Dysfunctional reward processing is implicated in various mental disorders, including attention deficit hyperactivity disorder (ADHD) and addictions. Such impairments might involve different components of the reward process, including brain activity during reward anticipation. We examined brain nodes engaged by reward anticipation in 1,544 adolescents and identified a network containing a core striatal node and cortical nodes facilitating outcome prediction and response preparation. Distinct nodes and functional connections were preferentially associated with either adolescent hyperactivity or alcohol consumption, thus conveying specificity of reward processing to clinically relevant behavior. We observed associations between the striatal node, hyperactivity, and the vacuolar protein sorting-associated protein 4A (VPS4A) gene in humans, and the causal role of Vps4 for hyperactivity was validated in Drosophila. Our data provide a neurobehavioral model explaining the heterogeneity of rewardrelated behaviors and generate a hypothesis accounting for their enduring nature.uccessful behavioral adaptation requires effective reward processing that determines whether a desired goal is approached and maintained. Reward processing can be separated into behavioral anticipation or reward expectancy as a consequence of learning and behavioral and subjective responses to rewarding outcomes (1). In humans, dysfunctional reward processing (in particular, dysfunctional reward anticipation) has been implicated in various externalizing disorders, including attention-deficit hyperactivity disorder (ADHD) (2) and addiction (3). Brain regions involved in reward anticipation include the ventral tegmental area, the medial forebrain bundle, and the nucleus accumbens/ventral striatum (VS; including the ventral caudate-putamen) as well as the ventromedial and insular cortices (4). More recently, observations have been reported to link reward processing in humans with cortical activation (5), including the primary somatosensory (6), primary visual (V1) (7), and auditory (8) cortices. Dopamine is the principal neurotransmitter regulating reward processing, particularly through the mesocorticolimbic pathway (9), the neuronal projection from the ventral tegmental area to the VS and prefrontal cortex. A general feature of striatal information processing is the control by rewardrelated dopamine signals of direct and indirect cortical inputs from different neurotransmitter systems, including noradrenaline, glutamate, and GABA as well as acetylcholine, endogenous opioids, and cannabinoids (10). As a consequence, striatal dopaminergic activity integrates cortical and subcortical inputs with reward response. In addition to direct and indirect regulation by heteroceptors, dopamine release is regulated by presynaptic autoreceptors of the D2 family, in particular D2 dopamine receptors (DRD2) that Author contributions: T.J., S.D., C.P.M., J.F., A.R., H.F., and G.S. designed research; T.J., C.M., S.D., D.A.G., C.T., B.R., F.N., T.B., G.J.B., A.L.W.B., U.B...