Predicting stress response trajectories: Differential contributions of limbic and prefrontal regions to cortisol and affective responses

Why do individuals respond differently to stress? Since rodent studies indicated that stress regulation relies on limbic and medial prefrontal cortex (mPFC) outputs, we aimed to investigate whether data from these regions could also predict cortisol and affect trajectories following psychosocial stress in humans. In this pre-registered study, 281 healthy adults (145 female) were exposed to ScanSTRESS. Repeated assessments of salivary cortisol and negative affect were used to identify response trajectories (i.e. groups of participants) using latent class mixture modelling (LCMM). LCMMs without brain predictors were compared to LCMMs including structural (volume, thickness) and functional (activation, exposure-time effect) predictors from the amygdala, hippocampus, or mPFC regions, using common fit indices including the Akaike Information Criterion. Results showed that cortisol LCMMs without brain predictors exhibited a single mean trajectory, indicative of homogeneous cortisol responses across the sample. Adding brain predictors resulted in three to four response trajectories, depending on region and outcome. Within identified models, cortisol ‘hyper-response’ trajectories were predicted by larger amygdala and hippocampus volumes. Cortisol ‘non-responses’ were predicted by greater amygdala activation and volume. ‘Elevated baseline’ cortisol was predicted by higher hippocampal activation. mPFC markers did not predict cortisol trajectories, however, medial orbitofrontal cortex parameters identified negative affect response profiles mirroring measures of long-term stress exposure and affect. Together, our findings suggest dissociated roles of limbic and mPFC regions in stress regulation: While limbic structures predicted cortisol responses, the mPFC shaped affective experience.