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Scientists at Mount Sinai have identified three important brain connections associated with long-term improvement in patients receiving deep brain stimulation (DBS) for severe depression that has not responded to conventional treatments. The discovery could help researchers make this experimental therapy more precise and effective.

Published October 1 in the American Journal of Psychiatry, the research examined the largest group of patients assembled across multiple independent cohorts to date who had received subcallosal cingulate deep brain stimulation (SCC DBS) for treatment-resistant depression.

The researchers found that lasting improvements were consistently associated with electrical stimulation reaching three specific white matter pathways: the cingulum bundle, forceps minor, and medial uncinate fasciculus/ventral amygdalofugal pathways.

These findings strengthen the case for using detailed maps of the brain’s connections to determine exactly where electrodes should be implanted, rather than choosing their positions based primarily on anatomical landmarks. Known as connectome-based targeting, this strategy has already helped shape the ongoing Abbott TRANSCEND clinical trial, a randomized, controlled study that uses individualized brain connectivity maps to guide SCC DBS treatment.

“This study underscores the importance of individualized surgical targeting for achieving optimal outcomes with deep brain stimulation for depression,” said Helen Mayberg, MD, Mount Sinai Professor in Neurotherapeutics and founding Director of the Nash Family Center for Advanced Circuit Therapeutics at the Icahn School of Medicine at Mount Sinai. “In any randomized controlled trial of a neuromodulation treatment, precise lead placement and confirmation that the intended brain target has been engaged are essential first steps. We still have much to learn about which patients are most likely to benefit from stimulation of this particular target, but developing imaging-based signatures that can match patients to their optimal treatment remains a central goal of our research.”

How Deep Brain Stimulation Targets Severe Depression

For people with treatment-resistant depression, standard therapies have failed to provide adequate relief. Researchers are investigating deep brain stimulation as a possible treatment for individuals living with severe, persistent symptoms.

The procedure involves surgically placing electrodes inside the brain to deliver controlled electrical signals to circuits involved in depression. However, positioning the electrodes correctly remains one of the greatest challenges.

Electrical stimulation does not simply affect the brain tissue closest to an implanted electrode. It can also influence larger networks through the white matter pathways that connect different brain regions. As a result, two patients with electrodes implanted in nearly identical locations may experience very different outcomes depending on which connections are actually stimulated.

Earlier research from Mount Sinai and Emory University helped establish the importance of these networks. In studies published between 2014 and 2023 in Biological Psychiatry, Molecular Psychiatry, and Nature, the teams identified white matter pathways associated with successful SCC DBS treatment and developed a method for planning electrode placement using brain connectivity maps.

The latest investigation sought to determine whether those connections were also important in patients treated at other research centers. Scientists also wanted to understand whether differences in the pathways reached by stimulation could help account for patients who did not benefit.

Three Brain Connections Linked to Lasting Improvement

To investigate, the researchers examined information from several clinical studies, including the BROADEN trial and a patient cohort at the University of Toronto, where SCC DBS was originally developed.

They used computer models of the electrical fields generated by implanted electrodes alongside maps of brain connectivity. This allowed them to estimate which pathways received stimulation and compare those patterns across different patient groups.

The results showed a consistent relationship between sustained improvement and stimulation of the cingulum bundle, forceps minor, and medial uncinate fasciculus/ventral amygdalofugal pathways.

One finding was especially notable. Across the study sites, patients who had not responded to treatment after two years showed a lack of stimulation engagement with the left cingulum bundle.

The researchers did not investigate whether moving electrodes to reach this pathway would improve those patients’ symptoms. Nevertheless, the pattern offers a possible explanation for why apparently similar electrode placements can produce different results. An electrode might be positioned in the correct general region but still fail to activate all the connections associated with lasting improvement.

“This study addresses an important question in DBS: not simply which area of the brain to stimulate, but which connections within that area need to be engaged,” said Brian Kopell, MD, Director of the Center for Neuromodulation at Mount Sinai. “For a network disorder such as depression, millimeters can determine whether stimulation reaches the pathways we intend to modulate. Identifying and reproducibly engaging those pathways gives us a more precise surgical target and a framework for understanding why otherwise similar electrode placements may produce different clinical outcomes.”

Toward More Personalized Depression Treatments

Although reaching these three pathways appears important, the researchers emphasize that electrode placement alone is unlikely to determine whether a patient improves.

The investigation concentrated on identifying the brain connections that should receive stimulation. Additional studies are needed to determine which individuals are most likely to benefit from SCC DBS and how electrical stimulation should be adjusted as treatment continues.

There were also limitations to the brain imaging data. Individual diffusion MRI scans, which can provide information about a person’s white matter connections, were not available for every participant. Consequently, much of the analysis used generalized maps of brain connectivity rather than maps created specifically for each patient.

For the Emory patient group, the researchers were able to compare results obtained from generalized connectivity maps with those based on individual diffusion imaging. Both approaches produced consistent findings, providing further support for the importance of the identified pathways. However, more research is needed to establish the value of patient-specific imaging.

Future investigations will explore whether additional brain imaging measurements, including white matter integrity and functional connectivity, can help identify suitable patients, improve electrode placement, and guide treatment settings.

“Our findings show precisely engaging these white matter pathways is a critical first step toward sustained response,” said Ki Sueng Choi, PhD, Associate Professor, Imaging Core Leader at the Center for Advanced Circuit Therapeutics at Mount Sinai, and corresponding author of the study. “The next step is to characterize abnormal functional and structural brain states along these pathways to build more detailed models for setting patient-specific stimulation parameters, including amplitude, frequency, and pulse width, for precision medicine.”

By combining increasingly detailed brain maps with personalized stimulation settings, scientists hope to better understand why some people experience lasting relief while others do not. The findings represent another step toward developing more targeted treatments for severe depression, although further clinical research is necessary to establish how much these approaches can improve outcomes.

Certain imagery-based psychotherapy techniques may help reduce fear of failure connected to painful childhood experiences, according to research from scientists at SWPS University and the Nencki Institute of Experimental Biology. The findings were published in the journal Frontiers in Psychology.

Difficult experiences early in life, including criticism, neglect, or severe reactions from caregivers, can influence emotional well-being and quality of life years later. How adults respond when a child makes a mistake may be especially important in shaping future patterns of thought and emotion. In some cases, those experiences can contribute to a fear of failure rooted in the belief that mistakes make a person less worthy in the eyes of others.

Researchers from the Poznań-based Laboratory of Affective Neuroscience at the Institute of Psychology, SWPS University, and the Laboratory of Brain Imaging at the Nencki Institute of Experimental Biology in Warsaw set out to determine whether imagery-based psychotherapy could reduce the ongoing effects of these painful memories on everyday life.

Testing Whether Memory Work Can Create Lasting Change

The randomized, controlled clinical trial included 180 young adults (between 18 and 35 years of age) who experienced fear of failure. During a two-week period, participants took part in four therapy sessions focused on difficult childhood memories involving criticism.

One group used the Imagery Exposure (IE) technique. Participants were asked to recall situations that had triggered fear or anxiety (the active control group).

A second group received Imagery Rescripting (ImRs), a technique designed to change the way a memory unfolds in the imagination. Participants brought a distressing experience to mind and then imagined a “defender” (e.g., a therapist) entering the scene, confronting the person delivering the criticism, and offering support to the child.

The third group used the same therapeutic approach, but with a 10-minute delay procedure (ImRs-DSR). Researchers designed this delay to interfere with the memory trace associated with the critical experience, potentially strengthening the intervention’s effects.

Participants completed questionnaires and interviews, while researchers also tracked physiological measures. Follow-up assessments took place three and six months later.

Fear, Guilt, and Stress Declined

All of the imagery-based approaches produced a significant and lasting reduction in fear of failure. Participants also reported lower levels of negative emotions, including sadness and guilt.

Their bodies appeared to respond differently as well. Physiological reactions to memories of criticism decreased, indicating that recalling distressing experiences no longer triggered the same level of intense stress. These improvements remained evident during follow-ups at three and six months, suggesting that the psychological effects were stable over time.

“The study shows that it is possible to reduce the intensity of negative emotions and arousal associated with memories of childhood criticism. Properly selected techniques can influence how these memories are experienced, making them less burdensome,” says study co-author Julia Bączek, a psychologist from the Laboratory of Affective Neuroscience at the Institute of Psychology, SWPS University.

Why Surprise May Matter

The researchers found that imagery rescripting worked especially well when it produced a moment of surprise. They linked this effect to prediction error, which occurs when there is a mismatch between what someone expects and what actually happens.

That unexpected difference may help loosen established emotional patterns and make it easier for the mind to replace old, painful responses with new ones.

“We have shown that a crucial part of imagery-based therapy is creating a discrepancy between what the patient expects and what actually happens in the new memory. It is this surprise that paves the way for a lasting therapeutic change,” says study co-author Stanisław Karkosz, a cognitive scientist from the Laboratory of Affective Neuroscience at the Institute of Psychology, SWPS University.

Most of the brain’s roughly 100 billion neurons are produced before birth. However, the small number of new neurons that continue to form in the adult hippocampus may play an important role in protecting against depression, according to new research from Columbia University Vagelos College of Physicians and Surgeons.

The findings provide the first evidence that neurogenesis, the process of producing new neurons, stalls in the brains of adults with major depressive disorder. Researchers also identified molecular programs involved in controlling this process, offering potential clues for developing new treatments.

“Historically, depression was thought to be a disease of neurotransmitter deficiency, especially serotonin, but we now think that depression stems from multiple issues that affect our neurons’ ability to adapt to stress and changing environments,” says Maura Dupont, professor of psychiatry, who led the research.

“Without the ability to create new neurons, people with depression may not have the resilience to effectively adapt to the environment.”

How New Neurons May Shape Memory and Emotion

The researchers focused on the hippocampus, a brain region that plays a major role in episodic memory and emotional responses to the environment. It is also one of the few areas of the adult brain that continues to generate new neurons.

Although the hippocampus is not the only brain region involved in depression, its influence over both memory and emotion has made it an important area of study. Researchers believe changes there may contribute to the tendency of people with depression to interpret experiences more negatively.

“The hippocampus is important for our ability to distinguish between similar but different memories and separate the emotional connotation of past memories and current events,” Dupont says.

This ability is known as pattern separation. When it becomes impaired, individual memories and the emotions attached to them may become less distinct, allowing separate experiences to blend together.

“You may be out with a friend for lunch, but she’s tired and doesn’t talk much. With intact pattern separation, you remember this as a unique event. With impaired pattern separation, it becomes mixed with previous memories of feeling rejected, leading you to think, ‘They’re upset with me’,” Dupont explains. “And I see this a lot in my patients, where they can only retrieve negative information from their memories.”

Research in mice has shown that adult neurogenesis is necessary for pattern separation. A recent study involving patients with brain tumors, in whom neurogenesis was eliminated by radiation therapy directed at the hippocampus, suggests that the same relationship may exist in humans.

“It’s important to emphasize that we do not yet know the complete mechanism, particularly in humans, but the newborn neurons seem to enhance pattern separation because they are especially responsive to new experiences and can be incorporated into new memory circuits more easily, allowing new memories to be stored separately from the old ones,” Dupont says. “Turning neurogenesis back on may be a way to treat depression in some people by rewiring their hippocampus circuit.”

Depression Affects More Than New Neuron Growth

The researchers found that the changes linked to depression extended well beyond neurogenesis. New neuron formation operates within a larger hippocampal circuit that stores episodic memories along with their emotional significance, and molecular disruptions appeared throughout that system.

The affected genes included those involved in building new connections between neurons, supporting communication among brain cells, supplying cellular energy, and moving materials within cells.

The trisynaptic circuit, the hippocampus’s primary pathway for establishing new emotional memories, also displayed evidence of inflammation and cellular stress in people with depression.

To identify these changes, researchers studied nearly half a million brain cells collected from people with depression and control subjects shortly after each donor’s death.

Using an array of recently developed techniques, the team measured the activity of every gene within individual cells and examined whether cellular proteins had been altered. This enormous dataset allowed researchers to see what individual cells were doing and determine exactly where affected cells were located within the hippocampal circuit.

Genes, Environment, and the Biology of Depression

The analysis revealed altered activity in several genes whose genetic variants have previously been associated with major depression.

Other disrupted genes showed epigenetic changes that may reflect the influence of environmental factors. Epigenetic mechanisms can adjust how strongly genes are turned on or off without altering the underlying DNA sequence.

“These are like dimmer switches that control how active genes are, and they are affected by life experiences such as stress, learning, aging, chemicals, etc.,” Dupont says.

The diversity of molecular changes may also help explain why depression can look so different from one person to another.

“Overall, the wide range of effects we found could reflect different pathogenetic mechanisms, perhaps indicating that depression is not just one disease,” she adds.

Researchers still have only a limited understanding of depression’s underlying biology, according to Dupont. By defining the disorder more precisely at the cellular and molecular levels, studies like this one could eventually provide new targets for treatment.

Toward Molecular Subtypes of Depression

Dupont and her colleagues hope that depression could eventually be classified according to its molecular characteristics, much as cancer increasingly is today.

“We want to reclassify depression based on its molecular features, similar to what has been done in cancer,” Dupont says. “Classifying cancers based on their cellular characteristics, not their locations, has led to new and improved treatments. We hope the same will be true for depression and other psychiatric or brain diseases.”

A smile or a frown may reveal more than emotion alone. The faces that capture a child’s attention could provide important clues about their mental health and how depression develops.

New research from Binghamton University, State University of New York, suggests that depression may influence how strongly children focus on emotional expressions such as happy or sad faces. The pattern appears to differ depending on whether a child has a family history of depression.

Researchers at the Mood Disorders Institute at Binghamton University study how depression develops in children and adolescents, with particular attention to how family history and emotional experiences may influence vulnerability over time. By identifying these patterns while children are still developing, scientists hope to better understand who may be at greater risk and eventually improve prevention strategies.

“Most of the vulnerabilities that we focus on are still developing during this time period,” said Brandon Gibb, director of the Mood Disorders Institute and SUNY distinguished professor of psychology. “You can catch things as they’re developing, rather than only studying them once they’re already there and pretty stable.”

Following Children’s Attention Over Time

Earlier research has linked depression with greater attention to sad faces. However, those associations have generally been modest, and scientists have not been sure whether biased attention contributes to depression or develops because of it.

The Binghamton study was designed to investigate that question by tracking both depressive symptoms and attention patterns over time. According to the researchers, it is the first study to examine how changes in each may predict later changes in the other among children.

“The real novel piece is that we looked at these transactional relations,” said Kelly Gair, a PhD student at Binghamton and lead author of the paper. “Between attentional biases and depressive symptoms, we looked at the way that they were mutually predicting one another across the time points, which is especially novel and hasn’t been done before.”

The research team, which also included Leslie A. Brick from the University of New Mexico, followed 242 children and their mothers for two years. Participants were assessed every six months.

During each visit, children viewed pairs of faces on a screen. One face showed a neutral expression, while the other displayed an emotion (happy, sad, or angry). Eye tracking technology measured which face held the child’s attention and for how long.

Children in the study looked at faces conveying different emotions onscreen, and eye tracking technology recorded where their attention veered. Photo credit: NimStim Set of Facial Expressions (Tottenham et al., 2009).

Family History Changes the Pattern

The results suggest that increasing depressive symptoms do not affect every child’s attention in the same way. Family history appeared to play an important role.

Among children whose mothers had a history of major depressive disorder, rising depressive symptoms were associated with greater attention to sad faces. In other words, as these children experienced more symptoms themselves, their attention became increasingly drawn toward expressions of sadness.

“For those who are already at risk, the more these children experience depression themselves, the more they lose their ability to pull their attention away from the sad things around them,” Gibb said.

“We know that when you’re depressed, it changes what you pay attention to,” Gair said. “Our results suggest that these changes may be more long-lasting and may differ depending on family history. One thought is that for children of mothers with depression, who are exposed to more facial displays of sadness from interactions with their mom, these types of facial expressions become even more salient when they experience depression themselves, so their attention becomes increasingly stuck on sad expressions.”

Happy Faces May Lose Their Pull

A different pattern emerged among children whose mothers had no history of depression.

When depressive symptoms increased in these children, they did not become more focused on sad expressions. Instead, they paid less attention to happy faces.

“In our lower-risk children, what seems to be happening is that experiences of depression are eroding a protective factor, which is how much they pay attention to happy faces,” Gibb said.

The distinction suggests that depression may alter emotional attention through different pathways depending on a child’s underlying level of familial risk. For some children, sadness may become increasingly difficult to ignore. For others, positive emotional signals may simply become less likely to capture their attention.

Two people diagnosed with depression can experience vastly different symptoms. One might struggle with persistent anxiety and repetitive negative thoughts, while another may experience trauma related symptoms or substance abuse. But do these differences also appear in the way their brains function?

Researchers at the University of Helsinki investigated this question and uncovered a striking finding: people with the same depression diagnosis can have dramatically different patterns of brain activity. In some cases, communication between brain regions was unusually strong, while in others, it was weaker than normal.

Depression is a major global health concern. According to the World Health Organization (WHO, 2025), approximately 332 million (5.2%) adults worldwide are affected. In Finland, depression is the leading individual cause of both extended sick leave and disability pensions.

Brain Study Reveals Five Distinct Depression Profiles

To investigate the biological differences associated with depression, researchers examined brain activity in 263 people diagnosed with major depressive disorder and 75 healthy participants who served as a comparison group.

The analysis revealed five distinct groups based on differences in functional connectivity, a measure of how closely activity in different brain regions is coordinated. When two regions show synchronized activity, it suggests they are working together as part of a larger brain network. However, stronger connectivity does not necessarily mean the brain is functioning better.

“What was particularly interesting was the contrasting patterns of brain activity found under the umbrella of the same depression diagnoses. In some individuals, the functional connectivity between brain regions was stronger than usual, while in others it was weaker,” says Director Satu Palva of the Neuroscience Center, University of Helsinki.

These differences were also associated with particular symptoms. Participants in one group showed especially strong connections between brain regions, along with more pronounced substance abuse problems. Another group displayed weaker connections and a greater prominence of post-traumatic stress disorder (PTSD) symptoms.

The contrasting results could help explain why earlier studies examining the brains of people with depression have sometimes reached conflicting conclusions. If researchers study different combinations of patients, they may observe very different patterns, even though everyone involved has received the same diagnosis.

The findings add to growing evidence that depression may not have a single, consistent biological signature. Instead, the condition could involve several distinct patterns of brain function.

The Five Brain Patterns Linked to Depression

The researchers classified participants with depression into five groups based on how strongly different brain areas communicated and the frequencies at which their activity was coordinated.

Each group had a characteristic pattern of brain connectivity and associated symptoms:

Group 1: Strong connectivity and severe symptoms

Participants generally showed relatively strong connections between brain regions. This profile was associated with more severe symptoms across several areas, including depression, anxiety, rumination, and reduced ability to function in daily life. Rumination refers to repeatedly dwelling on distressing thoughts, worries, or negative experiences.

Group 2: Weaker connectivity and milder depression

This group was characterized by relatively weak communication between brain regions. Compared with the other groups, participants generally experienced milder symptoms.

Group 3: Widespread weak connectivity and trauma symptoms

People in this group showed reduced connectivity across substantial portions of the brain. Symptoms associated with post-traumatic stress disorder (PTSD) were particularly prominent.

Group 4: Mixed connectivity and multiple challenges

This profile combined unusually strong connections in some brain regions with weaker connections in others. Participants tended to experience more severe depression, greater substance abuse problems, and lower overall well-being.

Group 5: The strongest connectivity and substance abuse symptoms

Participants in the fifth group had the strongest connections between brain regions of any group identified in the study. Substance abuse was a particularly prominent issue, while trauma related symptoms were less pronounced than in the other groups.

Importantly, all five groups also showed differences from the healthy participants. These distinctions extended beyond whether brain connections were strong or weak. The groups also differed in which brain regions were involved and the frequencies at which their activity was synchronized.

Together, the patterns suggest that people diagnosed with depression may experience substantially different changes in how their brain networks operate.

Measuring Brain Activity With Millisecond Precision

To capture these differences, the scientists used magnetoencephalography (MEG), a brain imaging technique that detects extremely faint magnetic fields produced by electrical activity in the brain.

Unlike methods that track slower changes associated with brain activity, MEG can follow electrical signals as they unfold over extremely short periods. This makes it particularly useful for investigating the timing and coordination of communication between brain regions.

Using MEG, the researchers recorded brain activity in all 263 participants with depression and the 75 healthy control subjects.

“MEG enabled us to monitor electrical brain activity with millisecond precision, helping us get closer to what actually happens in the brain at any given moment. Previously, depression phenotypes have been studied using methods with slower responses,” Palva notes.

This high level of temporal precision allowed the team to examine rapid changes in brain activity that might be difficult to distinguish using slower measurement techniques.

By studying these fast signals, the researchers were able to identify differences not only in the strength of connectivity but also in the frequencies at which brain regions appeared to work together.

Could Brain Activity Lead to More Personalized Depression Treatments?

The discovery raises an important possibility for the future of mental health care: treatments might eventually be selected partly according to a person’s individual pattern of brain activity.

Today, finding an effective depression treatment can involve trying different medications or therapies and evaluating how well each works. Because patients can respond differently to the same treatment, identifying the most suitable approach is not always straightforward.

Brain activity measurements could eventually provide additional information to help guide these decisions. However, the researchers emphasize that their findings are not yet ready for clinical use.

“We’re not yet at the point where brain measurements can be used to choose the right treatment for patients, but the study does show one possible route,” Palva says.

A major long-term goal is to better understand how particular symptoms relate to the way brain networks function. Connecting these biological patterns with patients’ experiences could help researchers develop more precise ways to identify and characterize depression.

Eventually, such knowledge might allow doctors to determine which therapies are most likely to help individual patients, potentially reducing the amount of trial and error involved in treatment.

For now, the five brain profiles offer a different way to understand depression. Rather than assuming that one diagnosis corresponds to one underlying pattern of brain activity, the findings suggest that depression can involve markedly different biological changes, sometimes even in opposite directions.