Scott, Z. S. | Search bioRxiv

bioRxiv2026

Extended amygdala function is governed by threat probability, not uncertainty

Anxiety is a universal experience that arises as we anticipate negative events that may or may not happen. When extreme, anxiety is a major cause of distress, suffering, and disability-adjusted life years, with nearly one in four individuals experiencing clinically relevant anxiety in their lifetime1-3. Elucidating the biological basis of anxiety has the potential to help people understand, cope with, and ultimately receive improved treatments for their anxiety. The canonical neuroscientific model of anxiety posits that distinct regions of the extended amygdala (EA) elicit distress that is conditional on threat uncertainty4. Here, we refute this model using a precise computational framework to disambiguate specific dimensional facets of threat uncertainty in a racially diverse sample of 104 individuals. We show that self-report, psychophysiological, and neural correlates of threat anticipation are much more strongly associated with threat probability than uncertainty per se. Importantly, EA regions, including the central nucleus of the amygdala (Ce) and bed nucleus of the stria terminalis (BST), were most reliably associated with threat probability--contrary to the canonical model. Re-examination of the pioneering experiments that motivated the canonical model reveal a previously unappreciated confound between probability and uncertainty, suggesting the novel hypothesis that EA regions differ in their sensitivity to low-probability threats. Our fMRI data support this, showing that BST is more sensitive to low-probability threats than Ce. Moreover, lesion experiments in rhesus monkeys (Macaca mulatta) demonstrate that BST causally contributes to defensive behavior in low-probability threat contexts. Together, these data reconcile previous empirical inconsistencies, provide a fresh theoretical perspective on the neurobiology of anxiety, and underscore the theoretical importance of a formal lingua franca for coordinated cross-species emotion research.

neuroscience↗

bioRxiv2024

A shared threat-anticipation circuit is dynamically engaged at different moments by certain and uncertain threat

Temporal dynamics play a central role in models of emotion: "fear" is widely conceptualized as a phasic response to certain-and-imminent danger, whereas "anxiety" is a sustained response to uncertain-or-distal harm. Yet the underlying neurobiology remains contentious. Leveraging a translationally relevant fMRI paradigm and theory-driven modeling approach in 220 adult humans, we demonstrate that certain- and uncertain-threat anticipation recruit a shared circuit that encompasses the central extended amygdala (EAc), periaqueductal gray, midcingulate, and anterior insula. This circuit exhibits persistently elevated activation when threat is uncertain and distal, and transient bursts of activation just before certain encounters with threat. Although there is agreement that the EAc plays a critical role in orchestrating responses to threat, confusion persists about the respective contributions of its major subdivisions, the bed nucleus of the stria terminalis (BST) and central nucleus of the amygdala (Ce). Here we used anatomical regions-of-interest to demonstrate that the BST and Ce exhibit statistically indistinguishable threat dynamics. Both regions exhibited activation dynamics that run counter to popular models, with the Ce showing sustained responses to uncertain-and-distal threat and the BST showing phasic responses to certain-and-imminent threat. For many scientists, feelings are the hallmark of fear and anxiety. Here we used an independently validated multivoxel brain signature to covertly probe the moment-by-moment dynamics of anticipatory distress for the first time. Results mirrored the dynamics of neural activation. These observations provide fresh insights into the neurobiology of threat-elicited emotions and set the stage for more ambitious clinical and mechanistic research. SIGNIFICANCE STATEMENT"Fear" is widely viewed as a phasic response to certain-and-imminent danger, whereas "anxiety" is a sustained response to uncertain-or-distal harm. Prior work has begun to reveal the neural systems recruited by certain and uncertain anticipated threats, but has yet to rigorously plumb the moment-by-moment dynamics anticipated by theory. Here we used a novel combination of neuroimaging techniques to demonstrate that certain and uncertain threat recruit a common threat-anticipation circuit. Activity in this circuit and covert measures of distress showed similar patterns of context-dependent dynamics, exhibiting persistent increases when anticipating uncertain-threat encounters and transient surges just before certain encounters. These observations provide fresh insights into the neurobiology of fear and anxiety, laying the groundwork for more ambitious clinical and mechanistic research.

neuroscience↗