Biology subjects

Grogans, S. E.

Publications and source records attributed to Grogans, S. E..

5 recordsLinked to original sources

bioRxiv2025

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). Fear and anxiety disorders are common, debilitating, and challenging to treat, underscoring the importance of developing accurate models of the underlying neurobiology. Although there is consensus 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. In contrast, frontocortical regions responded preferentially to uncertain-threat anticipation. Together, these observations underscore the need to reformulate conceptual models that posit a strict segregation of temporally certain and uncertain threat processing in the EA.

neuroscience↗

bioRxiv2025

Heightened subcortical reactivity to uncertain-threat is associated with future internalizing symptoms, conditional on stress exposure

BackgroundAnxiety, depression, and related internalizing illnesses are a leading burden on global public health, and often emerge during times of stress. Yet the underlying neurobiology has remained enigmatic, hindering treatment development. MethodsHere we used a combination of tools--including a well-established threat-anticipation fMRI paradigm and longitudinal assessments of internalizing symptoms and negative life events (NLEs)--to identify the neural systems associated with future internalizing illness in a risk-enriched sample of 224 emerging adults followed for 2.5 years. We performed parallel analyses in an overlapping sample of 209 participants who completed a popular threat-related faces paradigm. ResultsHere we show that heightened reactivity to uncertain-threat anticipation in the bed nucleus of the stria terminalis and the periaqueductal gray is associated with a worsening longitudinal course of broadband internalizing symptoms among individuals with low levels of NLE exposure. These associations were specific to uncertain threat and generally remained significant when controlling for concurrent measures of threat-elicited distress or psychophysiological arousal, highlighting the added value of the neuroimaging measures. Symptom trajectories were unrelated to amygdala and frontocortical reactivity to anticipated threat. Contrary to past research, amygdala reactivity to threat-related faces was unrelated to future symptoms. ConclusionsThese observations provide a novel neurobiological framework for conceptualizing transdiagnostic internalizing risk and lay the groundwork for mechanistic and therapeutics research. A racially diverse, risk-enriched sample and pre-registered, best-practices approach enhance confidence in the robustness and translational relevance of these results.

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↗

bioRxiv2023

Neuroticism/negative emotionality is associated with increased reactivity to uncertain threat in the bed nucleus of the stria terminalis, not the amygdala

Neuroticism/Negative Emotionality (N/NE)--the tendency to experience anxiety, fear, and other negative emotions--is a fundamental dimension of temperament with profound consequences for health, wealth, and wellbeing. Elevated N/NE is associated with a panoply of adverse outcomes, from reduced socioeconomic attainment to psychiatric illness. Animal research suggests that N/NE reflects heightened reactivity to uncertain threat in the bed nucleus of the stria terminalis (BST) and central nucleus of the amygdala (Ce), but the relevance of these discoveries to humans has remained unclear. Here we used a novel combination of psychometric, psychophysiological, and neuroimaging approaches to rigorously test this hypothesis in an ethnoracially diverse, sex-balanced sample of 220 emerging adults selectively recruited to encompass a broad spectrum of N/NE. Cross-validated robust-regression analyses demonstrated that N/NE is preferentially associated with heightened BST activation during the uncertain anticipation of a genuinely distressing threat (aversive multimodal stimulation), whereas N/NE was unrelated to BST activation during certain-threat anticipation, Ce activation during either type of threat anticipation, or BST/Ce reactivity to threat-related faces. It is often assumed that different threat paradigms are interchangeable assays of individual differences in brain function, yet this has rarely been tested. Our results revealed negligible associations between BST/Ce reactivity to the anticipation of threat and the presentation of threat-related faces, indicating that the two tasks are non-fungible. These observations provide a framework for conceptualizing emotional traits and disorders; for guiding the design and interpretation of biobank and other neuroimaging studies of psychiatric risk, disease, and treatment; and for informing mechanistic research. SIGNIFICANCE STATEMENTNeuroticism/Negative Emotionality (N/NE) is a core dimension of mammalian temperament. Elevated levels of N/NE confer risk for a panoply of adversities--from reduced wealth and divorce to depression and death--yet the underlying neurobiology remains unclear. Here we show that N/NE is associated with heightened activation in the bed nucleus of the stria terminalis (BST) during the uncertain anticipation of a genuinely distressing threat. In contrast, N/NE was unrelated to BST reactivity during the certain anticipation of threat or the acute presentation of threat-related faces, two popular probes of the emotional brain. These findings refine our understanding of what has been termed the single most important psychological risk factor in public health, with implications for on-going biobank and therapeutics research.

neuroscience↗

bioRxiv2021

Anxiety-related frontocortical activity is associated with dampened stressor reactivity in the real world

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 has 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 >10,000 momentary assessments of emotional experience--to demonstrate that individuals showing greater activation in a cingulo-opercular circuit during an anxiety-eliciting laboratory paradigm experience lower levels of stressor-dependent distress in their daily lives (n=202-208). 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. STATEMENT OF RELEVANCEAnxiety, sadness, and other negative emotions are hallmarks of the human condition. When extreme, they contribute to a variety of adverse outcomes--from physical and mental illness to divorce and premature death--pointing to the need to develop a better understanding of the underlying brain circuitry. Recent work has begun to reveal the neural systems governing negative affect, but the relevance of these tantalizing laboratory discoveries to the real world has remained unclear. Here we used a combination of brain imaging and smartphone-based survey techniques to show that individuals marked by greater activation in a cingulo-opercular circuit during an anxiety-promoting laboratory paradigm tend to experience diminished distress in response to everyday stressors. These observations provide new insights into the brain systems most relevant to moment-by-moment fluctuations in negative mood, underscoring the importance of more recently evolved cortical association areas.

neuroscience↗