BACKGROUND: Anticipation involves preparatory resource allocation to optimize upcoming responses, linked to insular cortex function. Although major depressive disorder (MDD) shows impairments in anticipatory processing and blunted insula activation, it is unclear whether this pattern holds across MDD with and without comorbid anxiety disorders (MDD+ANX). The Monetary Incentive Delay task (MID), combined with magnetic resonance imaging (MRI)-guided electroencephalogram (EEG) source localization, offers a robust approach to study anticipatory mechanisms in MDD subtypes. METHOD: Participants with MDD (n=53) or MDD+ANX (n=108) and healthy controls (CTL
n=38) completed the MID task during simultaneous EEG-MRI recording. Stimulus-preceding negativity event-related potentials were source-localized to identify insular cortical activity differences across groups (MDD, MDD+ANX, CTL), sex (male, female), MID conditions (gain, loss), hemisphere (left, right), and six insular subregions. RESULTS: Behavioral performance revealed that the CTL group reacted faster than the MDD+ANX in both gain and loss conditions (p=.03). Insular source analysis showed lower activity in MDD+ANX (p<
.001) and MDD (p=.06) compared to CTL during gain anticipation, and lower activity in MDD+ANX than both CTL (p=.003) and MDD (p<
.001) during loss anticipation. CONCLUSIONS: Results highlight potential intervention targets for improving anticipatory deficits in MDD+ANX. The MDD+ANX group exhibited distinctive patterns of insular cortical activity, with lower activity during the anticipation of both gain and loss feedback compared to the control and MDD groups, suggesting significant neural alterations. Moreover, in MDD+ANX, higher anxiety severity was linked to increased insula activity during loss anticipation, indicating a specific neural correlate of anxiety in this comorbid condition.