Stress-related hypofrontality in depression and its relation to altered activation prior to the stress response

Stress responses unfold across distinct phases, including anticipation, stressor confrontation, and recovery, yet research in depression has predominantly focused on neural processes during stress exposure itself. A robust finding in this context is reduced prefrontal activation under stress in patients with depression (DP). However, neural processes preceding stress exposure may critically shape task-related activation and bias group comparisons. To date, no study has directly examined the impact of this anticipatory neural activation on prefrontal hypoactivation under stress. Here, data from two functional near-infrared spectroscopy (fNIRS) studies employing the Trier Social Stress Test (TSST) in DP and healthy controls (HC) were pooled. Results revealed pronounced group differences prior to task onset, namely increased activation in the DP group compared to HC. With respect to stress-related brain activation, we replicated the well-established finding of reduced stress-related prefrontal activation in DP compared to HC when activation prior to the beginning of each trial was not accounted for. However, when it was accounted for, group differences in stress-related activation were no longer evident. Together, these findings suggest that apparent prefrontal hypoactivation may partly reflect heightened anticipatory recruitment of regulatory brain regions rather than insufficient engagement during task execution, underscoring the importance of (re-)considering the baseline problem in future studies.