups of neurons, with the same rhythms used in aiTBS. The team showed that stimulating the same prefrontal region targeted by aiTBS reverses stress-induced, depression-like behaviors in the mice.

Next, the scientists identified the specific prefrontal neurons that mediate this effect, and revealed changes that occur in these neurons, including denser growths of connections between brain cells in response to the stimulation. They then traced these neurons’ connections, finding that a connection to the insular cortex is necessary for the antidepressant effect.

The functions of the insular cortex, or “insula,” are complex and not completely understood; but they include processing bodily sensations – such as hunger and pain – and integrating them with emotion-related signals.

“The insula hasn’t been covered much in TMS research, in part because it is too deep in the brain to reach with ordinary TMS protocols, but it is one of the most consistently altered brain regions in studies of patients with depression,” Liston said.

Experiments in mice don’t always translate to humans. So, the researchers used functional magnetic resonance imaging to map brain connections and electroencephalography to measure neuronal responses in consented patients receiving TMS. They found that TMS stimulation of the prefrontal cortex has a downstream effect on the insula in these patients.

The results overall suggest that aiTBS’s antidepressant effect might be improved by maximizing its downstream stimulation of the insula – a prospect Liston and his colleagues now plan to investigate further using their mouse model and in future clinical trials.

The identification of the neurons that are important for aiTBS’s effects and the changes that occur in them could also lead to new drug therapies targeting those neurons, Liston said.

“In the meantime, another exciting strategy with great potential is to pair drug treatment with TMS to accelerate the antidepressant response,” he said.

The research reported in this story was supported in part by the National Institute of Mental Health and the National Institute on Deafness and Other Communication Disorders, both part of the National Institutes of Health. Additional support was provided by the Hope for Depression Research Foundation, the Foundation for OCD Research and the Wellcome Leap foundation, and a Burroughs Wellcome Fund Career Award.

Many Weill Cornell Medicine physicians and scientists maintain relationships and collaborate with external organizations to foster scientific innovation and provide expert guidance. The institution makes these disclosures public to ensure transparency. For this information, please see the profile for Dr. Conor Liston.

Jim Schnabel is a freelance writer for Weill Cornell Medicine.