Anxiety and the neurobiology of temporally uncertain threat anticipation

Abstract

When extreme, anxiety—a state of distress and arousal prototypically evoked by uncertain danger—can be debilitating. Uncertain anticipation is a shared feature of situations that elicit signs of anxiety across disorders, species, and assays. Despite the 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 men and women. Results revealed that uncertain and certain threat are anatomically co-localized in fronto-cortical regions and the 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 temporally uncertain and certain threat. 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 extreme anxiety.SIGNIFICANCE STATEMENTAnxiety—an emotion prototypically associated with the anticipation of uncertain harm—has profound significance for public health and wellbeing, yet it is unclear how the human brain responds to uncertain threat. Leveraging a novel neuroimaging paradigm in a large sample, we identify a core network responsive to both uncertain and certain threat anticipation, and show that this network bifurcates into regions with a bias for one kind of threat over the other. The extended-amygdala occupies center-stage in neuroscientific models of anxiety, but its functional architecture has remained contentious. Here we demonstrate that its major subdivisions show statistically indistinguishable responses to temporally uncertain and certain threat. Collectively, these observations indicate the need to revise how we think about anxiety and fear.

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“…Anatomical data. Methods were similar to those employed in recent reports by our group (e.g., Hur, Smith, et al, 2020). T1-weighted images were inhomogeneity corrected using N4 software (Tustison et al, 2010) and filtered using the denoise function in Advanced Neuroimaging Tools (ANTs; Avants et al, 2011).…”