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.

Objective To provide a comprehensive quantitative review of biological, environmental, and behavioral correlates across domains of cognitive function in sickle cell disease (SCD). Methods Forty-seven studies were identified in PubMed, MedLine, and PsycINFO involving 2573 participants with SCD. Results Meta-analytic findings across all identified samples indicate that hemoglobin and hematocrit were positively correlated with Full Scale IQ [FSIQ; r = .15, 95% confidence interval (CI) = .10 to .21], language and verbal reasoning (r = .18, 95% CI = .11 to .24), and executive function (r = .10, 95% CI = .01 to .19) with small effects and significant heterogeneity. Transcranial Doppler velocity was negatively associated with visual spatial and perceptual reasoning (r = −.18, 95% CI = −.31 to −.05). Socioeconomic status was positively associated with FSIQ (r = .23, 95% CI = .17 to .28), language and verbal reasoning (r = .28, 95% CI = .09 to .45), visual spatial and perceptual reasoning (r = .26, 95% CI = .09 to .41), and executive function (r = .18, 95% CI = .07 to .28) with small to medium effects. Finally, total behavioral problems were negatively associated with FSIQ (r = −.12, 95% CI = −.21 to −.02) such that participants with lower FSIQ exhibited greater behavioral and emotional problems. Conclusions Findings provide evidence for biological, environmental, and psychosocial corelates across multiple domains of cognitive function in SCD. More research on more specific cognitive domains and psychosocial correlates is needed in addition to assessments of interactional models among risk factors.

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.

Negative affect is a fundamental dimension of human emotion. When extreme, it contributes to a variety of adverse outcomes, from physical and mental illness to divorce and premature death. Mechanistic work in animals and neuroimaging research in humans and monkeys have begun to reveal the broad contours of the neural circuits governing negative affect, but the relevance of these discoveries to everyday distress remains incompletely understood. Here, we used a combination of approaches—including neuroimaging assays of threat anticipation and emotional-face perception and more than 10,000 momentary assessments of emotional experience—to demonstrate that individuals who showed greater activation in a cingulo-opercular circuit during an anxiety-eliciting laboratory paradigm experienced lower levels of stressor-dependent distress in their daily lives ( ns = 202–208 university students). Extended amygdala activation was not significantly related to momentary negative affect. These observations provide a framework for understanding the neurobiology of negative affect in the laboratory and in the real world.