Study finds brain signals in people with severe depression flow in the wrong direction

Biomarker for depression

The researchers used functional magnetic resonance imaging (fMRI) to identify active areas in the brains of people suffering from major depressive disorder (MDD). The anterior cingulate cortex and the anterior insula were the two identified brain regions that showcased abnormal signal flow. 

The anterior insula involves various behaviors, including pain, sensations, temperature, and other subjective feelings. This is accomplished by sending neural signals to the anterior cingulate cortex, which triggers these emotions.

The anterior insula sends signals to the anterior cingulate cortex in healthy individuals. In the case of depression, however, communication between the two regions is observed to be backward, i.e., the anterior cingulate cortex sends brain signals to the anterior insula.

“What we saw is that who’s the sender and who’s the receiver in the relationship seems to matter in terms of whether someone is depressed,” said Anish Mitra, lead author of the study. 

Mitra further explained, “It’s almost as if you’d already decided how you would feel, and then everything you were sensing was filtered through that. The mood has become primary. That’s consistent with how a lot of psychiatrists see depression. Even things that are quite joyful to a patient normally are suddenly not bringing them any pleasure.” 

According to the study, the higher the proportion of reversed signals, the more severe the depression. Nearly three-quarters of the 33 study patients demonstrated this wrong flow of brain signals. 

Reversing the brain signals 

Researchers used this understanding of biomarkers to diagnose depression to find a potential treatment. The good news is that the FDA has already approved the treatment. 

Stanford neuromodulation therapy (SNT) is a treatment that uses advanced imaging techniques to guide brain signals with high-dose magnetic pulses. In this study, this therapy has shown promise in modifying brain activity in patients suffering from major depression.

The researchers tested SNT on study participants; 23 received the therapy, and 10 received a placebo treatment without magnetic pulses. They also enrolled people who were not depressed to compare the data.

Within a week of SNT treatment, the depressed patients experienced regular signal flow activity in the brain regions. As a result, patients reported that their depression symptoms had improved slightly. Previously, all patients chosen for this study had failed to respond to standard depression treatment. 

The team believes that those suffering from the most severe forms of depression are likely to benefit the most from the treatment. "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," Mitra said.

This study is an essential step toward understanding the biological mechanisms of Major Depressive Disorder, which is a leading cause of morbidity worldwide.

The researchers aim to conduct trials on a larger group of patients in the coming months.

The results have been reported in the journal Proceedings of the National Academy of Sciences.

Study abstract:

Major depressive disorder (MDD) is widely hypothesized to result from disordered communication across brain-wide networks. Yet, prior resting-state-functional MRI (rs-fMRI) studies of MDD have studied zero-lag temporal synchrony (functional connectivity) in brain activity absent directional information. We utilize the recent discovery of stereotyped brain-wide directed signaling patterns in humans to investigate the relationship between directed rs-fMRI activity, MDD, and treatment response to FDA-approved neurostimulation paradigm termed Stanford neuromodulation therapy (SNT). We find that SNT over the left dorsolateral prefrontal cortex (DLPFC) induces directed signaling shifts in the left DLPFC and bilateral anterior cingulate cortex (ACC). Directional signaling shifts in the ACC, but not the DLPFC, predict improvement in depression symptoms, and moreover, pretreatment ACC signaling predicts both depression severity and the likelihood of SNT treatment response. Taken together, our findings suggest that ACC-based directed signaling patterns in rs-fMRI are a potential biomarker of MDD.