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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.

Researchers led by the University of Texas at Austin have created a soft wearable patch that improved REM sleep in real-world testing without medication or surgery. Known as NEUSLeeP, the device combines gentle ultrasound stimulation with electrodes that track brain activity as it happens. This allows the patch to influence deep areas of the brain involved in sleep while also monitoring the brain’s response.

“This is the first time we’ve been able to noninvasively target deep brain regions involved in REM sleep, while simultaneously monitoring brain activity,” said Kai Wing “Kevin” Tang, a recent UT biomedical engineering Ph.D. graduate who led the research effort. “Our skin-attached NEUSLeeP patch opens up new possibilities for understanding sleep and treating sleep disorders in home settings,” added Huiliang “Evan” Wang, assistant professor in the Cockrell School of Engineering’s Department of Biomedical Engineering, who supervised Tang’s work and served as the principal investigator (PI) directing the overall project.

Wearable Patch Helps People Reach REM Faster

The researchers tested the technology in a study involving 28 people, with the results published in Nature Communications. On average, participants entered REM sleep 43 minutes sooner and remained in that stage for about 16 minutes longer.

The benefits were observed in both healthy sleepers and participants experiencing some sleep difficulties. Users also described the patch as comfortable and safe, and the study reported minimal adverse effects.

Possible Benefits for Stress and Emotional Health

Among healthy participants, NEUSLeeP stimulation also increased heart rate variability, which is commonly used as an indicator of the body’s ability to respond to stress. Brain imaging revealed changes in circuits associated with emotion, raising the possibility that the technology could support mood regulation and psychological resilience.

“REM sleep is not just about dreaming — it’s about emotional reset and stress adaptation,” explained Gregory Fonzo, assistant professor in the Dell Medical School’s Department of Psychiatry and Behavioral Sciences and one of the project’s co-PIs. “By enhancing REM, we may help people better cope with stress and improve their overall well-being.”

REM sleep disruptions have been associated with depression, anxiety and post-traumatic stress disorder (PTSD). Current approaches to sleep problems, including medication and behavioral therapy, may cause side effects or may not directly address the underlying factors that interfere with REM sleep.

Future Trials for Insomnia, Depression and PTSD

The team plans to conduct larger studies to verify the initial results and evaluate whether NEUSLeeP could help people with PTSD, depression and chronic insomnia. The researchers also see potential uses in home sleep monitoring, neuroscience research and personalized sleep treatments.

“Our vision is a future where patients with mental health disorders can optimize their sleep with a noninvasive and safe treatment,” said Vincent Mysliwiec, M.D., a professor at UT Health San Antonio, a leading expert in sleep disorders, and another co-PI on the project. “This technology could help millions of people get the restorative sleep they need.”

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.

Nightmares can be one of the most distressing symptoms of post-traumatic stress disorder (PTSD), a condition that may develop after a person experiences a disaster, serious accident, violence, combat, or another severe trauma. During sleep, people with PTSD may feel as though they are living through the event again in vivid detail. These repeated episodes can cause severe sleep loss and make some people afraid to go to bed.

Available medications often provide limited relief from trauma-related nightmares. Researchers at Charité — Universitätsmedizin Berlin therefore examined whether a prescription drug containing THC, one of the active compounds found in cannabis, could help. The findings, published in Nature Medicine, showed that more than half of the participants responded to the treatment. More than one-third said their nightmares disappeared completely.

Why PTSD Nightmares Are So Difficult to Treat

The effects of a terrifying or life-threatening experience can continue long after the immediate danger has passed. In post-traumatic stress disorder (PTSD), the brain has difficulty processing overwhelming events. The memories may be stored in a way that makes them return involuntarily and without conscious control.

This can happen during the day and at night. While sleeping, people with PTSD may repeatedly relive the trauma until they wake in panic. Antidepressants and medications that lower blood pressure are among the treatments sometimes used, but their effectiveness is limited. They also often do little to relieve the nightmares themselves. Germany has not yet approved a medication specifically for trauma-related nightmares.

Prof. Stefan Röpke studies trauma-related disorders at the Department of Psychiatry and Neurosciences on the Benjamin Franklin Campus of Charité. While exploring possible new treatments, he and his team, working with additional research partners, turned their attention to tetrahydrocannabinol, commonly known as THC. It is the primary psychoactive compound in cannabis.

THC interacts with the body’s endocannabinoid system, which helps regulate sleep, stress, and the way emotional memories are processed. Stefan Röpke explains: “There is evidence suggesting that during REM sleep — the intense dream phases in which the brain processes experiences and regulates emotions — THC reduces dream activity and thereby alleviates nocturnal stress responses.”

Testing Dronabinol for PTSD Nightmares

Cannabis-based medicines are already used in pain treatment, especially when standard therapies do not work well enough or cause intolerable side effects. In Germany, access became easier after the so-called “Cannabis for medical purposes” law went into effect in 2017. The legislation expanded the medical and scientific use of cannabinoids derived from plants or produced synthetically.

For the study, the researchers used Dronabinol, a prescription medication containing THC obtained directly from the cannabis plant and administered as drops. They wanted to find out whether the drug could safely reduce nightmares linked to PTSD.

More than 170 people with post-traumatic stress disorder and frequent, severe nightmares took part. For ten weeks, participants received either Dronabinol or a cannabis-flavored placebo that looked identical. They took the drops each evening before going to bed.

Neither the participants nor the healthcare professionals knew who received the medication and who received the placebo. This double-blind, placebo-controlled design is considered the gold standard for testing medical treatments.

Nightmares Declined More With THC Treatment

At the end of the ten weeks, nightmare severity had fallen significantly more in the Dronabinol group than in the placebo group. On a scale ranging from zero to eight, the average nightmare burden dropped by 3.7 points among participants taking Dronabinol. The placebo group experienced an average decrease of 2.2 points. For the people affected, the difference was clearly noticeable.

“More than a third of the patients treated with Dronabinol reported that they no longer experienced any nightmares after ten weeks. Another 21 percent reported that their nightmare burden had been at least halved,” as Stefan Röpke stated. “And about five out of six patients in the dronabinol group felt their health had markedly improved.”

No Severe Side Effects or Signs of Dependence

The cannabinoid appeared to act specifically on nightmares and sleep rather than on every aspect of PTSD. The researchers could not conclusively show that it reduced the overall severity of post-traumatic stress disorder or any accompanying depression.

Even so, most participants experienced meaningful relief. By interrupting the repeated nighttime reliving of trauma, the treatment allowed many of them to sleep more peacefully.

No severe side effects were reported. Mild and moderate effects, including dizziness, headaches, and increased appetite, occurred more frequently among those receiving Dronabinol. The researchers also found no withdrawal symptoms after participants stopped taking the evening doses at the end of the study.

Future studies will examine whether the treatment remains safe and effective when used for longer periods. Researchers also want to determine whether patients may gradually develop tolerance to the drug.

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.