People experiencing major depressive disorder often report feeling trapped in a cycle of negative thoughts and stagnant moods that they find difficult to break free of. Recent mapping of the human brain reveals that this psychological stagnation mirrors physical reality, showing that depressed brains become stuck in frequent loops between specific patterns of activity. This research nature communicationshighlights how changes in energy pathways within the brain keep individuals trapped in these maladaptive states.
Historically, researchers have studied depression by identifying increased or decreased activity in specific areas of the brain. Many imaging techniques take snapshots of the brain to find static differences between healthy people and depressed people. However, the brain is a highly active organ, constantly changing between different broad patterns of electrical and chemical activity. These distinct patterns are known as brain states.
Just as a person walking down a street takes different routes depending on the layout of the streets, brain signals travel along physical paths made up 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 active 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 climbing up hills. Similarly, the brain naturally enters certain states of activity based on the layout of its white matter. Transitioning to a less natural state requires more energy to be injected, making the transition more difficult to achieve. Researchers wanted to know whether people with major depressive disorder have an altered energy landscape that forces the brain to expend more effort moving back and forth between normal states.
To investigate this question, researchers at the Icahn School of Medicine at Mount Sinai in New York investigated how the physical structure of the brain limits or facilitates brain activity. The team was led by B. Urgen Kilic, a postdoctoral fellow in the Center for Depression and Anxiety, and Yael Yacob, 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 energetic 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 a sophisticated magnetic resonance imaging scanner, which used powerful magnetic fields to take highly detailed pictures of their brains. Scientists used special techniques that measure changes in blood flow to track spontaneous brain activity while participants were simply resting.
At the same time, the researchers mapped the physical neural 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 sheath of white matter fibers. By tracking this water movement, scientists can create a three-dimensional map of the brain’s structural wiring.
By combining activity data and structural maps, the team was able to 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. The algorithm classified the continuous stream of brain activity into four different repeating whole-brain patterns. Each of these four brain states represents a different functional configuration.
For example, some configurations are characterized by high activity on the default mode network. This is a system of connected brain regions that becomes highly active when a person engages in reflective thinking, such as remembering the past or imagining the future. Other configurations are characterized by high activity of attention and sensory networks, which help a person interact with the outside world.
By observing how often participants jumped from one state to another, scientists noticed distinct behavioral differences in the depressed group. One particular pattern of activity, which the researchers dubbed state 3, stood out. This state involves high activity in areas associated with external attention and sensory processing, and low activity in networks associated with internal thinking.
People with major depressive disorder entered state 3 much more frequently than healthy participants, but remained in this state for shorter periods of time. They were constantly coming in and out of this particular configuration. The researchers found that this rapid change is associated with a clinical condition called anhedonia, which causes people to experience pleasure and enjoyment in normally rewarding activities.
“One of the most interesting findings is that these brain states are not necessarily strong,” Kilic said. “Instead, they appeared more frequently and were more difficult for the brain to disengage from. This shows that depression is a disturbance in brain dynamics, not simply a change in activity levels.”
Depressed brains showed a marked tendency to get stuck in a loop. Depressed participants frequently moved back and forth between state 3 and state 2. State 2 is characterized by high activity in regions associated with the default mode network and cognitive control. This pattern is often associated with rumination, a common symptom of depression that involves repeatedly focusing on negative thoughts.
While moving back and forth between these two states, the depressed brain largely ignored other available patterns. Healthy participants smoothly transitioned between visually focused and emotionally regulated states. People with depression have been shown to have a significantly reduced 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. Healthy human brains prefer transitions that are physically facilitated by white matter wiring. Because the physical structure supports this change, energy costs remain low. In the energy landscape, this corresponds to a ball rolling down a gentle slope.
People with major depressive disorder showed the opposite behavior. They consistently made state transitions that required higher energy costs. Even though physically easier routes were available, the depressed brain was fighting against its own structural particles. The researchers concluded that the brain is trapped in a deep basin of energy environment, forced to work extra hard just to maintain basic functional loops.
“The pattern is consistent with the idea of a system trap,” Kilic says. “This suggests that the brain may be stuck in a repeating loop of maladaptive states.”
“Many patients describe depression as feeling trapped in negative patterns of thought, mood, and behavior,” Jacob says. “Our findings suggest that this experience of being ‘stuck’ may reflect measurable changes in the brain’s underlying dynamics.”
This study has several limitations that require future investigation. The sample size for structural wiring scans is relatively small, meaning that the results need to be tested on a larger population. The results are also not statistically significant across all measured transitions, indicating that more data are needed to confirm broader patterns.
Additionally, energy landscape calculations rely on mathematical models that simulate external control inputs. These models do not measure raw biological energy expenditure such as calorie burn. Instead, they serve as a theoretical framework for understanding the difficulties of state transitions. The scientists noted that changing certain modeling parameters can slightly change the exact energy cost estimate.
Looking to the future, researchers hope that this mapping technology will help guide specific medical treatments. Doctors may be able to use energy status to predict how much stimulation is needed to break a patient’s brain out of a maladaptive loop. This approach could ultimately optimize treatments that use magnetic fields or electrical currents to stimulate specific brain regions.
It may also help clinicians understand how drugs change the brain’s landscape, making it easier to reach a healthy state. For example, treatments such as psychedelics and ketamine are thought to increase overall brain integration. Energy landscape models could help scientists visualize exactly how these drugs flatten the barriers between different brain states.
“In principle, this study could help researchers model how much input the brain needs, where stimulation should occur, and when interventions are most effective in bringing the brain out of a maladaptive state,” Jacob said. “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 us closer to more precise, biologically informed interventions for mental illness.”
The research team plans to test whether similar patterns of entrapment exist in other mental illnesses, such as anxiety and bipolar disorder. We also aim to follow patients over time to see if their energy situation levels out as their clinical symptoms improve.
James Murrow 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 combining high-resolution neuroimaging with sophisticated mathematical modeling, we are beginning to understand how the brain moves between large-scale patterns of activity over time, and how depression can become stuck in maladaptive patterns.” “Ultimately, this research aims to advance our fundamental understanding of depression and accelerate the discovery of new treatments that improve patient outcomes.”
The study, titled “Spatiotemporal asymmetries in brain energy landscape reveals system entrapment associated with depression severity,” was authored by B. Ülgen Kilic, Jenna Jubeir, Priti Balchandani, James W. Murrough, Laurel S. Morris, and Yael Jacob.
