Despite Recovery from Depression, the Brain Retains Sensitivity to Negative Cues

Researchers have found that even after recovery, individuals who previously experienced depression may retain a heightened sensitivity to negative cues and face challenges in regulating responses to potential punishment. The findings from the new study opens in new tab/window in Biological Psychiatry: Cognitive Neuroscience and Neuroimaging opens in new tab/window, published by Elsevier, could lead to better ways to identify individuals at risk for relapse and help develop more targeted interventions to improve long-term recovery and prevent future episodes of depression.

Depression is characterized by high relapse rates, with up to 80% of individuals experiencing a return of symptoms within five years, demonstrating that recovery does not always guarantee lasting resilience. To improve prevention, a better understanding of the underlying mechanisms that contribute to an individual's vulnerability to relapse is needed.

Lead investigator Henricus G. Ruhé, MD, PhD, Radboud University Medical Center, Department of Psychiatry, and Donders Institute for Brain-Cognition and Behavior, Nijmegen, Netherlands, says, “The high relapse rates observed in depression suggest that there must be ongoing processes in the brain that continue to make individuals vulnerable to future episodes, even after symptoms have improved. Prior research has shown that people with depression often remain sensitive to punishment, even after remission. This led us to focus on aversive learning—a type of Pavlovian classical conditioning where a person learns to avoid a stimulus or behavior by associating it with an unpleasant outcome. We focused on the habenula—a small region of the brain involved in processing negative feedback. We wanted to find out whether abnormalities in this system persist even after someone has recovered from depressive symptoms.”

For this study, researchers used functional MRI (fMRI) to assess brain activity during an aversive learning task in 36 patients with recurrent depression and 27 healthy controls. Participants learned associations between a picture and an unpleasant bitter taste while undergoing the fMRI scan.

Imaging revealed evidence that individuals with remitted depression showed increased habenula activity specifically during the expectation of punishment, along with reduced connectivity between the habenula and the ventral tegmental area, an important midbrain nucleus responsible for producing the reward related neurotransmitter dopamine and an area thought to be regulated by habenula activity. These patterns suggest a heightened sensitivity to negative cues and a reduced ability to regulate responses to potential punishment, even after symptoms have subsided.

Editor-in-Chief of Biological Psychiatry: Cognitive Neuroscience and Neuroimaging Cameron S. Carter, MD, University of California Irvine, concludes, “While much is known about how depression affects brain function during active illness, we have little understanding of whether these changes persist after recovery. This study highlights that even when individuals no longer show obvious symptoms of depression, they may still experience heightened sensitivity to negative cues, which could contribute to relapse risk. Understanding these lingering effects could lead to better ways to identify at-risk individuals and help develop more targeted interventions to improve long-term recovery and prevent future episodes of depression.”

Notes for editors

The article is "Aberrant Aversive Learning Signals in the Habenula in Remitted Patients with Recurrent Depression," by Jessica M. de Klerk-Sluis, Hanneke Geugies, Roel J.T. Mocking, Caroline A. Figueroa, Paul F.C. Groot, Jan-Bernard C. Marsman, Philip F.P. van Eijndhoven, Dirk E.M. Geurts, and Henricus G. Ruhé (https://doi.org/10.1016/j.bpsc.2025.04.006 opens in new tab/window). It appears online in advance of volume 10, issue 9 (September 2025) of Biological Psychiatry: Cognitive Neuroscience and Neuroimaging opens in new tab/window, published by Elsevier.

The article is openly available athttps://www.biologicalpsychiatrycnni.org/article/S2451-9022(25)00134-X/fulltext opens in new tab/window.

Copies of this paper are also available to credentialed journalists upon request; please contact Rhiannon Bugno at [email protected] opens in new tab/window. Journalists wishing to interview the study’s authors should contact Jessica M. de Klerk-Sluis, MD, at [email protected] opens in new tab/window.

The authors’ affiliations and disclosures of financial and conflicts of interest are available in the article.

Cameron S. Carter, MD, is Chair of the Department of Psychiatry & Human Behavior at the University of California, Irvine School of Medicine. His disclosures of financial and conflicts of interest are available here opens in new tab/window.

This work was supported by a dedicated grant from the Dutch Brain Foundation (Hersenstichting Nederland: 2009(2)-72) and by an NWO/ZonMW VENI-Grant #016.126.059.

About Biological Psychiatry: Cognitive Neuroscience and Neuroimaging

Biological Psychiatry: Cognitive Neuroscience and Neuroimaging opens in new tab/window is an official journal of the Society of Biological Psychiatry opens in new tab/window, whose purpose is to promote excellence in scientific research and education in fields that investigate the nature, causes, mechanisms and treatments of disorders of thought, emotion, or behavior. In accord with this mission, this peer-reviewed, rapid-publication, international journal focuses on studies using the tools and constructs of cognitive neuroscience, including the full range of non-invasive neuroimaging and human extra- and intracranial physiological recording methodologies. It publishes both basic and clinical studies, including those that incorporate genetic data, pharmacological challenges, and computational modeling approaches. The 2024 Journal Impact Factor^TM score, from Clarivate, for Biological Psychiatry: Cognitive Neuroscience and Neuroimaging is 4.8. www.sobp.org/bpcnni opens in new tab/window

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