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.

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 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 nature and neurobiology of fear and anxiety: State of the science and opportunities for accelerating discovery.

Fear and anxiety play a central role in mammalian life, and there is considerable interest in clarifying their nature, identifying their biological underpinnings, and determining their consequences for health and disease. Here we provide a roundtable discussion on the nature and biological bases of fear- and anxiety-related states, traits, and disorders. The discussants include scientists familiar with a wide variety of populations and a broad spectrum of techniques. The goal of the roundtable was to take stock of the state of the science and provide a roadmap to the next generation of fear and anxiety research. Much of the discussion centered on the key challenges facing the field, the most fruitful avenues for future research, and emerging opportunities for accelerating discovery, with implications for scientists, funders, and other stakeholders. Understanding fear and anxiety is a matter of practical importance. Anxiety disorders are a leading burden on public health and existing treatments are far from curative, underscoring the urgency of developing a deeper understanding of the factors governing threat-related emotions.

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.

Clinical correlation but no elevation of striatal dopamine synthesis capacity in two independent cohorts of medication-free individuals with schizophrenia.

Dysregulation of dopamine systems has been considered a foundational driver of pathophysiological processes in schizophrenia, an illness characterized by diverse domains of symptomatology. Prior work observing elevated presynaptic dopamine synthesis capacity in some patient groups has not always identified consistent symptom correlates, and studies of affected individuals in medication-free states have been challenging to obtain. Here we report on two separate cohorts of individuals with schizophrenia spectrum illness who underwent blinded medication withdrawal and medication-free neuroimaging with [18F]-FDOPA PET to assess striatal dopamine synthesis capacity. Consistently in both cohorts, we found no significant differences between patient and matched, healthy comparison groups; however, we did identify and replicate robust inverse relationships between negative symptom severity and tracer-specific uptake widely throughout the striatum: [18F]-FDOPA specific uptake was lower in patients with a greater preponderance of negative symptoms. Complementary voxel-wise and region of interest analyses, both with and without partial volume correction, yielded consistent results. These data suggest that for some individuals, striatal hyperdopaminergia may not be a defining or enduring feature of primary psychotic illness. However, clinical differences across individuals may be significantly linked to variability in striatal dopaminergic tone. These findings call for further experimentation aimed at parsing the heterogeneity of dopaminergic systems function in schizophrenia.

Longitudinal Positron Emission Tomography of Dopamine Synthesis in Subjects with GBA1 Mutations.

Mutations in GBA1, the gene mutated in Gaucher disease, are a common genetic risk factor for Parkinson disease, although the penetrance is low. We performed [18 F]-fluorodopa positron emission tomography studies of 57 homozygous and heterozygous GBA1 mutation carriers (15 with parkinsonism) and 98 controls looking for early indications of dopamine loss using voxelwise analyses to identify group differences in striatal [18 F]-fluorodopa uptake (Ki ). Forty-eight subjects were followed longitudinally. Cross-sectional and longitudinal comparisons of Ki and Ki change found significant effects of Parkinson disease. However, at baseline and over time, striatal [18 F]-fluorodopa uptake in mutation carriers without parkinsonism did not significantly differ from controls. ANN NEUROL 2020;87:652-657.

Single-trial EEG dissociates motivation and conflict processes during decision-making under risk.

In making decisions under risk (i.e., choosing whether to gamble when the outcome probabilities are known), two aspects of decision are of particular concern. The first, if gambling, is how large are potential gains compared to losses? The subjectively larger, the more rewarding to gamble. Thus, this aspect of decision-making, quantified through expected utility (EU), is motivation-related. The second concern is how easy is it to reach the decision? When subjective desirability between gambling and not-gambling is clearly different from each other (regardless of the direction), it is easier to decide. This aspect, quantified through utility distance (UD), is conflict-related. It is unclear how the brain simultaneously processes these two aspects of decision-making. Forty-five participants decided whether to gamble during electroencephalogram (EEG) recording. To compute trial-by-trial variability in EU and UD, we fit participants' choices to models inspired by Expected-Utility and Prospect theories using hierarchical-Bayesian modeling. To examine unique influences of EU and UD, we conducted model-based single-trial EEG analyses with EU and UD as simultaneous regressors. While both EU and UD were positively associated with P3-like activity and delta-band power, the contribution of EU was around 200 ms earlier. Thus, during decision-making under risk, people may allocate their attention to motivation-related aspects before conflict-related aspects. Next, following learning the options and before reporting their decision, higher EU was associated with stronger alpha and beta suppression, while higher UD was associated with a stronger contingent-negativity-variation-like activity. This suggests distinct roles of EU and UD on anticipation-related processes. Overall, we identified time and frequency characteristics of EEG signals that differentially traced motivation-related and conflict-related information during decision-making under risk.