Differential Insular Cortex Activation During Reward Anticipation in Major Depressive Disorder With and Without Anxiety.

Background: Anticipation involves preparatory resource allocation to optimize upcoming responses, linked to insular cortex function. Although individuals with major depressive disorder (MDD) show impairments in anticipatory processing and blunted insula activation, it is unclear whether this pattern holds across MDD with comorbid anxiety disorders (MDD+ANX) and MDD without comorbid anxiety disorders. The monetary incentive delay (MID) task, combined with magnetic resonance imaging (MRI)-guided electroencephalography (EEG) source localization, offers a robust approach to study anticipatory mechanisms in MDD subtypes.

Methods: Participants with MDD (n = 53) or MDD+ANX (n = 108) and healthy control participants (CTLs; 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 task conditions (gain, loss), hemisphere (left, right), and 6 insular subregions.

Results: Behavioral performance revealed that the CTL group reacted faster than the MDD+ANX group in both gain and loss conditions (p = .03). Insular source analysis showed lower activity in the MDD+ANX (p < .001) and MDD (p = .06) groups than in the CTL group during gain anticipation and lower activity in the MDD+ANX group than in both CTL (p = .003) and MDD (p < .001) groups 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 than the CTL and MDD groups, suggesting significant neural alterations. Moreover, in the MDD+ANX group, higher anxiety severity was linked to increased insula activity during loss anticipation, indicating a specific neural correlate of anxiety in this comorbid condition.