Neuroscientists make fascinating breakthrough linking disinhibited brain networks to depression

A new study published in Nature Communications offers rare insight into the brain activity of people experiencing major depressive disorder by directly recording electrical signals inside key regions of the prefrontal cortex. The researchers found that daily shifts in depression symptoms correspond to increased low-frequency communication between specific prefrontal areas and to an imbalance in brain activity between the left and right hemispheres. The findings support the view that depression involves disinhibited brain networks, where reduced control in the prefrontal cortex may lead to persistent rumination and impaired emotion regulation.

Major depression remains one of the most disabling mental health conditions worldwide. Many people do not respond to first-line treatments such as medication or therapy, and researchers have increasingly turned to brain-based interventions, including deep brain stimulation, to help those with severe, treatment-resistant depression.

A long-standing theory in neuroscience suggests that depression arises from disruptions in how inhibitory neurons regulate brain activity—especially in the prefrontal cortex, an area responsible for attention, decision-making, and emotional control. However, because direct recordings from the human brain are rarely possible, especially in psychiatric populations, this theory has been difficult to test.

“Major depressive disorder was labeled by the World Health Organization as the single largest contributor to global disability,” said study author John Myers, a postdoctoral cognitive neuroscientist at Baylor College of Medicine and member of the Functional and Cognitive Neurophysiology laboratory led by Sameer Sheth.

The prevalence of depression is palpable, and we all know someone close to us who has experienced an episode. Too many of us have also experienced these episodes firsthand. The frontline treatments for depression , such as pharmaceutical medications and psychological therapy, are ineffective for at least 30% of the people seeking help.”

In the current study, the researchers took advantage of a unique opportunity to study patients undergoing deep brain stimulation for treatment-resistant depression. As part of the surgical process, six patients were temporarily implanted with intracranial electrodes in the dorsolateral prefrontal cortex, orbitofrontal cortex, and anterior cingulate cortex—three prefrontal regions thought to play important roles in mood regulation. These electrodes allowed the team to directly measure neural communication while patients rested quietly and reported their mood levels multiple times a day over a 10-day monitoring period.

“Our project is part of a BRAIN Initiative clinical trial (UH3 NS103549) where the goal is to alleviate treatment-resistant depression using deep brain stimulation,” Myers said. “We monitor patients for several days in the hospital following the initial implant, checking their depression levels and brain activity prior to activating the device.”

Participants completed a validated, computerized assessment of depression symptoms several times each day. These scores captured fluctuations in mood from hour to hour, producing a rich time series of psychological data. Neural recordings were collected during brief five-minute sessions in which participants fixated on a dot on a screen. The researchers then analyzed the electrical signals to examine how different prefrontal regions were communicating with one another, focusing on slow-wave activity in the delta frequency range (1–3 Hz), which previous research has linked to inhibitory brain processes.

The results showed that when participants reported more severe depression symptoms, the brain’s low-frequency signals—particularly between the orbitofrontal and dorsolateral prefrontal cortices—increased in strength and directionality. That is, these regions were not just more active, but also more engaged in sending and receiving signals to each other in a coordinated pattern. This was especially evident in the left hemisphere. At the same time, the anterior cingulate cortex, a region involved in regulating emotional conflict, became more involved in these interactions during periods of higher symptom severity.

Interestingly, the researchers also discovered that symptom severity increased when communication patterns became imbalanced between the hemispheres. When the right hemisphere’s orbitofrontal and dorsolateral regions were more active than their left-sided counterparts, participants tended to feel worse. Conversely, stronger connections involving the left anterior cingulate cortex were more predictive of symptom severity. These patterns suggest that both hemispheres of the prefrontal cortex contribute to depression, but in distinct and complementary ways.

“Our focus was on three specific subregions of the prefrontal network, the dorsolateral prefrontal cortex, the orbitofrontal cortex, and the anterior cingulate cortex,” Myers told PsyPost. “We were surprised to find that so much of the information shared between those subregions correlated with depressive symptoms. Some activity patterns occurred when patients were feeling better, while others occurred when they were feeling worse.”

The researchers also examined the spectral power of local brain activity—that is, the intensity of oscillations within each region on their own. They found that higher power in the delta band within the right prefrontal cortex was associated with more severe depression, aligning with the connectivity findings.

In contrast, higher-frequency activity, especially in the gamma range (above 30 Hz), was often linked to improved mood. This supports the idea that depression is associated with a shift toward lower-frequency, less efficient brain communication, while recovery may involve restoration of higher-frequency signaling.

The findings provide direct evidence that depression symptoms are linked to dynamic changes in how prefrontal brain regions communicate with each other. Rather than being fixed, these networks appear to shift throughout the day as mood fluctuates. The data also support the broader theory that depression arises from a loss of inhibitory control in the brain. When inhibitory signals break down, prefrontal regions may over-communicate in an uncoordinated way, leading to the persistent negative thinking and poor emotion regulation that characterizes depression.

“The prefrontal cortex is crucial for higher order cognitive functions such as emotion regulation and attention control,” Myers said. “When this area is damaged, either through injury or psychological stress, we lose critical functionality. The existential toll of depression – that feeling of losing control during intrusive ruminations – is linked to disinhibition and dysfunction in the prefrontal cortex.”

This study stands out for its use of intracranial recordings, which provide a much more precise view of brain activity than traditional brain imaging techniques. The fine-grained temporal resolution allowed the researchers to link specific frequency bands of neural activity to moment-to-moment changes in mood. These insights may be especially helpful for designing future neuromodulation treatments, such as adaptive deep brain stimulation devices that respond to changes in brain state in real time.

However, the study also has some limitations. The sample size was small, involving only six participants, all of whom were undergoing an invasive medical procedure for severe, treatment-resistant depression. This means the findings may not generalize to people with milder forms of depression or to those who are not candidates for deep brain stimulation. The study was also limited to prefrontal regions of the brain, leaving out other important areas such as the amygdala and hippocampus, which are known to play roles in emotional processing.

“The opportunity to record brain activity intracranially in patients with depression is very rare, and deep brain stimulation is still being evaluated for its effectiveness,” Myers explained. “Thus, clinical trials of this nature often treat very few patients when compared to larger scale trials testing drugs on thousands of people. Although our sample size limitations are mitigated by repeated measures across several days, it is important to keep mind the difference in scale.”

Future research will likely explore how these patterns of brain communication change with treatment and whether they can be used to guide individualized neuromodulation therapies. The researchers also plan to investigate how the prefrontal cortex interacts with other brain regions across different psychiatric disorders, many of which involve problems with emotion regulation. By mapping out these brain networks in greater detail, scientists hope to identify reliable biomarkers of mood states and develop more effective interventions for those living with depression.

“Our next steps are to further explore the role of the prefrontal cortex in depression and other psychiatric disorders,” Myers said. “Diminished emotion regulation is common to most if not all of these disorders, and the prefrontal cortex seems to sit at the top of the hierarchy for that function.”

“Research like this is vital to the mental health of future societies, both here in the United States and across the Earth. The tiny seeds of knowledge we plant today will grow to nourish our children and children’s children. Knowledge empowers!”

The study, “Intracranial directed connectivity links subregions of the prefrontal cortex to major depression,” was authored by John Myers, Jiayang Xiao, Raissa K. Mathura, Ben Shofty, Victoria Gates, Joshua Adkinson, Anusha B. Allawala, Adrish Anand, Ron Gadot, Ricardo Najera, Hernan G. Rey, Sanjay J. Mathew, Kelly Bijanki, Garrett Banks, Andrew Watrous, Eleonora Bartoli, Sarah R. Heilbronner, Nicole Provenza, Wayne K. Goodman, Nader Pouratian, Benjamin Y. Hayden, and Sameer A. Sheth.