Effect of Stress Response on Functional Connectivity in Young Adults With Bipolar Disorder

Two different colored heads facing each other. Concept: Bipolar Disorder
Investigators evaluated the impact of acute psychosocial stress on changes in amygdala activation and functional connectivity among young adults with bipolar disorder.

Study data published in Bipolar Disorders indicate differences in neural stress response in young adults with bipolar disorder compared with typically developing controls. The study results also suggest that aspects of stress response in early illness may inform mood symptoms in later disease. 

This preliminary study assessed changes in amygdala activation and amygdala-prefrontal cortex functional connectivity in young adults participating in an acute psychological stress test. The study participants included young adults with and without bipolar disorder who were recruited at the University of Texas at Austin. A diagnosis of bipolar disorder was confirmed through a formal assessment. Participants with symptoms of moderate to severe bipolar disorder were excluded to ensure that the study represented an early disease course.

All patients completed a modified version of the Montreal Imaging Stress Task (MIST), an acute psychological stress-inducing tool, consisting of a control math task condition involving easy arithmetic problems and a stress math task condition involving more difficult arithmetic problems with prerecorded negative auditory feedback given at fixed timepoints. Functional magnetic resonance imaging (fMRI) was performed and images acquired throughout task completion. Changes in amygdala activation and connectivity between tasks were calculated; main effects of patient group, task condition, and patient group by task condition were modeled. Participants with bipolar disorder were invited to complete a clinical follow-up assessment at 1 year, and symptoms captured at this timepoint were modeled against baseline fMRI data.

A total of 42 young adults were enrolled, among whom 19 were diagnosed with bipolar disorder. Mean age in the total cohort was 21.4 ± 2.2 years, and 71.4% were women. Demographic features were comparable between groups. During the control condition, there were no between-group differences reported in amygdala activation or functional connectivity. Amygdala activation was not found to be increased in patients compared with control participants during the stress condition. However, the stress condition elicited a significant increase in positive functional connectivity between right amygdala and the right rostral prefrontal cortex (P =.004) in patients with bipolar disorder. Among patients with bipolar disorder, increases in right amygdala-right rostral prefrontal cortex functional connectivity in response to stress were correlated with less cannabis use (P =.008), fewer weeks of depression symptoms (P <.05), and less severe depression symptoms (P <.05) over the 1-year follow-up period.

Results from this study indicate that compared with typically developing control individuals, young adults with bipolar disorder experience an increase in functional connectivity between the right amygdala and the right rostral prefrontal cortex during exposure to stress. Increased connectivity also appeared to influence later disease course and was associated with less severe mood symptoms.

As study limitations, the investigators noted the small cohort, short follow-up period, and exclusion of participants with more severe mood symptoms. Further study is therefore necessary to better understand psychosocial stress response and its impact on the clinical trajectories of bipolar disorder.

“[Our] findings…suggest that differences in neural responses to stress are evident in young adults with bipolar disorder, that is, earlier in illness course than previously investigated,” the authors wrote. “Additionally, exploratory findings support our hypothesis that neural responses to stress early in the course of illness are associated with clinical features and prospective clinical trajectories.”

Disclosure: Two study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures. 


Kirsch DE, Preston A, Tretyak V, et al. Neural functional connectivity changes to psychosocial stress in young adults with bipolar disorder and preliminary associations with clinical trajectories. Bipolar Disord. Published online September 17, 2021. doi:10.1111/bdi.13127