Researchers at the Icahn School of Medicine at Mount Sinai have identified distinctive patterns in how the brain transitions between activity states in people with depression, providing new insight into why depressive symptoms can feel persistent and difficult to overcome.
Published online in Nature Communications [DOI: https://doi.org/10.1038/s41467-026-71961-4], the study combined advanced neuroimaging techniques with mathematical modeling to examine how the brain moves between functional activity states over time. The findings suggest that depression may involve a form of "brain-state entrapment," in which the brain becomes more likely to enter certain patterns of activity and less likely to transition out of them.
"Many patients describe depression as feeling stuck in negative patterns of thought, mood, and behavior," said Yael Jacob, PhD, Assistant Professor of Psychiatry at the Dennis S. Charney, MD, Depression and Anxiety Discovery Center at the Icahn School of Medicine at Mount Sinai and senior author of the paper. "Our findings suggest that this experience of being 'stuck' may reflect measurable changes in the brain's underlying dynamics."
Most neuroimaging studies of depression have focused on differences in activity levels across brain regions. In contrast, the Mount Sinai team approached depression as a dynamical systems challenge, examining how the brain continuously transitions among different activity states.
Investigators combined resting-state functional magnetic resonance imaging with diffusion tractography, a technique used to map the brain's structural connections. Together, these approaches enabled researchers to model the brain's "energy landscape," a framework that estimates how easy or difficult it is for the brain to move between different patterns of activity.
The researchers found that certain brain states associated with depression occurred more frequently but lasted for shorter periods of time, suggesting instability in brain activity patterns rather than increases or decreases in activity.
"One of the most intriguing findings was that these brain states were not necessarily stronger," said Ülgen Kilic, PhD, a postdoctoral fellow at the Depression and Anxiety Center and the first author of the paper. "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 study also revealed asymmetries in the brain's energy landscape. Some transitions appeared easier for the brain to enter than to exit, and individuals with depression more frequently followed energetically demanding pathways even when lower-energy alternatives existed.
"That pattern is consistent with the idea of system entrapment," said Dr. Kilic. "It suggests the brain may become caught in repeating loops among maladaptive states."
Researchers say the findings could ultimately contribute to more personalized approaches to diagnosing and treating depression. The framework may help scientists better understand how interventions such as transcranial magnetic stimulation, deep brain stimulation, antidepressant medications, ketamine, and psychedelics influence the brain's energy landscape and state transitions.
"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 Dr. 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's next steps include testing whether similar brain-state dynamics are present across other psychiatric disorders and studying whether these patterns change with treatment or predict clinical improvement.
"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 James Murrough, MD, PhD, Director of The Dennis S. Charney, MD, Depression and Anxiety Discovery Center at the Icahn School of Medicine at co-author of the paper. "Ultimately, this work aims to advance our fundamental understanding of depression and accelerate the discovery of novel treatments that improve outcomes for patients."
About the Icahn School of Medicine at Mount Sinai
The Icahn School of Medicine at Mount Sinai is internationally renowned for its outstanding research, educational, and clinical care programs. It is the sole academic partner for the seven member hospitals* of the Mount Sinai Health System, one of the largest academic health systems in the United States, providing care to New York City's large and diverse patient population.
The Icahn School of Medicine at Mount Sinai offers highly competitive MD, PhD, MD-PhD, and master's degree programs, with enrollment of more than 1,200 students. It has the largest graduate medical education program in the country, with more than 2,700 clinical residents and fellows training throughout the Health System. The Graduate School of Biomedical Sciences offers 13 degree-granting programs, conducts innovative basic and translational research, and trains more than 4705 postdoctoral research fellows.
Ranked 11th nationwide in National Institutes of Health (NIH) funding, the Icahn School of Medicine at Mount Sinai is among the 90th percentile of U.S. private medical schools in Sponsored Programs Direct Expenditures per Principal Investigator, according to the Association of American Medical Colleges. More than 6,900 scientists, educators, and clinicians work within and across dozens of academic departments and multidisciplinary institutes with an emphasis on translational research and therapeutics. Through Mount Sinai Innovation Partners (MSIP), the Health System facilitates the real-world application and commercialization of medical breakthroughs made at Mount Sinai.
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* Mount Sinai Health System member hospitals: The Mount Sinai Hospital; Mount Sinai Brooklyn; Mount Sinai Morningside; Mount Sinai Queens; Mount Sinai South Nassau; Mount Sinai West; and New York Eye and Ear Infirmary of Mount Sinai.
