Stanford researchers have discovered that certain brain signals actually flow the wrong way in people with treatment-resistant depression — and that magnets can correct the misdirection and help patients feel better.

“This is the first time in psychiatry that this particular change in a biology — the flow of signals between these two brain regions — predicts the change in clinical symptoms,” said Nolan Williams, senior author of a paper describing the discovery.

The challenge: While most people living with depression can find some relief with medication, approximately 84 million people globally have treatment-resistant depression, meaning they still don’t feel better even after trying multiple antidepressants.

But about 50% of people with treatment-resistant depression do respond to transcranial magnetic stimulation (TMS), according to Adam P. Stern, MD, an assistant professor of psychiatry at Harvard Medical School, who was not involved in the new study. TMS uses magnetic fields to painlessly and non-invasively stimulate nerve cells in the brain, usually for 20-50 minutes a day, five days a week, for several weeks or even months.

“To be honest, I was quite skeptical.”

Anish Mitra

This has been a life-changing discovery for many people with stubborn depression, but exactly how it works has remained a mystery. This has made it difficult to know which patients are likely to benefit from TMS before committing to the treatment.

“The leading hypothesis has been that TMS could change the flow of neural activity in the brain,” said Anish Mitra, lead author of the new paper. “But to be honest, I was quite skeptical.”

What is new? To test his skepticism, Mitra and his colleagues recruited 33 people with treatment-resistant depression for the study, published in PNAS.

Twenty-three of the participants underwent an accelerated, highly effective version of TMS—known as “Stanford neuromodulation therapy”—consisting of 10 sessions a day for five days. The others received a skin treatment.

All participants had their brain activity mapped using fMRI before and after the study’s treatment phase. Data were also collected on 85 people without depression.

In 75% of people with depression, some of the signals flowed in the opposite direction.

The results: When they analyzed the fMRI data, something stood out: a connection between a brain region that regulates physical sensations (the anterior insula) and a region that controls emotions (the anterior cingulate cortex).

As expected, signals in the brains of people without depression traveled from the physical sensory area to the emotional area.

“You could think of it as the anterior cingulate cortex receiving this information about the body — like heart rate or temperature — and then deciding how to feel based on all those signals,” Mitra explained.

Within 3 days of completing the TMS treatment, the reversed signals flowed in the correct direction.

However, in 75% of people with depression, some of the signals flowed the opposite way, and the more severe a person’s depression, the greater the proportion of wrong signals.

“It’s almost as if you had already decided how you wanted to feel, and then everything you sensed was filtered through that,” Mitra said. “The mood has become primal.”

Within 3 days of ending the TMS treatment, the reversed signals flowed in the right direction and the patients reported an improvement in their mood – the more severe their depression was to begin with, the greater the reported improvement.

“Technology is now approaching the complexity of the problems we’re trying to understand.”

Mark Raichle

The bottom line: Not everyone with treatment-resistant depression showed the wrong signals, but this finding may prove to be a useful indicator that a person has depression and is likely to respond to TMS.

“Behavioral conditions like depression have been difficult to capture with imaging because, unlike an obvious brain lesion, they deal with the subtleties of relationships between different parts of the brain,” said senior author Mark Raichle.

“It’s incredibly promising that the technology is now approaching the complexity of the problems we’re trying to understand,” he continued.

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