Familial risk and illness burden jointly shape prefrontal hypoactivation in depression: An fNIRS study

Prefrontal dysfunction is a well-documented deficit in major depressive disorder (MDD), yet it remains unclear whether this represents a genetic endophenotype or a persistent "scar" of the illness. This study aimed to disentangle familial risk from disease chronicity by simultaneously examining remitted MDD (rMDD) patients, unaffected high-risk (HR) individuals, and healthy controls (HC). We recruited 87 participants: 35 with rMDD, 15 unaffected HR individuals, and 37 HCs. Hemodynamic responses in the bilateral prefrontal cortex (PFC) were recorded using functional near-infrared spectroscopy (fNIRS) during an emotional Verbal Fluency Task (VFT). Resting-state network topology (global/local efficiency) was analyzed via graph theory. The rMDD group exhibited significantly attenuated PFC activation compared to HCs (p = 0.024) during VFT. The HR group displayed an intermediate level of activation that did not statistically differ from either HCs (p = 0.700) or the rMDD group (p = 1.000). Behaviorally, rMDD patients showed blunted emotional modulation of performance compared to HCs (p < 0.05). No significant group differences were found in resting-state network topology. In conclusion, prefrontal hypoactivation during emotional processing appears to be a graded deficit shaped by both familial vulnerability and illness burden, rather than by a simple heritable trait. Combined with blunted behavioral reactivity to emotional cues in remission, these measures shift in their utility from predicting onset to tracking illness impact. Thus, fNIRS-derived prefrontal activation may serve as a biomarker for monitoring incomplete neural recovery rather than predicting initial disease onset.