Same depression, different brains: Studying map hidden patterns

Two patients walked into the office of a psychiatrist with the same symptoms of depression, which was depressed, fatigue and concentration problems. But their brain scans tell completely different stories.

New research from the University of Washington shows that depression is much more complex than clinical symptoms suggest, and multiple brain patterns may produce the same mental health struggles.

The study, published in Biopsychiatry, challenges how we understand the neurobiological basis of depression. Using brain imaging data from more than 6,000 people in the UK biobank, the researchers found that patients with matching depression symptoms can have significantly different brain activity patterns, a phenomenon called “many-to-one-pair brain symptoms mapping.”

The basis of decomposition of depression

“The heterogeneity of depression, i.e. the difference between patients with the same diagnosis, has been a topic in our field,” explains lead investigator Janine D. Bijsterbosch, Ph.D., the Mallinckrodt Institute of Radiology, University of Washington. The team wanted to understand whether clinical symptoms and brain changes followed a simple one-to-one relationship or a more complex pattern.

Instead of studying depression as a single disease, the researchers isolated specific components: Anhedonia (unable to feel pleasure), emotional depression, physical symptoms, chronic onset, late onset and acute severe impairment. Each group showed a different brain signature compared to those with mixed symptoms.

The advanced depression group showed particularly surprising results. Rather than expected brain tissue loss, these patients show even an increase in gray matter volume in key areas. This contradicts the previous hypothesis: brain atrophy drives late depression, suggesting that larger brain volumes may represent protective mechanisms related to recovery.

Hidden cognitive split

The most compelling findings emerged when researchers looked more deeply into patients with acute depression. Despite the same symptom characteristics, brain imaging revealed two different subgroups with distinct cognitive abilities.

“Our study also shows that multiple brain profiles in patients with acute depression cause the same clinical manifestations, the first time providing concrete evidence of a more one-to-one brain symptom mapping,” said Yvette I. Sheline, a co-investor at the University of Pennsylvania, MD.

Despite severe depression, one subgroup maintained normal cognitive function while the other showed severe cognitive impairment. The standard depression questionnaire cannot distinguish these groups – only brain scans showed differences.

Major findings that reshape depression understanding:

• Patients grouped by isolated symptoms exhibit stronger brain abnormalities than those with mixed symptoms
• Advanced depression is associated with retained brain volume without expected tissue loss
• There are two cognitively different subgroups in severe depression cases
• Depressed, specifically connected to brain areas involved in introspection

Advantages of standardized modeling

The researchers used a complex technique called normative modeling, which measures how each patient’s brain deviates from healthy population norms while taking into account differences in age, gender, and scanners. This approach proved to be more sensitive than traditional group comparisons, revealing brain patterns that might still be hidden.

Crucially, studies have found that when depression symptoms are mixed together, often in clinical practice, brain signals become weaker and harder to detect. This explains why previous neuroimaging studies of depression have produced inconsistent results.

Clinical significance and future direction

“Depression is a very heterogeneous medical condition. The inability to accurately subtype patients is a major obstacle to matching individual patients with more likely treatments,” said John Krystal, editor of biopsychiatry.

Cognitive differences found in the subgroup of acute depression suggest practical applications. Brain imaging may ultimately help predict which patients will experience cognitive problems in their emotional symptoms as well as targeted interventions.

However, the problem remains. The study focused on the elderly (average 61 years old) in the UK biobank, limiting the prevalence of young people and different races. The researchers also created artificial populations by isolating a single symptom—most real patients experience multiple depressive characteristics simultaneously.

“Identifying a subtype of depression that may differ in treatment can greatly improve clinical care in future patients with depression,” concluded Deanna M. Barch, Ph.D., co-invader at the University of Washington. “However, our findings suggest that clinical care for this type of depression can be determined only by addressing this clinical and neurobiological depression.”

The study suggests that effective depression treatment may require symptom assessment and brain imaging, a personalized drug approach that can identify hidden complexity of the disease under seemingly similar manifestations.

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