Targeted Stimulation of an Orbitofrontal Network Disrupts Decisions Based on Inferred, Not Experienced Outcomes

Abstract

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. SIGNIFICANCE STATEMENT It is widely accepted that the orbitofrontal cortex (OFC) is important for decision-making. However, it is less clear how exactly this region contributes to behavior. Here we test the hypothesis that the human OFC is only required for decision-making when future outcomes have to be mentally simulated, but not when direct experience with stimulus–outcome associations is available. We show that targeting OFC network activity in humans using network-based continuous theta burst stimulation selectively impairs behavior that requires inference but does not affect responding that can be based solely on direct experience. These results are in line with previous findings in animals and suggest a critical role for human OFC in model-based but not model-free behavior.

Neural representations of others’ traits predict social decisions

“…Evidence that the lateral OFC mediates the effect of trait representations on social decision-making connects to a large body of evidence in humans and other species that the OFC contributes to decision-making that is guided by inference or imagination of outcomes. Previous studies used paradigms such as outcome devaluation or preconditioning to demonstrate that the OFC (in particular, the lateral OFC) is necessary for inference-based decision-making in rats ( 43 , 44 ), monkeys ( 45 , 46 ), and humans ( 47 – 49 ). Furthermore, recent neuroimaging and electrophysiological studies revealed that the OFC represents latent features of the environment, such as the hidden state of the present trial in sequential or learning tasks, that are not directly observable but are critical for outcome prediction ( 29 , 30 , 50 – 54 ).…”

Olfactory perceptual decision-making is biased by motivational state

“…Pure odors and odor mixtures were presented to participants via a computer-controlled olfactometer at a steady flow rate of 3.2 L/min, as in our previous studies [ 16 , 42 , 67 ]. The olfactometer included 2 mass flow controllers (Alicat Scientific, Tucscon, Arizona, USA) that operated independently, so pure odors could be diluted with odorless air, and food and nonfood food odors could be combined to form custom mixtures.…”

A double-blind study assessing the impact of orbitofrontal theta burst stimulation on goal-directed behavior.

“…Reducing activity in OFC seems counterproductive at first glance: the OFC is responsible for the very behaviors that are deficient in disorders of compulsivity. In addition, cTBS to the right dlPFC, including areas selected based on OFC connectivity, has been found to reduce—not increase—model-based planning and use of learned cue-cue associations in nonclinical populations (Smittenaar et al, 2013; Wang et al, 2020). Disorders of compulsivity are linked to maladaptive behavior in interconnected cortico-striatal-thalamic loops, not just OFC activity.…”

“…We previously found good test–retest reliability and temporal stability of model-based planning in people with elevated compulsivity symptoms (Brown et al, 2020) and that OCD symptom improvement after exposure and response prevention did not significantly change model-based planning (Wheaton et al, 2019), suggesting that behavioral measures of compulsivity are stable and persistent. However, acute neural circuit modification, via transcranial magnetic stimulation, can rapidly reduce use of model-based planning, as measured by behavioral indices (Smittenaar et al, 2013; Wang et al, 2020). In addition, although several behavioral tasks correlate with compulsive behaviors in separate investigations, little work has investigated whether measures from different tasks are measuring the same construct.…”