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 human neurobiology remains contentious. Leveraging an ethnoracially diverse sample, translationally relevant paradigm, and theory-driven modeling approach, we demonstrate that certain and uncertain threat recruit a shared threat-anticipation circuit. This circuit exhibits persistently elevated activation when anticipating uncertain threat encounters and a transient burst of activation in the moments before certain encounters. For many scientists and clinicians, feelings are the defining feature of human fear and anxiety. Here we used an independently validated brain signature to covertly decode the momentary 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.

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 statement Neuroticism/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.

Adolescent social anxiety is associated with diminished discrimination of anticipated threat and safety in the bed nucleus of the stria terminalis.

Social anxiety-which typically emerges in adolescence-lies on a continuum and, when extreme, can be devastating. Socially anxious individuals are prone to heightened fear, anxiety, and the avoidance of contexts associated with potential social scrutiny. Yet most neuroimaging research has focused on acute social threat. Much less attention has been devoted to understanding the neural systems recruited during the uncertain anticipation of potential encounters with social threat. Here we used a novel fMRI paradigm to probe the neural circuitry engaged during the anticipation and acute presentation of threatening faces and voices in a racially diverse sample of 66 adolescents selectively recruited to encompass a range of social anxiety and enriched for clinically significant levels of distress and impairment. Results demonstrated that adolescents with more severe social anxiety symptoms experience heightened distress when anticipating encounters with social threat, and reduced discrimination of uncertain social threat and safety in the bed nucleus of the stria terminalis (BST), a key division of the central extended amygdala (EAc). Although the EAc-including the BST and central nucleus of the amygdala-was robustly engaged by the acute presentation of threatening faces and voices, the degree of EAc engagement was unrelated to the severity of social anxiety. Together, these observations provide a neurobiologically grounded framework for conceptualizing adolescent social anxiety and set the stage for the kinds of prospective-longitudinal and mechanistic research that will be necessary to determine causation and, ultimately, to develop improved interventions for this often-debilitating illness.

Investigation of factors regarding the effects of COVID-19 pandemic on college students' depression by quantum annealer.

Diverse cases regarding the impact, with its related factors, of the COVID-19 pandemic on mental health have been reported in previous studies. In this study, multivariable datasets were collected from 751 college students who could be easily affected by pandemics based on the complex relationships between various mental health factors. We utilized quantum annealing (QA)-based feature selection algorithms that were executed by commercial D-Wave quantum computers to determine the changes in the relative importance of the associated factors before and after the pandemic. Multivariable linear regression (MLR) and XGBoost models were also applied to validate the QA-based algorithms. Based on the experimental results, we confirm that QA-based algorithms have comparable capabilities in factor analysis research to the MLR models that have been widely used in previous studies. Furthermore, the performance of the QA-based algorithms was validated through the important factor results from the algorithms. Pandemic-related factors (e.g., confidence in the social system) and psychological factors (e.g. decision-making in uncertain situations) were more important in post-pandemic conditions. Although the results should be validated using other mental health variables or national datasets, this study will serve as a reference for researchers regarding the use of the quantum annealing approach in factor analysis with validation through real-world survey dataset analysis.

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 and divorce to mental illness and premature death. Work in animals 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 the human brain and temperament have remained unclear. Here we used a combination of psychometric, psychophysiological, and neuroimaging approaches to rigorously test this hypothesis in an ethnoracially diverse 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 selectively associated with heightened BST activation during the uncertain anticipation of a genuinely distressing threat. In contrast, 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. Implicit in much of the neuroimaging literature is the assumption that different threat paradigms are statistically interchangeable probes of individual differences in neural function, yet our results revealed negligible evidence of convergence between popular threat-anticipation and emotional-face tasks. 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 the next generation of mechanistic research.

The interactive effects of different facets of threat uncertainty and cognitive load in shaping fear and anxiety responses.

A large body of research indicates that exaggerated response to uncertainty of a future threat is at the core of anxiety and related disorders, underscoring the need for a better understanding of the underlying mechanisms. Although behavioral and neuroimaging studies have suggested a close relationship between uncertainty responses and cognitive control, little is known about what elements of uncertainty are more or less vulnerable to cognitive modulation in shaping aversive responses. Leveraging a novel paradigm, an n-back working memory task embedded within a modified threat-of-shock paradigm, we examined how the influences of different facets of uncertainty (i.e., occurrence and timing) on psychophysiological responses were modulated by cognitive load. Psychophysiological responses were assessed using the acoustic startle reflex. Replicating prior work, the effects of cognitive load and temporal unpredictability of threat on startle responses were evident. The effect of occurrence unpredictability appears to depend on other factors. Under low cognitive load, startle response was potentiated when both the occurrence and the timing of threat were predictable. Under high cognitive load, startle response was significantly reduced, especially when a threat context involves uncertainty in both temporal and probability domains. These observations provide a framework for refining the model of fear and anxiety and for understanding the etiology of psychological disorders characterized by maladaptive uncertainty responses.

Identification and comparison of pandemic-to-symptom networks of South Korea and the United States.

Background: The Coronavirus (COVID-19) pandemic resulted in a dramatic increase in the prevalence of anxiety and depression globally. Although the impact on the mental health of young adults was especially strong, its underlying mechanisms remain elusive. Materials and methods: Using a network approach, the present study investigated the putative pathways between pandemic-related factors and anxiety and depressive symptoms among young adults in South Korea and the U.S. Network analyses were conducted on cross-country data collected during the COVID-19 lockdown period (n = 1,036). Our model included depression symptoms (PHQ-9), generalized anxiety symptoms (GAD-7), and COVID-19-related factors (e.g., COVID-19-related traumatic stress, pandemic concerns, access to medical/mental health services). Results: The overall structure of pandemic-to-symptom networks of South Korea and the U.S. were found to be similar. In both countries, COVID-related stress and negative future anticipation (an anxiety symptom) were identified as bridging nodes between pandemic-related factors and psychological distress. In addition, worry-related symptoms (e.g., excessive worry, uncontrollable worry) were identified as key contributors in maintaining the overall pandemic-to-symptom network in both countries. Conclusion: The similar network structures and patterns observed in both countries imply that there may exist a stable relationship between the pandemic and internalizing symptoms above and beyond the sociocultural differences. The current findings provide new insights into the common potential pathway between the pandemic and internalizing symptoms in South Korea and in the U.S. and inform policymakers and mental health professionals of potential intervention targets to alleviate internalizing symptoms.

Understanding the Consequences of Moment-by-Moment Fluctuations in Mood and Social Experience for Paranoid Ideation in Psychotic Disorders.

Among individuals with psychotic disorders, paranoid ideation is common and associated with increased impairment, decreased quality of life, and a more pessimistic prognosis. Although accumulating research indicates negative affect is a key precipitant of paranoid ideation, the possible protective role of positive affect has not been examined. Further, despite the interpersonal nature of paranoid ideation, there are limited and inconsistent findings regarding how social context, perceptions, and motivation influence paranoid ideation in real-world contexts. In this pilot study, we used smartphone ecological momentary assessment to understand the relevance of hour-by-hour fluctuations in mood and social experience for paranoid ideation in adults with psychotic disorders. Multilevel modeling results indicated that greater negative affect is associated with higher concurrent levels of paranoid ideation and that it is marginally related to elevated levels of future paranoid ideation. In contrast, positive affect was unrelated to momentary experiences of paranoid ideation. More severe momentary paranoid ideation was also associated with an elevated desire to withdraw from social encounters, irrespective of when with familiar or unfamiliar others. These observations underscore the role of negative affect in promoting paranoid ideation and highlight the contribution of paranoid ideation to the motivation to socially withdraw in psychotic disorders.

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 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.

Anxiety and the Neurobiology of Temporally Uncertain Threat Anticipation.

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.SIGNIFICANCE STATEMENT Anxiety-an emotion prototypically associated with the anticipation of uncertain harm-has profound significance for public health, yet the underlying neurobiology remains unclear. Leveraging a novel neuroimaging paradigm in a relatively large sample, we identify a core circuit responsive to both uncertain and certain threat anticipation, and show that this circuitry can be fractionated into subdivisions with a bias for one kind of threat or the other. The extended amygdala occupies center stage in neuropsychiatric 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 the neurobiology of anxiety and fear.

Social context and the real-world consequences of social anxiety.

BACKGROUND: Social anxiety lies on a continuum, and young adults with elevated symptoms are at risk for developing a range of psychiatric disorders. Yet relatively little is known about the factors that govern the hour-by-hour experience and expression of social anxiety in the real world. METHODS: Here we used smartphone-based ecological momentary assessment (EMA) to intensively sample emotional experience across different social contexts in the daily lives of 228 young adults selectively recruited to represent a broad spectrum of social anxiety symptoms. RESULTS: Leveraging data from over 11 000 real-world assessments, our results highlight the central role of close friends, family members, and romantic partners. The presence of such close companions was associated with enhanced mood, yet socially anxious individuals had fewer confidants and spent less time with the close companions that they do have. Although higher levels of social anxiety were associated with a general worsening of mood, socially anxious individuals appear to derive larger benefits - lower levels of negative affect, anxiety, and depression - from their close companions. In contrast, variation in social anxiety was unrelated to the amount of time spent with strangers, co-workers, and acquaintances; and we uncovered no evidence of emotional hypersensitivity to these less-familiar individuals. CONCLUSIONS: These findings provide a framework for understanding the deleterious consequences of social anxiety in emerging adulthood and set the stage for developing improved intervention strategies.

Dispositional negativity, cognition, and anxiety disorders: An integrative translational neuroscience framework.

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.

The value of clinical and translational neuroscience approaches to psychiatric illness.

Borsboom et al. confuse biological approaches with extreme biological reductionism and common-cause models of psychopathology. In muddling these concepts, they mistakenly throw the baby out with the bathwater. Here, we highlight recent work underscoring the unique value of clinical and translational neuroscience approaches for understanding the nature and origins of psychopathology and for developing improved intervention strategies.

Acute alcohol administration dampens central extended amygdala reactivity.

Alcohol use is common, imposes a staggering burden on public health, and often resists treatment. The central extended amygdala (EAc)-including the bed nucleus of the stria terminalis (BST) and the central nucleus of the amygdala (Ce)-plays a key role in prominent neuroscientific models of alcohol drinking, but the relevance of these regions to acute alcohol consumption in humans remains poorly understood. Using a single-blind, randomized-groups design, multiband fMRI data were acquired from 49 social drinkers while they performed a well-established emotional faces paradigm after consuming either alcohol or placebo. Relative to placebo, alcohol significantly dampened reactivity to emotional faces in the BST. To rigorously assess potential regional differences in activation, data were extracted from unbiased, anatomically predefined regions of interest. Analyses revealed similar levels of dampening in the BST and Ce. In short, alcohol transiently reduces reactivity to emotional faces and it does so similarly across the two major divisions of the human EAc. These observations reinforce the translational relevance of addiction models derived from preclinical work in rodents and provide new insights into the neural systems most relevant to the consumption of alcohol and to the initial development of alcohol abuse in humans.

Emotional influences on perception and working memory.

Although there has been steady progress elucidating the influence of emotion on cognition, it remains unclear precisely when and why emotion impairs or facilitates cognition. The present study investigated the mechanisms involved in the influence of emotion on perception and working memory (WM), using modified 0-back and 2-back tasks, respectively. First, results showed that attentional focus modulated the impact of emotion on perception. Specifically, emotion facilitated perceptual task performance when it was relevant to the task, but it impaired performance when it was irrelevant to the task. The differential behavioural effect of emotion on perception as a function of attentional focus diminished under high WM load. Second, attentional focus did not directly modulate the impact of emotion on WM, but rather its influence depended on the dynamic relationship between internal representations. Specifically, WM performance was worse when the material already being held online and the new input were of matching emotions (e.g. both were negative), compared to when they were not. We propose that the competition between "bottom-up" and "top-down" processing for limited cognitive resources explains the nature of the influence of emotion on both perception and WM.

Emotion-attention interactions in fear conditioning: Moderation by executive load, neuroticism, and awareness.

Despite increasing evidence suggesting interactive effects of emotion and attention on perceptual processing, it still remains unclear how their interplay influences affective learning, such as fear conditioning. In the present study, a conditioning procedure using threat-related conditioned stimuli (CSs) was implemented while executive load and attentional focus were manipulated. The modulation effects of neuroticism and contingency awareness were also examined. Results showed that fear conditioning depended on the available executive resources even with threat-related CSs. In addition, although individuals with high neuroticism showed an enhanced conditioning effect overall, this facilitation effect still depended on the availability of executive resources. Finally, the impact of attentional focus was most evident among individuals with high neuroticism who were aware of the contingency. Overall, the present study demonstrates interactive effects of emotion and attention in fear conditioning, while illuminating mechanisms of individual differences and clarifying the controversial role of contingency awareness in fear conditioning.

Interactive effects of trait and state affect on top-down control of attention.

Few studies have investigated how attentional control is affected by transient affective states while taking individual differences in affective traits into consideration. In this study, participants completed a color-word Stroop task immediately after undergoing a positive, neutral or negative affective context manipulation (ACM). Behavioral performance was unaffected by any ACM considered in isolation. For individuals high in trait negative affect (NA), performance was impaired by the negative but not the positive or neutral ACM. Neuroimaging results indicate that activity in primarily top-down control regions of the brain (inferior frontal gyrus and dorsal anterior cingulate cortex) was suppressed in the presence of emotional arousal (both negative and positive ACMs). This effect appears to have been exacerbated or offset by co-occurring activity in other top-down control regions (parietal) and emotion processing regions (orbitofrontal cortex, amygdala and nucleus accumbens) as a function of the valence of state affect (positive or negative) and trait affect (trait NA or trait PA). Neuroimaging results are consistent with behavioral findings. In combination, they indicate both additive and interactive influences of trait and state affect on top-down control of attention.