Anxiety and the neurobiology of uncertain threat anticipation

When extreme, anxiety--a state of distress and arousal prototypically evoked by uncertain danger--can become debilitating. Uncertain anticipation is a shared feature of situations that elicit signs of anxiety across disorders, species, and assays. Despite the profound significance of anxiety for human health and wellbeing, the neurobiology of uncertain threat anticipation remains remarkably unsettled. Leveraging a paradigm adapted from animal research and optimized for functional MRI, we examined the neural circuits engaged during the anticipation of temporally uncertain and certain threat in 99 individuals. Results revealed that uncertain and certain threat are anatomically co-localized in the neocortex and extended amygdala (EA). Comparison of the two threat conditions demonstrated that this core network can be fractionated, with fronto-cortical regions showing relatively stronger engagement during the anticipation of uncertain threat, and the EA showing the reverse pattern. Although there is widespread agreement that the bed nucleus of the stria terminalis and dorsal amygdala--the two major subdivisions of the EA--play a critical role in orchestrating adaptive responses to potential danger, their precise contributions to human anxiety have remained contentious. Follow-up analyses demonstrated that these regions show statistically indistinguishable responses to uncertain and certain threat, indicating the need to reformulate prominent models of anxiety, including the National Institute of Mental Health9s Research Domain Criteria. These observations provide a framework for conceptualizing anxiety and fear, for understanding the functional neuroanatomy of threat anticipation in humans, and for guiding the development of more effective intervention strategies for pathological anxiety.