Altered stress responses are closely linked to mental disorders, but the role of brain structure in acute cortisol responses to psychosocial stress remains underexplored, particularly in healthy individuals. Previous studies, with predominantly small samples, primarily focused on selected limbic regions and functional measures. Thus, this study investigates associations between brain structure and cortisol responses to psychosocial stress, exploring if hypothalamic–pituitary–adrenal axis reactivity can be predicted from brain morphology.

Our study included 291 subjects (157 females, 18–62 years) and consisted of two parts. First, a confirmatory analysis examined associations between specific cortical surface area, thickness, and subcortical volume with stress-induced cortisol increases using Permutation Analysis of Linear Models (PALM). Second, we conducted an exploratory whole-brain vertex-wise analysis, followed by out-of-sample prediction of cortisol increases from structural measures.

We found consistent negative associations between cingulate cortex (CC) sub-structures and acute cortisol increases. In PALM- and whole-brain analysis, a smaller surface area of the left rostral and caudal anterior cingulate cortex (cACC), posterior cingulate cortex, and right cACC were associated with higher cortisol stress responses, particularly in males. The left cACC surface area emerged as the most promising predictor in machine learning analyses. Additionally, other fronto-limbic structures were also associated with or predictive of acute cortisol reactivity.

Our findings demonstrate that cortical and subcortical structural measures, particularly smaller surface areas of the CC, predict acute hormonal stress responses. Notably, the left cACC emerged as the most consistent predictor, emphasizing its important role in stress reactivity.