Dissociable neurofunctional and molecular characterizations of reward and punishment sensitivity

While the hyper-and hypo-reward or punishment sensitivities (RS, PS) have received considerable attention as prominent transdiagnostic features of psychopathology, the lack of an overarching neurobiological characterization currently limits their early identifications and neuromodulations. Here we combined microarray data from the Allen Human Brain Atlas with a multimodal fMRI approach to uncover the neurobiological signatures of RS and PS in a discovery-replication design (N=655 participants). Both RS and PS were mapped separately in the brain, with the intrinsic functional connectome in the fronto-striatal network encoding reward responsiveness, while the fronto-insular system was particularly engaged in punishment sensitivity. This dissociable functional connectome patterns related to RS and PS were also specific in differentiating decisions driven by social or monetary reward and punishment motivations. Further imaging transcriptomic analyses revealed that functional connectome variations for RS and PS were associated with topography of specific gene sets enriched in ontological pathways, including synaptic transmission, dopaminergic metabolism, immune response and stress adaptation. On the neurotransmitter level, the serotonin neuromodulator was identified as a pivotal hub regulating the intrinsic functional connectome patterns of RS and PS, with this process critically dependent on its interactions with dopaminergic, opioid and GABAergic systems. Overall, these findings indicate dissociable neural connectome mapping of RS and PS and highlight their linkage with transcriptomic profiles, which may offer valuable insights into the treatment evaluation for symptomatology relevant to reward/punishment processing deficits.