Powerful magnetic pulses applied to the scalp to stimulate the brain can bring fast relief to many severely depressed patients for whom standard treatments have failed. Yet it’s been a mystery exactly how transcranial magnetic stimulation, as the treatment is known, changes the brain to dissipate depression. Now, researchers found that the treatment works by reversing the direction of abnormal brain signals.
The findings also suggest that backward streams of neural activity between key areas of the brain could be used as a biomarker to help diagnose depression.
“The leading hypothesis has been that TMS could change the flow of neural activity in the brain,” said the lead author. “But to be honest, I was pretty skeptical. I wanted to test it.”
The author had developed a mathematical tool to analyze functional magnetic resonance imaging, or fMRI — commonly used to locate active areas in the brain. The new analysis used minute differences in timing between the activation of different areas to also reveal the direction of that activity.
In the new study published in the Proceedings of the National Academy of Sciences, the researchers used the FDA-cleared treatment, known as Stanford Neuromodulation Therapy, incorporates advanced imaging technologies to guide stimulation with high-dose patterns of magnetic pulses that can modify brain activity related to major depression. Compared with traditional TMS, which requires daily sessions over several weeks or months, SNT works on an accelerated timeline of 10 sessions each day for just five days.
“This was the perfect test to see if TMS has the ability to change the way that signals flow through the brain,” said the lead author of the study. “If this doesn’t do it, nothing will.”
The researchers recruited 33 patients who had been diagnosed with treatment-resistant major depressive disorder. Twenty-three received SNT treatment, and 10 received a sham treatment that mimicked SNT but without magnetic stimulation. They compared data from these patients with that of 85 healthy controls without depression.
When they analyzed fMRI data across the whole brain, one connection stood out. In the normal brain, the anterior insula, a region that integrates bodily sensations, sends signals to a region that governs emotions, the anterior cingulate cortex.
“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 on the basis of all these signals,” the lead said.
In three-quarters of the participants with depression, however, the typical flow of activity was reversed: The anterior cingulate cortex sent signals to the anterior insula. The more severe the depression, the higher the proportion of signals that traveled the wrong way.
“What we saw is that who’s the sender and who’s the receiver in the relationship seems to really matter in terms of whether someone is depressed,” the author said.
“It’s almost as if you’d already decided how you were going to feel, and then everything you were sensing was filtered through that,” the author said. “The mood has become primary.”
“That’s consistent with how a lot of psychiatrists see depression,” he added. “Even things that are quite joyful to a patient normally are suddenly not bringing them any pleasure.”
When depressed patients were treated with SNT, the flow of neural activity shifted to the normal direction within a week, coinciding with a lifting of their depression.
Those with the most severe depression — and the most misdirected brain signals — were the most likely to benefit from the treatment.
“We’re able to undo the spatio-temporal abnormality so that people’s brains look like those of normal, healthy controls,” one of the senior authors said.
A challenge of treating depression has been the lack of insight into its biological mechanisms. If a patient has a fever, there are various tests — for a bacterial or viral infection, for example — that could determine the appropriate treatment. But for a patient with depression, there are no analogous tests.
“This is the first time in psychiatry where this particular change in a biology — the flow of signals between these two brain regions — predicts the change in clinical symptoms,” the senior author said.
Not everyone with depression has this abnormal flow of neural activity, and it may be rare in less severe cases of depression, the author said, but it could serve as an important biomarker for triaging treatment for the disorder. “The fMRI data that allows precision treatment with SNT can be used both as a biomarker for depression and a method of personalized targeting to treat its underlying cause,” the author said.
“When we get a person with severe depression, we can look for this biomarker to decide how likely they are to respond well to SNT treatment,” the lead said.
“Behavioral conditions like depression have been difficult to capture with imaging because, unlike an obvious brain lesion, they deal with the subtlety of relationships between various parts of the brain,” said another senior author. “It’s incredibly promising that the technology now is approaching the complexity of the problems we’re trying to understand.”
The researchers plan to replicate the study in a larger group of patients. They also hope others will adopt their analytic technique to uncover more clues about the direction of brain activity hidden in fMRI data. “As long as you have good clean fMRI data, you can study this property of the signals,” the lead said.
Reversing treatment-resistant depression with targeted neurostimulation
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