Investigating functional connectivity differences during food vs. monetary reward processing across appetitive phenotypes of major depressive disorder.

Motivation for food intake is shaped not only by physiological energy needs (i.e., homeostatic signals) but also by hedonic and reward-related processes; the anticipation of a pleasurable eating experience or the consumption of comfort foods to alleviate feelings of sadness can drive food intake even in the absence of hunger (). Homeostatic and interoceptive processes are commonly associated with viscerosensory regions such as the insula and related interoceptive networks, whereas hedonic valuation and incentive salience are more strongly supported by mesocorticolimbic circuitry, including the nucleus accumbens (NAcc), orbitofrontal cortex (OFC), ventromedial prefrontal cortex (vmPFC), and dorsal anterior cingulate cortex (dACC). In major depressive disorder (MDD), disruptions in hedonic valuation (i.e., reward processing), including food reward, contribute to the complexity of MDD, emphasizing the need for a clearer understanding of how these impairments manifest across various clinical presentations (). Recent research has deepened the understanding of distinct MDD phenotypes, particularly appetitive phenotypes, due to their profound effects on behavior, motivation, and neurobiological functioning (). Resting-state connectivity studies reveal divergent neural patterns associated with appetite changes in MDD; individuals with MDD who experience decreases in appetite (i.e., hypophagic MDD; HypoMDD) show decreased NAcc connectivity with the vmPFC and hippocampus () and greater connectivity between the right lateral OFC and left precentral gyrus, compared to healthy controls (), while individuals with MDD who experience increases in appetite (i.e., hyperphagic MDD; HyperMDD) show weaker NAcc connectivity to the insular gustatory cortex (), suggesting alterations in reward valuation network function. While prior work has identified regional activation differences in appetitive MDD phenotypes, activation alone does not capture how neural regions interact as functional networks during reward processing. Functional connectivity analyses provide a complementary perspective by examining the coordination among key nodes within reward-related circuits, which may be particularly relevant for understanding the network-level mechanisms that drive aberrant anticipatory and consummatory responses to food and monetary rewards. For instance, evidence from task-based functional MRI investigations demonstrate divergent network activation in appetitive MDD phenotypes. Individuals with HyperMDD show greater activation in the mesocorticolimbic reward system when viewing food cues compared to healthy controls and to those with HypoMDD (; ; ). HypoMDD individuals, on the other hand, are characterized by reduced activation in neural regions involved in interoceptive (homeostatic) processing, suggesting differential patterns of activities when processing food-related stimuli (). While these studies provide valuable insights into neurobiological substrates of appetite changes in MDD, little is known about how neural patterns differ between these groups in response to specific reward types (e.g., food vs. monetary incentives) or during distinct reward processing phases (e.g., anticipation vs. outcome). This distinction is important because disruptions in these processes may clarify how individuals with different appetitive profiles of MDD anticipate, evaluate, and respond to rewards, and may also identify altered sensitivity to reward and loss.