Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.04.24.059808v1?rss=1 Authors: Wang, F., Howard, J. D., Voss, J. L., Schoenbaum, G., Kahnt, T. Abstract: Decisions are typically guided by what we have experienced in the past. However, when direct experience is unavailable, animals and humans can imagine or infer the future to make choices. Outcome expectations that are based on direct experience and inference may compete for guiding behavior [1, 2], and they may recruit distinct but overlapping brain circuits [3-5]. In rodents, the orbitofrontal cortex (OFC) contains neural signatures of inferred outcomes and is necessary for behavior that requires inference, but it is not necessary when responding can be based on direct experience [6-10]. In humans, OFC activity is also correlated with inferred outcome expectations [11, 12], but it is unclear whether the human OFC is selectively required for inference-based behavior. To test this, here we used non-invasive targeted continuous theta burst stimulation (cTBS) [13] to inactivate the human OFC in a sensory preconditioning task designed to isolate inference-based behavior from responding that can be based on direct experience [6, 12, 14]. We show that OFC-targeted cTBS disrupts reward-related behavior only in conditions in which outcome expectations have to be mentally inferred, but that it does not impair behavior that can be based on stimulus-outcome associations that were directly experienced. These findings suggest that OFC is necessary for decision making when outcomes have to be mentally simulated, providing converging cross-species evidence for a critical role of OFC in model-based but not model-free behavior. Copy rights belong to original authors. Visit the link for more info