Philadelphia, June 26, 2025 – 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 in Biological Psychiatry: Cognitive Neuroscience and Neuroimaging , 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."
