Enhanced late positive potential to conditioned threat cue during delayed extinction in anxious youth.

BACKGROUND: Deficits in threat learning relate to anxiety symptoms. Since several anxiety disorders arise in adolescence, impaired adolescent threat learning could contribute to adolescent changes in risk for anxiety. This study compared threat learning among anxious and non-anxious youth using self-reports, peripheral psychophysiology measures, and event-related potentials. Because exposure therapy, the first-line treatment for anxiety disorders, is largely based on principles of extinction learning, the study also examined the link between extinction learning and treatment outcomes among anxious youth. METHODS: Clinically anxious (n = 28) and non-anxious (n = 33) youth completed differential threat acquisition and immediate extinction. They returned to the lab a week later to complete a threat generalization test and a delayed extinction task. Following these two experimental visits, anxious youth received exposure therapy for 12 weeks. RESULTS: Anxious as compared to non-anxious youth demonstrated elevated cognitive and physiological responses across acquisition and immediate extinction learning, as well as greater threat generalization. In addition, anxious youth showed enhanced late positive potential response to the conditioned threat cue compared to the safety cue during delayed extinction. Finally, aberrant neural response during delayed extinction was associated with poorer treatment outcomes. CONCLUSIONS: The study emphasizes differences between anxious and non-anxious youth in threat learning processes and provides preliminary support for a link between neural processing during delayed extinction and exposure-based treatment outcome in pediatric anxiety.

Induced error-related theta activity, not error-related negativity, predicts task performance as well as anxiety and worry during real-life stress in a youth sample.

OBJECTIVE: The study examined differences between induced error-related theta activity (4-7 Hz) and error-related negativity (ERN) in youth and their unique associations with task performance as well as anxiety and worry during real-life stress a year later. We hypothesized that induced theta, but not the ERN, would predict task performance. We also hypothesized that induced theta would predict less anxiety and worries during situational stress a year later, while ERN would predict more anxiety and worries. METHOD: Participants included 76 children aged 8-13 years who completed a flanker task while electroencephalogram (EEG) and behavioral data (t0 ) were collected. Approximately 1 year later (t1 ), during the first COVID-19 lockdown, 40 families from the original sample completed a battery of online questionnaires to assess the children's stress-related symptoms (anxiety, negative emotions and worries). We employed an analytical method that allowed us to differentiate between induced error-related theta and the evoked ERN. RESULTS: Induced error-related theta, but not ERN, was associated with behavioral changes during the task, such as post-error speeding. Furthermore, induced error-related theta, but not ERN, was prospectively associated with less anxiety, worries, and fewer negative emotions a year later during COVID-19 lockdown. CONCLUSIONS: Findings suggest ERN and error-related theta are dissociable processes reflecting error monitoring in youth. Specifically, induced error-related theta is more robustly associated with changes in behavior in the laboratory and with less anxiety and worries in real-world settings.

Evaluating the effect of action-like video game play and of casual video game play on anxiety in adolescents with elevated anxiety: protocol for a multi-center, parallel group, assessor-blind, randomized controlled trial.

BACKGROUND: Adolescence is a critical period for the onset and maintenance of anxiety disorders, which raises the importance of intervening early; one possibility of doing so is via digital interventions. Within that research field, at least two important research paths have been explored in the past years. On the one hand, the anxiolytic effect of casual video games has been tested as such gaming activity may distract away from anxious thoughts through the induction of flow and redirection of attention toward the game and thus away of anxious thoughts. On the other hand, the bidirectional link between weak attentional control and higher anxiety has led to the design of interventions aiming at improving attentional control such as working memory training studies. Taking stock that another genre of gaming, action video games, improves attentional control, game-based interventions that combines cognitive training and action-like game features would seem relevant. This three-arm randomized controlled trial aims to evaluate the feasibility and the efficacy of two video game interventions to document how each may potentially alleviate adolescent anxiety-related symptoms when deployed fully on-line. METHODS: The study aims to recruit 150 individuals, 12 to 14 years of age, with high levels of anxiety as reported by the parents' online form of the Screen for Child Anxiety Related Disorders questionnaire. This trial contrasts a child-friendly, "action-like" video game designed to improve attentional control abilities in a progressive and stepwise manner (Eco-Rescue), a casual puzzle video game selected to act as a positive distraction tool (Bejeweled) and finally a control group with no assigned training intervention to control for possible test-retest effects (No-training). Participants will be assigned randomly to one of the three study arms. They will be assessed for main (anxiety) and secondary outcomes (attentional control, affective working memory) at three time points, before training (T1), one week after the 6-week training (T2) and four months after completing the training (T3). DISCUSSION: The results will provide evidence for the feasibility and the efficacy of two online video game interventions at improving mental health and emotional well-being in adolescents with high levels of anxiety. This project will contribute unique knowledge to the field, as few studies have examined the effects of video game play in the context of digital mental health interventions for adolescents. TRIAL REGISTRATION: The trial is registered on ClinicalTrials.gov (NCT05923944, June 20, 2023).

Using a novel paradigm to examine observational fear-learning across development.

BACKGROUND: Fear-learning through observing others begins early in life. Yet, most observational fear-learning research has focused on adults. The current study used a novel developmentally appropriate observational fear conditioning paradigm to examine differences in observational fear-learning among children, adolescents, and adults. METHOD: Thirty-six typically developing children, 41 typically developing adolescents, and 40 adults underwent differential observational fear conditioning followed by a direct exposure test. Skin conductance response (SCR) and self-reported fear were measured. RESULTS: Successful differential observational fear-learning was demonstrated in all three age groups as indexed by SCR, yet developmental differences emerged. Children showed overall higher physiological arousal during acquisition compared to adolescents and adults. Additionally, children reported less differential fear and were less successful at reporting the conditioned stimulus-unconditioned stimulus contingency compared to adolescents and adults. Finally, adolescents tended to overgeneralize their fear compared with adults. CONCLUSIONS: This is the first study to compare observational fear-learning among children, adolescents, and adults. The novel task effectively induced observational fear-learning, particularly among adolescents and adults. Findings revealed developmental differences that have both theoretical and clinical implications.

Return of fear following extinction in youth: An event-related potential study.

The ability to learn to differentiate safety from danger matures gradually, particularly when such learning occurs over an extended time period. And yet, most research on fear learning examines the early phases of such learning and mainly in adults. The current study examined fear conditioning and extinction, as well as one form of extended learning, return of fear (ROF). Thirty-three typically developing children (age range: 7-14 years) completed fear conditioning and extinction; self-reports and psychophysiological indices were measured at this point. Two weeks later, children completed a ROF test (n = 23), and event-related potentials (ERPs) were recorded. Results indicated successful fear acquisition and extinction. Moreover, participants reported greater fear of the conditioned stimulus (CS+) than the safety stimulus (CS-) in the ROF test 2 weeks later. In electrophysiology data, ROF manifested as a larger late positive potential (LPP) response to the CS+ than the CS-. Finally, these differences in LPP responses were positively correlated with poorer extinction, as indicated by the GSR responses 2 weeks earlier. This is the first ERP study to demonstrate ROF in children. The LPP measure may index an interplay between inhibitory and excitatory brain-related processes underlying the long-term effects of fear learning.

Social relevance modulates multivariate neural representations of threat generalization in children and adults.

Few studies have examined threat generalization across development and no developmental studies have compared the generalization of social versus nonsocial threat, making it difficult to identify contextual factors that contribute to threat learning across development. The present study assessed youth and adults' multivoxel neural representations of social versus nonsocial threat stimuli. Twenty adults (Mage  = 25.7 ± 4.9) and 16 youth (Mage  = 14.1 ± 1.7) completed two conditioning and extinction recall paradigms: one social and one nonsocial paradigm. Three weeks after conditioning, participants underwent a functional magnetic resonance imaging extinction recall task that presented the extinguished threat cue (CS+), a safety cue (CS-), and generalization stimuli (GS) consisting of CS-/CS+ blends. Across age groups, neural activity patterns and self-reported fear and memory ratings followed a linear generalization gradient for social threat stimuli and a quadratic generalization gradient for nonsocial threat stimuli, indicating enhanced threat/safety discrimination for social relative to nonsocial threat stimuli. The amygdala and ventromedial prefrontal cortex displayed the greatest neural pattern differentiation between the CS+ and GS/CS-, reinforcing their role in threat learning and extinction recall. Contrary to predictions, age did not influence threat representations. These findings highlight the importance of the social relevance of threat on generalization across development.

Levels of early-childhood behavioral inhibition predict distinct neurodevelopmental pathways to pediatric anxiety.

BACKGROUND: Anxiety symptoms gradually emerge during childhood and adolescence. Individual differences in behavioral inhibition (BI), an early-childhood temperament, may shape developmental paths through which these symptoms arise. Cross-sectional research suggests that level of early-childhood BI moderates associations between later anxiety symptoms and threat-related amygdala-prefrontal cortex (PFC) circuitry function. However, no study has characterized these associations longitudinally. Here, we tested whether level of early-childhood BI predicts distinct evolving associations between amygdala-PFC function and anxiety symptoms across development. METHODS: Eighty-seven children previously assessed for BI level in early childhood provided data at ages 10 and/or 13 years, consisting of assessments of anxiety and an fMRI-based dot-probe task (including threat, happy, and neutral stimuli). Using linear-mixed-effects models, we investigated longitudinal changes in associations between anxiety symptoms and threat-related amygdala-PFC connectivity, as a function of early-childhood BI. RESULTS: In children with a history of high early-childhood BI, anxiety symptoms became, with age, more negatively associated with right amygdala-left dorsolateral-PFC connectivity when attention was to be maintained on threat. In contrast, with age, low-BI children showed an increasingly positive anxiety-connectivity association during the same task condition. Behaviorally, at age 10, anxiety symptoms did not relate to fluctuations in attention bias (attention bias variability, ABV) in either group; by age 13, low-BI children showed a negative anxiety-ABV association, whereas high-BI children showed a positive anxiety-ABV association. CONCLUSIONS: Early-childhood BI levels predict distinct neurodevelopmental pathways to pediatric anxiety symptoms. These pathways involve distinct relations among brain function, behavior, and anxiety symptoms, which may inform diagnosis and treatment.

Reducing avoidance in adults with high spider fear using perceptual discrimination training.

BACKGROUND: Fear overgeneralization is a central feature of anxiety disorders and can lead to excessive avoidance. As perceptual discrimination is a key component of fear overgeneralization, a perceptual discrimination training task was created aimed at improving perceptual discrimination and reducing fear overgeneralization. METHODS: Participants with high spider fear were randomized into training or placebo conditions. After completing their assigned task, perceptual discrimination was tested. Thereafter, participants completed a behavioral avoidance test, consisting of five stimuli ranging from a paper spider to a live tarantula. Last, participants completed a threat/safety discrimination task using schematic morphs ranging from a flower to a spider, while self-report and skin conductance responses were collected. RESULTS: The training group showed better perceptual discrimination during the test than did the placebo group. Furthermore, as stimuli became increasingly similar to a live spider, participants in the training group exhibited decreased avoidance behavior. Finally, participants in the training group indicated that schematic morphs were less similar to a spider and showed less physiological arousal than did the placebo group. CONCLUSIONS: Together, these results attest to the possible clinical relevance of the perceptual discrimination training.

Differences in neural response to extinction recall in young adults with or without history of behavioral inhibition.

Behavioral inhibition (BI) is a temperament identified in early childhood that is associated with risk for anxiety disorders, yet only about half of behaviorally inhibited children manifest anxiety later in life. We compared brain function and behavior during extinction recall in a sample of nonanxious young adults characterized in childhood with BI (n = 22) or with no BI (n = 28). Three weeks after undergoing fear conditioning and extinction, participants completed a functional magnetic resonance imaging extinction recall task assessing memory and threat differentiation for conditioned stimuli. While self-report and psychophysiological measures of differential conditioning and extinction were similar across groups, BI-related differences in brain function emerged during extinction recall. Childhood BI was associated with greater activation in subgenual anterior cingulate cortex in response to cues signaling safety. This pattern of results may reflect neural correlates that promote resilience against anxiety in a temperamentally at-risk population.

Developmental Relations Among Behavioral Inhibition, Anxiety, and Attention Biases to Threat and Positive Information.

This study examined relations between behavioral inhibition (BI) assessed in toddlerhood (n = 268) and attention biases (AB) to threat and positive faces and maternal-reported anxiety assessed when children were 5- and 7-year-old. Results revealed that BI predicted anxiety at age 7 in children with AB toward threat, away from positive, or with no bias, at age 7; BI did not predict anxiety for children displaying AB away from threat or toward positive. Five-year AB did not moderate the link between BI and 7-year anxiety. No direct association between AB and BI or anxiety was detected; moreover, children did not show stable AB across development. These findings extend our understanding of the developmental links among BI, AB, and anxiety.

Behavioral and neural stability of attention bias to threat in healthy adolescents.

Considerable translational research on anxiety examines attention bias to threat and the efficacy of attention training in reducing symptoms. Imaging research on the stability of brain functions engaged by attention bias tasks could inform such research. Perturbed fronto-amygdala function consistently arises in attention bias research on adolescent anxiety. The current report examines the stability of the activation and functional connectivity of these regions on the dot-probe task. Functional magnetic resonance imaging (fMRI) activation and connectivity data were acquired with the dot-probe task in 39 healthy youth (f=18, Mean Age=13.71years, SD=2.31) at two time points, separated by approximately nine weeks. Intraclass-correlations demonstrate good reliability in both neural activation for the ventrolateral PFC and task-specific connectivity for fronto-amygdala circuitry. Behavioral measures showed generally poor test-retest reliability. These findings suggest potential avenues for future brain imaging work by highlighting brain circuitry manifesting stable functioning on the dot-probe attention bias task.

Early-Childhood Social Reticence Predicts Brain Function in Preadolescent Youths During Distinct Forms of Peer Evaluation.

Social reticence is expressed as shy, anxiously avoidant behavior in early childhood. With development, overt signs of social reticence may diminish but could still manifest themselves in neural responses to peers. We obtained measures of social reticence across 2 to 7 years of age. At age 11, preadolescents previously characterized as high (n = 30) or low (n = 23) in social reticence completed a novel functional-MRI-based peer-interaction task that quantifies neural responses to the anticipation and receipt of distinct forms of social evaluation. High (but not low) social reticence in early childhood predicted greater activity in dorsal anterior cingulate cortex and left and right insula, brain regions implicated in processing salience and distress, when participants anticipated unpredictable compared with predictable feedback. High social reticence was also associated with negative functional connectivity between insula and ventromedial prefrontal cortex, a region commonly implicated in affect regulation. Finally, among participants with high social reticence, negative evaluation was associated with increased amygdala activity, but only during feedback from unpredictable peers.

Amygdala-Cortical Connectivity: Associations with Anxiety, Development, and Threat.

BACKGROUND: Amygdala-prefrontal cortex (PFC) functional connectivity may be influenced by anxiety and development. A prior study on anxiety found age-specific dysfunction in the ventromedial PFC (vmPFC), but not amygdala, associated with threat-safety discrimination during extinction recall (Britton et al.). However, translational research suggests that amygdala-PFC circuitry mediates responses following learned extinction. Anxiety-related perturbations may emerge in functional connectivity within this circuit during extinction recall tasks. The current report uses data from the prior study to examine how anxiety and development relate to task-dependent amygdala-PFC connectivity. METHODS: Eighty-two subjects (14 anxious youths, 15 anxious adults, 25 healthy youths, 28 healthy adults) completed an extinction recall task, which directed attention to different aspects of stimuli. Generalized psychophysiological interaction analysis tested whether task-dependent functional connectivity with anatomically defined amygdala seed regions differed across anxiety and age groups. RESULTS: Whole-brain analyses showed significant interactions of anxiety, age, and attention task (i.e., threat appraisal, explicit threat memory, physical discrimination) on left amygdala functional connectivity with the vmPFC and ventral anterior cingulate cortex (Talairach XYZ coordinates: -16, 31, -6 and 1, 36, -4). During threat appraisal and explicit threat memory (vs. physical discrimination), anxious youth showed more negative amygdala-PFC coupling, whereas anxious adults showed more positive coupling. CONCLUSIONS: In the context of extinction recall, anxious youths and adults manifested opposite directions of amygdala-vmPFC coupling, specifically when appraising and explicitly remembering previously learned threat. Future research on anxiety should consider associations of both development and attention to threat with functional connectivity perturbations.

A developmental analysis of threat/safety learning and extinction recall during middle childhood.

The current study examined developmental changes in fear learning and generalization in 54 healthy 5-10-year old children using a novel fear conditioning paradigm. In this task, the conditioned stimuli (CS+/CS-) were two blue and yellow colored cartoon bells, and the unconditioned stimulus was an unpleasant loud alarm sound presented with a red cartoon bell. Physiological and subjective data were acquired. Three weeks after conditioning, 48 of these participants viewed the CS-, CS+, and morphed images resembling the CS+. Participants made threat-safety discriminations while appraising threat and remembering the CS+. Although no age-related differences in fear learning emerged, patterns of generalization were qualified by child age. Older children demonstrated better discrimination between the CS+ and CS morphs than younger age groups and also reported more fear to stimuli resembling the CS+ than younger children. Clinical implications and future directions are discussed.

Incidental threat during visuospatial working memory in adolescent anxiety: an emotional memory-guided saccade task.

BACKGROUND: Pediatric anxiety disorders are among the most common psychiatric mental illnesses in children and adolescents, and are associated with abnormal cognitive control in emotional, particularly threat, contexts. In a series of studies using eye movement saccade tasks, we reported anxiety-related alterations in the interplay of inhibitory control with incentives, or with emotional distractors. The present study extends these findings to working memory (WM), and queries the interaction of spatial WM with emotional stimuli in pediatric clinical anxiety. METHODS: Participants were 33 children/adolescents diagnosed with an anxiety disorder, and 22 age-matched healthy comparison youths. Participants completed a novel eye movement task, an affective variant of the memory-guided saccade task. This task assessed the influence of incidental threat on spatial WM processes during high and low cognitive load. RESULTS: Healthy but not anxious children/adolescents showed slowed saccade latencies during incidental threat in low-load but not high-load WM conditions. No other group effects emerged on saccade latency or accuracy. CONCLUSIONS: The current data suggest a differential pattern of how emotion interacts with cognitive control in healthy youth relative to anxious youth. These findings extend data from inhibitory processes, reported previously, to spatial WM in pediatric anxiety.

Fear conditioning and extinction in anxious and nonanxious youth and adults: examining a novel developmentally appropriate fear-conditioning task.

BACKGROUND: Fear conditioning and extinction have been implicated in the pathogenesis of anxiety disorders. However, due to ethical and methodological limitations, few studies have examined these learning processes across development, particularly among anxious individuals. The present study examined differences in fear conditioning and extinction in anxious and nonanxious youth and adults using a novel task designed to be more tolerable for children than existing paradigms. METHODS: Twenty-two anxious adults, 15 anxious youth, 30 healthy adults, and 17 healthy youth completed two discriminative fear-conditioning tasks. A well-validated task paired a woman's fearful face with a scream as the unconditioned stimulus. The novel task paired a bell with an aversive alarm as the unconditioned stimulus. Self-reported fear, skin conductance response, and fear-potentiated startle eye blink were measured. RESULTS: Both tasks were well tolerated and elicited fear responses with moderate stability. Anxious youth and adults reported overall greater fear than healthy participants during the tasks, although no group differences occurred in discriminative fear conditioning or extinction, as assessed by self-report or physiology. CONCLUSION: The novel bell-conditioning task is potent in eliciting fear responses but tolerable for pediatric and anxious populations. Our findings are consistent with prior studies that have shown comparable fear learning processes in anxious and nonanxious youth, but dissimilar from studies exhibiting between-group differences in extinction. Given the limited research on fear conditioning in youth, methodological issues and suggestions for future work are discussed.

Enduring influence of early temperament on neural mechanisms mediating attention-emotion conflict in adults.

BACKGROUND: Behavioral inhibition, a temperament identified in early childhood, is often associated with dysregulated attention and affective processing, particularly in response to threat. Longitudinal studies find that the manifestation of perturbed attention and affective processing often dissipates with age. Yet, childhood behavioral inhibition continues to predict perturbed brain function into adulthood. This suggests that adults with childhood behavioral inhibition may engage compensatory processes to effectively regulate emotion-related attention. However, it is unknown whether perturbations in brain function reflect compensation for attention bias to emotional stimuli generally, or to threatening contexts more specifically. The present study tests these possibilities. METHODS: Adults with and without a history of stable childhood behavioral inhibition completed an attention-control task in the context of threatening and nonthreatening stimuli while undergoing functional magnetic resonance imaging. Participants were asked to identify the gender of fearful (threatening) and happy (nonthreatening) faces, while ignoring both the face emotion and overlaid congruent (low attention control, LAC) or incongruent (high attention control, HAC) gender words. RESULTS: When fearful faces were present, adults with stable childhood behavioral inhibition exhibited more activity in striatum, cingulate, and dorsolateral prefrontal cortex for HAC trials compared with LAC trials, relative to those without behavioral inhibition. When happy faces were present, the opposite activation pattern emerged. No group differences in behavior were observed. CONCLUSIONS: Among adults, stable childhood behavioral inhibition predicts neural, but not behavioral, responding when attention control is engaged in discrete emotional contexts. This suggests a mechanism by which adults may compensate for the behavioral manifestation of threat-based attention biases.

Attention bias of anxious youth during extended exposure of emotional face pairs: an eye-tracking study.

BACKGROUND: Previous studies demonstrate that anxiety is characterized by biased attention toward threats, typically measured by differences in motor reaction time to threat and neutral cues. Using eye-tracking methodology, the current study measured attention biases in anxious and nonanxious youth, using unrestricted free viewing of angry, happy, and neutral faces. METHODS: Eighteen anxious and 15 nonanxious youth (8-17 years old) passively viewed angry-neutral and happy-neutral face pairs for 10 s while their eye movements were recorded. RESULTS: Anxious youth displayed a greater attention bias toward angry faces than nonanxious youth, and this bias occurred in the earliest phases of stimulus presentation. Specifically, anxious youth were more likely to direct their first fixation to angry faces, and they made faster fixations to angry than neutral faces. CONCLUSIONS: Consistent with findings from earlier, reaction-time studies, the current study shows that anxious youth, like anxious adults, exhibit biased orienting to threat-related stimuli. This study adds to the existing literature by documenting that threat biases in eye-tracking patterns are manifest at initial attention orienting.

Family accommodation in pediatric anxiety disorders.

BACKGROUND: Family accommodation has been studied in obsessive compulsive disorder using the Family Accommodation Scale (FAS) and predicts greater symptom severity, more impairment, and poorer treatment outcomes. However, family accommodation has yet to be systematically studied among families of children with other anxiety disorders. We developed the Family Accommodation Scale-Anxiety (FASA) that includes modified questions from the FAS to study accommodation across childhood anxiety disorders. The objectives of this study were to report on the first study of family accommodation across childhood anxiety disorders and to test the utility of the FASA for assessing the phenomenon. METHODS: Participants were parents (n = 75) of anxious children from two anxiety disorder specialty clinics (n = 50) and a general outpatient clinic (n = 25). Measures included FASA, structured diagnostic interviews, and measures of anxiety and depression. RESULTS: Accommodation was highly prevalent across all anxiety disorders and particularly associated with separation anxiety. Most parents reported participation in symptoms and modification of family routines as well as distress resulting from accommodation and undesirable consequences of not accommodating. The FASA displayed good internal consistency and convergent and divergent validity. Accommodation correlated significantly with anxious but not depressive symptoms, when controlling for the association between anxiety and depression. Factor analysis of the FASA pointed to a two-factor solution; one relating to modifications, the other to participation in symptoms. CONCLUSIONS: Accommodation is common across childhood anxiety disorders and associated with severity of anxiety symptoms. The FASA shows promise as a means of assessing family accommodation in childhood anxiety disorders.