Targeted stimulation of an orbitofrontal network disrupts decisions based on inferred, not experienced outcomes

When direct experience is unavailable, animals and humans can imagine or infer the future to guide decisions. Behavior based on direct experience versus inference may recruit partially distinct brain circuits. In rodents, the orbitofrontal cortex (OFC) contains neural signatures of inferred outcomes, and OFC is necessary for behavior that requires inference but not for responding driven by direct experience. In humans, OFC activity is also correlated with inferred outcomes, but it is unclear whether OFC activity is required for inference-based behavior. To test this, we used noninvasive network-based continuous theta burst stimulation (cTBS) in human subjects (male and female) to target lateral OFC networks in the context of a sensory preconditioning task that was designed to isolate inference-based behavior from responding that can be based on direct experience alone. We show that, relative to sham, cTBS targeting this network impairs reward-related behavior in conditions in which outcome expectations have to be mentally inferred. In contrast, OFC-targeted stimulation does not impair behavior that can be based on previously experienced stimulus-outcome associations. These findings suggest that activity in the targeted OFC network supports 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 control of behavior.