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.

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.

Physiology and emotions: Within individual associations during caregiver-adolescent conflict.

Concordance between physiological and emotional responses is central to models of emotion and has been shown to correspond to effective responses and well-being in adults. A deeper understanding of physiological-emotional concordance during ecologically relevant scenarios is essential to then determine if these associations predict mental health problems or can serve as a helpful biomarker of risk or resilience in adults and youth. The present study assessed the minute-to-minute associations between sympathetic (i.e., skin conductance level [SCL]) and parasympathetic (i.e., respiratory sinus arrhythmia [RSA]) nervous system activity and self-reported emotions, assessed via video-mediated recall procedures, during a parent-adolescent conflict discussion task. Associations between emotion ratings and physiological activity were assessed in adolescents (N = 97; ages 10-15) and their adult caregivers (N = 97). Utilizing a multilevel modeling approach, findings demonstrated a significant positive association between SCL and emotion ratings for youth, suggesting that increased engagement and alertness contributed to more positive emotion. RSA was unrelated to emotion ratings. The presence of significant variability in associations indicated the presence of potential moderators. This could include clinically relevant processes (e.g., emotion regulation, relationship quality, and mental health). Future research should continue to build on findings to determine if, when, and for whom, physiological-emotional concordance occurs, and whether the degree of concordance predicts risk for mental and physical health problems.

Acute nicotine abstinence amplifies subjective withdrawal symptoms and threat-evoked fear and anxiety, but not extended amygdala reactivity.

Tobacco smoking imposes a staggering burden on public health, underscoring the urgency of developing a deeper understanding of the processes that maintain addiction. Clinical and experience-sampling data highlight the importance of anxious withdrawal symptoms, but the underlying neurobiology has remained elusive. Mechanistic work in animals implicates the central extended amygdala (EAc)-including the central nucleus of the amygdala and the neighboring bed nucleus of the stria terminalis-but the translational relevance of these discoveries remains unexplored. Here we leveraged a randomized trial design, well-established threat-anticipation paradigm, and multidimensional battery of assessments to understand the consequences of 24-hour nicotine abstinence. The threat-anticipation paradigm had the expected consequences, amplifying subjective distress and arousal, and recruiting the canonical threat-anticipation network. Abstinence increased smoking urges and withdrawal symptoms, and potentiated threat-evoked distress, but had negligible consequences for EAc threat reactivity, raising questions about the translational relevance of prominent animal and human models of addiction. These observations provide a framework for conceptualizing nicotine abstinence and withdrawal, with implications for basic, translational, and clinical science.

Adolescents' Coping and Internalizing Symptoms: Role of Maternal Socialization of Coping and Depression Symptoms.

Parental emotion socialization, including processes of the socialization of coping and emotion regulation, is a key factor in shaping children's adjustment in response to acute and chronic stress. Given well-established links between parental depression and youth psychopathology, levels of parental depression symptoms are an important factor for understanding emotion socialization and regulation processes. The present study examined associations among maternal coping and depression symptoms with their adolescents' coping and internalizing problems. A sample of 120 adolescents (45% female, M = 12.27, SD = 1.90) and their mothers participated in a cross-sectional, multi-informant study. Mothers' depression symptoms and adolescents' coping were significantly related to adolescents' internalizing problems. Adolescents' coping moderated the association between maternal depression symptoms and adolescents' internalizing problems, where at low and moderate levels of primary control coping, maternal depression predicted greater internalizing symptoms in adolescents. Further, this study expanded on prior work, demonstrating that the relationship between adolescents' coping and internalizing symptoms was associated with the degree to which mothers model coping. Taken together, results suggest that maternal coping and adolescent coping serve as salient risk and protective factors in the context of family stress. Findings emphasize a need for researchers to further clarify the role of emotion socialization processes in adolescents' development of coping in the context of family stress.

Parental drug use disorders and youth psychopathology: Meta-analytic review.

Parental drug use disorders (PDUDs) represent a highly prevalent risk factor for youth's development of psychological and substance misuse. However, most research on associations between parental substance use and child mental health focuses on composites of parental drug, alcohol, and tobacco use. PDUDs are associated with a range of legal, health, and environmental risks that make them substantially distinct from tobacco and alcohol misuse, yet associations between PDUDs and youth psychopathology symptoms have yet to be assessed quantitatively using meta-analytic techniques. Accordingly, the present meta-analysis assessed the association between PDUDs and youth's internalizing, externalizing, substance use, and total psychological problems across 30 studies (N = 8433). Meta-analytic findings showed that PDUDs were associated with greater substance use and total psychological problems in youth. Across studies, PDUDs were not associated with broad dimensions of youth internalizing and externalizing symptoms but demonstrated a positive relation with youth ADHD and conduct disorder symptoms. There were significant moderation effects for study quality, symptom informant, and child age, where the association between PDUDs and child symptoms of psychopathology was stronger for older youth, in higher quality studies, and studies using joint parent-child symptom informants. Taken together, the meta-analytic findings suggest that PDUDs present a significant risk factor for youth. Future research targeting the relation between parental drug use and youth psychopathology is warranted for prevention and intervention efforts. Implication of findings, mechanisms of interest, and an agenda for future research are discussed.

Mean-level correspondence and moment-to-moment synchrony in adolescent and parent affect: Exploring associations with adolescent age and internalizing and externalizing symptoms.

Interactions with parents are integral in shaping the development of children's emotional processes. Important aspects of these interactions are overall (mean level) affective experience and affective synchrony (linkages between parent and child affect across time). Respectively, mean-level affect and affective synchrony reflect aspects of the content and structure of dyadic interactions. Most research on parent-child affect during dyadic interactions has focused on infancy and early childhood; adolescence, however, is a key period for both normative emotional development and the emergence of emotional disorders. We examined affect in early to mid-adolescents (N = 55, Mage = 12.27) and their parents using a video-mediated recall task of 10-min conflict-topic discussions. Using multilevel modeling, we found evidence of significant level-2 effects (mean affect) and level-1 effects (affective synchrony) for parents and their adolescents. Level-2 and level-1 associations were differentially moderated by adolescent age and adolescent internalizing and externalizing symptoms. More specifically, parent-adolescent synchrony was stronger when adolescents were older and had more internalizing problems. Further, more positive adolescent mean affect was associated with more positive parent affect (and vice versa), but only for dyads with low adolescent externalizing problems. Results underscore the importance of additional research examining parent-child affect in adolescence.

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.

Autonomic nervous system correlates of posttraumatic stress symptoms in youth: Meta-analysis and qualitative review.

Physiological dysregulation is a key diagnostic criterion for posttraumatic stress disorder (PTSD). While PTSD is defined by trauma exposure, symptom presentations are varied. Similarly, findings of autonomic nervous system (ANS), including parasympathetic (PNS) and sympathetic nervous system (SNS), function in youth exposed to trauma are mixed (e.g., hyporeactivity and hyperreactivity). The present meta-analysis quantitatively assesses the relation between ANS measures broadly, and PNS- and SNS-specific measures, and posttraumatic stress symptoms (PTSS) in youth (ages 4.98 to 19.55 years) across 38 cross-sectional and longitudinal studies (N = 3488). Findings demonstrate that heightened ANS activity is related to increased PTSS during stress tasks (r = 0.07), while decreased SNS activity at rest corresponded to increased PTSS (r = -0.09). The correlation between PNS measures and PTSS was non-significant. The moderation effect of age on the relation between PNS activity measured during stress tasks and PTSS approached significance, such that younger children showed a stronger negative relation between symptoms and PNS activity compared to older youth. Qualitative review of included studies revealed significant variability across sample and stressor characteristics and study methodology. Findings indicate the importance of autonomic dysregulation in youth with PTSS. Additional considerations for future research are discussed.

Adverse childhood experiences, parenting, and socioeconomic status: Associations with internalizing and externalizing symptoms in adolescence.

BACKGROUND: Adverse childhood experiences (ACEs), low socioeconomic status (SES), and harsh parenting practices each represent well-established risk factors for mental health problems. However, research supporting these links has often focused on only one of these predictors and psychopathology, and interactions among these variables in association with symptoms are not well understood. OBJECTIVE: The current study utilized a cross-sectional, multi-informant, and multi-method design to investigate the associations of ACEs, SES, parenting, and concurrent internalizing and externalizing problems in adolescents. PARTICIPANTS AND SETTING: Data are from a volunteer sample of 97 adolescents and their caregivers recruited from 2018 to 2021 in a southern U.S. metropolitan area to sample a range of exposure to ACEs. METHODS: Multiple linear regression models were used to assess associations among adolescents' ACEs exposure, SES, observed parenting practices, and symptoms of internalizing and externalizing psychopathology. RESULTS: Lower SES was associated with higher levels of internalizing and externalizing symptoms, while higher ACEs exposure and observed parenting were related to externalizing but not internalizing symptoms. Associations of adolescents' exposure to physical abuse and perceived financial insecurity with externalizing symptoms were moderated by warm and supportive parenting behaviors. Conversely, harsh parenting was linked to increased levels of externalizing symptoms, particularly in the context of low income. CONCLUSIONS: Findings suggest that the presence of multiple risk factors may incur greater vulnerability to externalizing problems, while warm and supportive parenting practices may provide a buffer against externalizing problems for adolescents exposed to physical abuse. Links between ACEs, SES, parenting, and youth adjustment should continue to be explored, highlighting parenting as a potentially important and malleable intervention target.

Observed Maternal Coping Socialization and Child Internalizing Symptoms: The Roles of Maternal Depressive Symptoms and Peer Stress.

Empirical evidence relying primarily on questionnaire reports indicates parent coping socialization messages play an important role in children's psychological functioning. The present study utilized a multi-informant, multi-method design to build on previous coping socialization research in childhood and adolescence. A novel coding system was developed to measure observed parental socialization of coping messages from observations of a discussion-based peer stress task. Questionnaires and direct observations were obtained from mothers with and without a history of depression (N = 116; 50% with a history of depression) and their children (9 to 15 years). Observed maternal coping socialization messages were not significantly correlated with mother or child reports of child internalizing symptoms in bivariate analyses. However, in multiple linear regression analyses, current maternal depressive symptoms and children's level of peer stress emerged as significant moderators of the association between observed maternal coping socialization messages and children's internalizing symptoms. The conceptual and methodological contributions of the current study are discussed, limitations and strengths are noted, and implications for future research are outlined.

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.

Correlates of Cognitive Function in Sickle Cell Disease: A Meta-Analysis.

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.

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.