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 and symptoms of anxiety across psychiatric disorders, species, and assays. Despite the profound significance of anxiety for human health and wellbeing, the neurobiology of uncertain-threat anticipation remains unsettled. Leveraging a paradigm adapted from animal research and optimized for fMRI signal decomposition, we examined the neural circuits engaged during the anticipation of temporally uncertain and certain threat in 99 men and women. Results revealed that the neural systems recruited by uncertain and certain threat anticipation are anatomically colocalized in frontocortical regions, extended amygdala, and periaqueductal gray. Comparison of the threat conditions demonstrated that this circuitry can be fractionated, with frontocortical regions showing relatively stronger engagement during the anticipation of uncertain threat, and the extended amygdala 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 extended amygdala-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 anticipation. These observations provide a framework for conceptualizing anxiety and fear, for understanding the functional neuroanatomy of threat anticipation in humans, and for accelerating the development of more effective intervention strategies for pathological anxiety.

When extreme, anxiety can become debilitating. Anxiety disorders, which often first emerge early in development, are common and challenging to treat, yet the underlying mechanisms have only recently begun to come into focus. Here, we review new insights into the nature and biological bases of dispositional negativity, a fundamental dimension of childhood temperament and adult personality and a prominent risk factor for the development of pediatric and adult anxiety disorders. Converging lines of epidemiological, neurobiological, and mechanistic evidence suggest that dispositional negativity increases the likelihood of psychopathology via specific neurocognitive mechanisms, including attentional biases to threat and deficits in executive control. Collectively, these observations provide an integrative translational framework for understanding the development and maintenance of anxiety disorders in adults and youth and set the stage for developing improved intervention strategies.

It remains unclear whether worry and rumination represent the same functional process, or if they are unique constructs. The current study examined the relationship between worry and rumination, focusing on the potential utility of a bi-factor approach as an alternative to "common" vs. "distinctive" approaches. The results indicated that the structural relationship between worry and rumination is best represented by a bi-factor model (compared to singlefactor and two-factor models), which is comprised of a single factor that captures common variance in worry and rumination, as well as separate worry-specific and rumination-specific factors that capture unique variance. Furthermore, three orthogonal factors derived from the bi-factor model showed diverging associations with motivational traits (avoidance and approach temperament) and distinct anxiety/depression symptoms. The bi-factor conceptualization provides a framework for reconciling the diverging perspectives regarding worry and rumination, suggesting the need to pay attention to both common and unique aspects of worry and rumination.

When extreme, anxiety can become debilitating. Anxiety disorders, which often first emerge early in development, are common and challenging to treat, yet the underlying mechanisms have only recently begun to come into focus. Here, we review new insights into the nature and biological bases of dispositional negativity, a fundamental dimension of childhood temperament and adult personality and a prominent risk factor for the development of pediatric and adult anxiety disorders. Converging lines of epidemiological, neurobiological, and mechanistic evidence suggest that dispositional negativity increases the likelihood of psychopathology via specific neurocognitive mechanisms, including attentional biases to threat and deficits in executive control. Collectively, these observations provide an integrative translational framework for understanding the development and maintenance of anxiety disorders in adults and youth and set the stage for developing improved intervention strategies.

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.