Researchers treat depression by reversing brain signals traveling the wrong way

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The findings also suggest that the regressive currents 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 might change the flow of neural activity in the brain,” said Anish Mitra, MD, PhD, a postdoctoral fellow in psychiatry and behavioral sciences. “But to be honest, I was pretty skeptical. I wanted to try it out.”

Mitra had just the right tool to do it. As a graduate student at Washington University in Saint Louis, in the lab of Mark Raichle, MD, he developed a mathematical tool for analyzing functional magnetic resonance imaging, or fMRI, commonly used to locate active areas in the brain. The new analysis used minute differences in time between the activation of different areas to also reveal the direction of that activity.

In the new study published May 15 in the Proceedings of the National Academy of Sciences, Mitra and Raichle partnered with Nolan Williams, MD, associate professor of psychiatry and behavioral sciences, whose team has advanced the use of magnetic stimulation, customized to each patient’s brain anatomy, to treat major depression. The FDA-approved 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 associated with major depression. Compared to traditional TMS, which requires daily sessions for several weeks or months, SNT works on an accelerated schedule 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 signals flow through the brain,” said Mitra, the study’s lead author. “If this won’t do it, nothing will.”

Raichle and Williams are the lead authors of the study.

timing is everything

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 mimicking SNT but without magnetic stimulation. They compared data from these patients with that of 85 healthy controls without depression.

When they looked at the whole-brain fMRI data, 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 might think that the anterior cingulate cortex receives this information about the body, like heart rate or temperature, and then decides how to feel based on all these signals,” Mitra said.

However, in three-quarters of the participants with depression, the typical flow of activity was reversed: the anterior cingulate cortex sent signals to the anterior insula. The more severe the depression, the greater the proportion of signals that traveled in the opposite direction.

“What we saw is that who is the sender and who is the receiver in the relationship seems to really matter in terms of whether someone is depressed,” Mitra said.

“It’s almost like you already decided how you were going to feel, and then whatever you were feeling seeped through that,” he said. “The mood has gone primal.”

“That’s consistent with how many psychiatrists view depression,” he added. “Even things that are quite joyful to a patient normally suddenly don’t bring them any pleasure at all.”

changing the flow

When depressed patients were treated with SNT, the flow of neural activity changed to the normal direction within a week, coinciding with a cessation of their depression.

Those with the most severe depression, and the most misdirected brain signals, were the most likely to benefit from treatment.

“We can undo the spatiotemporal anomaly so that people’s brains look like those of normal, healthy controls,” Williams said.

A biomarker for depression

A challenge in the treatment of depression has been the lack of understanding of its biological mechanisms. If a patient has a fever, there are several tests, for example for a bacterial or viral infection, that could determine the appropriate treatment. But for a patient with depression, there is no analogous evidence.

“This is the first time in psychiatry where this particular change in biology, the signal flow between these two brain regions, predicts change in clinical symptoms,” Williams said.

Not everyone with depression has this abnormal flow of neural activity, and it may be rare in less severe cases of depression, Williams said, but it could serve as an important biomarker for classifying treatment of the disorder. “fMRI data that enables precision treatment with SNT can be used both as a biomarker for depression and as a personalized targeting method to treat its underlying cause,” she said.

“When we find a person with severe depression, we can look for this biomarker to decide how likely they are to respond well to SNT treatment,” Mitra said.

“Behavioral conditions like depression have been difficult to image because, unlike obvious brain injury, they deal with the subtlety of relationships between various parts of the brain,” said Raichle, who has studied brain imaging for more four decades. “It’s incredibly promising that technology is now getting closer to 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 that others will adopt their analytical technique to uncover more clues about the direction of hidden brain activity in the fMRI data. “As long as you have good, clean fMRI data, you can study this property of the signals,” Mitra said.

The study was funded by a Brain and Behavior Research Foundation Young Investigator Award, the NIMH Biobehavioral Research Awards for Innovative New Scientists (grant R01 5R01MH122754-02), the Charles R. Schwab, David and Amanda Chao Fund II , the Amy Roth PhD Fund, the Neuromodulation Research Fund, the Lehman Family, the Still Charitable Trust, the Marshall and Dee Ann Payne Fund, the Gordie Brookstone Fund, the Mellam Family Foundation, and the Baszucki Brain Research Fund.