People experiencing major depressive disorder often report feeling trapped in a cycle of negative thoughts and stagnant moods that are difficult to escape. A recent mapping of the human brain reveals that this psychological stagnation mirrors a physical reality, showing that the depressed brain frequently gets stuck looping between certain patterns of activity. The research, published in Nature Communications, highlights how altered energetic pathways in the brain keep individuals trapped in these maladaptive states.
Historically, researchers have studied depression by identifying which specific areas of the brain show increased or decreased activity. Many imaging techniques take a snapshot of the brain to find static differences between healthy individuals and those with depression. However, the brain is a highly active organ that constantly shifts among different broad patterns of electrical and chemical activity. These distinct patterns are known as brain states.
Just like a person walking through a city might take different routes depending on the layout of the streets, brain signals travel along physical pathways made of nerve fibers. This physical wiring is called white matter. Researchers use an approach known as network control theory to model how the layout of these white matter pathways guides the brain from one activity state to another. This concept is often described as an energy landscape.
In a physical landscape, water naturally flows down into valleys because it requires less energy than moving up a hill. Similarly, the brain naturally flows into certain activity states based on the layout of its white matter. Moving to a less natural state requires a higher injection of energy, making that transition harder to achieve. Researchers wanted to know if individuals with major depressive disorder possess an altered energy landscape that forces their brain to expend more effort navigating between normal states.
To investigate this problem, researchers from the Icahn School of Medicine at Mount Sinai in New York explored how the brain’s physical structure limits or promotes its activity. The team was led by B. Ülgen Kilic, a postdoctoral fellow at the Depression and Anxiety Center, along with Yael Jacob, an assistant professor of psychiatry. They hypothesized that the subjective feeling of being stuck in depression might correspond to physical changes in how the brain navigates its energy landscape.
The research team recruited a group of individuals diagnosed with major depressive disorder and a group of healthy control participants. They placed the participants in an advanced magnetic resonance imaging scanner, which uses powerful magnetic fields to take highly detailed pictures of the brain. The scientists used a specific technique that measures blood flow changes to track spontaneous brain activity while the participants were simply resting.
At the same time, the researchers mapped the physical nerve connections in each participant’s brain. They used an imaging method called diffusion tractography. This technique tracks the movement of water molecules along the protective sheaths of white matter fibers. By tracking this water movement, scientists can create a three-dimensional map of the brain’s structural wiring.
By combining the activity data with the structural maps, the team could calculate the specific energy costs required for the brain to transition between different states. The researchers fed the brain activity data into a mathematical clustering algorithm. This algorithm sorted the continuous stream of brain activity into four distinct, recurring whole-brain patterns. Each of these four brain states represents a different functional configuration.
For example, some configurations feature high activity in the default mode network. This is a system of connected brain areas that becomes highly active when a person is engaged in introspective thought, such as remembering the past or imagining the future. Other configurations feature high activity in attention and sensory networks, which help a person interact with the outside world.
By looking at how often participants jumped from one state to another, the scientists noticed distinct behavioral differences in the depressed group. One specific activity pattern, which the researchers labeled State 3, stood out. This state involves high activity in regions associated with external attention and sensory processing, and low activity in networks related to internal thought.
Individuals with major depressive disorder entered State 3 much more frequently than healthy participants, but they stayed in this state for shorter periods of time. They constantly popped in and out of this specific configuration. The team found that this rapid shifting was linked to a clinical symptom called anhedonia, which is the inability to feel pleasure or enjoyment in normally rewarding activities.
“One of the most intriguing findings was that these brain states were not necessarily stronger,” said Kilic. “Instead, they appeared more often and were harder for the brain to move away from, which points to depression as a disorder of brain dynamics rather than simply altered activity levels.”
The depressed brain showed a pronounced tendency to become caught in a loop. Participants with depression frequently bounced between State 3 and State 2. State 2 is characterized by high activity in the default mode network and regions related to cognitive control. This pattern is often associated with rumination, a common symptom of depression where a person repetitively focuses on negative thoughts.
While bouncing between these two states, the depressed brain largely ignored other available patterns. Healthy participants smoothly transitioned between a visually focused state and an emotional regulation state. Individuals with depression showed a marked reduction in their ability to make this same transition. This lack of movement between states indicates a high level of cognitive rigidity.
The team then evaluated these transitions through the lens of the energy landscape. In healthy individuals, the brain prefers to make transitions that are physically facilitated by its white matter wiring. Because the physical structure supports the shift, the energy cost remains low. In an energy landscape, this is the equivalent of a ball rolling down a gentle slope.
Individuals with major depressive disorder displayed the opposite behavior. They consistently made state transitions that required a higher energy cost. Despite having physically easier pathways available, the depressed brain fought against its own structural grain. The researchers concluded that the brain gets trapped in a deep basin within the energy landscape, forcing it to expend extra effort just to maintain basic functional loops.
“That pattern is consistent with the idea of system entrapment,” said Kilic. “It suggests the brain may become caught in repeating loops among maladaptive states.”
“Many patients describe depression as feeling stuck in negative patterns of thought, mood, and behavior,” said Jacob. “Our findings suggest that this experience of being ‘stuck’ may reflect measurable changes in the brain’s underlying dynamics.”
The study has a few limitations that warrant future investigation. The sample size for the structural wiring scans was relatively small, which means the results should be tested in larger populations. The results were also not statistically significant across every single transition measured, indicating that more data is needed to confirm the broader patterns.
Additionally, the calculations for the energy landscape rely on mathematical models that simulate external control inputs. These models do not measure raw biological energy consumption like calorie burning. Instead, they serve as a theoretical framework for understanding the difficulty of state transitions. The scientists noted that changing the specific modeling parameters could slightly alter the exact energy cost estimates.
Looking forward, the researchers hope this mapping technique can guide specific medical treatments. Doctors could use the energy landscape to predict how much stimulation is required to bump a patient’s brain out of a maladaptive loop. This approach might eventually optimize therapies that use magnetic fields or electric currents to stimulate specific brain regions.
It might also help clinicians understand how medications alter the brain’s landscape to make healthy states easier to reach. For example, treatments like psychedelics or ketamine are thought to increase global brain integration. The energy landscape model could help scientists visualize exactly how these drugs flatten the barriers between different brain states.
“In principle, this work could help researchers model how much input the brain may need, where stimulation should occur, and when interventions may be most effective in helping the brain shift out of maladaptive states,” said Jacob. “These findings move us beyond a static view of depression. By studying how brain structure and brain dynamics interact over time, we hope to move closer to more precise, biologically informed interventions for psychiatric illness.”
The team plans to test whether similar entrapment patterns exist in other psychiatric conditions like anxiety or bipolar disorder. They also aim to track patients over time to see if the energy landscape smooths out as clinical symptoms improve.
James Murrough is a co-author of the study and director of the Depression and Anxiety Discovery Center at the Icahn School of Medicine at Mount Sinai. He emphasized the clinical potential of this dynamic perspective.
“This study represents an important step forward in understanding major depressive disorder as a disorder of brain dynamics, rather than simply a problem of isolated brain regions. By pairing high-resolution neuroimaging with sophisticated mathematical modeling, we are beginning to see how the brain moves between large-scale patterns of activity over time, and how depression may involve becoming trapped in maladaptive patterns,” said Murrough. “Ultimately, this work aims to advance our fundamental understanding of depression and accelerate the discovery of novel treatments that improve outcomes for patients.”
The study, “Spatiotemporal asymmetries on brain energy landscape uncover system entrapment related to depression severity,” was authored by B. Ülgen Kilic, Jenna Jubeir, Priti Balchandani, James W. Murrough, Laurel S. Morris, and Yael Jacob.