Bivalent habenula modulation of human monoaminergic midbrain and cortical pathways

The habenula is implicated in signaling negative reward prediction errors (RPE), yet direct causal evidence demonstrating its influence on downstream human brain circuits is limited. Using ultra-high field (7T) fMRI and dynamic causal modelling across two negative RPE-inducing experimental tasks, we characterize habenula-directed connectivity with monoaminergic midbrain and cortical pathways in healthy adults. Negative feedback drove strong habenula inhibition of ventral tegmental area and dorsal raphe nucleus activity, while positive feedback had an excitatory effect. These core effects are replicated across reversal learning and perceptual decision uncertainty tasks, establishing a generalizable mechanism for behavioral adaptation. Task-specific modulatory effects emerged in pathways between the subcortical and cortical regions (ventral tegmental area[->]dorsal anterior cingulate cortex, dorsal raphe nucleus[->]medial prefrontal cortex, and dorsal anterior cingulate cortex[->]habenula), revealing context-dependent cortical elaboration of negative RPE-driven habenula signals. This provides the first evidence in humans for bivalent causal modulation of habenula function on monoaminergic midbrain and cortical pathways, demonstrating how the brain integrates negative and positive signals to guide adaptive behavior.