Uncertainty, not mental content, drives dorsomedial prefrontal engagement during inferences about others.

To navigate social life, humans make inferences about the intentions, beliefs, emotions, and personalities of other people, i.e., they mentalize. A network of brain regions consistently engages more during mentalizing than during carefully controlled comparison tasks, sometimes cited as evidence of domain-specific mentalizing processes. Here we investigated the possibility that engagement of these regions during mentalizing may be due to uncertainty. We scanned 46 participants (33 female, 13 male) using fMRI as they made mental and non-mental inferences (about human minds, human bodies, and physical objects) under varying levels of uncertainty. Uncertainty explained activation in a key region of the mentalizing network: the dorsal medial prefrontal cortex (DMPFC). Higher uncertainty was associated with greater DMPFC engagement across conditions, and, when controlling for uncertainty, DMPFC engagement did not differentiate mental from non-mental inferences. Results suggest that the apparently selective DMPFC engagement during social inference may be better understood as a response to uncertainty, which is often elevated in social contexts, with implications for the cognitive architecture of the social brain and disorders of social function.Significance statement Human social behavior often hinges on inferences about minds of other people (mentalizing), as highlighted by cases of atypical mentalizing, including autism. Longstanding debate surrounds whether mentalizing arises from specialized cognitive processes or more general mechanisms. In past research, the brain's "mentalizing network" is consistently more engaged during mentalizing than other activities, possibly supporting domain-specificity. In contrast, here we show that the engagement of a key brain region in the mentalizing network, the dorsal medial prefrontal cortex, can be explained as a response to uncertainty rather than mental content. This suggests a revision of scientific understanding of social cognition's neural basis, with possible implications for the origins of atypicalities in social behavior. .