Fear, anxiety, and the extended amygdala— Absence of evidence for strict functional segregation

Since the time of Freud, the distinction between fear and anxiety has been a hallmark of influential models of emotion and emotional illness, including the Diagnostic and Statistical Manual of Mental Disorders (DSM) and Research Domain Criteria (RDoC) framework. Fear and anxiety disorders are a leading cause of human misery and morbidity. Existing treatments are inconsistently effective, underscoring the importance of developing accurate models of the underlying neurobiology. Although there is agreement that the extended amygdala (EA) plays a central role in orchestrating responses to threat, the respective contributions of its two major subdivisions—the central nucleus of the amygdala (Ce) and bed nucleus of the stria terminalis (BST)—remain contentious. To help adjudicate this debate, we performed a harmonized mega-analysis of fMRI data acquired from 295 adults as they completed a well-established threat-anticipation paradigm. Contrary to popular double-dissociation models, results demonstrated that the Ce responds to temporally uncertain threat and the BST responds to certain threat. In direct comparisons, the two regions showed statistically indistinguishable responses, with strong Bayesian evidence of regional equivalence. These observations underscore the need to reformulate conceptual models that posit a strict segregation of temporally certain and uncertain threat processing in the EA.